Súrefnisbúskapur sjónhimnu og aldursbundin augnbotnahrörnun

Purpose: Neovascular age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness in elderly persons in the industrialised areas. This impairment in vision is caused by pathological neovascularisation and hemorrhages in the fundus with subsequent fibrovascular scar formation. Neovascularisation is generally related to ischaemia and hypoxia, which induces formation of growth factors. One of which is vascular endothelial growth factor (VEGF) but the main treatment of neovascular AMD is with antibodies against VEGF. This, as well as results from other studies, suggests that the retinal oxygen metabolism is disturbed in neovascular AMD. Limited technology has been available to measure oxygenation of the fundus in humans, until recently when our research group developed such apparatus. The aim of the studies in this thesis is to determine if retinal vessel oxygen saturation is abnormal in patients with neovascular AMD. To reach that goal, the retinal oxygen saturation was first measured in healthy persons to standardise the retinal oximetry imaging technique and establish a normal control group. Subsequently, the retinal oxygen saturation was measured in patients with neovascular AMD. Finally, the scope of neovascular AMD and its intravitreal anti-VEGF treatment in Iceland was assessed to evaluate the health-care impact of the disease in Iceland. Methods: The retinal oximetry studies included 120 healthy subjects aged 18-80 years and 46 treatment-naïve neovascular AMD patients aged 66-95 years. The retinal oximeter is based on a fundus camera. With a coupled image splitter it is possible to simultaneously capture two retinal images at two different wavelengths, 570 and 600 nm, with two separate digital cameras. Specialised software calculates the retinal vessel oxygen saturation from the different reflection of light in both arterioles and venules at these two different wavelengths. The population-based AMD incidence study was a prospective study on 439 consecutive patients aged 60 years and older with neovascular AMD that started intravitreal anti-VEGF treatment with ranibizumab for neovascular AMD in Iceland from March 2007 to December 2009. The estimated annual incidence of neovascular AMD in Iceland was determined as well as the number of intravitreal injections required for each treated eye and on a population scale. Results: Retinal vessel oxygen saturation in the healthy subjects was 92.2±3.7% (mean±SD) in arterioles and 55.6±6.3% in venules. The arteriovenous (AV) difference of oxygen saturation was 36.7±5.4%. The oximeter was reliable with no difference in oxygen saturation between right and left eyes in arterioles (p=0.30) and venules (p=0.07). The standard deviation of repeated oximetry measurements in a single vessel was 1.0% in arterioles and 1.4% in venules. The inferotemporal quadrant had the lowest oxygen saturation in arterioles and venules (p0.23). The oxygen saturation of venules decreased by 1.9±0.6% (mean±SEM) per 10 years of age in males (p=0.003) and by 0.7±0.4% in females (p=0.068). The AV difference increased by 1.5±0.5% per 10 years in males (p=0.004) and 1.0±0.4% (p=0.007) in females. In comparison to the healthy group, the venular oxygen saturation increased with age in AMD patients but decreased with age in the healthy subjects (p=0.0003). Similary, the AV difference decreased with age in AMD patients but increased with age in healthy (p=0.0017). No significant difference was found between the groups in the retinal oxygen saturation of arterioles (p=0.075). The annual incidence of neovascular AMD in the Icelandic population of 60 years and older was 0.29%. With advancing age, the incidence increased. During the first 12 months after initiation of intravitreal ranibizumab treatment, each eye received 5.0±2.3 (mean±SD; median 4; range 3-12) injections. With this rate of injections, it can be expected that around 2 400 intravitreal ranibizumab injections would be required each year for treatment of neovascular AMD per 100 000 persons