Maria Soffia Gottfredsdottir

Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma

We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[A], odds ratio (OR) = 1.36, P = 5.0 × 10−10). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.

Age-dependent Prevalence of Mutations at the GLC1A Locus in Primary Open-angle Glaucoma

PURPOSE To screen a population with primary open-angle glaucoma for mutations in the gene that encodes the trabecular meshwork inducible glucocorticoid response protein (TIGR), also known as myocilin (MYOC). METHODS Ophthalmologic information was collected for study subjects with primary open-angle glaucoma and their relatives. Mutation screening of 74 primary open-angle glaucoma probands was conducted by sequencing TIGR/MYOC coding sequence and splice sites. RESULTS In 23 families we detected 13 nonsynonymous sequence changes, nine of which appear to be mutations likely to cause or contribute to primary open-angle glaucoma. Two mutations, Arg272Gly and Ile499Ser, and one nonsynonymous sequence variant, Asn57Asp, are novel. We found mutations in nine of 25 juvenile glaucoma probands (36%) and two of 49 adult-onset glaucoma probands (4%). Age classification of families rather than individual probands revealed mutations in three of nine families with strictly juvenile primary open-angle glaucoma (33%), and no mutations in 39 families with strictly adult-onset primary open-angle glaucoma (0%). In families with mixed-onset primary open-angle glaucoma containing both juvenile primary open-angle glaucoma and adult-onset primary open-angle glaucoma cases, we found mutations in eight of 26 families (31%). CONCLUSIONS Our data suggest that Gly252Arg, Arg272Gly, Glu323Lys, Gln368STOP, Pro370Leu, Thr377Met, Val426Phe, Ile477Asn, and Ile499Ser are likely to play roles that cause or contribute to the etiology of autosomal dominant primary open-angle glaucoma. Our finding of more TIGR/MYOC mutations in families with mixed-onset primary open-angle glaucoma than in the families with strictly adult-onset primary open-angle glaucoma implies that the presence of relatives with juvenile primary open-angle glaucoma in a family could be used as a basis for identifying a subset of the population with adult-onset primary open-angle glaucoma with higher prevalence of TIGR/MYOC mutations. To address this issue, and to refine estimations of mutation prevalence in these age-defined subpopulations, prospective study of a larger population ascertained entirely through adult-onset primary open-angle glaucoma probands will be needed.

Retinal vessel dilatation and elongation precedes diabetic macular oedema

AIMS/BACKGROUND Retinal vessel dilatation is a well known phenomenon in diabetes. In this study, the theory of whether excessive changes in diameter and length of retinal vessels occur in the development of diabetic macular oedema was tested, supporting a hypothesis that the development of diabetic macular oedema may be linked to hydrostatic pressure changes described in Starling’s law. METHODS From fundus photographs of diabetic patients attending a regular eye screening programme, the diameter and segment length of retinal vessels were measured in three retinopathy groups (12 patients each) with diabetic macular oedema (DMO), background retinopathy and no retinopathy, over a period of approximately 4 years, ending at the time of diagnosis of diabetic macular oedema in the DMO group. RESULTS A statistically significant dilatation and elongation of retinal arterioles, venules, and their macular branches was found before the diagnosis of macular oedema in the DMO group. No significant changes were found in the other two groups. CONCLUSION It is suggested that Starling’s law applies to the formation of oedema in the retina as in other tissues.

Retinal oximetry in primary open-angle glaucoma

PURPOSE. To determine whether retinal vessel oxygen saturation is affected in primary open-angle glaucoma (POAG) patients. METHODS. Retinal oxygen saturation in patients with POAG was measured in retinal vessels with a spectrophotometric retinal oximeter in darkness, and visual fields were obtained. Oxygen tension (Po(2)) was calculated from oxygen saturation values. Statistical analysis was performed using Pearsons correlation and Students t-test. RESULTS. Mean oxygen saturation in venules was higher in persons with poor visual fields (68% ± 4%, mean ± SD) than in those with good visual fields (62% ± 3%; P = 0.0018). The mean arteriovenous difference in oxygen saturation was lower in persons with poor visual fields (30% ± 4%, n = 9) than in those with good visual fields (37% ± 4%; P = 0.0003; n = 12). No correlation was found between saturation in retinal arterioles and visual field mean defect (n = 31; r = -0.16; P = 0.38). Oxygen saturation in retinal venules correlated positively with worsening visual field mean defect (r = 0.43; P = 0.015). Arteriovenous difference in oxygen saturation decreased significantly as the visual field mean defect worsened (r = -0.55; P = 0.0013). Mean Po(2) in venules was 38 ± 3 mm Hg. It was significantly higher in persons with poor visual field fields (40 ± 3 mm Hg) than in those with good visual fields (36 ± 2 mm Hg; P = 0.0016). CONCLUSIONS. Deeper glaucomatous visual field defects are associated with increased oxygen saturation in venules and decreased arteriovenous difference in retinal oxygen saturation. The data suggest that oxygen metabolism is affected in the glaucomatous retina, possibly related to tissue atrophy.

