Kaija Polak

INTRAVITREAL BEVACIZUMAB (AVASTIN) FOR MACULAR OEDEMA SECONDARY TO RETINAL VEIN OCCLUSION: 12-MONTH RESULTS OF A PROSPECTIVE CLINICAL TRIAL

Aims: The aim of the study was to evaluate functional and anatomical changes after intravitreal bevacizumab (Avastin®) in eyes with persistent macular oedema secondary to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Methods: Twenty-nine consecutive eyes with macular oedema secondary to BRVO (21 eyes) or CRVO (eight eyes) were included in a prospective clinical trial. Eyes were treated with three initial intravitreal bevacizumab injections of 1 mg at a monthly interval. Retreatment was based on central retinal thickness (CRT) based on optical coherence tomography. If continuous injections were indicated up to month 6, the dose was increased to 2.5 mg. Results: After 12 months of follow-up, mean visual acuity increased from 50 letters (20/100) at baseline to 66 letters (20/50+1; +16 letters; p<0.001) at month 12 and CRT decreased from 558 μm at baseline to 309 μm at month 12 (−249 μm; p<0.001). Patients received a mean of eight out of 13 possible injections. No drug-related systemic or ocular side effects following intravitreal bevacizumab treatment were observed. Fluorescein angiography revealed no progression of avascular areas. Conclusions: Intravitreal therapy using bevacizumab appears to be a safe and effective treatment in patients with macular oedema secondary to retinal vein occlusion. However, the main limitations of this treatment modality are its short-term effectiveness and high recurrence rate.

Evaluation of the Zeiss retinal vessel analyser.

AIM To investigate the reproducibility and sensitivity of the Zeiss retinal vessel analyser, a new method for the online determination of retinal vessel diameters in healthy subjects. METHODS Two model drugs were administered, a peripheral vasoconstrictor (the α receptor agonist phenylephrine) and a peripheral vasodilator (the nitric oxide donor sodium nitroprusside) in stepwise increasing doses. Nine healthy young subjects were studied in a placebo controlled double masked three way crossover design. Subjects received intravenous infusions of either placebo or stepwise increasing doses of phenylephrine (0.5, 1, or 2 μg/kg/min) or sodium nitroprusside (0.5, 1, or 2 μg/kg/min). Retinal vessel diameters were measured with the new Zeiss retinal vessel analyser. Retinal leucocyte velocity, flow, and density were measured with the blue field entoptic technique. The reproducibility of measurements was assessed with coefficients of variation and intraclass correlation coefficients. RESULTS Placebo and phenylephrine did not influence retinal haemodynamics, although the α receptor antagonist significantly increased blood pressure. Sodium nitroprusside induced a significant increase in retinal venous and arterial diameters (p<0.001 each), leucocyte density (p=0.001), and leucocyte flow (p=0.024) despite lowering blood pressure to a significant degree. For venous and arterial vessel size measurements short term coefficients of variation were 1.3% and 2.6% and intraclass correlation coefficients were 0.98 and 0.96, respectively. The sensitivity was between 3% and 5% for retinal veins and 5% and 7% for retinal arteries. CONCLUSIONS These data indicate that the Zeiss retinal vessel analyser is an accurate system for the assessment of retinal diameters in healthy subjects. In addition, nitric oxide appears to have a strong influence on retinal vascular tone.

Role of nitric oxide in the control of ocular blood flow.

In the recent years it has been recognized that nitric oxide is an important regulator of ocular blood flow. Nitric oxide is involved in the control of basal blood flow in the choroid, optic nerve and the retina. In addition, nitric oxide mediates a number of vasodilator responses in ocular vessels to agonists such as acetylcholine, bradykinin, histamine, substance P and insulin. Nitric oxide also plays a role in hypercapnia-induced vasodilation in the choroid and is a modulator of pressure autoregulation in this vascular bed. Abnormalities of the L-arginine/nitric oxide system have been observed in a variety of ocular diseases including glaucoma, diabetic retinopathy and retinopathy of prematurity. This makes the L-arginine/nitric oxide pathway an attractive target for therapeutic interventions. Additional research is required, particularly in characterizing the role of the three nitric oxide synthase isoforms in the control of ocular perfusion, to implement this concept into the clinical management of ocular diseases.

