Pilot study to evaluate the role of high-dose ranibizumab 2.0 mg in the management of neovascular age-related macular degeneration in patients with persistent/recurrent macular fluid <30 days following treatment with intravitreal anti-VEGF therapy (the LAST Study).

PURPOSE: To determine the efficacy of intravitreal ranibizumab 2.0 mg in patients with recalcitrant neovascular age-related macular degeneration (AMD). METHODS: This single-masked, randomized, prospective, pilot study enrolled patients with subfoveal neovascular AMD. All study eyes had persistent subretinal (SRF) or intraretinal fluid (IRF) on spectral-domain optical coherence tomography (SD-OCT) <30 days following at least 6 monthly intravitreal injections of ranibizumab or bevacizumab. Patients were randomized 2 : 1 to receive either ranibizumab 2.0 or 0.5 mg. Following three-loading treatments 4-weeks apart, both groups were treated using a 'treat and extend' regimen guided by eye-tracked SD-OCT through month 12. The primary end point was the mean change in best-corrected visual acuity (BCVA) at month 6. RESULTS: Nine eyes of 9 patients (mean age ± SD, 82.0 ± 5.8 years) were enrolled. Seven eyes received ranibizumab 2.0 mg and two eyes received 0.5 mg. Owing to the small number of patients enrolled, no statistical comparison could be made between the two dosages. At month 6, the mean improvement in BCVA was +6.1 ± 3.7 (W=0, P<0.001) ETDRS letters and +2.0 ETDRS letters in the 2.0 and 0.5 mg groups, respectively. In the 2.0 mg group, there was a statistically significant decline in central foveal thickness, SRF and maximum pigment epithelial detachment height at 6 months compared with baseline. No adverse events were reported in either group. CONCLUSION: Ranibizumab 2.0 mg has the potential to maintain or improve BCVA in some patients with persistent or recurrent SRF or IRF secondary to neovascular AMD despite prior monthly intravitreal anti-vascular endothelial growth factor therapy with the standard dose.

Meta-analysis of randomised controlled trials comparing latanoprost with brimonidine in the treatment of open-angle glaucoma, ocular hypertension or normal-tension glaucoma.

AIM: To compare the efficacy and tolerability of latanoprost versus brimonidine in the treatment of open-angle glaucoma, ocular hypertension or normal-tension glaucoma. METHOD: Systematic review of randomised controlled trials comparing latanoprost and brimondine, identified by searches including Medline, Embase and Cochrane Controlled Trials Register. Two reviewers independently assessed trials for eligibility and quality and extracted data. Data were synthesised (random effects model) and expressed as the absolute mean intraocular pressure (IOP) reduction difference from baseline to end point for efficacy and relative risk for adverse events. Subgroup analysis and regression were used to explore heterogeneity according to patient characteristics, trial design and quality. RESULTS: 15 publications reporting on 14 trials (1784 participants) were included for meta-analysis. IOP reduction favoured latanoprost (weighted mean difference (WMD) = 1.10 mm Hg (95% confidence interval (CI) 0.57 to 1.63)). Significant heterogeneity was present (chi(2)(13) = 38.29, p = 0.001, I(2) = 66.0%). Subgroup analysis showed greater WMD for studies where data were analysed from end points >6 months duration, cross-over design, open-angle glaucoma or ocular hypertension and monotherapy. Multiple regression showed no significant association of WMD with trial duration (t(9) = 1.92, p = 0.09), trial design (t(9) = 1.79, p = 0.11), trial quality (t(9) = -0.46, p = 0.66), or monotherapy or adjunctive therapy (t(9) = -2.14, p = 0.06). Fatigue was less commonly associated with latanoprost (RR = 0.27, 95% CI 0.08 to 0.88). Publication bias was not evident on visual inspection of a funnel plot. CONCLUSION: Latanoprost is more effective than brimonidine as monotherapy in lowering IOP. Brimonidine is associated with a higher rate of fatigue.

Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients.

