Macular Degeneration: Immonen I

Laine M, Jarva H, Seitsonen S, Haapasalo K, Lehtinen MJ, Lindeman N, Anderson DH, Johnson PT, Järvelä I, Jokiranta TS, Hageman GS, Immonen I, Meri S. · Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Haartmaninkatu 3, FI-00014 Helsinki, Finland. · J Immunol. · Pubmed #17339482 links to  free full text

Abstract: Complement factor H (FH) is an important regulator of the alternative complement pathway. The Y402H polymorphism within the seventh short consensus repeat of FH was recently shown to be associated with age-related macular degeneration, the most common cause of irreversible blindness in the Western world. We examined the effects of this polymorphism on various FH functions. FH purified from sera of age-related macular degeneration patients homozygous for the FH(402H) variant showed a significantly reduced binding to C-reactive protein (CRP), an acute phase protein, as compared with FH derived from unaffected controls homozygous for the FH(402Y) variant. Strongly reduced binding to CRP was also observed with a recombinant fragment of FH (short consensus repeat 5-7) containing the same amino acid change. Because the interaction of CRP and FH promotes complement-mediated clearance of cellular debris in a noninflammatory fashion, we propose that the reduced binding of FH(402H) to CRP could lead to an impaired targeting of FH to cellular debris and a reduction in debris clearance and enhanced inflammation along the macular retinal pigmented epithelium-choroid interface in individuals with age-related macular degeneration.

Azab M, Boyer DS, Bressler NM, Bressler SB, Cihelkova I, Hao Y, Immonen I, Lim JI, Menchini U, Naor J, Potter MJ, Reaves A, Rosenfeld PJ, Slakter JS, Soucek P, Strong HA, Wenkstern A, Su XY, Yang YC, Anonymous00313. · No affiliation provided · Arch Ophthalmol. · Pubmed #15824216 No free full text.

Abstract: OBJECTIVE: To compare the treatment effect and safety of photodynamic therapy with verteporfin using a standard (SF) or reduced (RF) light fluence rate with that of placebo therapy in patients with subfoveal minimally classic choroidal neovascularization (CNV) with age-related macular degeneration. DESIGN: Phase 2, multicenter, double-masked, placebo-controlled, randomized clinical trial. SETTING: Nineteen ophthalmology practices in North America and Europe. PARTICIPANTS: Patients with initial best-corrected visual acuity of at least 20/250 and a lesion size of no greater than 6 Macular Photocoagulation Study (MPS) disc areas. METHODS: We randomly assigned 117 patients (1:1:1) to verteporfin infusion (6 mg/m(2)) and light application with an RF rate (300 mW/cm(2)) for 83 seconds (light dose of 25 J/cm(2)) or an SF rate (600 mW/cm(2)) for 83 seconds (light dose of 50 J/cm(2)) or to placebo infusion with RF or SF. Treatment was repeated every 3 months if the treating physician noted fluorescein leakage from CNV on angiography. Patients in whom a predominantly classic lesion developed could receive open-label standard verteporfin treatment. Best-corrected visual acuity was measured every 3 months, and angiographic changes were assessed by the Photograph Reading Center through the 3-month examination unless an ocular adverse event or conversion to a predominantly classic lesion was identified by an investigator. Safety was assessed throughout the study. All outcomes were on an intent-to-treat basis. RESULTS: One hundred three (88%) of 117 patients completed the 24-month examination. Twelve (30%) of 40 patients assigned to placebo received open-label standard verteporfin treatment after confirmation of presence of predominantly classic CNV. At month 12, a loss of at least 3 lines of visual acuity occurred in 5 (14%) of 36 eyes assigned to RF and 10 (28%) of 36 eyes assigned to SF, compared with 18 (47%) of 38 eyes assigned to placebo (RF, P = .002; SF, P = .08; RF + SF, P = .004). At month 24, this loss occurred in 9 (26%) of 34 eyes assigned to RF and 17 (53%) of 32 assigned to SF, compared with 23 (62%) of 37 eyes assigned to placebo (RF, P = .003; SF, P = .45; RF + SF, P = .03). Progression to predominantly classic CNV by 24 months was more common in the placebo group (11 [28%] of 39 patients compared with 2 [5%] of 38 in the RF group [P = .007] and 1 [3%] of 37 in the SF group [P = .002]). No unexpected ocular or systemic adverse events were identified. Treatment-related, usually transient visual disturbances were 13% with SF, 10% with placebo, and 5% with RF. CONCLUSIONS: Verteporfin therapy safely reduced the risks of losing at least 15 letters (> or =3 lines) of visual acuity and progression to predominantly classic CNV for at least 2 years in individuals with subfoveal minimally classic lesions due to age-related macular degeneration measuring 6 MPS disc areas or less. Based on the overall evidence available on verteporfin therapy for these lesions, the VIM Study Group would consider recommending verteporfin therapy for relatively small minimally classic lesions similar to those enrolled in the VIM Trial.

