National trends, demographic disparities, and phenotypic shifts in encephalopathy-associated mortality in the United States: A CDC WONDER analysis, 1999-2024

Encephalopathy is a lethal manifestation of global cerebral dysfunction spanning hypoxic, metabolic, toxic, and vascular etiologies, yet its population burden is difficult to quantify because it predominantly appears as a contributing rather than underlying cause of death. Here, we analyzed US multiple-cause death records from 1999 through 2024 using harmonized CDC WONDER datasets. A longitudinally consistent core definition of 10 ICD-10 codes identified 953,846 encephalopathy-associated deaths. The national age-adjusted mortality rate increased 28.4%, from 9.143 per 100,000 in 1999 to 11.738 in 2024, after peaking at 14.391 in 2021. Segmented log-linear regression identified four temporal phases: 1999-2004 (annual percent change [APC],-1.76%), 2004-2018 (APC, 2.57%), 2018-2021 (APC, 6.54%), and 2021-2024 (APC, -5.98%). Encephalopathy was listed as the underlying cause in only 21.6% of deaths in 2024. Unspecified encephalopathy surged more than 3.6-fold, while anoxic brain injury remained stable. Mortality remained higher in males than females (13.973 versus 9.778 per 100,000), and rates among non-Hispanic Black individuals were 1.90-fold those of non-Hispanic White individuals. Geographically, mortality clustered in the Midwest and South (13.144 and 13.120 per 100,000 in 2024), with persistent state-level dispersion across the study period. COVID-19 accounted for 10.9% of associated deaths in 2021 before falling to 1.4% in 2024. These findings reveal a nonlinear trajectory shaped by diagnostic shifts, pandemic disruption, and persistent demographic and geographic disparities.