aged 60 years and older in Iceland and comparable Caucasian populations. Conclusions: Variability in the retinal vessel oxygen saturation is relatively small in human eyes and differences with age are minor, though significant. The oximetry technique appears reliable and both technical and biological variation is small. The results suggest that significant difference exists in retinal vessel oxygen saturation between healthy persons and patients with neovascular AMD. However, it cannot be confirmed if retinal hypoxia is present in patients with neovascular AMD; further studies are required to determine this. Neovascular AMD is common in Iceland and the burden of its effective treatment is large and growing in Iceland as well as in comparable populations. Keywords: Retina, oximetry, age-related macular degeneration, antibodies for vascular endothelial growth factor, incidence.Tilgangur: Vot aldursbundin augnbotnahrörnun er algengasta orsök sjónskerðingar og blindu í vestrænum ríkjum en sjóntapið tengist sjúklegri nýæðamyndun og blæðingum í augnbotninum sem að lokum leiða til örvefsmyndunar. Nýæðamyndun er almennt talin tengjast blóðþurrð og súrefnisskorti sem hvetur til myndunar vaxtarþátta. Einn þeirra er vaxtarþáttur æðaþels (e. vascular endothelial growth factor, VEGF) en meðferð við votri augnbotnahrörnun byggist að stærstum hluta á mótefnum gegn VEGF sem sprautað er inn í glerhlaup augans. Út frá þessum athugunum og niðurstöðum annarra rannsókna hafa grunsemdir vaknað um að í votri augnbotnahrörnun sé um að ræða truflun á súrefnisbúskap sjónhimnunnar. Takmörkuð tækni hefur verið í boði til að mæla súrefnismettun í augnbotnum manna, þar til rannsóknarhópur okkar þróaði slíkan tækjabúnað nýlega. Tilgangur rannsóknanna í þessari ritgerð er að kanna hvort súrefnismettun augnbotna sé óeðlileg í votri augnbotnahrörnun. Til að ná því takmarki var í fyrsta lagi mæld súrefnismettun í sjónhimnuæðum heilbrigðra til að staðla tækni við súrefnismælingar og fá heilbrigðan samanburðarhóp. Í öðru lagi var mæld súrefnismettun í sjónhimnuæðum sjúklinga með vota augnbotnahrörnun. Að lokum var kannað umfang votrar augnbotnahrörnunar og mótefnameðferðarinnar til að meta áhrif sjúkdómsins á heilbrigðisþjónustu á Íslandi. Aðferðir: Súrefnismælingar sjónhimnu heilbrigðra og sjúklinga með vota augnbotnahrörnun: Þátttakendur í rannsóknum á súrefnismettun í sjónhimnu voru alls 120 heilbrigðir á aldrinum 18-80 ára og 46 sjúklingar á aldrinum 66-95 ára með vota augnbotnahrörnun sem ekki höfðu áður fengið sprautumeðferð í glerhlaup augans. Súrefnismælirinn er byggður á augnbotnamyndavél. Með áföstum mynddeili er samtímis unnt að taka tvær augnbotnamyndir á tveimur mismunandi bylgjulengdum, 570 og 600 nm, inn á tvær stafrænar myndavélar. Sérhæfður hugbúnaður reiknar súrefnismettun sjónhimnuæða út frá mismunandi ljósendurkasti bæði slag- og bláæðlinga á þessum tveimur bylgjulengdum. Faraldsfræði votrar augnbotnahrörnunar á Íslandi: Þátttakendur í framsýnu faraldsfræðirannsókninni voru allir 60 ára og eldri með vota augnbotnahrörnun á leið í sína fyrstu mótefnameðferð með ranibizumab sem sprautað var í glerhlaup augans. Alls voru 439 einstaklingar sem hófu meðferð á tímabilinu mars 2007 til desember 2009. Árlegt nýgengi votrar augnbotnahrörnunar á Íslandi var áætlað og fjöldi sprautumeðferða á fyrstu 12 mánuðum eftir upphaf meðferðar var metinn fyrir sérhvert auga í meðferðinni og fyrir þýðið í heild. Niðurstöður: Súrefnismælingar sjónhimnu heilbrigðra og sjúklinga með vota augnbotnahrörnun: Súrefnismettun sjónhimnuæða í heilbrigðum var 92,2±3,7% (meðaltal±staðalfrávik) í slagæðlingum og 55,6±6,3% í bláæðlingum. Mismunur súrefnismettunar slag- og bláæðlinga var 36,7±5,4%. Súrefnismælirinn reyndist áreiðanlegur og sýndi engan mun á súrefnismettun í hægra og vinstra auga í slagæðlingum (p=0,30) og bláæðlingum (p=0,07). Staðalfrávik endurtekinna mælinga í sömu æð var 1,0% í slagæðlingum og 1,4% í bláæðlingum. Súrefnismettun í neðri gagnauga (e. temporal) fjórðungi sjónhimnunnar mældist marktækt lægri í bæði slagæðlingum (p<0,0001) og bláæðlingum (p