Jaakkola A, Heikkonen J, Tommila P, Laatikainen L, Immonen I. · Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland. · Ophthalmology. · Pubmed #15808245 No free full text.

Abstract: OBJECTIVE: To determine the efficacy of strontium plaque (Sr90) brachytherapy for age-related macular degeneration (AMD) with subfoveal choroidal neovascularization (CNV). DESIGN: Randomized clinical trial. PARTICIPANTS: Eighty-eight eyes of 86 patients with subfoveal CNV secondary to AMD were randomized either to plaque radiotherapy or to observation. INTERVENTION: Radiotherapy was given as episcleral brachytherapy using Sr90 plaques. Two different plaque types were used. Plaque I had a diameter of 8 mm and delivered a dose of 15 Gy at a depth of 1.75 mm in 54 minutes. With plaque II, the corresponding values were 4 mm, 12.6 Gy, and 11 minutes. The control group was observed without any treatment. MAIN OUTCOME MEASURES: The primary outcome measure was visual acuity at 6, 12, 24, and 36 months. Other outcome variables were contrast sensitivity, fluorescein angiographic, and clinically evaluated changes in the macula. RESULTS: Eighty-two patients (84 eyes [95%]) completed the 1-year follow-up, and 80 (93%) and 74 (86%) patients completed the 2- and 3-year follow-ups, respectively. At 6 months, visual loss of > or =3 lines occurred in 20% of treated patients and 42% of control patients (P = 0.031). At 12 months, a visual loss of > or =3 lines occurred in 45% (treated) and 56% (controls) (P = 0.325); at 24 months, in 73% and 71% (P = 0.914); and at 36 months, in 80% and 84% of patients (P = 0.591), respectively. Patients irradiated with plaque I had better results: a visual loss of > or =3 lines occurred in 6% at 6 months (P = 0.008, relative to controls), in 18% at 12 months (P = 0.007), in 59% at 24 months (P = 0.348), and in 71% at 36 months (P = 0.212). In patients treated with plaque II, the corresponding values were 29% (P = 0.032), 65% (P = 0.459), 83% (P = 0.317), and 80% (P = 0.687) at 6, 12, 24, and 36 months, respectively. CONCLUSIONS: The short-term clinical course of exudative AMD is affected by Sr90 brachytherapy, but by 12 months, there was no treatment benefit. This article contains additional online-only material available at http://www.ophsource.org/periodicals/ophtha.

Jaakkola A, Tommila P, Laatikainen L, Immonen I. · Department of Ophthalmology, Helsinki University Hospital, Finland. · Eur J Ophthalmol. · Pubmed #11681507 No free full text.

