THE NONINVASIVE LOCALISATION OF BRAIN ABNORMALITY IN INTRACTABLE FOCAL EPILEPSY IN CHILDHOOD Thesis submitted for the Degree of Doctor of Philosophy in the Faculty of Medicine by Judith Helen Cross Institute of Child Health University of London 1998 ProQuest Number: U644132 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U644132 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT The work described in this thesis evaluates the role of noninvasive magnetic resonance and nuclear medicine techniques in the investigation of focal epilepsy of childhood, and more specifically in the presurgical evaluation of children who are potential candidates for surgery. Seventy five children were prospectively investigated after referral for assessment and investigation of intractable focal epilepsy. Initial clinical localisation was made on the basis of full clinical assessment with EEG. All underwent magnetic resonance imaging. Abnormalities were found in 88% of children, concordant with the seizure focus in 80%. Further magnetic resonance techniques were assessed with regard to latéralisation of temporal lobe epilepsy (TLE). T2 relaxometry of the hippocampi and proton magnetic resonance spectroscopy (^H MRS) of the mesial temporal lobes were demonstrated to be lateralising in a high proportion of these children, and also showed a high rate of bilateral abnormality. In order to relate these structural abnormalities to the epileptogenic focus, the technique of ictal single photon emission computed tomography (SPECT), using Tc'" HMPAO as a marker of cerebral blood flow, was developed for this study. Focal hyperperfusion was seen in 72% of ictal scans when compared to interictal scans, concordant with the seizure focus in all. Where no perfusion change was noted after an ictal injection, slowing of the EEG was present at the time of injection consistent with ischaemia, suggesting rCBF does not increase in all focal seizures. Correlation of interictal SPECT scans with MRS of the mesial temporal regions in children with TLE demonstrated correlation between neuronal loss or dysfunction and hypoperfusion. Where similar damage on the two sides was demonstrated by MRS, no asymmetry of interictal perfusion was seen. These findings have led to a better understanding of the underlying pathophysiology of intractable focal epilepsy of childhood and have resulted in an increase in the number of children evaluated for epilepsy surgery. The thesis concludes with a discussion of an optimised noninvasive strategy for presurgical evaluation in children. DECLARATION I, Judith Helen Cross, declare that this thesis is all my own work. I clinically reviewed all 75 children within the study. All ictal EEG’s were initially read by me, with subsequent verification of the report, and review of all interictal EEG’s with the Consultant Neurophysiologist, Dr Stewart Boyd. The magnetic resonance images and spectroscopy were performed and processed by the research radiographer. Miss Cheryl Johnson, but I reviewed all the magnetic resonance images in conjunction with the independent observer. Dr Graeme Jackson. I read all T2 maps as the second independent observer following the first observer. Miss Cheryl Johnson. All T2 relaxometry and MRS results were analysed by me. The technique of ictal ^^Tc*" HMPAO SPECT was developed for routine clinical use on the ward by me in conjunction with the Consultant in Nuclear Medicine, Dr I sky Gordon. All but a small number of ictal injections were given by me; the remaining injections were given by the Epilepsy Liaison Nurse, Sister Alison Harper. I processed and read all ictal, postictal and interictal scans and subsequently analysed the results, and performed the correlative studies with MRI, EEG and *H MRS. J Helen Cross Professor BGR Neville PhD Student Professor DG Gadian Supervisors TABLE OF CONTENTS ABSTRACT,.................................................................................................... 2 DECLARATION.............................................................................................3 CONTENTS.....................................................................................................4 LIST OF TABLES......................................................................... 