## Abstract

Malformations of cortical development (MCD) are responsible for many cases of refractory epilepsy in adults and children. The results of surgical treatment are difficult to assess from the published literature. Judging from the limited number of adequately reported cases, approximately 40% of all cases of MCD treated surgically may be rendered seizure-free over a minimum 2-year follow-up period. This figure is the same for focal cortical dysplasia (FCD), the most common variety of MCD in surgical reports. In comparison with outcome for epilepsy associated with hippocampal sclerosis, this figure is low. Part of the difference may be artificial and related to limited reporting. Much of the difference is likely to relate to the complex underlying biology of MCD. Analysis of epileptogenesis in MCD has been undertaken. Different types of MCD have different sequelae. Some varieties are intrinsically epileptogenic; these include FCD and heterotopia. Although in most cases, the visualized MCD lies within the region of brain responsible for generating seizures (the epileptogenic zone), it may not constitute the entire epileptogenic zone in all cases. For polymicrogyria and schizencephaly in particular, the visualized abnormalities are probably not the most important component of the epileptogenic zone. There is evidence that the epileptogenic zone is spatially distributed and also, in some cases, temporally distributed. These findings may explain poor surgical outcome and the inadequacy of current presurgical evaluative methods. New preoperative techniques offer the opportunity of improved presurgical planning and selection of cases more likely to be rendered seizure-free by current surgical techniques. Of paramount importance is improved reporting. The establishment of a central registry may facilitate this aim. Specific recommendations are made for surgical strategies based on current experience and understanding.

## Introduction

Malformation of cortical development (MCD) describes a variety of structural abnormalities of the brain arising during gestation. In this review, the following entities will be considered: focal cortical dysplasia (FCD), characterized by dyslamination, abnormal cortical components and blurring of the grey–white interface; heterotopia, the presence of ectopic neurons in nodular or laminar aggregations, either in periventricular nodular or subcortical distribution; polymicrogyria (PMG) of unlayered and layered varieties, consisting of multiple small gyri, occasionally with fusion of the overlying molecular layers; schizencephaly (SZ), marked by a cleft with open or fused lips, passing through the entire thickness of the cortical mantle; lissencephaly (LIS), the absence of gyri, associated with gross cortical disorganization or the loss of specific neuronal laminae; and hemimegalencephaly (HM), in which varying combinations of the preceding pathologies are present enlarging an entire hemisphere. Detailed clinical, imaging and pathological aspects of these varied malformations are considered in a number of excellent monographs (e.g. Norman et al., 1995; Guerrini et al., 1996).

The application of MRI to epilepsy has revealed a higher prevalence of MCD than previously recognized. In patients with refractory epilepsy, MCD may be seen in 8–12% of cases (Li et al., 1995; Semah et al., 1998) and in up to 14% of children with refractory epilepsy and retardation (Brodtkorb et al., 1992; Steffenburg et al., 1998). In a prospective incident study using high-resolution MRI in patients having their first seizure, 3% of cases with partial onset were found to have MCD (Everitt et al., 1998). Even with high-resolution MRI, MCD may remain undetected preoperatively and only be found at histology after surgery (Spreafico et al., 1998a; Ying et al., 1998), so that a proportion of the 25% of cases with refractory epilepsy and normal MRI (Li et al., 1995) may also harbour MCD. Therefore, current prevalence figures are probably underestimates. The management of epilepsy due to MCD thus presents a significant clinical issue. Most cases are refractory to medical treatment (Raymond et al., 1995a; Semah et al., 1998).

Surgical treatment of refractory partial epilepsy is gaining ground (Engel, 1996). For cases due to tumours or hippocampal sclerosis (HS), extensive surgical series confirm an excellent seizure outcome in a high proportion, typically 70–80%, of patients (Berkovic et al., 1995; Spencer, 1995; Engel, 1996; Eliashiv et al., 1997). This chance of becoming seizure-free is higher than that offered by modern antiepileptic drugs (Marson et al., 1996) and may generate benefits in quality of life beyond simply an improvement in seizure frequency (Vickrey et al., 1995; Sperling et al., 1996; Gilliam et al., 1997).

Surgical treatment is thus often considered for patients with refractory epilepsy due to MCD. The purpose of this review is to explore the surgical option in patients with MCD. The questions to be addressed are: does surgery have anything to offer? If so, then to which patients should it be offered? How should it be best directed? If it is less than perfect as a treatment, why is this? Can its efficacy be improved? The field is complex and incompletely understood, but some recent advances offer new insights into MCD biology and allow a more reasoned understanding of the role of surgery in the treatment of epilepsy associated with MCD.

## Surgery in epilepsy: literature issues

Epilepsy surgery is most commonly considered for the syndrome of mesial temporal lobe epilepsy (MTLE) due to HS (Engel, 1996). MTLE is a distinct syndrome with a known underlying substrate in the mesial temporal structures, even though debate about the precise pathology, mechanisms and aetiology continues (e.g. Shinnar et al., 1998). The homogeneity and definition of the key elements of MTLE facilitate its study. Comprehensive documentation has identified clinically useful prognostic indicators, guiding clinical decision-making and patient information (Engel, 1996).