Abstract: PURPOSE: To analyze angiographic changes in choroidal neovascular membranes (CNVM) after strontium-plaque (90Sr) irradiation for exudative age-related macular degeneration (AMD) using masked measurement of the CNVM areas and a masked subjective comparison of CNVM size and leakage. METHODS: We studied the baseline, 3, 6, and 12-month angiograms of 19 eyes treated with 90Sr-plaque irradiation for exudative AMD. The area of CNVM-related hyperfluorescence was measured quantitatively, and the angiograms were subjectively evaluated by a masked grader. RESULTS: In 7 of the 19 eyes the CNVM-related hyperfluorescence was too scattered to be analyzed by planimetry but masked subjective grading correlated with the clinical response to irradiation. In the remaining 12 eyes, the CNVM decreased in size in 67% of the eyes and showed leakage in 67%. Planimetry and subjective assessment of the size and leakage of the CNVMs similarly reflected the regression after irradiation. CONCLUSIONS: CNVM size and leakage frequently diminish after 90Sr-plaque irradiation. Quantitative measurement of the CNVM areas, or a grading system based on masked subjective assessment, give similar results for evaluating these changes. Masked subjective grading can be used even in cases where the CNVM is too scattered to be outlined for planimetry.

Tolppanen AM, Nevalainen T, Kolehmainen M, Seitsonen S, Immonen I, Uusitupa M, Kaarniranta K, Pulkkinen L. · Department of Clinical Nutrition and Food and Health Research Centre, University of Kuopio, Kuopio, Finland. · Mol Vis. · Pubmed #19381347 links to  free full text

Abstract: PURPOSE: Tenomodulin (TNMD) is located in the X-chromosome encoding a putative angiogenesis inhibitor which is expressed in retina. Associations of single nucleotide polymorphisms of TNMD with the prevalence of age-related macular degeneration (AMD) were examined. METHODS: Six markers covering 75% of the common sequence variation in the coding region of TNMD and 10 kb up- and downstream were genotyped in a sample consisting of 89 men and 175 women with exudative AMD, 18 men and 25 women with atrophic AMD, and 55 men and 113 women without AMD. All participants were over 65 years old and did not have diabetes mellitus. Due to the chromosomal locus, the association of genotypes with AMD was assessed genderwise. RESULTS: Three markers, rs1155974, rs2073163, and rs7890586, were associated with a risk of AMD in women. In comparison to women with other genotypes, the women who were homozygous for the minor allele (genotypes rs1155974-TT or rs2073163-CC) had 2.6 fold (p=0.021) or 1.9 fold (p=0.067) risk for having AMD, respectively. These differences were due to the unequal prevalence of exudative AMD. In comparison to women who were homozygous for the major alleles, the women with rs1155974-TT genotype had a 2.8 fold risk (p=0.021 in additive model; p=0.022 in recessive model) for exudative AMD, and the women with rs2073163-CC genotype had a 1.8 fold risk (p=0.09 in additive model; p=0.038 in recessive model). Furthermore, women carrying the rare rs7890586-AA genotype had a significantly smaller risk for having AMD than women with the other genotypes (odds ratio 0.083; p=0.001 in recessive model), but due to the low frequency of this genotype, this finding must be interpreted cautiously. The false discovery rate was <10% for all of the aforementioned results. CONCLUSIONS: On the basis of the putative antiangiogenic role of TNMD and the present genetic associations of TNMD with AMD in women, we suggest that TNMD could be a novel candidate gene for AMD. These results should be confirmed in further studies.

Kaarniranta K, Seitsonen S, Paimela T, Meri S, Immonen I. · Kuopion yliopisto ja KYS:n silmätautien yksikkö. · Duodecim. · Pubmed #19341030 No free full text.

Abstract: Age-related macular degeneration is a multiform disease of the macula, the region responsible for detailed central vision. In recent years, plenty of new knowledge of the pathogenesis of this disease has been obtained, and the treatment of exudative macular degeneration has greatly progressed. The number of patients with age-related macular degeneration will multiply in the following decades, because knowledge of mechanisms of development of macular degeneration that could be subject to therapeutic measures is insufficient. Central underlying factors are genetic inheritance, exposure of the retina to chronic oxidative stress and accumulation of inflammation-inducing harmful proteins into or outside of retinal cells.

