DEFINICION DE TERMINOS ECONOMICOS

It has been postulated that human cerebral dysgenesis is likely to be an extensive disorder, with structural abnormalities beyond the visualised lesion alone (see Chapter 1). Whilst there is much evidence in favour of this in animals and some circumstantial evidence in humans, direct evidence has not been available in humans. The difficulties involved in showing such extralesional abnormalities have been described previously. In summary, in vivo, brain outside a lesion may appear normal on visual inspection alone (of MR I or at operation), and there is usually no justification for its excision at surgery. Postmortem, the effort needed to detect areas of abnormality in normal-looking brain is, if anything, greater, requiring extensive sampling and tedious techniques

(eg Golgi staining; Huttenlocher, 1974). As some abnormalities may be purely quantitative (cell counts), histopathology would be further complicated by stereological considerations, which have seldom been addressed in postmortem studies. Lastly, few brains with dysgenesis are available postmortem to centres with the interest and ability to examine them adequately. Hence other methods were devised to address the question in v i v o .

Using MR I technology and a novel methodology based on biological consideration of the nature of dysgenesis, results from this work show that there are abnormalities of cerebral structure, associated with frank dysgenesis, in regions well beyond the visually-determined lesion in 79% of cases.

Cerebral tissue within extralesionally abnormal block variables appears to be normal on visual inspection alone of MRI data. In these cases, cerebral structure is extensively disrupted: there are quantifiable changes in shape (regional volume distribution) that are not apparent to the human eye on

inspection alone, and are not present in control subjects.

Such changes are not present in patients whose epilepsy is due to hippocampal sclerosis alone (as judged by seizure- freedom postoperatively and the absence of other lesions identified on routine inspection or reconstruction). In terms of the occurrence of secondarily generalised seizures or duration of epilepsy, there is no difference between the patients with hippocampal sclerosis and those with dysgenesis. Thus epilepsy need not produce the block abnormalities seen: these are more likely to be associated with the cause of the epilepsy.

Examination of the patients with visually normal scans and chronic partial epilepsy confirms the finding that structural abnormalities of the cortex may be present where none can be seen on inspection alone. These patients had no neocortical abnormalities detected even when the images had been examined by an experienced neuroradiologist with an interest in dysgenesis, and when the images had been previously reformatted by another, independent, researcher examining the utility of reformatting (Raymond et al.,1993). In 52% of these patients there were abnormalities of the regional distribution of volume (see section 4.3.2) . Thus structural abnormality may exist in brains in which inspection fails to reveal any abnormalities, dysgenetic or otherwise. The revelation of abnormalities by quantitation is also seen

in the study of the hippocampus (Reutens et al.,1995; Van Paesschen et al.,1995) and may be seen as a natural extension of the original hypothesis: abnormalities are present in visually normal areas of scans with definite dysgenesis and in visually normal scans of other patients with partial epilepsy.

That the majority of extralesional abnormalities in the group with visible dysgenesis are noncontiguous (see 4.2.3) suggests that changes may not only be locally extensive (as now shown by Palmini et al.,1995), but also multifocal, as postulated by Awad et al. (1991). This may be because the cause of the dysgenesis itself - not investigated at all in this work - acts diffusely or because of extensive interneuronal connectivity (see section 1.6.). The latter is discussed further below. Note that Palmini et al. (1995) show that dysgenesis may be demonstrable histologically in areas that are normal on inspection.

Visualisation of the three-dimensional surfaces of the cerebral hemispheres is another way in which the spread of dysgenesis may be shown to extend beyond the lesion visualised on two-dimensional images. Given that gyral morphology is affected by cortical architecture (Rademacher et al.,1993), additional gyral abnormalities are likely to represent additional areas of structural disruption. Three-dimensional reconstruction has revealed additional gyral abnormalities in 6/22 patients with obvious dysgenesis and in 18/45 patients in whom no abnormalities were seen at all on routine inspection (see 4.2.1 and 4.3.1). It should be emphasised that the patients in the latter group did not all have quantitative abnormalities, and those with quantitative abnormalities did not all have gyral changes: the techniques explore different aspects of cerebral structure and are complementary. In both cases the changes may be due to CD. It may be that if gyral volumes, rather than arbitrary (but strictly defined) regions, were examined, then the two techniques might reveal changes in similar locations, although problems of measuring the volumes of specific gyri, and comparing them between individuals, are daunting, especially given the unique gyral patterns sometimes seen in CD (see 2.3.1.).

Clinically, these findings are important. Firstly, they provide a possible explanation for the poor outcome after

surgical resection of apparently focal dysgenetic lesions in patients with refractory epilepsy. To explore this further, a cohort of patients undergoing surgery for epilepsy ought to be studied prospectively using these techniques, and the outcome compared to the quantitative preoperative findings and lesional histopathology, as is being done for hippocampal volumetry and mesial temporal epilepsy (Spencer, 19 95) . If the presence of extralesional abnormalities is associated with a poor outcome, then quantitative preoperative analysis may prevent lesional surgery in patients doomed to a poor outcome. Secondly, the findings demonstrate that areas of scans and whole scans that appear normal may harbour quantifiable abnormalities, so that the large number of patients with partial epilepsy said to be cryptogenic may in the future decline.

There is evidence therefore in support of the hypothesis that there may be abnormalities of cerebral structure beyond the visualised lesion in brains affected by dysgenesis.