Postępująca epilepsja mioklonalna w zespole Downa z chorobą Alzheimera: 11-letnie badanie obserwacyjne i proponowane symptomy ostrzegawcze

OBJECTIVE: Individuals with Down syndrome (DS) face an ultra-high 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-term natural history and pathological substrate. METHODS: We conducted an 11-year longitudinal study of the original cohort of 12 DS patients with PME. Clinical progression was monitored via a three-stage model. Two additional illustrative cases (aged 50 and 58 years) underwent 18F-Flutemetamol PET to document in vivo amyloid load. RESULTS: The study reached a 100% mortality rate. Median survival from myoclonus onset was 4.2 years (95% CI: 3.8-4.6). All patients progressed to the terminal phase within 2.5 ± 1.1 years. Both Amyloid-PET-scanned patients revealed a massive cortical burden (Global Z-scores 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-AD association, a core clinical triad (myoclonus, ataxia, seizures), and supportive biomarkers. PME-DS appears to be driven by an amyloid-related excitatory-inhibitory imbalance. Massive amyloid-beta 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. SIGNIFICANCE: PME-DS with AD represents a severe electroclinical phenotype within the AD-DS continuum, likely overlapping with the widely recognized LOMEDS (Late-Onset Myoclonic Epilepsy in Down Syndrome). Myoclonus onset serves as a definitive "red flag" of a severe amyloid-driven excitatory-inhibitory imbalance and peak cortical burden, predicting rapid progression to terminal stage (median survival 4.2 years). 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. PLAIN LANGUAGE SUMMARY: 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 years. 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-third of patients. Recognizing this pattern early helps doctors provide better care, avoid harmful medications, and prepare families for what to expect.