In comparison with this gold standard, surgical data on MCD are much less complete. The dearth of information partly reflects incomplete understanding of MCD biology. Cases are individual in their seizure characteristics and their anatomy and pathology (Jay et al., 1993). Adequate surgical series of pure cultures' of MCD are not as large as those for MTLE and HS. Differing philosophies in different centres, for example, with respect to the meaning attached to epileptic discharges distant from the structural lesion, hinder the establishment of common ground. Meaningful prediction based on syndromic classification is difficult.

Non-biological issues complicate assessment of surgical outcome. The single most important variable is duration of follow-up. Although the most widely used outcome scale does not specify a minimum follow-up duration, quoted global outcome statistics employ a 2-year follow-up period (Engel et al., 1993). For refractory epilepsy due to HS, 96% of seizure recurrences after surgery occur within the first 2 years of follow-up (Sperling et al., 1996). Engel and colleagues have shown that irrespective of pathology, late recurrences may also develop (Engel et al., 1987). Paillas and colleagues documented recurrence in a still higher proportion of patients over a longer follow-up (Paillas et al., 1983). Bruton (Bruton, 1988), Gilliam and colleagues (Gilliam et al., 1997), and Döring and colleagues (Döring et al., 1999) report late recurrence for MCD specifically. The basis of recurrence may or may not differ for HS and MCD, but it does not seem unreasonable to set a minimum duration of follow-up when reporting outcome. While a period of 1 year might be considered adequate, the most rigorous current epilepsy surgery series favour a minimum of 2 years (Engel et al., 1993; Berkovic et al., 1995; Li et al., 1997). Unfortunately, for some large series of surgically treated MCD patients, no follow-up at all is given.

There are other significant issues concerning reporting. The absence of individual patient data is troublesome. Mean follow-up periods may be given without specific periods for individual patients. Follow-up scales may not be universally adopted or may be local modifications of Engel's scheme. Pathological diagnoses may not be clear or may be outmoded. Patients may be included inextricably in more than one series. For series with longer follow-up, certain data (e.g. MRI) may inevitably be unavailable. In many reports details are simply insufficient to allow meaningful interpretation. Reporting is improving, however, and there are sufficient data in the literature to allow discussion.

## Current outcome data for MCD surgery

The results of a survey of the English language literature detailing individual outcome from surgery for MCD with a minimum period of follow-up are given in Table 1. Studies provided only in abstract form have been excluded. Not all single case reports can be claimed to have been included, but it is hoped that most, if not all, series have been included. The outcome measure chosen is stringent: seizure-freedom (class I) according to the Engel scale. This criterion has been adopted to permit comparison with outcome figures for HS and because, at least following temporal resection in adults, decreased mortality and increased employment are associated with seizure-free outcome, but not with seizure reduction (Sperling et al., 1995, 1999). In children, a reduction in seizures may allow developmental progress (Duchowny et al., 1996). In the treatment of epilepsy, the ideal outcome must still be seizure-freedom (Walker and Sander, 1996). Quality of life measures have not been taken into account because so few series report outcome for this measure.

The most striking outcomes of this survey are (i) the small number of cases and (ii) the poor outcome in comparison with surgery for HS. Over 5000 cases of surgery for MTLE had been reported by 1990 alone (Engel et al., 1993); of these, about 70% of cases were free of seizures postoperatively for at least the last 2 years to follow-up. The paucity of MCD cases cannot be attributed only to the survey's stringent inclusion criteria. Older series could not benefit from MRI, so fewer cases may have been considered for surgery than might be the case now. The provision of adequate follow-up data in larger series might have altered the seizure-free percentage in this survey. Recent large series (e.g. Edwards et al., 1998) suggest that 50–60% seizure-free outcome may be the best obtained. As the proportion of studies using high-resolution MRI increases, it may be that the proportion of patients becoming seizure-free rises. There is a danger, however, that continuing incomplete reporting will perpetuate a potentially misleading view of outcome from surgery for MCD. Currently, compared with outcome for other apparently focal pathologies treated surgically for epilepsy, outcome is clearly less good.

Outcome is no better, purely in terms of seizure-freedom, for surgery performed in childhood (ages 1–16 years) as opposed to adulthood (over 16 years), within the limitations to analysis imposed by the reported data (Table 2). This does not take into account quality of life measures or the benefit that even temporary cessation of seizures may have during development. Outcome may seem excellent for surgery in infancy (Table 2), but refractory epilepsy occurring at this age is quite different from that occurring later. Comparison with later surgery figures would not be appropriate.

With respect to location of surgery (Table 3), again within the limitations of the data, there is probably little difference between temporal and extratemporal surgery in the literature overall. Recent detailed individual studies support this view (Edwards et al., 1998). Hemispherectomy can only rarely be performed in view of the neurological deficits inevitably incurred. The outcome is therefore not comparable with surgery for MCD as a whole.

