{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:52:43Z","timestamp":1791355963114,"version":"4.3.1"},"reference-count":28,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"19","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"\n Background<\/jats:title>\n The Ischemic Stroke Phenotyping System 2025 (ISPS25) expands the minimum diagnostic evaluation and introduces causality grading to improve stroke classification but lacks formal validation. We assessed its real\u2010world applicability in a large embolic stroke of undetermined source (ESUS) cohort and explored additional potential embolic sources (PESs) not captured by the original framework.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We conducted a single\u2010center study including consecutive patients with embolic stroke of undetermined source admitted to Niguarda Hospital (Milan, Italy). Two neurologists independently reviewed records, assigned ISPS25 categories (large\u2010artery atherosclerosis, cardioembolism, small\u2010vessel disease, other determined, undetermined) and the highest causality grade (definite\/probable\/possible); equal\u2010grade categories were classified as multiple causes. Prespecified additional PESs (cardioembolic\/large\u2010artery atherosclerosis\/other) not included in ISPS25 were collected. We quantified pathogenetic redistribution after ISPS25 application and compared second\u2010pass testing and PES prevalence between ISPS25\u2010reclassified and ISPS25\u2010undetermined patients.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 802 patients (median age, 69\u2009years; 44.9% women;\n National Institutes of Health Stroke Scale score,<\/jats:styled-content>\n 5),\n ISPS25<\/jats:styled-content>\n reassigned pathogenesis in 313 (39.0%): cardioembolic, 186 (23.2%); large\u2010artery atherosclerosis, 68 (8.5%); other determined, 54 (6.7%); and multiple causes, 5 (0.6%). Causality was definite in 24 (7.7%), probable in 112 (35.8%), and possible in 177 (56.5%). Undetermined cases (489 [61.0%]) underwent less second\u2010pass testing than reclassified patients (46.2% versus 70.3%,\n P<\/jats:italic>\n <0.001) yet more frequently harbored additional\n PESs<\/jats:styled-content>\n (62.0% versus 42.5%,\n P<\/jats:italic>\n <0.001) and overlapping\n PESs<\/jats:styled-content>\n (25.1% versus 10.5%,\n P<\/jats:italic>\n <0.001). Considering additional\n PESs<\/jats:styled-content>\n , predominantly cardioembolic, as candidate mechanisms reduced undetermined cases to 23.2%.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n ISPS25 is feasible and recategorizes many embolic stroke of undetermined source cases, but attribution is largely probabilistic and most patients remain undetermined. Limited extended diagnostics and frequent overlapping PESs reveal gaps in both diagnostic workup and the ISPS25 construct, supporting expansion and further refinement.<\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.126.050581","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:42:58Z","timestamp":1790311378000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Application of the Ischemic Stroke Phenotyping System 2025 in a Real\u2010World Embolic Stroke of Undetermined Source Cohort: Advantages and Limitations"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3258-5061","authenticated-orcid":false,"given":"Angelo","family":"Cascio Rizzo","sequence":"first","affiliation":[{"name":"ASST Grande Ospedale Metropolitano Niguarda","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8465-3946","authenticated-orcid":false,"given":"Ghil","family":"Schwarz","sequence":"additional","affiliation":[{"name":"ASST Grande Ospedale Metropolitano Niguarda","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30034-1"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.24.1.35"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20617"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.107.490896"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1159\/000352050"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70310-7"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-022-00663-4"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.125.051169"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/ehjci\/jev014"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehae150"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2020.0458"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jstrokecerebrovasdis.2019.07.005"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.014818"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.120.029404"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002978"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmg.2023.09.005"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000214801"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/str.0000000000000517"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.27188"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0735-1097(99)00033-9"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003588"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1177\/23969873241311331"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001092"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1313600"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30167-4"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.113.002551"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2020.5573"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1177\/1747493019852177"}],"container-title":["Journal 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