Decreased hippocampal volume on MRI is associated with increased extracellular glutamate in epilepsy patients

Abstract

SUMMARYPurpose: 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 medicationresistant 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 μM. 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. KEY WORDS: Hippocampal volume, Glutamate, GABA, Microdialysis, MRI, Epilepsy, TLE.Hippocampal atrophy on MRI is seen in 60%-75% of patients with medication-resistant temporal lobe epilepsy (TLE), as well as in other neurodegenerative conditions including Alzheimer's, Huntington's and Parkinson's disor-

Relationship between fluid-attenuated inversion-recovery (FLAIR) signal intensity and inflammatory mediator's levels in the hippocampus of patients with temporal lobe epilepsy and mesial temporal sclerosis

“…Our data are supported by previous report 21 , which demonstrated increased extracellular glutamate levels (increased release), using microdialysis probes in humans with TLE. A deficiency in glutamine synthesis in astrocytes, found by several authors 22 , can also explain the high levels of glutamate in extracellular space, suggesting increased release of this amino acid.…”

A meta-analysis on progressive atrophy in intractable temporal lobe epilepsy

“…41 This caveat appears particularly relevant for cross-sectional studies. In 18 of the latter (47.4%), 14,16,[20][21][22]24,30,[33][34][35][36][37][38]40,42,[50][51][52] no statistical approaches were implemented to correct for the effects of age. Although the remaining studies addressed aging, no consistent method was chosen: 3 reported no significant effects of age on morphometric measures in controls, 15,32,48 3 found no effect of age or no effect of age at epilepsy onset in patients, 19,29,53 2 corrected for age at onset, 18,28 5 corrected for age in patients, 17,26,47,49,54 4 utilized MRI measures adjusted for age 13,31,39,46 (based on regression models derived from controls), 1 calculated epilepsy duration/age ratios, 23 2 statistically compared chronological age effects between patients and controls.…”

Astrocytes and Epilepsy

“…43 The increased interictal basal extracellular glutamate levels negatively correlate with hippocampal volume being significantly increased in the atrophic 43 hippocampus compared to nonatrophic ones. 71 The hippocampal volume negatively correlates with seizure frequency. 71 Magnetic resonance spectroscopic measurements show that cellular glutamate levels are also lower in the atrophic (sclerotic) hippocampus compared to the nonatrophic one.…”

“…71 The hippocampal volume negatively correlates with seizure frequency. 71 Magnetic resonance spectroscopic measurements show that cellular glutamate levels are also lower in the atrophic (sclerotic) hippocampus compared to the nonatrophic one. 72 However, tissue glutamate levels measured by proton magnetic resonance spectroscopy of perchloric acid tissue extracts show that the cellular glutamate content is increased above normal levels in the epileptogenic human hippocampus.…”