Seitsonen S, Järvelä I, Meri S, Tommila P, Ranta P, Immonen I. · Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland. · Acta Ophthalmol. · Pubmed #17995985 No free full text.

Abstract: PURPOSE: The Y402H polymorphism of the complement factor H (CFH) gene is associated with age-related macular degeneration (AMD) in many populations. The reported genotype-phenotype correlations in the CFH Y402H polymorphism have not been pronounced and no studies on the effect of the polymorphism on the subgroups within wet AMD have been performed. In this study, we wanted to evaluate whether the CFH Y402H polymorphism has an effect on clinical variables in recent exudative AMD lesions. METHODS: The study included 172 patients with exudative AMD. The size of AMD lesions and the presence and area of other AMD lesion variables were recorded in fluorescein angiography (FA) and analysed in relation to the Y402H genotypes. RESULTS: The median lesion size (classic + occult choroidal neovascularization [CNV] + serous pigment epithelium detachment [PED] + haemorrhage, if present) was 8.15 mm(2) in patients homozygous for the CFH risk allele (CC), 7.50 mm(2) in heterozygous patients (CT), and 7.05 mm(2) in those with the normal genotype (TT) (p = 0.599). Areas of classic and occult CNV, combined, without serous PED or haemorrhage were 6.37 mm(2), 5.00 mm(2) and 5.18 mm(2), respectively (p = 0.407). There was a trend for CC patients to have more frequently minimally classic and less frequently predominantly classic lesion composition than CT or TT subjects. CONCLUSIONS: We detected no clear impact of the CFH Y402H polymorphism on recent exudative AMD lesion characteristics. Although the complement cascade is implicated in CNV formation and scarring processes in the retina, the Y402H polymorphism appears relatively neutral in these functions.

Kaarniranta K, Holopainen JM, Karvonen MK, Koulu M, Kallio J, Pesonen U, Teräsvirta M, Uusitalo H, Immonen I. · Department of Ophthalmology, University of Kuopio, Kuopio, Finland. · Acta Ophthalmol Scand. · Pubmed #17305733 No free full text.

Abstract: PURPOSE: Because of the regulatory role of neuropeptide Y (NPY) in angiogenesis, we set out to determine the presence of the leucine 7-proline 7 (Leu7Pro) polymorphism in exudative age-related macular degeneration (AMD) patients and to analyse its implications. METHODS: Genotype analysis of the Leu7Pro polymorphism in the signal peptide region of the human prepro-NPY was performed in blood samples from exudative AMD patients (n = 240) and control subjects (n = 79). RESULTS: In all, 11% of exudative AMD patients and 14% of control subjects exhibited the NPY signal peptide Leu7Pro polymorphism. There were no statistically significant differences in Leu7Pro polymorphism frequency between the exudative AMD and control cases, as analysed by Fisher's exact two-sided test. CONCLUSIONS: Leu7Pro polymorphism in the signal peptide region of the human prepro-NPY is not a risk factor for exudative AMD.

Seitsonen S, Lemmelä S, Holopainen J, Tommila P, Ranta P, Kotamies A, Moilanen J, Palosaari T, Kaarniranta K, Meri S, Immonen I, Järvelä I. · Department of Ophthalmology, University of Helsinki, Helsinki, Finland. · Mol Vis. · Pubmed #16885922 links to  free full text

Abstract: PURPOSE: A strong association of a Tyr402His polymorphism in the complement factor H (CFH) gene and a Met299Val polymorphism in the elongation of very long chain fatty acids-like 4 (ELOVL4) gene with age-related macular degeneration (AMD) has been identified in Caucasian populations in the United States. Earlier a Gln5345Arg variant in the hemicentin 1 (HMCN1) gene was reported in a large AMD family in the United States. We wanted to investigate whether the polymorphisms of the CFH and the ELOVL4 genes or the mutation of the HMCN1 gene are associated with AMD in patients originating from the Finnish population with characteristics of a genetic isolate. METHODS: The material consisted of familial (n=181) and sporadic cases (n=154) with AMD, a control group with no AMD (non-AMD controls, n=105), and a control group of anonymous blood donors (blood donor controls, n =350). The DNA of the subjects was sequenced to analyze the variants of the three genes. RESULTS: We detected a strong association between the C/C-genotype compared to the T/T-genotype of Tyr402His polymorphism (first base of the Tyr-codon changes) of the CFH gene and AMD in the AMD cases compared to the non-AMD (p=8.86x10(-12)) or to blood donor controls (p=2.02x10(-13)). The frequency of the C/C genotype was significantly increased in both familial cases compared to non-AMD controls with non-adjusted odds ratio (OR) 10.1 (confidence intervals [CI] 95% 4.64-22.2) or compared to blood donor controls with non-adjusted OR 5.50 (CI 95% 3.17-9.55) and in sporadic cases with non-adjusted OR 9.33 (CI 95% 4.10-21.3; non-AMD-controls), OR 5.06 (CI 95% 2.75-9.28; blood donor controls). Frequency of C allele differed significantly between cases and controls (p=1.32x10(-11); non-AMD-controls and p=3.94x10(-14); blood donor controls). No association with AMD was detected with Met299Val polymorphism in the ELOVL4 gene in the familial or sporadic cases compared to non-AMD or blood donor controls. None of our subjects (258 AMD cases, 72 non-AMD controls) had the Gln5345Arg variant in the HMCN1 gene. CONCLUSIONS: The CFH gene polymorphism seems to be an important etiologic factor for AMD also in the isolated Finnish population.

Riusala A, Sarna S, Immonen I. · Department of Ophthalmology, Helsinki University Hospital, Haartmaninkatu 4 C, FIN-00029 JP 220 Helsinki, Finland. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #15834599 No free full text.

Abstract: BACKGROUND: Although exudative age-related macular degeneration (AMD) leads to a substantial visual loss in most patients there is still significant variation in the end- stage visual acuity level. We analysed lesions in eyes with long-standing AMD in order to find contributing factors for this variation. METHODS: Sixty-one out of 121 patients examined for exudative AMD and still alive 4.8-9.2 (mean 6.8) years after the acute phase were re-examined. The lesion size, area of subretinal fibrosis, geographic atrophy, presence of a persistent exudative process, and shortest distance to normal looking retina were measured from digital fundus photographs taken at the re-examination and correlated with visual acuity. RESULTS: Lesion size, the presence of a continuing exudative process, or subretinal fibrosis were independent predictors for poor vision. Better vision in the other eye was connected with poor vision in the affected study eye. CONCLUSIONS: In addition to lesion size, the presence of a continuing exudative process and subretinal fibrosis also have deleterious effects on long-term visual acuity after exudative AMD.

Riusala A, Sarna S, Immonen I. · Department of Ophthalmology, Helsinki University Hospital, Helsinki, Finland. · Am J Ophthalmol. · Pubmed #12566025 No free full text.

Abstract: PURPOSE: To evaluate the Visual Function Index (VF-14) questionnaire for its effectiveness in assessing visual function in patients with longstanding exudative age-related macular degeneration (AMD). DESIGN: Observational case series. METHODS: The records of 167 consecutive patients with recent neovascularization related to AMD between June 1990 and December 1994 at the Helsinki University Eye Clinic were analyzed in 1999. Of 121 patients still living, 74 (61%) attended the reexamination. After exclusions, data from 62 patients were analyzed. The VF-14 score, plus global assessment scores of satisfaction with vision and quality of vision, in which patients graded the subjective level of difficulty with their vision, best-corrected visual acuity (BCVA), contrast sensitivity, the area of the AMD lesion, and the shortest distance and direction from the center of the fovea to the edge of the subfoveal lesion, were analyzed. RESULTS: The VF-14 score correlated significantly with BCVA (P <.01), contrast sensitivity (P <.01), and global assessment scores (P <.01), showing stronger correlations with global assessment scores than did BCVA. In multivariate regression analysis, the global assessment scale of overall quality of vision and BCVA in the better eye were significant predictors (P <.001) of the variability in the VF-14 score. CONCLUSIONS: The VF-14 reflects visual function of patients with late AMD more effectively than BCVA measurement alone. The VF-14 can thus be used to compare the visual handicap of late AMD patients with that of patients with other eye diseases.

