title: Decreased hippocampal volume on MRI is associated with increased extracellular glutamate in epilepsy patients.
abstract: OBJECTIVE
  Temporal lobe epilepsy (TLE) is associated with smaller hippocampal volume and with elevated extracellular (EC) glutamate levels. We investigated the relationship between the hippocampal volume and glutamate in refractory TLE patients.
  
  
  METHODS
  We used quantitative MRI volumetrics to measure the hippocampal volume and zero-flow microdialysis to measure the interictal glutamate, glutamine, and GABA levels in the epileptogenic hippocampus of 17 patients with medication-resistant epilepsy undergoing intracranial EEG evaluation. The relationships between hippocampal volume, neurochemical levels, and relevant clinical factors were examined.
  
  
  RESULTS
  Increased EC glutamate in the epileptogenic hippocampus was significantly related to smaller ipsilateral (R(2)= 0.75, p < 0.0001), but not contralateral hippocampal volume when controlled for glutamine and GABA levels, and for clinical factors known to influence hippocampal volume. Glutamate in the atrophic hippocampus was significantly higher (p = 0.008, n = 9), with the threshold for hippocampal atrophy estimated as 5 microM. GABA and glutamine levels in the atrophic and nonatrophic hippocampus were comparable. Decreased hippocampal volume was related to higher seizure frequency (p = 0.008), but not to disease duration or febrile seizure history. None of these clinical factors were related to the neurochemical levels.
  
  
  CONCLUSIONS
  We provide evidence for a significant association between increased EC glutamate and decreased ipsilateral epileptogenic hippocampal volume in TLE. Future work will be needed to determine whether the increase in glutamate has a causal relationship with hippocampal atrophy, or whether another, yet unknown factor results in both. This work has implications for the understanding and treatment of epilepsy as well as other neurodegenerative disorders associated with hippocampal atrophy.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511, USA. idil.cavus@yale.edu
authors.forename: Idil
authors.initials: I
authors.lastname: Cavus
authors.forename: Jullie W
authors.initials: JW
authors.lastname: Pan
authors.forename: Hoby P
authors.initials: HP
authors.lastname: Hetherington
authors.forename: Walid
authors.initials: W
authors.lastname: Abi-Saab
authors.forename: Hitten P
authors.initials: HP
authors.lastname: Zaveri
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Vives
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.forename: Susan S
authors.initials: SS
authors.lastname: Spencer
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Spencer
mesh_terms: D000293:Adolescent; D000328:Adult; D001284:Atrophy / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000033:anatomy & histology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D012720:Severity of Illness Index; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid