{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:56:51Z","timestamp":1790654211702,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Individuals with Down syndrome (DS) face an ultra\u2010high risk of Alzheimer's disease (AD). Within this continuum, Progressive Myoclonus Epilepsy (PME) has emerged as a marker of advanced neurodegeneration. Building on our 2014 characterization of this syndrome, we aimed to define its long\u2010term natural history and pathological substrate.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted an 11\u2010year longitudinal study of the original cohort of 12 DS patients with PME. Clinical progression was monitored via a three\u2010stage model. Two additional illustrative cases (aged 50 and 58\u2009years) underwent 18F\u2010Flutemetamol PET to document in\u00a0vivo amyloid load.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The study reached a 100% mortality rate. Median survival from myoclonus onset was 4.2\u2009years (95% CI: 3.8\u20134.6). All patients progressed to the terminal phase within 2.5\u2009\u00b1\u20091.1\u2009years. Both Amyloid\u2010PET\u2010scanned patients revealed a massive cortical burden (Global\n                      <jats:italic>Z<\/jats:italic>\n                      \u2010scores up to 11.55). Iatrogenic clinical worsening due to sodium channel blockers or phenobarbital was observed in 38% of cases. The high uniformity of these findings allowed for the proposal of diagnostic criteria based on a mandatory DS\u2010AD association, a core clinical triad (myoclonus, ataxia, seizures), and supportive biomarkers. PME\u2010DS appears to be driven by an amyloid\u2010related excitatory\u2010inhibitory imbalance. Massive amyloid\u2010beta deposition in motor cortices impairs GABAergic interneurons, triggering cortical hyperexcitability. Thus, the onset of myoclonus serves as a functional marker of peak amyloid burden and terminal neurodegeneration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>PME\u2010DS with AD represents a severe electroclinical phenotype within the AD\u2010DS continuum, likely overlapping with the widely recognized LOMEDS (Late\u2010Onset Myoclonic Epilepsy in Down Syndrome). Myoclonus onset serves as a definitive \u201cred flag\u201d of a severe amyloid\u2010driven excitatory\u2010inhibitory imbalance and peak cortical burden, predicting rapid progression to terminal stage (median survival 4.2\u2009years). Standardizing the proposed diagnostic criteria is essential for accurate prognostic counseling and, crucially, to avoid iatrogenic pitfalls in pharmacological management, particularly regarding the use of sodium channel blockers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Plain Language Summary<\/jats:title>\n                    <jats:p>This study followed 12 adults with Down syndrome who developed a severe form of epilepsy linked to Alzheimer's disease. We found that when people with Down syndrome develop jerking movements (myoclonus), it signals advanced brain changes and predicts a rapid decline, with most patients surviving only about 4\u2009years. Brain scans showed a massive buildup of abnormal proteins in the brain. Importantly, certain common seizure medications (like phenytoin and carbamazepine) made symptoms worse in over one\u2010third of patients. Recognizing this pattern early helps doctors provide better care, avoid harmful medications, and prepare families for what to expect.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi4.70277","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T17:46:51Z","timestamp":1779385611000},"page":"1200-1213","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Progressive myoclonus epilepsy in Down syndrome with Alzheimer's disease: An 11\u2010year longitudinal study and proposed diagnostic red flags"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3465-7540","authenticated-orcid":false,"given":"Giuseppe","family":"d'Orsi","sequence":"first","affiliation":[{"name":"Neurology Unit \u2013 Epilepsy Center Fondazione IRCCS Casa Sollievo della Sofferenza  San Giovanni Rotondo Foggia 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2325-4137","authenticated-orcid":false,"given":"Umberto","family":"Costantino","sequence":"additional","affiliation":[{"name":"Neurology Unit \u2013 Epilepsy Center Fondazione IRCCS Casa Sollievo della Sofferenza  San Giovanni Rotondo Foggia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elio","family":"Perrone","sequence":"additional","affiliation":[{"name":"Nuclear Medicine Service Fondazione IRCCS Casa Sollievo della Sofferenza  San Giovanni Rotondo Foggia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaela Rita","family":"Latino","sequence":"additional","affiliation":[{"name":"Neurology Unit \u2013 Epilepsy Center Fondazione IRCCS Casa Sollievo della Sofferenza  San Giovanni Rotondo Foggia 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