Later onset focal epilepsy with roots in childhood: Evidence from early learning difficulty and brain volumes in the Human Epilepsy Project

Jacob Pellinen; Heath Pardoe; Stefan Sillau; Sarah Barnard; Jacqueline French; Robert Knowlton; Daniel Lowenstein; Gregory D Cascino; Simon Glynn; Graeme Jackson; Jerzy Szaflarski; Chris Morrison; Kimford J Meador; Ruben Kuzniecky; Human Epilepsy Project Investigators

doi:10.1111/epi.17727

Later onset focal epilepsy with roots in childhood: Evidence from early learning difficulty and brain volumes in the Human Epilepsy Project

Epilepsia. 2023 Oct;64(10):2761-2770. doi: 10.1111/epi.17727. Epub 2023 Aug 4.

Authors

Collaborators

Human Epilepsy Project Investigators:
Sabrina Cristofaro, Kevin McKenna, Vickie Mays, Darrell Shack, Cheryl Burke, Manu Hegde, Tracy Glauser, Terence O'Brien, John Pollard, Tricia Ting, Patricia Penovich, David Darby, Andres Kanner, Hamada Hamid Altalib, John Barry, Dale Hesdorffer, Omotola Hope, Siddhartha Nadkarni, Michael Sperling, Melodie Winawer, Dennis Dlugos, Jules Beal, Alexis Boro, Susan Herman, Rani Singh, John Halford, Gregory Bergey, Eric Geller, David Gloss, Rani Singh, Gregory Worrell, Liu Lin Thio, Barry Gidal, Bassel Abou-Khalil, Brian Alldredge, Edward Faught, David Ficker, Pavel Klein, Scott Mintzer, James Cloyd, Manisha Holmes, Kamil Detyniecki, Sheryl Haut, John Hixson, Reetta Kälviäinen, Peter Widdess-Walsh, Kaarkuzhali Krishnamurthy, Kristen Park, Michael Gelfand, Joon Kang, Gregory Krauss, Andrew Cole, Jonathan Halford, Paul Atkinson, Eugen Trinka, Margarita Kirschner, Elisabeth Schmid, Ernest Somerville, Christian Zentner, Hanka Laue-Gizzi, Andy Rodriguez, Orrin Devinsky, Mangala Nadkarni, Mark Cook, Sam Berkovic, Martina Bebin, Charles Szabo, Jorge Burneo, Judy Weisenberg, Charles Lu, George Michel, Mirza Baig, Gary Cutter

Affiliations

¹ University of Colorado School of Medicine, Aurora, Colorado, USA.
² Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.
³ Monash University, Melbourne, Victoria, Australia.
⁴ New York University Comprehensive Epilepsy Center, New York, New York, USA.
⁵ University of California, San Francisco, San Francisco, California, USA.
⁶ Mayo Clinic, Rochester, Minnesota, USA.
⁷ University of Michigan, Ann Arbor, Michigan, USA.
⁸ University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁹ Stanford University Neuroscience Health Center, Palo Alto, California, USA.
¹⁰ Northwell Health, New York, New York, USA.

PMID: 37517050
DOI: 10.1111/epi.17727

Abstract

Objective: Visual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1.

Methods: Enrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12-60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient <70, and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1-weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics.

Results: Brain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = -.007 to -.002, p = .0003). Each 10-year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = -.007 to -.005, p < .0001). For male participants, the ratio was .011 less than for female participants (95% CI = -.014 to -.007, p < .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities.

Significance: This study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population.

Keywords: clinical neurology; cognition; development; magnetic resonance imaging; seizures.