helmholtzeyeinstituteРоссийский офтальмологический журналRussian Ophthalmological Journal2072-00762587-5760Real time Publishers10.21516/2072-0076-2021-14-3-32-39helmholtzeyeinstitute-716Research ArticleКЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯCLINICAL STUDIESЭлектрофизиологические признаки ремоделирования колбочковой системы сетчатки при географической атрофии пигментного эпителия у больных с неэкссудативной возрастной макулярной дегенерациейElectrophysiological signs of retinal cone remodeling in geographic atrophy of the pigment epithelium in patients with non-exudative age-related macular degenerationНероеваН. В.NeroevaN. V.

 канд. мед. наук, врач-офтальмолог отдела патологии сетчатки и зрительного нерва 

 ул. Садовая-Черногрязская, д. 14/19, Москва, 105062, Россия 

 Cand. of Med. Sci., ophthalmologist, department of retinal and optic nerve pathology 

 14/19, Sadovaya Chernogryazskaya St., Moscow, 105062, Russia 

ЗуеваМ. В.ZuevaM. V.

 д-р биол. наук, профессор, начальник отдела клинической физиологии зрения им. С.В. Кравкова 

 ул. Садовая-Черногрязская, д. 14/19, Москва, 105062, Россия 

 Dr. of Biol. Sci., professor, head of the department of clinical physiology of vision S.V. Kravkov 

 14/19, Sadovaya Chernogryazskaya St., Moscow, 105062, Russia 

visionlab@yandex.ruНероевВ. В.NeroevV. V.

 академик РАН, д-р мед. наук, профессор, начальник отдела патологии сетчатки и зрительного нерва, директор 

 ул. Садовая-Черногрязская, д. 14/19, Москва, 105062, Россия 

 Academician of the RAS, Dr. of Med. Sci., professor, head of the department of pathology of the retina and optic nerve, director 

 14/19, Sadovaya Chernogryazskaya St., Moscow, 105062, Russia 

ЦапенкоИ. В.TsapenkoI. V.

 канд. биол. наук, старший научный сотрудник отдела клинической физиологии зрения им. С.В. Кравкова 

 ул. Садовая-Черногрязская, д. 14/19, Москва, 105062, Россия 

 Cand. of Biol. Sci., senior researcher, department of clinical physiology of vision S.V. Kravkov 

 14/19, Sadovaya Chernogryazskaya St., Moscow, 105062, Russia 

РябинаМ. В.RyabinaM. V.

 канд. мед. наук, научный сотрудник отдела патологии сетчатки и зрительного нерва 

 ул. Садовая-Черногрязская, д. 14/19, Москва, 105062, Россия 

 Cand. of Med. Sci., researcher, department of pathology of the retina and optic nerve 

 14/19, Sadovaya Chernogryazskaya St., Moscow, 105062, Russia 

ЛосановаО. А.LosanovaO. A.

 аспирант отдела патологии сетчатки и зрительного нерва 

 ул. Садовая-Черногрязская, д. 14/19, Москва, 105062, Россия 

 PhD student, department of pathology of the retina and optic nerve 

 14/19, Sadovaya Chernogryazskaya St., Moscow, 105062, Russia 

КатаргинаЛ. А.KatarginaL. A.

 д-р мед. наук, профессор, заместитель директора по научной работе 

 ул. Садовая-Черногрязская, д. 14/19, Москва, 105062, Россия 

 Dr. of Med. Sci., professor, deputy director 

 14/19, Sadovaya Chernogryazskaya St., Moscow, 105062, Russia 

ФГБУ «НМИЦ глазных болезней им. Гельмгольца» Минздрава РоссииРоссияHelmholtz National Medical Research Center of Eye DiseasesRussian Federation2021110920211433239Copyright © Нероева Н.В., Зуева М.В., Нероев В.В., Цапенко И.В., Рябина М.В., Лосанова О.А., Катаргина Л.А., 20212021Нероева Н.В., Зуева М.В., Нероев В.В., Цапенко И.В., Рябина М.В., Лосанова О.А., Катаргина Л.А.Neroeva N.V., Zueva M.V., Neroev V.V., Tsapenko I.V., Ryabina M.V., Losanova O.A., Katargina L.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://roj.igb.ru/jour/article/view/716

Исследование пациентов с первичной географической атрофией (ГА) требует мультимодального подхода и определения функциональных биомаркеров, характеризующих структурное ремоделирование сетчатки.

Цель работы — определить изменения функциональной активности колбочковой системы сетчатки, которые могут служить биомаркерами первичной ГА в глазах с неэкссудативной возрастной макулярной дегенерацией (ВМД).

