Objective: To investigate the presence of hippocampal atrophy (HA) and other magnetic resonance imaging (MRI) signs of hippocampal sclerosis (HS) in asymptomatic relatives of patients with familial mesial temporal lobe epilepsy (FMTLE). Methods: We invited first-degree, asymptomatic relatives of patients with FMTLE to participate in our MRI protocol. After obtaining informed consent, all participating individuals underwent an MRI examination. Hippocampal abnormality was determined by qualitative and volumetric analyses, using a standard protocol. Results: We studied 52 asymptomatic individuals (27 men), with a mean age of 32 years (range, 7-71 years), from 11 families with FMTLE. Volumetric studies showed HA in 18 (34%) of 52 individuals: 11 had left HA and 7 had bilateral HA. In addition, careful visual analysis of T1- and T2-weighted images showed additional classic MRI signs of HS (such as abnormal T2 signal and/or abnormal internal structure) in 14 of these 18 individuals. There was no age difference between individuals with and without HA (t test, P=.80). Conclusions: Our findings indicate that MRI evidence of HS is not necessarily related to seizure severity and may occur in individuals who never had seizures. In addition, these observations strongly indicate that HS in FMTLE is not a consequence of recurrent seizures and is determined by a strong genetic predisposition. The determination of seizure severity in patients with FMTLE probably depends on the interaction of different factors, both genetic and environmental.591218911894Kobayashi, E., Sousa, S.C., Lopes-Cendes, I., Guerreiro, C.A.M., Guerreiro, M.M., Cendes, F., Seizure outcome and hippocampal atrophy in familial mesial temporal lobe epilepsy (2001) Neurology, 56, pp. 166-172Cendes, F., Lopes-Cendes, I., Andermann, E., Andermann, F., Familial temporal lobe epilepsy: A clinically heterogeneous syndrome (1998) Neurology, 50, pp. 554-557Kobayashi, E., Andermann, F., Li, M.L., Volumetric studies in familial mesial temporal lobe epilepsy [abstract] (2001) Neurology, 56 (SUPPL.), pp. A153Fernandez, G., Effenberger, O., Vinz, B., Hippocampal malformation as a cause of familial febrile convulsions and hippocampal sclerosis (1998) Neurology, 50, pp. 909-916Watson, C., Jack, C.R., Cendes, F., Volumetric magnetic resonance imaging: Clinical applications and contributions to the understanding of temporal lobe epilepsy (1997) Arch Neurol, 54, pp. 1521-1531Meencke, H.J., Veith, G., Hippocampal sclerosis in epilepsy (1991) Epilepsy Surgery, pp. 705-715. , Luders H, ed. New York, NY: Raven PressBabb, T.L., Brown, W.J., Pathological findings in epilepsy (1987) Surgical Treatment of the Epilepsies, pp. 511-540. , Engel J Jr, ed. New York, NY: Raven PressJack C.R., Jr., Sharbrough, F.W., Cascino, G.D., Hirschorn, K.A., O'Brien, P.C., Marsh, W.R., Magnetic resonance image-based hippocampal volumetry: Correlation with outcome after temporal lobectomy (1992) Ann Neurol, 31, pp. 138-146Cascino, G.D., Jack, C.R., Parisi, J.E., Magnetic resonance imaging-based volume studies in temporal lobe epilepsy: Pathological correlations (1991) Ann Neurol, 30, pp. 31-36Van Paesschen, W., Connelly, A., King, M.D., Jackson, G.D., Duncan, J.S., The spectrum of hippocampal sclerosis: A quantitative magnetic resonance imaging study (1997) Ann Neurol, 41, pp. 41-51Duvernoy, H.M., (1988) The Human Hippocampus: An Atlas of Applied Anatomy, , Munich, Germany: J F Bergman VerlagBaulac, M., De Grissac, N., Hasboun, D., Hippocampal developmental changes in patients with partial epilepsy: Magnetic resonance imaging and clinical aspects (1998) Ann Neurol, 44, pp. 223-233Thom, M., Sisodiya, S.M., Lin, W.R., Bilateral isolated hippocampal malformation in temporal lobe epilepsy (2002) Neurology, 58, pp. 1683-1686Curtis, M., Avanzini, G., Interictal spikes in focal epileptogenesis (2001) Prog Neurobiol, 63, pp. 541-567