September 22, 2022

CURE Epilepsy Discovery: Brain Aging in Childhood-Onset Epilepsy: A Long-Term, Population-Based Study

Key Points:

  • Little is known about how the brain and brain function change with aging in older people with epilepsy, particularly among those with childhood-onset epilepsy (COE).
  • CURE Epilepsy funded Dr. Bruce Hermann (University of Wisconsin, United States) and Dr. Matti Sillanpää (University of Turku, Finland) to study the intersection of epilepsy and aging in a unique population-based group of people with epilepsy [1]. This group of people, whom Dr. Sillanpää had been following over decades, consists of persons diagnosed with COE when they were less than 16 years old (4.6 years of age on average).
  • The current study examined these individuals 55 years after the initial epilepsy diagnosis. Individuals with COE showed signs of brain aging that in several respects were more accelerated than those without epilepsy. Additionally, specific risk factors predictive of problematic brain aging outcomes were identified.  
  •  If confirmed with a larger group of people, these data could impact epilepsy treatment and our understanding of how epilepsy and aging overlap.


Deep Dive:

Studies in the general population have shown that the aging process changes brain functioning and cognition [2] and there is now much interest in discovering ways to protect the brain and cognition with aging. Through multiple grants funded by CURE Epilepsy including a CURE Innovator Award, a CURE  Epilepsy Award, and an Epilepsy Research Continuity Fund Award, Drs. Bruce Hermann at the University of Wisconsin and Matti Sillanpää at the University of Turku studied a unique patient population of individuals with childhood-onset epilepsy (COE) to investigate neurological and cognitive outcomes 55 years after the initial diagnosis [1].

Earlier studies with this same group (at 50 years after the initial diagnosis) showed that while seizure outcomes in this population were excellent, subsets of people with COE showed some signs of possible neurological and cognitive decline [3, 4]. However, the apparent declines could have been due to multiple factors including epilepsy, aging that was intensified by epilepsy, or simply longstanding abnormalities independent of aging. To get further clarity, Drs. Hermann and Sillanpää recruited many of the same individuals five years after the previous study (i.e., 55 years after the initial diagnosis) [1] to describe the seizure and neurological status of this population and identify the prospective changes at 55 years post-initial diagnosis by comparison to their status at 50 years post-initial diagnosis [4].

The study population, developed by Dr. Sillanpää, consisted of people in Turku, Finland who were diagnosed with active epilepsy between 1961 – 1964 when they were less than 16 years old. The initial population consisted of 245 people of which approximately 100 had epilepsy without other initial neurologic impairments, who were the focus of this investigation [3, 5]. The study performed 50 years after the initial diagnosis consisted of 51 subjects with COE and 52 non-epilepsy controls [4], and the current study at 55 years had complete data sets for 37 subjects with COE and 39 controls [1]. The following outcomes were examined in people with COE and controls:

  1.     clinical neurological signs including but not limited to consciousness, behavior, orientation, reflexes, and sensory functions.
  2.     magnetic resonance imaging (MRI) abnormalities in the brain identified on structured clinical review.
  3.     non-neurologic disorders such as high blood pressure, hypercholesteremia, and obesity.

The rationale for examining non-neurologic outcomes was based on previous studies that have shown a link between epilepsy and obesity [6], and between elevated cholesterol and triglycerides and epilepsy [7], and their roles in the brain aging process remained to be determined. As part of neurologic outcomes, an area of the brain called the cerebellum was also examined since abnormalities in this area have long been documented in epilepsy but are poorly understood [8]. The presence of seizures and their types were also assessed. Additionally, the dose of four commonly prescribed antiseizure medications (ASMs) was assessed to calculate lifelong ASM doses, and associations between ASMs and biological parameters were assessed.

In the current cohort, the average age of the participants was 63.2 years for the COE group and 63.0 years for the control group. A quarter of individuals with COE had active epilepsy and the rest were seizure-free for 10 years or more. Subjects with COE that had active epilepsy had more severe neurologic changes in general, and cerebellar abnormalities specifically. This is important because while the role of the cerebellum in epilepsy has been documented [8], it remains unclear whether abnormalities in the cerebellum are a cause for seizures, a consequence of seizures or their treatment, or purely coincidental. In this study, subjects with COE did not originally have cerebellar abnormalities, suggesting that changes are related to ongoing epilepsy and/or medical treatment [9]. Data analyses also revealed other interesting associations including that a high lifetime dose of ASMs was correlated with an increase in neurologic changes, and there was a link between peripheral neuropathy (damage of nerves outside the central nervous system) and use of ASMs. Another significant association that was noted was a decreased volume of a part of the brain called the hippocampus as seen on MRI and high arterial hypertension (vs. normal blood pressure) in people with COE. In addition, high cholesterol was more prevalent in people with focal epilepsy as compared to generalized epilepsy [4]. When the entire cohort (those with COE and controls) was compared to earlier results at 50 years post-initial diagnoses, the authors found that overall, more people exhibited neurologic changes at the 55-year follow-up [4].

In conclusion, when examined decades after diagnosis, adults with COE who continue to have active epilepsy appear to have an accelerated tendency towards brain aging as compared to controls. The study provides a unique and exceptionally long-term perspective on the intersection of aging and epilepsy. This is also the first study to explore changes in the brain through MRI and neurologic functioning in individuals with COE as compared to controls. Additional findings to follow from this investigation will address prospective quantitative MRI changes, biomarkers of abnormal aging, and prospective cognitive trajectories over the five years. While results from the current study will need to be confirmed, it has the potential to impact the treatment of epilepsy and change the way we think of the intersection of epilepsy and aging.


Literature Cited:

  1.       Sillanpää M, Hermann B, Rinne JO, Parkkola R, Saarinen MM, Karrasch M, et al. Differences in brain changes between adults with childhood-onset epilepsy and controls: A prospective population-based study Acta Neurol Scand. 2022 Mar;145:322-331.
  2.       How the aging brain affects thinking Available at: Accessed September 5.
  3.       Sillanpää M. Medico-social prognosis of children with epilepsy. Epidemiological study and analysis of 245 patients Acta Paediatr Scand Suppl. 1973;237:3-104.
  4.       Sillanpää M, Anttinen A, Rinne JO, Joutsa J, Sonninen P, Erkinjuntti M, et al. Childhood-onset epilepsy five decades later. A prospective population-based cohort study Epilepsia. 2015 Nov;56:1774-1783.
  5.       Sillanpää M, Jalava M, Kaleva O, Shinnar S. Long-Term Prognosis of Seizures with Onset in Childhood New England Journal of Medicine. 1998;338:1715-1722.
  6.       Ladino LD, Téllez-Zenteno JF. Chapter 7 – Epilepsy and obesity: A complex interaction. In: Mula M, editor. The Comorbidities of Epilepsy: Academic Press; 2019. p. 131-158.
  7.       Harnod T, Chen HJ, Li TC, Sung FC, Kao CH. A high risk of hyperlipidemia in epilepsy patients: a nationwide population-based cohort study Ann Epidemiol. 2014 Dec;24:910-914.
  8.       Streng ML, Krook-Magnuson E. The cerebellum and epilepsy Epilepsy & Behavior. 2021 2021/08/01/;121:106909.
  9.       Hagemann G, Lemieux L, Free SL, Krakow K, Everitt AD, Kendall BE, et al. Cerebellar volumes in newly diagnosed and chronic epilepsy J Neurol. 2002 Dec;249:1651-1658.