Материал и методы

Материал и методы. Обследованы 22 пациента (30 глаз) 45–83 лет (в среднем 72,1 ± 10,8 года) с неэкссудативной ВМД и 18 лиц группы контроля, сопоставимых по возрасту (60,2 ± 7,6 года). Выполнены стандартные офтальмологические обследования, оптическая когерентная томография (ОКТ), исследование аутофлуоресценции (АФ) и фундус-фотография. Регистрировали стандартные фотопические ЭРГ, фотопические ритмические ЭРГ (РЭРГ) на стимулы частотой 8,3, 10, 12 и 24 Гц, мультифокальную ЭРГ (мфЭРГ) и электроокулограмму (ЭОГ).

Результаты

Результаты. Описаны электроретинографические признаки глаз с ГА ретинального пигментного эпителия сетчатки (РПЭ) и атрофией хориокапиллярного слоя. Подтверждено раннее нарушение активности колбочек при ГА и ослабление функционального взаимодействия клеток Мюллера с колбочковыми биполярными клетками. Удлинение латентности пика Р1 мфЭРГ указывает на снижение функции всей центральной сетчатки при неэкссудативной ВМД. При этом избирательное угнетение мфЭРГ в фовеа может служить биомаркером первичной ГА, в то время как распространение аномалии Р1 на соседние кольца свидетельствует о возможном риске прогрессирования заболевания. Снижение темнового спада на ЭОГ и возрастание отношения Ардена могут служить биомаркером первичной ГА.

Заключение

Заключение. Определены электрофизиологические признаки, которые могут служить маркерами ранних нарушений ретинальной функции в глазах с первичной ГА при неэкссудативной ВМД.

Testing patients with primary geographic atrophy (GA) requires a multimodal approach and identification of functional biomarkers characterizing retinal structural remodeling.

Purpose

Purpose: to identify the changes in the functional activity of the retinal cone system, which may serve as biomarkers of primary GA in non-exudative age-related macular degeneration (AMD).

Material and methods

Material and methods. We tested 22 patients (30 eyes) aged 45–83 (ave. 72.1 ± 10.8 years) with non-exudative AMD and 18 age matched controls (60.2 ± 7.6 years) all of which underwent standard ophthalmological examinations, optical coherence tomography, autofluorescence study, and fundus photography. Standard photopic ERGs, photopic flicker ERGs to stimuli with frequencies of 8.3, 10, 12, and 24 Hz, multifocal ERG (mfERG), and electrooculogram (EOG) were recorded.

Results

Results. Electroretinographic signs for GA of retinal pigment epithelium and choriocapillary layer atrophy were described. The results confirm early impairment of the activity of cones in GA and weakening of the functional interaction of M ller cells with the cone bipolar cells. The delayed P1 peak latency of mfERG indicates a decrease in the entire central retina function in non-exudative AMD. A selective reduction in the fovea's mfERG magnitude can serve as a biomarker of primary GA. The spread of the P1 anomaly to adjacent rings may indicate a possible risk of disease progression. A decrease in the dark trough on the EOG and an increase in the Arden ratio can serve as a biomarker of primary GA.

Conclusion

Conclusion. We determined electrophysiological signs which can serve as markers of early retinal dysfunction in eyes with primary GA and non-exudative AMD.