10 LIST OF FIGURES.......................................................................................14 ABBREVIA TIONS.........................................................................................18 ACKNOWLEDGEMENTS...........................................................................19 CHAPTER 1: The presurgical evaluation of focal epilepsy in childhood ..................................................................................20 1.1 Introduction 20 1.2 Definitions and epidemiology 21 1.3 Prognosis and the concept of intractability 24 1.4 The argument for epilepsy surgery in childhood 26 1.5 The problem of localisation 30 1.7 Structural vs functional abnormality 32 1.8 Aims o f the study 36 CHAPTER 2: Clinical and electroencephalographic localisation of the ‘seizure focus’ .................................................................. 38 2.1 Introduction 38 2.2 The problem o f seizure localisation 40 2.3 The problem o f seizure detection 41 2.4 Patient population 42 2.5 Clinical localisation 43 2.5.1 Methods 43 2.5.2 Results 44 2.6 EEG localisation 49 2.6.1 Methods 49 2.6.2 Results 51 2.7 Clinical and EEG localisation 53 2.8 Clinical features o f the patient population 54 2.9 Discussion 56 CHAPTER 3: Magnetic resonance imaging ............................................... 59 3.1 Pathological substrates in epilepsy 59 3.1.1 Cortical development and implications of its disruption 60 3.1.2 Tumours 62 3.1.3 The hippocampus and its role in epilepsy 63 3.1.4 Progressive disorders 66 3.1.5 Ischaemic lesions 6 7 3.2 Magnetic resonance imaging in epilepsy 67 3.3 Methods 68 3.4 Results 74 3.4.1 Temporal lobe epilepsy 74 3.4.2 Extratemporal epilepsy 77 3.4.3 Hemisyndromes 79 3.4.4 Unlocalised epilepsy 81 3.5 Discussion 82 CHAPTER 4: Quantitative T2 relaxometry in focal epilepsy ................................................................................. 85 4.1 Introduction 85 4.2 Methods 88 4.3 Control data 90 4.4 Patient population 93 4.5 Data analysis 94 4.6 Results 94 4.6.1 Temporal lobe epilepsy 94 4.6.2 Extratemporal epilepsy 98 4.6.3 Hemisyndromes 99 4.7 Summary o f results 100 4.8 Relationship between T2 relaxometry, a history o f early childhood convulsions and status epilepticus 100 4.9 Discussion 102 Appendix 108 CHAPTER 5: Proton magnetic resonance spectroscopy ......................112 5.1 Introduction 112 5.2 Methods 116 5.3 Control data 117 5.4 Patient population 118 5.5 Data analysis 119 5.6 Results 119 5.6.1 Temporal lobe epilepsy 119 5.6.2 Repeated studies 123 5.6.3 Extratemporal epilepsy 124 5.7 Comparison o f MRS and T2 relaxometry 125 5.7.1 Temporal lobe epilepsy 125 5.7.2 Extratemporal epilepsy 126 5.8 Discussion 127 Appendix 132 CHAPTER 6: Regional cerebral blood flow in localisation of the seizure focus ..............................................................133 6.1 Introduction 133 6.2 Single photon emission computed tomography 135 6.3 SPECT in epilepsy 136 6.4 Methods 138 6.4.1 Definitions 138 6.4.2 Radioisotope injection 139 6.4.3 Scan acquisition 141 6.4.4 Data reconstruction and interpretation 141 6.5 Results 146 6.5.1 Scans performed 146 6.5.2 Limitedframe acqusition 148 6.5.3 Asymmetry of perfusion 149 6.5.4 Ictal scans 155 6.5.5 Postictal scans 155 6.5.6 Interictal scans 158 6.5.7 Ictal/postictal vs interictal scans 160 6.6 Ictal/postictal rCBF in special situations 160 6.6.1 Secondary generalisation 160 6.6.2 Hyperventilation 162 6.6.3 Ictal/postictal scans in unlocalised epilepsy 162 6.7 Discussion 163 Appendix 171 CHAPTER 7: Specific patterns of regional cerebral blood flow during seizures ...............................................................175 7.1 Introduction 175 7.2 Relationship of ictal/postictal rCBF to magnetic resonance imaging 177 7.2.1 Patient population 178 7.2.2 Results 178 7.3 Regional cerebral blood flow in subcortical structures 185 7.3.1 Basal ganglia 185 7.3.2 Cerebellum 186 7.4 Regional cerebral blood flow in relation to the ‘seizure focus ’ 186 7.4.1 Patient population 187 7.4.2 Results 188 7.5 Discussion 197 7.5.1 Relationship of ictal rCBF to pathilogy 197 7.5.2 Ictal perfusion of subcortical structure s 198 7.5.3 Focal hypoperfusion in relation to the ‘seizure focus’ 200 7.5.4 Conclusions to ictal rCBF to pathology 202 CHAPTER 8: The pathology underlying interictal SPECT ..................204 8.1 Introduction 204 8.2 Relationship o f interictal rCBF to MRI 207 8.2.1 Patient population 207 8.2.2 Results 207 8.3 Repeat interictal studies 211 8.4 Relationship of interictal hypoperfusion to neuronal loss or damage 213 8.4.1 Patient population 214 8.4.2 Results 214 8.5 Discussion 220 CHAPTER 9\ The presurgical evaluation of children with drug resistant focal epilepsy: An optimised