648 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.73.6.656 on 1 December 2002. Downloaded from PAPER Voxel based morphometry of grey matter abnormalities in patients with medically intractable temporal lobe epilepsy: effects of side of seizure onset and epilepsy duration S S Keller, U C Wieshmann, C E Mackay, C E Denby, J Webb, N Roberts ............................................................................................................................. J Neurol Neurosurg Psychiatry 2002;73:648–656 Objectives: To investigate the use of whole brain voxel based morphometry (VBM) and stereological analysis to study brain morphology in patients with medically intractable temporal lobe epilepsy; and to determine the relation between side, duration, and age of onset of temporal lobe epilepsy, history of childhood febrile convulsions, and grey matter structure. Methods: Three dimensional magnetic resonance images were obtained from 58 patients with left sided seizure onset (LSSO) and 58 patients with right sided seizure onset (RSSO), defined using EEG and foramen ovale recordings in the course of presurgical evaluation for temporal lobectomy. Fifty eight normal controls formed a comparison group. VBM was used to characterise whole brain grey matter concentration, while the Cavalieri method of modern design stereology in conjunction with point counting was used to estimate hippocampal and amygdala volume. Age and sex were used as con- founding covariates in analyses. See end of article for Results: LSSO and RSSO patients showed significant reductions in volume (using stereology) and grey authors’ affiliations matter concentration (using VBM) of the hippocampus, but not of the amygdala, in the presumed epi- ....................... leptogenic zone when compared with controls, but hippocampal (and amygdala) volume and grey matter concentration were not related to duration or age of onset of epilepsy. LSSO and RSSO patients Correspondence to: copyright. Dr S Keller, MARIARC, with a history of childhood febrile convulsions had reduced hippocampal volumes in the presumed epi- University of Liverpool, leptogenic zone compared with patients without such a history. Left amygdala volume was also Pembroke Place, Liverpool reduced in LSSO patients with a history of childhood convulsions. VBM results indicated bilateral tha- L69 3BX, UK; [email protected] lamic, prefrontal, and cerebellar GMC reduction in patients, which correlated with duration and age of onset of epilepsy. Received 19 April 2002 Conclusions: Hippocampal sclerosis is not necessarily the consequence of recurrent temporal lobe In revised form 12 August 2002 seizures. A major cause of hippocampal sclerosis appears to be an early aberrant neurological insult, Accepted 20 August 2002 such as childhood febrile seizures. Secondary brain abnormalities exist in regions outside the ....................... presumed epileptogenic zone and may result from recurrent seizures. http://jnnp.bmj.com/ ippocampal sclerosis is the most common finding in VBM allows the investigation of grey matter abnormalities patients with medically intractable temporal lobe with no a priori region of interest, enabling a comprehensive Hepilepsy.1 However, the relation between the duration of and even handed analysis of global brain structure.18 VBM has epilepsy and hippocampal sclerosis is not fully understood. previously been used to indicate region specific grey matter Some cross sectional research has found evidence for progres- abnormalities in patients with temporal lobe epilepsy and sive hippocampal volume loss in patients with temporal lobe hippocampal atrophy,19 juvenile myoclonic epilepsy,20 affective epilepsy,2–5 suggesting that hippocampal atrophy is a conse- aggression and temporal lobe epilepsy,21 and malformations of quence of recurrent temporal lobe seizures. Conversely, others 22 cortical development causing epilepsy. In particular, we per- on September 28, 2021 by guest. Protected have found no relation between hippocampal volume and formed voxelwise statistical analyses on grey matter concen- 67 duration of epilepsy, which suggests that hippocampal tration of patients with left sided seizure onset (LSSO) and abnormalities do not result from repeated seizures. Hippocam- right sided seizure onset (RSSO), defined by EEG and invasive pal sclerosis has been related to the age of onset of epilepsy foramen ovale recordings. We also investigated the effects of and a history of childhood febrile convulsions in some temporal lobe epilepsy on hippocampal and amygdala volume, 37 89 studies. However, although atrophy of the amygdala, which were estimated by application of the Cavalieri method entorhinal cortex,10–12 parahippocampal gyrus,13 14 lateral tem- 15 16 17 of modern