возрастная макулярная дегенерациягеографическая атрофияремоделирование сетчаткиэлектроретинографияage related macular degenerationgeographic atrophyretinal remodelingelectroretinographyReferencesWong W.L., Su X., Li X., et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014; 2 (2): 106–16. doi: 10.1016/S2214-109X(13)70145-1Wong W.L., Su X., Li X., et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014; 2 (2): 106–16. doi: 10.1016/S2214-109X(13)70145-1Rein D.B., Wittenborn J.S., Zhang X., et al. Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. Arch. Ophthalmol. 2009; 127: 533–40. doi: 10.1001/archophthalmol.2009.58Rein D.B., Wittenborn J.S., Zhang X., et al. Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. Arch. Ophthalmol. 2009; 127: 533–40. doi: 10.1001/archophthalmol.2009.58Gehrs K.M., Anderson D.H., Johnson L.V., et al. Age-related macular degeneration – emerging pathogenetic and therapeutic concepts. Ann. Med. 2006; 38: 450–71. doi: 10.1080/07853890600946724Gehrs K.M., Anderson D.H., Johnson L.V., et al. Age-related macular degeneration – emerging pathogenetic and therapeutic concepts. Ann. Med. 2006; 38: 450–71. doi: 10.1080/07853890600946724Hamann S. Molecular mechanisms of water transport in the eye. Int. Rev. Cytol. 2002; 215: 395–431. doi: 10.1016/s0074-7696(02)15016-9Hamann S. Molecular mechanisms of water transport in the eye. Int. Rev. Cytol. 2002; 215: 395–431. doi: 10.1016/s0074-7696(02)15016-9Strauss O. The retinal pigment epithelium in visual function. Physiol Rev. 2005;85:845–81. doi: 10.1152/physrev.00021.2004Strauss O. The retinal pigment epithelium in visual function. Physiol Rev. 2005;85:845–81. doi: 10.1152/physrev.00021.2004Bhutto I., Lutty G. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane / choriocapillaris complex. Mol. Aspects Med. 2012; 33 (4): 295–317. doi: 10.1016/j.mam.2012.04.005Bhutto I., Lutty G. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane / choriocapillaris complex. Mol. Aspects Med. 2012; 33 (4): 295–317. doi: 10.1016/j.mam.2012.04.005Sarks J.P., Sarks S.H., Killingsworth M.C. Evolution of geographic atrophy of the retinal pigment epithelium. Eye (Lond). 1988; 2 (Pt.5): 552–77. doi: 10.1038/eye.1988.106Sarks J.P., Sarks S.H., Killingsworth M.C. Evolution of geographic atrophy of the retinal pigment epithelium. Eye (Lond). 1988; 2 (Pt.5): 552–77. doi: 10.1038/eye.1988.106Curcio C.A. Photoreceptor topography in ageing and age-related maculopathy. Eye (Lond). 2001; 15: 376–83. doi: 10.1038/eye.2001.140Curcio C.A. Photoreceptor topography in ageing and age-related maculopathy. Eye (Lond). 2001; 15: 376–83. doi: 10.1038/eye.2001.140Sunness J.S. Geographic atrophy in Age Related Macular Degeneration (Berger J.W., Fine S.L., Maguire M.G., eds.). St. Louis: Mosby, 1999; 155.Sunness J.S. Geographic atrophy in Age Related Macular Degeneration (Berger J.W., Fine S.L., Maguire M.G., eds.). St. Louis: Mosby, 1999; 155.Bonilha V.L. Age and disease-related structural changes in the retinal pigment epithelium. Clin. Ophthalmol. 2008; 2: 413–24. doi: 10.2147/opth.s2151Bonilha V.L. Age and disease-related structural changes in the retinal pigment epithelium. Clin. Ophthalmol. 2008; 2: 413–24. doi: 10.2147/opth.s2151Snodderly D.M., Sandstrom M.M., Leung I., et al. Retinal pigment epithelial cell distribution in central retina of rhesus monkeys. Invest. Ophthalmol. Vis. Sci. 2002; 43: 2815–8.Snodderly D.M., Sandstrom M.M., Leung I., et al. Retinal pigment epithelial cell distribution in central retina of rhesus monkeys. Invest. Ophthalmol. Vis. Sci. 2002; 43: 2815–8.Sadda S.R., Chakravarthy U., Birch D.G., et al. Clinical endpoints for the study of geographic atrophy secondary to Age-Related Macular Degeneration. Retina. 2016 October; 36 (10): 1806–22. doi:10.1097/IAE.0000000000001283Sadda S.R., Chakravarthy U., Birch D.G., et al. Clinical endpoints for the study of geographic atrophy secondary to Age-Related Macular Degeneration. Retina. 2016 October; 36 (10): 1806–22. doi:10.1097/IAE.0000000000001283McCulloch D.L., Marmor M.F., Brigell M.G., et al. ISCEV Standard for full-field clinical electroretinography (2015 update). Doc. Ophthalmol. 2015; 130 (1): 1–12. doi: 10.1007/s10633-014-9473-7McCulloch D.L., Marmor M.F., Brigell M.G., et al. ISCEV Standard for full-field clinical electroretinography (2015 update). Doc. Ophthalmol. 