Jaakkola A, Heikkonen J, Tarkkanen A, Immonen I. · Department of Ophthalmology, Helsinki University Central Hospital, Finland. · Acta Ophthalmol Scand. · Pubmed #10071150 No free full text.

Abstract: PURPOSE: To report 2-year visual and angiographic results in eyes treated with strontium plaque irradiation for subfoveal choroidal neovascular membranes (CNVM) in age-related macular degeneration. METHODS: Twenty eyes with recent subfoveal CNVM were treated with local irradiation. The impact of the treatment on visual function was evaluated by visual acuity, contrast sensitivity and reading speed testing. RESULTS: At 12 months visual acuity had improved or remained the same in 9/ 20 eyes (45%). At 24 months visual acuity was stable in 5/18 eyes (28%). Eyes with signs of CNVM regression (13/18, 72%) lost a mean of 3.3 lines, but eyes with recurrent CNVM lost a mean of 5.1 lines of vision. The mean contrast sensitivity was better in the irradiated eyes than in the fellow eyes with late age-related macular degeneration at 24 months. Six of 17 irradiated eyes (35%) could read at least some words at 24 months. CONCLUSIONS: Visual function decreases in patients treated with strontium irradiation, but less in eyes showing regression of the CNVM than in eyes with further growth of the CNVM.

Jaakkola A, Vesti E, Immonen I. · Department of Ophthalmology, Helsinki University Central Hospital, Finland. · Ophthalmology. · Pubmed #9951476 No free full text.

Abstract: OBJECTIVE: To evaluate the feasibility of using confocal scanning laser tomography in the analysis of macular topography in patients with subfoveal choroidal neovascularization associated with age-related macular degeneration (AMD) and to analyze quantitatively the changes in topography after local strontium-plaque radiation therapy. DESIGN: Prospective case series. PARTICIPANTS: A total of 16 eyes with subfoveal choroidal neovascular membranes (CNVM) treated with strontium-90 (90Sr)-plaque radiation therapy and 16 fellow eyes of 16 patients were examined. INTERVENTION: Confocal scanning laser analysis of macular surface topography before and after irradiation of the macula was performed. MAIN OUTCOME MEASURES: Parameters describing the height and volume of the retinal elevation in the macula were measured. RESULTS: The maximum height of the macular lesion at baseline was 0.25 mm (standard deviation [SD], 0.12 mm) in eyes showing regression of the CNVM during follow-up and 0.34 mm (SD, 0.19 mm) in eyes showing continued growth of the CNVM. During follow-up, a mean decrease in the maximum height of the macular lesion ranging from 0.03 to 0.10 mm occurred in eyes with regression of the CNVM, whereas the mean maximum height increased by 0.07 to 0.15 mm during follow-up visits in eyes with continued growth of the CNVM. All parameters describing the mean height and volume of the lesion also decreased significantly in patients showing angiographic regression, whereas they increased or remained unchanged in patients with continuous growth of the CNVM despite irradiation. The corresponding parameters also were higher in fellow eyes with untreated CNVM than in eyes without exudative AMD. CONCLUSIONS: Confocal scanning laser tomography can be used to monitor the amount of the change in neurosensory detachment in AMD. The parameters obtained by confocal scanning laser tomography correlate with CNVM perfusion after 90Sr-plaque radiation therapy. This technology is a useful tool for objective evaluation of morphologic change after institution of new therapeutic methods for the treatment of AMD.