Retinal vasoconstriction after laser treatment for diabetic macular edema.

The diameter of retinal arterioles, venules, and their macular branches was measured before and after macular laser photocoagulation in one eye each of six men and eight women with diabetic macular edema. The macular arteriolar branches constricted 20.2% (P < .001) and the venular branches constricted 13.8% (P < .001). This autoregulatory vasoconstriction results from the improved retinal oxygenation caused by the laser treatment. By extrapolating the principles of tissue edema formation in general, we hypothesized how macular laser treatment affects diabetic macular edema. Starlings law predicts that (laser-induced) vasoconstriction and reduced intravascular hydrostatic pressure should reduce edema formation in any tissue, including the retina.

Chronic open-angle glaucoma and associated ophthalmic findings in monozygotic twins and their spouses in Iceland

PURPOSE To determine the concordance of glaucoma and ocular parameters in monozygotic twins and their spouses. METHODS This was a prospective study that included 50 twin pairs 55 years of age or older and 47 of their spouses. Zygosity was determined by genetic laboratory testing. RESULTS The concordance of open-angle glaucoma in monozygotic twin pairs was 98.0%, which significantly exceeded that of twin/spouse pairs (70.2%). There was a significant association in mean intraocular pressure (IOP), mean axial length, anterior chamber depth, and refractive error in the twin pairs. However, there was no association between the twins and their spouses for these ocular parameters. Eight twin pairs were found to have pseudoexfoliation syndrome (PXFS), five of which were concordant. There was no association between glaucoma and mean axial length or glaucoma and refractive error in the twin pairs studied. CONCLUSION The statistically significant higher concordance of glaucoma--and the high correlation of mean IOP, mean axial length, anterior chamber depth, and refractive error--in twin pairs and the lack of association of these factors in twin/spouse pairs strongly suggests the importance of genetic factors for these ocular parameters.

Glaucoma Filtration Surgery and Retinal Oxygen Saturation

PURPOSE Glaucoma may involve disturbances in retinal oxygenation and blood flow. The purpose of this study was to measure the effect of glaucoma filtration surgery on retinal vessel oxygen saturation. METHODS A noninvasive spectrophotometric retinal oximeter was used to measure hemoglobin oxygen saturation in retinal arterioles and venules before and after glaucoma filtration surgery. Twenty-five consecutive patients were recruited, and 19 had adequate image quality. Fourteen underwent trabeculectomy and five glaucoma tube surgery. Twelve had primary open-angle glaucoma and seven had exfoliative glaucoma. IOP decreased from 23 +/- 7 to 10 +/- 4 mm Hg (mean +/- SD, P = 0.0001). RESULTS Oxygen saturation increased in retinal arterioles from 97% +/- 4% to 99% +/- 6% (n = 19; P = 0.046) after surgery and was unchanged in venules (63% +/- 5% before surgery and 64% +/- 6% after, P = 0.76). There were no significant changes in saturation in the fellow eyes (P > 0.60). The arteriovenous difference was 34% before and 36% after surgery (P = 0.35). CONCLUSIONS Glaucoma filtration surgery had almost no effect on retinal vessel oxygen saturation.