2015; 130 (1): 1–12. doi: 10.1007/s10633-014-9473-7Зуева М.В., Нероев В.В., Цапенко И.В., и др. Топографическая диагностика нарушений ретинальной функции при регматогенной отслойке сетчатки методом ритмической ЭРГ широкого спектра частот. Российский офтальмологический журнал. 2009; 1 (2): 18–23.Zueva M.V., Neroev V.V., Tsapenko I.V., et al. Topographic diagnosis of retinal dysfunction in case of rhegmatogenous retinal detachment by the rhythmic ERG method of a wide range of frequencies. Russian ophthalmological journal. 2009; 1 (2): 18–23 (in Russian).Зуева М.В., Цапенко И.В. Клетки Мюллера: спектр и профиль глионейро нальных взаимодействий в сетчатке. Российский физиологический журнал им. Сеченова. 2004; 90 (8): 435–6.Zueva M.V., Tsapenko I.V. Muller cells: spectrum and profile of glio-neuronal interactions in the retina. Rossijskij fiziologicheskij zhurnal im. Sechenova. 2004; 90 (8): 435–6 (in Russian).Hood D.C., Bach M., Brigell M., et al. ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition). Doc. Ophthalmol. 2012; 124 (1): 1–13. doi: 10.1007/s10633-011-9296-8Hood D.C., Bach M., Brigell M., et al. ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition). Doc. Ophthalmol. 2012; 124 (1): 1–13. doi: 10.1007/s10633-011-9296-8Constable P.A., Bach M., Frishman L.J., et al. ISCEV Standard for clinical electro-oculography (2017 update). Doc. Ophthalmol. 134, 1–9 (2017). doi: 10.1007/s10633-017-9573-2Constable P.A., Bach M., Frishman L.J., et al. ISCEV Standard for clinical electro-oculography (2017 update). Doc. Ophthalmol. 134, 1–9 (2017). doi: 10.1007/s10633-017-9573-2Ronan Sh., Nusinowitz S., Swaroop A., et al. Senile panretinal cone dysfunction in age-related macular degeneration (AMD): a report of 52 AMD patients compared to age-matched controls. Trans. Am. Ophthalmol. Soc. 2006; 104: 232–40.Ronan Sh., Nusinowitz S., Swaroop A., et al. Senile panretinal cone dysfunction in age-related macular degeneration (AMD): a report of 52 AMD patients compared to age-matched controls. Trans. Am. Ophthalmol. Soc. 2006; 104: 232–40.Kader M.A. Electrophysiological study of age related macular degeneration. New Front. Ophthalmol. 2017; 3 (1): 1–6. doi: 10.15761/NFO.1000156Kader M.A. Electrophysiological study of age related macular degeneration. New Front. Ophthalmol. 2017; 3 (1): 1–6. doi: 10.15761/NFO.1000156Parisi V., Perillo L., Tedeschi M., et al. Macular function in eyes with early age-related macular degeneration with or without contralateral late agerelated macular degeneration. Retina. 2007; 27: 879–90. doi: 10.1097/IAE.0b013e318042d6aaParisi V., Perillo L., Tedeschi M., et al. Macular function in eyes with early age-related macular degeneration with or without contralateral late agerelated macular degeneration. Retina. 2007; 27: 879–90. doi: 10.1097/IAE.0b013e318042d6aaWu Z., Ayton L.N., Guymer R.H., et al. Low-luminance visual acuity and microperimetry in age-related macular degeneration. Ophthalmology. 2014; 121: 1612–9. doi: 10.1016/j.ophtha.2014.02.005Wu Z., Ayton L.N., Guymer R.H., et al. Low-luminance visual acuity and microperimetry in age-related macular degeneration. Ophthalmology. 2014; 121: 1612–9. doi: 10.1016/j.ophtha.2014.02.005Owsley C., Jackson G.R., Cideciyan A.V., et al. Psychophysical evidence for rod vulnerability in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2000; 41: 267–73.Owsley C., Jackson G.R., Cideciyan A.V., et al. Psychophysical evidence for rod vulnerability in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2000; 41: 267–73.Schmitz-Valckenberg S., B ltmann S., Dreyhaupt J., et al.Fundus autofluorescence and fundus perimetry in the junctional zone of geographic atrophy in patients with age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2004; 45: 4470–6. doi: 10.1167/iovs.03-1311Schmitz-Valckenberg S., B ltmann S., Dreyhaupt J., et al.Fundus autofluorescence and fundus perimetry in the junctional zone of geographic atrophy in patients with age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2004; 45: 4470–6. doi: 10.1167/iovs.03-1311Li J., Tso M.O., Lam T.T. Reduced amplitude and delayed latency in foveal response of multifocal electroretinogram in early age related macular degeneration. Br. J. Ophthalmol. 