Assessment of optic disk blood flow in patients with open-angle glaucoma

PURPOSE To characterize optic disk blood flow in patients with open-angle glaucoma compared with age-matched healthy control subjects. METHODS In this prospective cross-sectional study, 90 eyes of 90 patients with open-angle glaucoma and 61 eyes of 61 age-matched healthy control subjects were evaluated. Flow in the optic disk cup and the neuroretinal rim were assessed with scanning laser Doppler flowmetry. Fundus pulsation amplitude in the cup and the macula were assessed with laser interferometry. Visual field mean deviation was measured with the Humphrey 30 to 2 program. RESULTS Flow in the neuroretinal rim (-18%, P =.002), and in the cup (-46%, P <.001) and fundus pulsation amplitude in the cup (-33%, P <.001) and in the macula (-24%, P <.001) were significantly lower in patients with open-angle glaucoma compared with healthy control subjects. A significant association between blood flow measurements in the cup and fundus pulsation amplitudes in the cup was observed in both study cohorts. A significant association was also observed between the mean defect from visual field testing and ocular hemodynamic parameters. CONCLUSIONS Reduced optic disk perfusion in patients with open-angle glaucoma is evidenced from two independent methods in the present study. Moreover, our data indicate that reduced ocular blood flow in these patients is linked to visual field changes. It remains to be established whether compromised optic disk and choroidal blood flow contributes to optic disk damage in glaucomatous eyes or is a secondary functional phenomenon.

Influence of operator experience on the performance of ultrasound biometry compared to optical biometry before cataract surgery

Purpose: To compare measurements performed with the IOLMaster (Carl Zeiss, Meditec AG) with those obtained by applanation ultrasound (US) and manual keratometry and to evaluate the effect of operator experience on US biometry. Setting: Department of Ophthalmology, University of Vienna, Vienna, Austria. Methods: The axial length (696 eyes) and anterior chamber depth (ACD) (462 eyes) were measured in 377 patients with cataract using the IOLMaster and applanation US. To assess the effect of operator experience on the biometric results, the operators were divided into 2 groups: experienced and less experienced in performing US biometry. The difference in measurements between the methods and the variability of the difference were compared between the 2 groups. Results: Applanation US measured axial length and ACD shorter than the IOLMaster; the mean numerical difference was 0.13 mm and 0.19 mm, respectively (P<.01). For axial length, the absolute difference was smaller with experienced operators than with less experienced operators (0.15 mm versus 0.22 mm) (P<.01). For ACD, experienced operators obtained a smaller difference between measurement techniques (0.21 mm versus 0.29 mm; P<.05). Conclusions: Experienced US operators had less difference and lower variability in the difference between applanation US and IOLMaster readings for axial length and ACD measurements. The noncontact optical method, which is essentially operator independent, gave significantly more reliable biometry before cataract surgery, especially in the case of less experienced operators.

Characteristics of severe intraocular inflammation following intravitreal injection of bevacizumab (Avastin

Background/aims: To report a series of severe intraocular inflammatory events following intravitreal injections of bevacizumab (Avastin). This procedure is performed on a rapidly increasing number worldwide, and rare complications such as intraocular inflammation, endophthalmitis or intraocular haemorrhage are gaining in importance in clinical routine. Methods: This is a single-centre retrospective interventional case series of eight patients with severe intraocular inflammation after intravitreal injection of bevacizumab at one referral centre consecutively seen out of approximately a total of 2500 injections performed in that time period. Patients who developed severe intraocular inflammation after intravitreal injection were evaluated clinically, including slit-lamp examination, best-corrected Snellen visual acuity (VA), slit-lamp photography, optical coherence tomography and fluorescein angiography prior to the event and during follow-up. Results: Patients noticed a painless drop in VA up to 2 days following the injection. All patients had a marked anterior chamber reaction with increased flare and cells, but no hypopyon. Typical posterior segment findings included vitreous cellular infiltrates of pseudogranulomatous aspect. Due to their initial clinical aspect suspicious of an endophthalmitis, three cases were treated with systemic antibiotics, but the final diagnosis was uveitis. Five cases showed a characteristic pseudogranulomatous vitreous infiltration as seen in vitritis and were treated only topically. Conclusions: Characteristic features of an inflammation induced by bevacizumab injection include an early onset with painless loss in VA mostly without conjunctival or ciliary injection. Patients respond to systemic or topical cortisone treatment with slow recovery but without permanent damage. Vitreous haemorrhage and infectious endophthalmitis might be differentiated by time course and symptoms.

Effect of inhalation of different mixtures of O2 and CO2 on retinal blood flow

Aim: To determine the effects of various mixtures of O2 and CO2 on retinal blood flow in healthy subjects. Methods: A randomised, double masked, four way crossover trial was carried out in 12 healthy male non-smoking subjects. Gas mixtures (100% O2, 97.5% O2 + 2.5% CO2, 95% O2 + 5% CO2, and 92% O2 + 8% CO2) were administered for 10 minutes each. Two non-invasive methods were used: laser Doppler velocimetry (LDV) for measurement of retinal blood velocity and fundus imaging with the Zeiss retinal vessel analyser (RVA) for the assessment of retinal vessel diameters. Arterial pH, pCO2, and pO2 were determined with an automatic blood gas analysis system. Retinal blood flow through a major temporal vein was calculated. Results: Retinal blood velocity, retinal vessel diameter, and retinal blood flow decreased during all breathing periods (p <0.001 each). Administration of 92% O2 + 8% CO2 significantly increased SBP, MAP, and PR (p <0.001 each, versus baseline), whereas the other gas mixtures had little effect on systemic haemodynamics. Addition of 2.5%, 5%, and 8% CO2 to oxygen caused a marked decrease in pH and an increase in pCO2 (p <0.001 versus pure oxygen). Conclusions: Breathing of pure oxygen and oxygen in combination with carbon dioxide significantly decreases retinal blood flow. Based on these data the authors speculate that hyperoxia induced vasoconstriction is not due to changes in intravascular pH and cannot be counteracted by an intravascular increase in pCO2.

Twelve hour reproducibility of choroidal blood flow parameters in healthy subjects

Aims/background: To investigate the reproducibility and potential diurnal variation of choroidal blood flow parameters in healthy subjects over a period of 12 hours. Methods: The choroidal blood flow parameters of 16 healthy non-smoking subjects were measured at five time points during the day (8:00, 11:00, 14:00, 17:00, and 20:00). Outcome parameters were pulsatile ocular blood flow as assessed by pneumotonometry, fundus pulsation amplitude as assessed by laser interferometry, blood velocities in the opthalmic and posterior ciliary arteries as assessed by colour Doppler imaging, and choroidal blood flow, volume, and velocity as assessed by fundus camera based laser Doppler flowmetry. The coefficient of variation and the maximum change from baseline in an individual were calculated for each outcome parameter. Results: None of the techniques used found a diurnal variation in choroidal blood flow. Coefficients of variation were within 2.9% and 13.6% for all outcome parameters. The maximum change from baseline in an individual was much higher, ranging from 11.2% to 58.8%. Conclusions: These data indicate that in healthy subjects the selected techniques provide adequate reproducibility to be used in clinical studies. Variability may, however, be considerably higher in older subjects or subjects with ocular disease. The higher individual differences in flow parameter readings limit the use of the techniques in clinical practice. To overcome problems with measurement validity, a clinical trial should include as many choroidal blood flow outcome parameters as possible to check for consistency.

Ocular haemodynamics and colour contrast sensitivity in patients with type 1 diabetes

BACKGROUND There is evidence that altered ocular blood flow is involved in the development and progression of diabetic retinopathy. However, the nature of these perfusion abnormalities is still a matter of controversy. Ocular haemodynamics were characterised with two recently introduced methods. METHODS The cross sectional study was performed in 59 patients with type 1 diabetes with a diabetes duration between 12 and 17 years and an age less than 32 years and a group of 25 age matched healthy controls. Scanning laser Doppler flowmetry and laser interferometric measurement of fundus pulsation amplitude were used to assess retinal and pulsatile choroidal blood flow, respectively. In addition, colour contrast sensitivity along the tritan axis was determined. RESULTS Fundus pulsation amplitude, but not retinal blood flow, increased with the progression of diabetic retinopathy. Retinal blood flow was influenced by plasma glucose levels (r = 0.32), whereas fundus pulsation amplitude was associated with HbA1c(r = 0.30). In addition, a negative correlation between the colour contrast sensitivity along the tritan axis and retinal blood flow was observed. CONCLUSIONS The present study indicates that pulsatile choroidal blood flow increases with the progression of diabetic retinopathy. Increased retinal blood flow appears to be related to loss of colour sensitivity in patents with type 1 diabetes.

Glucose and insulin exert additive ocular and renal vasodilator effects on healthy humans.

Aims/hypothesis. There is evidence that insulin and glucose cause renal and ocular vasodilation. There is, however, currently no data on the effect of combined hyperglycaemia and hyperinsulinaemia on the renal and ocular blood flow seen in diabetic patients on insulin therapy.¶Methods. We carried out two different 3-way cross-over studies in healthy subjects (each, n = 9). In study one, hyperglycaemic clamps (5.6 mmol/l, 11.1 mmol/l, 16.7 mmol/l) were carried out during placebo or insulin (dose 1: 1 mU/kg/min; dose 2: 2 mU/kg/min) infusion. The second study was identical but endogenous insulin secretion was blocked with somatostatin. The renal plasma flow, glomerular filtration rate and pulsatile choroidal blood flow were measured using the paraaminohippurate method, the inulin method and a laser interferometric measurement of fundus pulsation amplitude, respectively.¶Results. Insulin increased renal plasma flow and fundus pulsation amplitude but not the glomerular filtration rate. Hyperglycaemia increased all the renal and ocular parameters studied. Haemodynamic effects of glucose and insulin were additive when somatostatin was co-administered but not under basal conditions.¶Conclusions/interpretation. Glucose and insulin can exert additive vasodilator properties on renal and ocular circulation. To find out whether this observation is related to the increased regional perfusion in diabetes longitudinal studies on patients with Type I (insulin-dependent) diabetes mellitus are needed. [Diabetologia (2001) 44: 95–103]