design stereology in conjunction with point count- poral lobe, and thalamus have been associated with tem- ing. The distribution of grey matter loss was investigated with poral lobe epilepsy, there is inadequate understanding of respect to laterality of seizure onset, duration of epilepsy, age whether extrahippocampal atrophy is related to these clinical of onset, and history of febrile convulsions. variables. Previous magnetic resonance (MR) image analysis tech- niques have employed region of interest measurements to METHODS investigate the relation between hippocampal volume and Participants and clinical information duration of epilepsy, age of onset, and febrile convulsions. In Laterality of seizure onset (presumed epileptogenic zone) was the present study, we have used whole brain voxel based mor- determined from EEG recordings, and from invasive foramen phometry (VBM), which automatically characterises grey ovale recordings when EEG recordings were non-localising. matter concentration on magnetic resonance (MR) images. Among 156 patients under evaluation for surgical remediation www.jnnp.com Voxel based morphometry of temporal lobe epilepsy 649 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.73.6.656 on 1 December 2002. Downloaded from lying within each transect through the hippocampus and Table 1 Clinical and demographic data on the amygdala was recorded. We did not employ a random grid ori- subjects. entation as difficulties are encountered in representing tilted Characteristic LSSO RSSO Controls test systems as relatively small brain structures within the image pixel matrix. However, orientation of the test system n 585858 Male342930 does not affect the unbiased nature of the volume estimate. Female242928 Separation between test points on the square grid used for Age (years) 34 (19 to 55) 34 (20 to 51) 40 (22 to 60) point counting was 0.234 cm (that is, three pixels) and slice Age of onset of 10 (1 to 34) 11 (1 to 34) – interval was also 0.234 cm for the hippocampus. The same grid epilepsy (years) spacing was used for the amygdala but with a slice interval of Duration of epilepsy 24 (2 to 47) 24 (4 to 48) – (years) 0.156 cm (two pixels). Unbiased estimates of transect area 1 to 10 years (n) 11 8 – were obtained by multiplying the total number of points 11 to 20 years (n) 13 11 – recorded by the area corresponding to each test point (for 21 to 30 years (n) 13 21 – example, 0.234 × 0.234 = 0.0548 cm2 for the hippocampus). >30 years (n) 21 18 – An unbiased estimate of structure volume was obtained as the History of febrile 22 18 – convulsions (n) sum of the estimated areas of the structure transects on con- secutive systematic sections multiplied by the distance Values are mean and range or n. between sections. For the hippocampus, approximately 150 LSSO, left sided seizure onset; RSSO, right sided seizure onset. points were recorded on 10 to 15 systematic random sections, while for the amygdala approximately 120 points were recorded on eight to 10 systematic random sections. Section- of complex partial seizures with temporal lobe origin, 58 had ing and point counting intensities were optimised to achieve a LSSO and 58 had RSSO. Patients with bilateral seizure onset coefficient of error on the Cavalieri volume estimates of (n = 19) and for whom side of seizure onset could not be between 3% and 5%, as described by Roberts et al.24 An determined (n = 21) were excluded from the analyses. Table 1 inter/intrarater reliability study was carried out by three raters gives demographic and clinical information on the patients. who estimated hippocampal volumes. Intraclass correlation Fifty eight subjects with no history of neurological or psychi- coefficients were calculated and were greater than 0.9. atric symptoms were used as a control population. MR image acquisition MR image analysis: voxel based morphometry T1 weighted images for all patients and controls were obtained Data were analysed in SPM99 (Wellcome Department of Cog- with a 1.5T SIGNA whole body MR imaging system (GE nitive Neurology, www.fil.ion.ucl.ac.uk) running in MATLAB Medical Systems, Milwaukee, Wisconsin, USA). A spoiled 5.3 (The MathWorks, Natick, Massachusetts, USA) on a Sun Ultra 10 workstation (Sun Microsystems). The technique of gradient echo (SPGR) pulse sequence (time of echo (TE) = 9 copyright. ms, time of repetition (TR) = 34 ms, flip angle = 30º) VBM used in the present study is illustrated in fig 1. produced 124 coronal T1 weighted images with a field of view (FOV) of 20 cm. Each image refers to a contiguous section of Spatial normalisation tissue of 1.6 mm thickness. Acquisition time was 13 minutes To enable intergroup comparisons, VBM corrects for interindi- and 56 seconds fora1NEXscan. vidual variability in brain size by