The functional significance of extralesional structural changes in patients with dysgenesis

The postprocessing methods have demonstrated various changes in cerebral structural constitution. Such changes are present in some patients with apparently cryptogenic epilepsy. However, the functional significance of these changes has not been proven in this study, though their frequent association with epilepsy suggests that they are relevant in some way.

in 17 patients with apparently normal scans. Whilst the location of gyral changes in 10/17 patients is compatible with the electroclinical seizure pattern (see 4.3.1), that the changes probably represent underlying dysgenesis (see 5.1.) means that still more extensive structural abnormality is likely to be present. Thus that electroclinical concordance is not present in the other 7 does not mean that the reconstruction findings are functionally unimportant. On the contrary, the implication is that these gyral changes are likely to be the tip of the iceberg of disordered cerebral structure, probably arising during development: extensive additional gyral abnormalities are also revealed in 2 7% of patients with definite dysgenesis. Such extensive structural disorder may be associated with extensive functional disorder.

Evidence for extensive functional changes in the brain in various forms of partial epilepsy does exist. Two lines of evidence will be discussed: the clinical study of patients with hypothalamic hamartomata and evidence from electrophysiological studies.

5.5.1. Hypothalalamic hamartoma

Epilepsy associated with hypothalamic hamartomata is characterised by the occurrence of gelastic seizures and is usually refractory to medical treatment (Cascino et al.,1993);

its pathogenesis is unclear. Surgical removal of the abnormal area of the hypothalamus has been attempted for some of the manifestations of the abnormality. Precocious puberty may be successfully treated thus, but there are few reports of cessation of seizure activity (Nishio et al.,1994; Machado et a l.,1991; Valdueza et al.,1994). Larger reviews (Breningstall, 1985; Cascino et al.,1993) suggest patients are unlikely to be rendered seizure-free (and that mortality and morbidity may be high) . Intracranial electrographic recordings and stimulation (Arroyo et al.,1993) suggest that the pathways subserving gelastic seizures in general might be complex and involve the

anterior cingulate gyrus, the mesial frontal cortex and the basal temporal cortex. Cascino et al. (1993) also report results of intracranial electroencephalography in patients with hypothalamic hamartoma and gelastic seizures; seizure onset was felt to be anterior mesial temporal in 7 patients and inferior frontal in one. However, none of the electrographically-guided focal cortical resections performed for seizure relief was successful. These findings together indicate that whilst gelastic seizures are strongly associated with the presence of a hypothalamic hamartoma, the cortical mechanism of laughter and epileptogenesis in these cases may involve other regions of the brain, possibly wider areas of the neocortex. Prefrontal cortical input to the hypothalamus and reciprocal connections with the limbic system provide a possible anatomical substrate for this. In one case PET studies support the possibility of functional abnormality beyond the hypothalamic hamartoma itself (Cascino et al.,1993).

The association of cognitive impairment and decline with the presence of a hypothalamic hamartoma and epilepsy raises the possibility of extensive cortical dysfunction. The hypothesis that this is due to the presence of widespread associated dysgenetic abnormalities (Breningstall, 1985; Berkovic et al.,1988), is supported by the results presented: two patients with typical hypothalamic hamartomata have associated neocortical abnormalities demonstrated by the block technique. The block technique may prove useful in assessment of other patients with apparently potentially resectable lesions.

5.5.2. Electrophysiology

Functional abnormalities extending beyond the visualised lesion have also been demonstrated using electrophysiological techniques. In a recent report, Palmini et al. (1995) investigated electrical discharge patterns recorded

peroperatively on patients subsequently shown to have cerebral dysgenesis. They showed that discharge patterns they hold to be specific for dysgenetic lesions extended contiguously beyond the lesional margins as visualised at operation or on MR I in at least 5 of their patients, and that subsequent histological analysis of these areas showed them to be dysgenetic. When the area from which the specific electrical abnormalities were recorded could be completely resected, the outcome was better than when such areas could not be completely resected. Indeed, they suggest that incomplete excision of all dysgenetic tissue may have been responsible for the poor outcome of patients they had previously reported (Palmini et al.,1991). Curiously, complete removal of the area producing the specific electrical abnormalities did not lead to seizure freedom in 25% of cases (Palmini et al.,1995). It is not clear from their report why this should be, but even more extensive, noncontiguous, areas of functional abnormality might have been present beyond the field exposed at surgery and these areas may have been capable of supporting epileptogenesis. More complete structural study preoperatively of patients with suspected dysgenesis might identify remote areas of structural abnormality associated with the functional abnormalities, modifying therapeutic decisions.

That extensive areas of cortex, even that which looks normal and is noncontiguous with the area presumed responsible for the epilepsy, may support epileptogenesis is also compatible with the findings and ideas of Gloor (1990) and Fish et al. (1993). In the latter study, similar clinical responses - including epileptic auras - could be elicited in some patients undergoing depth electrode studies by stimulation of more than one noncontiguous anatomical site; this supported the hypothesis that at least some features of seizures, including the persistence of auras in patients rendered otherwise seizure-free by resective surgery, could be explained by "the activation of a widespread matrix of excitation in a widely distributed population of neurons not

necessarily located in contiguous areas..". Whether similar phenomena might operate in patients with epilepsy due to cerebral dysgenesis is not clear, but in some such patients, the findings presented here show that there are certainly anatomical abnormalities beyond the lesion: these may maintain unchanged seizure semiology by Gloor's hypothesis. However, the complexity of changes in functional circuitry associated with CD cannot be underestimated (Calabrese et al.,1994), and it would be simplistic to suggest that "distributed matrices" were the direct functional correlate of the extralesional abnormalities shown here.

Nevertheless, it is important to realise that the existence of abnormalities of connectivity have been shown in this thesis, albeit by surrogate measures (the use of histological methods over similar cerebral extents would be prohibitively tedious; Huttenlocher, 1974) . The "distributed matrices" discussed above need not in themselves be qualitatively abnormal (eg polymicrogyria etc), but are connected, however obscurely, to pathogenic areas. Abnormalities of neuronal connections may be more important for abnormal function than are abnormalities of neuronal position (as seen in conditions generally accepted to be 'dysgenetic', eg pachygyria etc). Abnormalities of neuronal position are not necessarily associated with epilepsy, either in humans (eg Kuzniecky et al.,1994; Huttenlocher et al.,1994) or in animals, such as the mutant 'reeler' mouse, in which there is complete laminar inversion in the neocortex but normal connectivity as far as has been examined (Simmons et al.,1982; Caviness et al.,1984) and no epilepsy. The importance of neuronal connectivity, rather than neuronal positioning, for human epileptogenesis has been examined (Sisodiya, 1995) and is supported by the findings in this thesis that there may be extensive connectional abnormalities in visually apparently normal hemispheres.