DEPARTMENT OF NEUROLOGY SERIES OF REPORTS NO 55, 2001 Tuuli Salmenperä DAMAGE IN THE HIPPOCAMPUS, AMYGDALA, ENTORHINAL AND PERIRHINAL CORTEX OF ADULTS WITH PARTIAL EPILEPSY

Epilepsy refers to a common group of neurologic conditions characterized by recurrent unprovoked seizures. Although the prognosis of epilepsy is usually favorable, up to 30% of patients continue to have seizures despite intensive treatment with antiepileptic drugs. Hippocampal sclerosis is found in 60 to 70% of patients with intractable temporal lobe epilepsy (TLE). However, it is not known whether the damage in the hippocampus is the cause or the consequence of TLE. The purpose of the present series of studies (I-V) was to investigate with magnetic resonance imaging (MRI) the appearance of medial temporal lobe damage during the course of partial epilepsy, and, particularly, to determine whether recurrent or prolonged seizures contribute to the damage. Altogether 259 partial epilepsy patients were investigated with quantitative MRI in studies I-IV. The patients were divided into two groups according to the localization of the seizure focus: patients with TLE (n=167), and patients with extratemporal/unclassified partial epilepsy (ETE/UC) (n=92). Study V comprised nine patients with status epilepticus requiring intravenous antiepileptic medication. High lifetime seizure number, complex febrile convulsions in the medical history, and early age at the onset of spontaneous seizures contributed to hippocampal damage in patients with TLE. The risk factors that predicted amygdaloid volume reduction were intracranial infection and complex febrile convulsions. Damage in the hippocampus or in the amygdala was rare at the time of first spontaneous seizures in TLE. In contrast, hippocampal damage was apparent in chronic TLE patients with years of frequent seizures. Chronic cryptogenic drug-resistant TLE patients had smaller mean hippocampal volumes and T2 relaxation times in the body of the hippocampus ipsilateral to the seizure focus than controls. In all TLE patients, ipsilateral hippocampal volume correlated negatively and T2 relaxation time positively with the lifetime seizure number. The mean amygdaloid volumes in chronic TLE patients did not differ from those in controls. However, about 20% of chronic patients had ≥ 20% volume reduction and T2 time prolongation in the amygdala. There were no differences in the hippocampal and amygdaloid volumes and T2 relaxation times between patients with different durations of ETE/UC and controls. The mean volumes of the entorhinal cortex ipsilateral to the epileptic focus in cryptogenic TLE patients did not differ from those in controls. However, the entorhinal cortex was damaged in a subpopulation of TLE patients with associated hippocampal damage. Status epilepticus did not lead to the development of marked volume reduction of the hippocampus, amygdala, or the entorhinal and perirhinal cortices in adult patients treated promptly in hospital with a predetermined protocol. The findings of the present series of studies support the hypothesis that damage in the medial temporal lobe structures may be both the cause and consequence of TLE. The data provide evidence that in some patients hippocampal damage may progress as a function of repeated seizures, and argue for efficient drug therapy or early surgery to reach complete seizure control. Future research should address strategies for disease-modifying therapies and ultimately remission of the epileptic process. National Library of Medicine Classification: WL385 Medical Subject Headings: amygdala; entorhinal cortex; epilepsy; hippocampus; magnetic resonance imaging; status epilepticus; temporal lobe ACKNOWLEDGEMENTS This study was carried out at the Departments of Neurology and Radiology at the University of Kuopio and the Kuopio University Hospital and at the A.I.Virtanen Institute during years 1995-2000. I am grateful to the principal supervisor of this study, professor Asla Pitkänen for her guidance and teaching of neuroscience and research. I owe my gratitude to the second supervisor, docent Reetta Kälviäinen for sharing with me her expert knowledge in clinical neurology and research. I express my gratitude to professor Hilkka Soininen, Head of the Department of Neurology, University of Kuopio for supervising and providing the excellent facilities to carry out this work. I am thankful to all the supervisors for their support to me during these years. I thank the collaborators of the study docent Kaarina Partanen, Pauli Vainio, PhL and docent Esa Mervaala for their valuable contributions. I am indebted to professor Ricardo Insausti, School of Medicine, University of Castilla-La Mancha and docent Jouko Isojärvi, Department of Neurology, University of Oulu for their expert reviewing of the manuscript. My thanks go to Pirjo Halonen, MSc for statistical advice, to Mrs Liisi Saarela for help in editing the manuscript and to Vivian Paganuzzi, MA for revising the language. I am thankful to my colleagues for the friedship and support they have provided. I would like to thank the staff of the Departments of Neurology and Radiology for the help and co-operation during the study. I thank also the members of the ”EpiClub” at the A.I.Virtanen Instute for our work together. I express my gratitude to all the patients who have participated in this study. My warmest thanks belong to my friends and to my family for their ample encouragement, support, patience and kindness to me during this work. This work was financially supported by the Finnish Epilepsy Society, the Finnish Medical Society Duodecim, the Instrumentarium Foundation, the Kuopio University Hospital, the Kuopio Doctoral Program of Medical Sciences, the Neurology Foundation, the North-Savo Regional Fund of the Finnish Cultural Foundation and the Vaajasalo Foundation.