CYP2C9 polymorphisms reported in Caucasians (Arg144Cys in exon 3 and Ile359Leu in exon 7) are extremely uncommon in Chinese persons. The genotype of CYP2C9 in this population was characterized to investigate its relation with the interindividual variation in warfarin dosages. Eighty-nine Chinese patients receiving warfarin were recruited. Target sequences in CYP2C9 in exons 1, 4, and 5 were amplified by polymerase chain reaction, followed by direct sequencing. Polymorphisms at 4 positions were demonstrated in exon 4. Heterozygosities for 608TTG>GTG (Leu208Val), 561CAG>CCG (Gln192Pro), 537CAT>CCT (His184Pro), and 527ATT>CTT (Ile181Leu) existed at frequencies 0.75, 0.20, 0.10, and 0.09, respectively. Seventeen patients (frequency, 0.19) were homozygous for Val208. The common genotypic combinations at these loci are Ile181/His184/Gln192/Leu208Val (n = 50), Ile181/His184/Gln192/Val208 (n = 15), Ile181/His184/Gln192/Leu208 (n = 4), Ile181/His184/Gln192Pro/Leu208Val (n = 6), Ile181/His184Pro/Gln192Pro/Leu208Val (n = 4), and Ile181Leu/His184/Gln192Pro/ Leu208Val (n = 4). At codon 208, heterozygous Leu208Val and homozygous Val208 appeared to have a lower warfarin dose requirement than the homozygous Leu208. Patients who are heterozygous for Ile181Leu had a higher warfarin dose requirement than the homozygous Ile181. Amplified sequences in exons 1 and 5 did not exhibit polymorphism. In conclusion, Chinese patients showed genetic polymorphisms of CYP2C9 in exon 4 and at codon 208; most were heterozygous Leu208Val and homozygous Val208. Homozygous Leu208, a common allele in Caucasians, is uncommon in this cohort. The significance of these CYP2C9 polymorphic alleles remains to be determined.

The effect of prepubertal diabetes duration on diabetes. Microvascular complications in early and late adolescence.

OBJECTIVE: To define the significance of prepubertal diabetes duration in the development of diabetic microvascular complications in adolescents. RESEARCH DESIGN AND METHODS: Study A compares complications in 38 prepubertal (PreP) and 140 pubertal (Pub) subjects of the same age (10-14 years) and diabetes duration (3-12 years) to determine if the absence of puberty itself confers a lower risk of complications. Study B examines the importance of prepubertal and pubertal diabetes duration in 193 older adolescents (ages 15-22 years) with prepubertal onset of diabetes. Retinopathy status was assessed using stereoscopic fundus photography of seven fields per eye. Albumin excretion rate (AER) was assessed by three consecutive overnight urine collections, using a polyclonal radioimmunoassay. RESULTS: In study A, there were no significant differences between the PreP and Pub groups for retinopathy (27 vs. 29%, P = 0.8) or differences in elevated AER (17 vs. 31%, P = 0.1). In study B, longer prepubertal diabetes duration improved the prediction for retinopathy over postpubertal duration alone (P < 0.0005). No relationship with duration was found for elevated AER (> 7.5, > 15, and > 30 micrograms/min). CONCLUSIONS: Prepubertal subjects with diabetes did not have less retinopathy or elevated albumin excretion compared with pubertal subjects of the same age. Prepubertal diabetes duration is significantly related to the presence of retinopathy in adolescents.

Prospective assessment of autonomic and peripheral nerve function in adolescents with diabetes.

Autonomic and peripheral nerve function were studied prospectively in 102 adolescents with Type 1 diabetes over a 5-year period. All adolescents were assessed three times; 54 were assessed four times. The median age at baseline was 14.5 (range 10.4-18.0) yr. The median diabetes duration at baseline was 6.8 (range 1.3-15.2) yr. Autonomic nerve function was assessed by measuring heart rate variation during deep breathing, valsalva manoeuvre, standing from a lying position (30/15 ratio), and the postural change in systolic blood pressure. Peripheral nerve function was assessed by determining the thermal threshold for heat and cold at the wrist and foot and the vibration threshold at the great toe and medial malleolus. At baseline, 29.5% adolescents had at least one abnormal autonomic nerve test and 28.4% had at least one abnormal peripheral nerve test. There was no significant increase in the number of abnormalities over the study period. Persisting abnormalities were present in only six individuals. Abnormalities were not related to age, diabetes duration or glycaemic control. In summary, a low rate of neurological abnormalities was found, suggesting that more than 3 years of follow-up is required to detect evolving neuropathy in this age group.

