{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T05:56:50Z","timestamp":1776491810197,"version":"3.51.2"},"reference-count":36,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T00:00:00Z","timestamp":1724630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Danish Multiple Sclerosis Society","award":["R634-A42.685"],"award-info":[{"award-number":["R634-A42.685"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Retinal hyperreflective foci, 25\u201350 \u00b5m in diameter, that can be imaged by noninvasive optical coherence tomography (OCT) may represent microglial activity related to inflammation. This study aimed to detect hyperreflective foci in the OCT-hyporeflective avascular outer nuclear layer of the retina in relapsing\u2013remitting MS (RRMS) patients without ongoing eye or optic nerve disease. Methods: A cohort of 13 RRMS patients (8 eyes with and 18 eyes without prior optic neuritis) underwent retinal OCT at baseline, after 1 month, after 6 months, and then every 6 months for 3 years. The data were compared with single-examination data from 106 eyes in 53 age-matched healthy subjects. Results: The prevalence of hyperreflective foci at baseline was higher in RRMS patients than in healthy subjects (46.2% vs. 1.8%, p &lt; 0.005). Patients with optic neuritis had much more foci than those without (p &lt; 0.001). Hyperreflective foci recurred in 23.1% of RRMS patients, bilaterally in one with prior optic neuritis and unilaterally in two without. Conclusions: Patients with RRMS, notably those with prior optic neuritis, had elevated rates of retinal infiltration in the absence of retinal disease, suggesting that the phenomenon may represent elevated activity of an immune surveillance or housekeeping mechanism rather than retinal disease.<\/jats:p>","DOI":"10.3390\/jcm13175056","type":"journal-article","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T10:01:51Z","timestamp":1724666511000},"page":"5056","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Longitudinal Optical Coherence Tomography Imaging Reveals Hyperreflective Foci Characteristics in Relapsing\u2013Remitting Multiple Sclerosis Patients"],"prefix":"10.3390","volume":"13","author":[{"given":"Mathias Falck","family":"Schmidt","sequence":"first","affiliation":[{"name":"Department of Neurology, Clinic of Optic Neuritis, The Danish Multiple Sclerosis Center (DMSC), Rigshospitalet and University of Copenhagen, Valdemar Hansens Vej 13, 2600 Glostrup, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gorm","family":"Pihl-Jensen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Clinic of Optic Neuritis, The Danish Multiple Sclerosis Center (DMSC), Rigshospitalet and University of Copenhagen, Valdemar Hansens Vej 13, 2600 Glostrup, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Rigshospitalet and University of Copenhagen, 2600 Glostrup, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1661-7438","authenticated-orcid":false,"given":"Jette Lautrup","family":"Frederiksen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Clinic of Optic Neuritis, The Danish Multiple Sclerosis Center (DMSC), Rigshospitalet and University of Copenhagen, Valdemar Hansens Vej 13, 2600 Glostrup, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6096017","DOI":"10.1155\/2021\/6096017","article-title":"Significance of Hyperreflective Foci as an Optical Coherence Tomography Biomarker in Retinal Diseases: Characterization and Clinical Implications","volume":"2021","author":"Fragiotta","year":"2021","journal-title":"J. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1167\/iovs.64.1.20","article-title":"Hyper-Reflective Foci in Intermediate Age-Related Macular Degeneration: Spatial Abundance and Impact on Retinal Morphology","volume":"64","author":"Vaisband","year":"2023","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1097\/IAE.0000000000000929","article-title":"Baseline spectral domain optical coherence tomographic hyperreflective foci as a predictor of visual outcome and recurrence for central serous chorioretinopathy","volume":"36","author":"Lee","year":"2016","journal-title":"Retina"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"613","DOI":"10.3389\/fimmu.2021.613051","article-title":"OCT Hyperreflective Retinal Foci in Diabetic Retinopathy: A Semi-Automatic Detection Comparative Study","volume":"12","author":"Midena","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1159\/000342159","article-title":"Hyperreflective Dots: A New Spectral-Domain Optical Coherence Tomography Entity for Follow-Up and Prognosis in Exudative Age-Related Macular Degeneration","volume":"229","author":"Coscas","year":"2013","journal-title":"Ophthalmology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1136\/bjophthalmol-2018-312461","article-title":"Early Retinal and Choroidal OCT and OCT Angiography Signs of Inflammation After Uncomplicated Cataract Surgery","volume":"103","author":"Pilotto","year":"2019","journal-title":"Br. J. Ophthalmol."},{"key":"ref_7","first-page":"211","article-title":"Activated retinal pigment epithelium, an optical coherence tomography biomarker for progression in age-related macular degeneration","volume":"58","author":"Curcio","year":"2017","journal-title":"Ophthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2316","DOI":"10.1016\/j.ophtha.2015.07.008","article-title":"The onion sign in neovascular age-related macular degeneration represents cholesterol crystals","volume":"122","author":"Pang","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5965","DOI":"10.1167\/iovs.10-5779","article-title":"Small dense particles in the retina observable by spectral-domain optical coherence tomography in age-related macular degeneration","volume":"51","author":"Framme","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_10","first-page":"710","article-title":"Association between hyperreflective foci in the outer retina, status of photoreceptor layer, and visual acuity in diabetic macular edema","volume":"153","author":"Uji","year":"2012","journal-title":"Arch. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.msard.2023.104617","article-title":"Hyperreflective dots in the avascular outer retina in relapsing-remitting multiple sclerosis","volume":"72","author":"Schmidt","year":"2023","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1016\/j.ophtha.2020.03.024","article-title":"Hyperreflective Foci in the Retina of Active Relapse-Onset Multiple Sclerosis","volume":"127","author":"Pilotto","year":"2020","journal-title":"Ophthalmology"},{"key":"ref_13","first-page":"4","article-title":"Retinal Hyperreflecting Foci Associate With Cortical Pathology in Multiple Sclerosis","volume":"23","author":"Pengo","year":"2022","journal-title":"Neurol. Neuroimmunol. Neuroinflammation"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Puthenparampil, M., Torresin, T., Franciotta, S., Marin, A., De Napoli, F., Mauceri, V.A., Miante, S., Pilotto, E., Midena, E., and Gallo, P. (2022). Hyper-Reflecting Foci in Multiple Sclerosis Retina Associate With Macro-phage\/Microglia-Derived Cytokines in Cerebrospinal Fluid. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.852183"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/j.ophtha.2008.12.039","article-title":"Optical coherence tomographic hyperreflective foci: A morphologic sign of lipid extravasation in diabetic macular edema","volume":"116","author":"Bolz","year":"2009","journal-title":"Ophthalmology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1016\/j.ophtha.2010.02.014","article-title":"Outer retinal hyperreflective spots on spectral-domain optical coherence tomography in macular telangiectasia type 2","volume":"117","author":"Issa","year":"2010","journal-title":"Ophthalmology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5366","DOI":"10.1167\/iovs.18-25611","article-title":"Hyperreflective intraretinal foci as an OCT biomarker of retinal inflammation in diabetic macular edema","volume":"59","author":"Midena","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1002\/ana.20703","article-title":"Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald Criteria","volume":"58","author":"Polman","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nrneurol.2012.227","article-title":"The retina as a window to the brainfrom eye research to CNS disorders","volume":"9","author":"London","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"a028936","DOI":"10.1101\/cshperspect.a028936","article-title":"Multiple Sclerosis Pathology","volume":"8","author":"Lassmann","year":"2018","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/nrn3722","article-title":"Microglia and brain macrophages in the molecular age: From origin to neuropsychiatric disease","volume":"15","author":"Prinz","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.molmed.2018.11.005","article-title":"Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology","volume":"25","author":"Voet","year":"2019","journal-title":"Trends Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1097\/IAE.0000000000001304","article-title":"Hyperreflective Retinal Spots In Normal And Diabetic Eyes: B-Scan and En Face Spectral Domain Optical Coherence Tomography Evaluation","volume":"37","author":"Vujosevic","year":"2017","journal-title":"Retina"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1177\/1120672119857511","article-title":"First-line treatment algorithmand guidelines in center-involving diabetic macular edema","volume":"6","author":"Kodjikian","year":"2019","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1177\/1352458514538110","article-title":"Quality control for retinal OCT in multiple sclerosis: Validation of the OSCAR-IB criteria","volume":"21","author":"Schippling","year":"2015","journal-title":"Mult Scler."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1212\/WNL.0000000000012125","article-title":"APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies","volume":"97","author":"Aytulun","year":"2021","journal-title":"Neurology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1038\/nn2014","article-title":"Local self-renewal can sustain CNS microglia maintenance and function throughout adult life","volume":"10","author":"Ajami","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.neuron.2018.05.014","article-title":"A combination of ontogeny and CNS environment establishes microglial identity","volume":"98","author":"Bennett","year":"2018","journal-title":"Neuron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.immuni.2019.02.007","article-title":"Microglial function is distinct in different anatomical locations during retinal homeostasis and degeneration","volume":"50","author":"Yu","year":"2019","journal-title":"Immunity"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Morris, D.R., Bounds, S.E., Liu, H., Ding, W.-Q., Chen, Y., Liu, Y., and Cai, J. (2020). Exosomal MiRNA transfer between retinal microglia and RPE. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103541"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.pneurobio.2018.05.006","article-title":"Retinal microglia\u2014A key player in healthy and diseased retina","volume":"173","author":"Rathnasamy","year":"2019","journal-title":"Prog. Neurobiol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Choi, S., Guo, L., and Cordeiro, M.F. (2021). Retinal and Brain Microglia in Multiple Sclerosis and Neurodegeneration. Cells, 10.","DOI":"10.3390\/cells10061507"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17562864211007687","DOI":"10.1177\/17562864211007687","article-title":"Inflammation in multiple sclerosis","volume":"14","author":"Haase","year":"2021","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1002\/ana.24497","article-title":"Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque","volume":"78","author":"Frischer","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1001\/jamaneurol.2019.2399","article-title":"Association of Chronic Active Multiple Sclerosis Lesions with Disability In Vivo","volume":"76","author":"Absinta","year":"2019","journal-title":"JAMA Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1097\/IAE.0000000000000527","article-title":"Directional Optical Coherence Tomography Provides Accurate Outer Nuclear Layer and Henle Fiber Layer Measurements","volume":"35","author":"Lujan","year":"2015","journal-title":"Retina"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/17\/5056\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:43:02Z","timestamp":1760110982000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/17\/5056"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,26]]},"references-count":36,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["jcm13175056"],"URL":"https:\/\/doi.org\/10.3390\/jcm13175056","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,26]]}}}