Retinal oxygen metabolism in healthy subjects and glaucoma patients

Background To test whether retinal oxygen metabolism is different in glaucoma patients compared with healthy subjects. Methods This was a two-centre study where retinal vessel oxygen saturation was measured in glaucoma patients and healthy individuals with a non-invasive spectrophotometric retinal oximeter. Visual fields were obtained in the glaucoma patients. Results No statistical difference was found in retinal oxygen saturation in arterioles (p=0.16), venules (p=0.16) and arteriovenous difference (p=0.24) when all glaucoma patients (n=74) were compared with healthy individuals (n=89). When patients with advanced glaucoma (visual field mean defect (MD ≥ 10 dB, n=21)) were compared with healthy individuals, the oxygen saturation in venules was higher in glaucoma patients (58.2%±5.4% vs 53.8%±6.4%; p=0.0054, mean±SD) and the arteriovenous difference was lower in glaucoma patients (36.4%±4.7% vs 39.5%±5.7%; p=0.021). In glaucoma patients with mild glaucoma (visual field MD ≤ 5 dB, n=33), no statistical differences were found in retinal oxygen saturation compared with healthy individuals. Conclusions Glaucoma patients with advanced glaucoma have higher oxygen saturation in venules and lower arteriovenous difference in oxygen saturation compared with healthy individuals. The decreased arteriovenous difference in severe glaucoma may be related to lower oxygen consumption secondary to neuropathy.

Dorzolamide-Timolol Combination and Retinal Vessel Oxygen Saturation in Patients with Glaucoma or Ocular Hypertension

Aims: To examine whether the addition of dorzolamide to timolol monotherapy influences oxygen saturation in the human retina. Methods: Non-invasive spectrophotometric retinal oximetry was used to measure oxygen saturation in retinal vessels. Twenty patients with open-angle glaucoma (11) and ocular hypertension (9) were recruited. The patients were randomised into receiving timolol monotherapy or dorzolamide–timolol combination for an 8-month test period, followed by a second test period, before which the patients switched treatments. Oximetry measurements were performed at 2-month intervals during each period. Of the 20 patients, 13 followed the study protocol into the second test period, and 10 managed all study visits. Results: The oxygen saturation in retinal vessels was stable within the test periods. The mean arteriolar saturation was 96 (2)% (mean (SD)) during timolol monotherapy and 97 (2)% during dorzolamide–timolol combination therapy (p = 0.17, all patients pooled, n = 13). Corresponding values in venules were 66 (5)% during timolol monotherapy and 65 (6)% during dorzolamide–timolol therapy (p = 0.13). Patients who started on dorzolamide–timolol combination showed a significant reduction in arteriolar (98 (2)% to 95 (2)%, p<0.01) and venular saturation (69 (5)% to 66 (6)%, p<0.05) when changing to timolol monotherapy. Conclusion: Adding dorzolamide to timolol monotherapy has a minimal effect, but going from dorzolamide–timolol combination to timolol alone lowered arteriolar and venular oxygen saturation. The retinal oxygen saturation measurements show a high degree of stability over an extended period of time. Previous studies have suggested increased retinal and optic nerve blood flow with dorzolamide. Unchanged oxygen saturation and increased blood flow would indicate increased oxygen delivery to the retina.

γ-Cyclodextrin Nanoparticle Eye Drops with Dorzolamide: Effect on Intraocular Pressure in Man

PURPOSE To test a new drug delivery platform with dorzolamide γ-cyclodextrin (γCD) nanoparticle eye drops for intraocular pressure (IOP) control and safety and compare with Trusopt.(®) METHODS Self-aggregating γCD nanoparticle eye drops containing 3% dorzolamide were given once a day (QD) and compared with Trusopt given three times a day (TID) in a prospective randomized single masked crossover trial over 24 h. Seventeen subjects with IOP over 18 mmHg were recruited. IOP was measured with an Icare Tonometer Pro.(®) RESULTS There was no statistically significant difference in the IOP lowering effect of dorzolamide nanoparticle eye drops QD and Trusopt TID. At peak (4 h), the IOP reduction from baseline was 3.8±2.6 mmHg (18%, P<0.05) in the nanoparticle eye drop group and 3.1±3.7 mmHg in the Trusopt group (14%, P<0.05, P=0.97 between groups). At trough (24 h), the IOP reduction was 1.4±2.8 mmHg (6%, P>0.05) in nanoparticle eye drop group and 1.5±2.0 mmHg (7%, P>0.05) in the Trusopt group (P=0.23 between groups). Burning sensation measured on the visual analogue scale (1-100) was less from the nanoparticle eye drops (12±15) than from the Trusopt (37±30), (P=0.0038). Visual acuity and conjunctival hyperemia did not differ between the two groups. CONCLUSIONS Dorzolamide cyclodextrin nanoparticle eye drops QD lower IOP and the effect seems comparable to Trusopt given TID. The nanoparticle eye drops are well tolerated and seem to have a better safety profile than Trusopt.