Vascular responses by transcutaneous oximetry in adolescents with and without diabetes.

The vascular response of the skin was evaluated by transcutaneous oximetry (TcPO2) in the forearm in 119 adolescents with type I diabetes aged 10.4-19.8 (median 15.3) years, with a duration of diabetes 0.7 to 18.3 (median 7.8) years, and 49 nondiabetic adolescents aged 11.3-18.8 (median 15.5) years. Two different vascular stimuli were used: heating of the probe to 43 degrees C and 5 min of ischemia. Baseline TcPO2 after 13 min of equilibration at a probe temperature of 43 degrees C, postischemic maximum TcPO2, and the postischemic TcPO2 increase were significantly lower in the diabetic group compared to the control group (p = 0.0001, p < 0.0001, and p = 0.0001, respectively). In both the diabetic and the control groups, gender differences were found for baseline TcPO2 (p = 0.0001 and p = 0.0009, respectively) and postischemic maximum TcPO2 (p = 0.0001 and p = 0.005, respectively), the girls having consistently higher values. After controlling for gender by multiple linear regression analysis, duration of diabetes showed a significant effect on postischemic maximum TcPO2 (R2 = 22%, p = 0.02). The postischemic TcPO2 increase was not affected by gender. Lower values for the postischemic TcPO2 increase were related to higher GHb values (R2 = 4%, p = 0.03). Abnormal values for oximetry were associated only with some autonomic nerve function abnormalities. Differences in the vascular response to heat and ischemia as measured by transcutaneous oximetry can be demonstrated between adolescents with type I diabetes and nondiabetic controls, as well as between girls and boys. Lower values in diabetic subjects are weakly associated with diabetes duration and metabolic control, independent of gender.

Development and progression of diabetic retinopathy: adolescents at risk.

The aims of this study were to evaluate short-term changes in retinopathy in adolescents, and to examine the relationship of these changes to risk factors. Two-hundred and three adolescents, with a median age of 14.5 (range 10.4 to 20.6) yr and a median duration of diabetes of 6.6 (1.1 to 16.3) yr, were included in the study. Retinopathy was assessed on two occasions, using stereoscopic fundus photography; the median time between assessment was 1.3 (0.5 to 3.0) yr. At baseline, 41% of the adolescents had background retinopathy. When patients were stratified according to the median diabetes duration (DD) (6.6 yr) and glycaemic control over the 12 months prior to assessment (HbA1C) (8.4%), the percentage of retinopathy in each group was: lowDD/lowHbA1C 13%; lowDD/highHbA1C 40%; highDD/lowHbA1C 42%; and highDD/highHbA1C 72%. Using a 2-step criteria for stability or change in retinopathy, 11% of the 203 adolescents showed progression of retinopathy, 41% had stable retinopathy, 5% showed regression, and 43% had no retinopathy at either assessment. Change in retinopathy was related to age at baseline assessment (borderline significance, p = 0.06), diabetes duration (p < 0.001), glycaemic control (p < 0.001) and total cholesterol (p = 0.04), and was also related to DD/HbA1C group membership (chi 2, p < 0.001). This study highlights the combined adverse effect of long diabetes duration and poor glycaemic control on the development and progression of retinopathy during adolescence, and identifies a group that is likely to show progression over a relatively short period.

The prospective assessment of autonomic nerve function by pupillometry in adolescents with type 1 diabetes mellitus.

