title: Tract-specific atrophy in focal epilepsy: Disease, genetics, or seizures?
abstract: OBJECTIVE
  To investigate whether genetics, underlying pathology, or repeated seizures contribute to atrophy in specific white matter tracts.
  
  
  METHODS
  Medically refractory unilateral temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS-TLE, n = 26) was studied as an archetype of focal epilepsy, using fixel-based analysis of diffusion-weighted imaging. A genetic effect was assessed in first-degree relatives of HS-TLE subjects who did not have epilepsy themselves (HS-1°Rel; n = 26). The role of disease process was uncovered by comparing HS-TLE to unilateral TLE with normal clinical magnetic resonance imaging (MRI-neg TLE; n = 26, matched for seizure severity). The effect of focal seizures was inferred from lateralized atrophy common to both HS-TLE and MRI-neg TLE, in comparison to healthy controls (n = 76).
  
  
  RESULTS
  HS-1 °Rel had bilaterally small hippocampi, but no focal white matter atrophy was detected, indicating a limited effect of genetics. HS-TLE subjects had lateralized atrophy of most temporal lobe tracts, and hippocampal volumes in HS-TLE correlated with parahippocampal cingulum and anterior commissure atrophy, indicating an effect of the underlying pathology. Ipsilateral atrophy of the tapetum, uncinate, and inferior fronto-occipital fasciculus was found in both HS-TLE and MRI-neg TLE, suggesting a common lateralized effect of focal seizures. Both epilepsy groups had bilateral atrophy of the dorsal cingulum and corpus callosum fibers, which we interpret as a consequence of bilateral insults (potentially generalized seizures and/or medications).
  
  
  CONCLUSIONS
  Underlying pathology, repeated focal seizures, and global insults each contribute to atrophy in specific tracts. Genetic factors make less of a contribution in this cohort. A multifactorial model of white matter atrophy in focal epilepsy is proposed. Ann Neurol 2017;81:240-250.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.|Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.|Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: David N
authors.initials: DN
authors.lastname: Vaughan
authors.affiliation: Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Raffelt
authors.affiliation: Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.
authors.forename: Evan
authors.initials: E
authors.lastname: Curwood
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.|Department of Nursing, Meiho University, Pingtung, Taiwan.
authors.forename: Meng-Han
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: Department of Biomedical Engineering, Division of Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom.|Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom.
authors.forename: Jacques-Donald
authors.initials: JD
authors.lastname: Tournier
authors.affiliation: Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.|Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Alan
authors.initials: A
authors.lastname: Connelly
authors.affiliation: Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.|Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.|Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Graeme D
authors.initials: GD
authors.lastname: Jackson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001284:Atrophy / Q000473:pathology; D056324:Diffusion Tensor Imaging; D004833:Epilepsy, Temporal Lobe / Q000000981:diagnostic imaging* / Q000235:genetics / Q000503:physiopathology; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000000981:diagnostic imaging*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D012598:Sclerosis / Q000473:pathology; D066127:White Matter / Q000000981:diagnostic imaging*; D055815:Young Adult