2001; 85: 287–90. doi: 10.1136/bjo.85.3.287Li J., Tso M.O., Lam T.T. Reduced amplitude and delayed latency in foveal response of multifocal electroretinogram in early age related macular degeneration. Br. J. Ophthalmol. 2001; 85: 287–90. doi: 10.1136/bjo.85.3.287Nunes R.P., Gregori G., Yehoshua Z., et al. Predicting the progression of geographic atrophy in age-related macular degeneration with SD-OCT en face imaging of the outer retina. Ophthalmic Surg. Lasers Imaging Retina. 2013; 44: 344–59. doi: 10.3928/23258160-20130715-06Nunes R.P., Gregori G., Yehoshua Z., et al. Predicting the progression of geographic atrophy in age-related macular degeneration with SD-OCT en face imaging of the outer retina. Ophthalmic Surg. Lasers Imaging Retina. 2013; 44: 344–59. doi: 10.3928/23258160-20130715-06Wu Z., Ayton L.N., Guymer R.H., et al. Relationship between the second reflective band on optical coherence tomography and multifocal electroretinography in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2013; 54: 2800–6. doi:10.1167/iovs.13-11613Wu Z., Ayton L.N., Guymer R.H., et al. Relationship between the second reflective band on optical coherence tomography and multifocal electroretinography in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2013; 54: 2800–6. doi:10.1167/iovs.13-11613Jurklies B., Weismann M., H sing J., et al. Monitoring retinal function in neovascular maculopathy using multifocal electroretinography early and long term correlation with clinical findings. Graefe’s Arch. Clin. Exp. Ophthalmol. 2002; 240: 244–64. doi:10.1007/s00417-002-0439-1Jurklies B., Weismann M., H sing J., et al. Monitoring retinal function in neovascular maculopathy using multifocal electroretinography early and long term correlation with clinical findings. Graefe’s Arch. Clin. Exp. Ophthalmol. 2002; 240: 244–64. doi:10.1007/s00417-002-0439-1Park J.Y., Kim S.H., Park T.K., et al. Multifocal electroretinogram findings after intravitreal Bevacizumab injection in choroidal neovascularization of age-related macular degeneration. Korean J. Ophthalmol. 2011; 25 (3): 161–5. doi: 10.3341/kjo.2011.25.3.161Park J.Y., Kim S.H., Park T.K., et al. Multifocal electroretinogram findings after intravitreal Bevacizumab injection in choroidal neovascularization of age-related macular degeneration. Korean J. Ophthalmol. 2011; 25 (3): 161–5. doi: 10.3341/kjo.2011.25.3.161Gonz lez-Garc a E., Vilela C., Navea A., et al. Electrophysiological and clinical tests in dry age-related macular degeneration follow-up: differences between mfERG and OCT. Doc. Ophthalmol. 2016; 133 (1): 31–9. doi: 10.1007/s10633-016-9545-yGonz lez-Garc a E., Vilela C., Navea A., et al. Electrophysiological and clinical tests in dry age-related macular degeneration follow-up: differences between mfERG and OCT. Doc. Ophthalmol. 2016; 133 (1): 31–9. doi: 10.1007/s10633-016-9545-yAlanko H.I. Clinical electro-oculography. Acta Ophthalmol. Suppl. 1984;161: 139–48.Alanko H.I. Clinical electro-oculography. Acta Ophthalmol. Suppl. 1984;161: 139–48.R ver J., Bach M. C-wave versus electrooculogram in diseases of the retinal pigment epithelium. Doc. Ophthalmol. 1987; 65: 385–91.R ver J., Bach M. C-wave versus electrooculogram in diseases of the retinal pigment epithelium. Doc. Ophthalmol. 1987; 65: 385–91.Gupta L.Y., Marmar M.F. Sequential recording of photic and non-photic electrooculogram responses in patients with extensive extra-macular drusen. Doc. Ophthalmol. 1994; 88: 49–55.Gupta L.Y., Marmar M.F. Sequential recording of photic and non-photic electrooculogram responses in patients with extensive extra-macular drusen. Doc. Ophthalmol. 1994; 88: 49–55.Friedman E. A hemodynamic model of the pathogenesis of age-related macular degeneration. Am. J. Ophthalmol. 1997; 124: 677–82.Friedman E. A hemodynamic model of the pathogenesis of age-related macular degeneration. Am. J. Ophthalmol. 1997; 124: 677–82.Walter P., Widder R.A., L ke C., et al. Electrophysiological abnormalities in age-related macular degeneration. Graefes Arch. Clin. Exp. Ophthalmol. 1999; 237: 962–8.Walter P., Widder R.A., L ke C., et al. Electrophysiological abnormalities in age-related macular degeneration. Graefes Arch. Clin. Exp. Ophthalmol. 1999; 237: 962–8.

The authors declare that there are no conflicts of interest present.