The study aimed to compare the longitudinal assessment of automatic nerve function by computerized infrared pupillometry and standard cardiovascular tests in adolescents with diabetes. Adolescents (n = 150) were assessed at two time points (T1 and T2). The median time interval between assessments was 1.5 (range 0.9-3) years. At T1 the median age was 14.5 (range 8.3-19.5) years and the median duration was 6.5 (range 1.1-16) years. The pupillary variables assessed included the resting pupil diameter, the maximum constriction velocity, and the reflex amplitude of constriction. Heart rate reflexes were assessed in response to deep breathing, the Valsalva manoeuvre, and on standing from a lying position (30/15 ratio). Between visits there was a significant decrease in maximum constriction velocity (6.0 mm s-1 vs 6.3 mm s-1, p = 0.0001) and resting pupil diameter (6.2 mm vs 6.3 mm, p = 0.001). At reassessment pupillary abnormalities increased from 32 (21%) to 45 (30%), with 17 (54%) of the initial abnormalities persisting. Adolescents with abnormally slow maximum constriction velocity compared to those with normal maximum constriction velocity had a higher glycated haemoglobin (HbA1c%) at T2 (p = 0.02) and between assessments (p = 0.01). Cardiovascular test abnormalities did not increase between visits and the persistence of initial abnormalities was low (21%). In summary, pupillometry appears a more sensitive test of automatic nerve dysfunction in adolescents with diabetes than assessment of cardiovascular reflexes.

Prevalence and risk factors for retinopathy in adolescents with type 1 diabetes.

OBJECTIVES: To establish the prevalence of, and risk factors associated with, diabetic retinopathy in an Australian adolescent diabetes clinic population. DESIGN: A prospective longitudinal study; baseline findings. PATIENTS: Two hundred and fifty-five patients with Type 1 (insulin-dependent) diabetes mellitus assessed by our service were studied. Entry criteria were: age 11.0-19.9 years; diabetes duration of at least two years; and gradable fundus photographs of at least one eye. MAIN OUTCOME MEASURES: The presence and severity of retinopathy, as assessed by the grading of stereoscopic fundus photographs. Possible risk factors assessed were age, sex, diabetes duration, pubertal stage, blood pressure, glycaemic control and total cholesterol level. RESULTS: The prevalence of retinopathy was 42%; all of those affected had mild background retinopathy. Highly significant associations were found with glycaemic control and both total and prepubertal duration of diabetes. No associations were found with age, sex, pubertal stage, blood pressure or total cholesterol level. CONCLUSIONS: The high prevalence of early diabetic retinopathy in this group of Australian adolescents is comparable to recent reports from other centres. The significant associations with glycaemic control and duration of diabetes provide further strong evidence for the benefit of optimal glycaemic control during adolescence. Our finding that the prepubertal years of diabetes contribute to the development of retinopathy suggests that glycaemic control before puberty should also be optimised. The planned follow-up of this cohort will establish the risk of progression to vision-threatening retinopathy and allow risk factors to be further evaluated.

Autonomic and peripheral nerve function in adolescents with and without diabetes.

In this study reference ranges were established for autonomic and peripheral nerve tests in 122 non-diabetic adolescents. Regression analysis was used to evaluate the effect of age and gender on neurological function. Increasing age was associated with: less heart rate variability during deep breathing (p = 0.03), higher thermal threshold for cold at the wrist (p = 0.009), and higher vibration threshold at the toe (p = 0.001) and medial malleolus (p = 0.01). Male gender was associated with higher Valsalva ratio (p = 0.0004), higher thermal threshold for hot at the foot (p = 0.002), and higher vibration threshold at the malleolus (p = 0.03). The REFVAL programme was used to determine parametric or non-parametric reference limits: the 5% limits for autonomic and 95% limits for peripheral tests. One hundred and eighty-one adolescents with diabetes were studied under identical conditions and similar effects of age and gender were found. Twenty-eight percent of the group with diabetes had at least one abnormal autonomic test result out of four (expected 18.5%); 24% had at least one abnormal peripheral test result out of six (expected 26.5%). Glycaemic control was associated with autonomic (p = 0.04) but not peripheral abnormalities. Using multiple regression analysis and adjusting for age and gender, there was no effect of diabetes duration or glycaemic control on neurological function.