## Evaluation of the epileptogenic zone: current methods

Historically, the epileptogenic zone was defined on functional grounds, using information from clinical findings (aura and ictal semiology; fixed, ictal or postictal neurological deficits) and EEG (most commonly scalp, possibly supplemented by acute or chronic intracranial studies). Additional functional methods may now be employed (PET, SPECT, functional MRI). However, numerous studies have shown that failure to resect an imaged underlying structural abnormality, or the absence of such an abnormality, is likely to lead to a poor outcome whatever is noted in other tests (e.g. Awad et al., 1991; Fish et al., 1991; Wyllie et al., 1994; Zentner et al., 1995; Ferrier et al., 1999). Thus, in current presurgical evaluations, much attention is paid to static neuroimaging findings (Engel et al., 1993; Wyllie et al., 1998; Scott et al., 1999), even though they cannot identify malfunction associated with an epileptogenic zone. Experience has led to an implicit construct identifying structural abnormalities, especially HS and MCD, with the epileptogenic zone.

The equation of the epileptogenic zone with underlying structural abnormalities parallels the general belief that completeness of resection of overt MCD, however identified, is the key to successful surgical outcome (Awad et al., 1991; Palmini et al., 1991, 1994, 1995; Wyllie et al., 1994, 1996a, 1998). However, few published data actually substantiate this claim. Most authors do not comment on how completeness of resection was actually judged. Others determine extent of resection by visual inspection at surgery. However, MCD, particularly FCD, may not cause any obvious alteration to normal cortical features (Palmini et al., 1995; Ying et al., 1998). EEG-based methods and neuroimaging offer the prospect of more rigorous determination of the completeness of resection of the epileptogenic zone or the malformation.

### The role of EEG

Scalp EEG findings in patients with MCD are diverse (Raymond and Fish, 1996), often showing widespread or multifocal interictal spiking, and tend to poorly localize ictal onset. Raymond and colleagues reported focal or lateralized interictal epileptiform discharges on scalp EEG in only 51 of 100 patients with localized MCD (Raymond et al., 1995a). Epileptiform discharges were often more widespread and sometimes only evident at sites distant from that anticipated by clinical features or imaging. Palmini and colleagues reported preoperative scalp EEGs in 30 patients with focal MCD (Palmini et al., 1991). Only one-third had EEG findings suggesting abnormalities confined to one lobe. Half the patients had multilobar interictal spiking, three patients had bitemporal and two generalized interictal abnormalities. Of 12 patients with apparently localized MCD reported by Hirabayashi and colleagues, only four showed localized interictal spiking (Hirabayashi et al., 1993). Kuzniecky and colleagues reported predominantly unilateral spiking in eight of 10 patients with temporal lobe MCD (Kuzniecky et al., 1991). However, in patients with frontal lobe MCD, only two of 11 showed focal spiking. These scalp EEG studies therefore demonstrate a high incidence of widespread interictal spiking in patients with focal MCD. There is, however, a subgroup of patients who demonstrate recurrent, reasonably well-localized, or at least lateralized, continuous or near-continuous runs of interictal spikes (Guerrini et al., 1992; Ambrosetto, 1993; Raymond et al., 1995b). These scalp EEG changes presumably reflect highly epileptogenic underlying cortex, but do not exclude more widespread abnormalities.

The disconcerting non-congruence of EEG abnormalities and structural changes may be due to the limitations of scalp EEG or the complex anatomical distribution of MCD, with modulation of epileptiform discharges before recording on the surface. Focal ictal or interictal scalp EEG changes have rarely been used as the sole guide to the identification of the epileptogenic zone in MCD. Most authors have concluded that scalp EEG studies do not correlate significantly with outcome (Hirabayashi et al., 1991; Palmini et al., 1991; Li et al., 1997; Döring et al., 1999), particularly with regard to ictal scalp EEG in MCD in infants (Wyllie et al., 1996a). As some patients have become seizure-free despite extensive scalp EEG changes, such findings should not preclude further presurgical evaluation. Thus, some authors have stopped altogether attempting to relate outcome to scalp EEG results (Edwards et al., 1998).

The role of intracranial recordings remains uncertain. The demonstration that some MCD have intrinsic epileptogenicity (Mattia et al., 1995; Palmini et al., 1995; Kothare et al., 1998; see below) suggests that detailed neurophysiological investigations should be helpful. Although many authors suggest that chronic subdural findings do not correlate with outcome (e.g. Hirabayashi et al., 1991; Wyllie et al., 1996a, 1998), there are insufficient published data to determine the place of chronic subdural recordings in management. Electrocorticography (ECoG) is widely used to guide resections intraoperatively (Desbiens et al., 1993; Kuzniecky et al., 1993, 1997; Wyllie et al., 1996a, 1998; Shaver et al., 1997; Chan et al., 1998; Keene et al., 1998). Most centres employ ECoG in locations identified by preoperative clinical and MRI findings (Bastos et al., 1999), precluding evaluation of ECoG alone. Palmini and colleagues recorded ictal/continuous epileptogenic discharges (I/CEDs)' from the surface of MCD cortex, and in some cases from surrounding cortex that appeared normal on inspection but was subsequently proven histologically to harbour MCD (Palmini et al., 1995). Completeness of resection of the cortex evincing I/CEDs, as demonstrated by disappearance of the I/CEDs on postoperative ECoG, was correlated with a significantly better outcome. However, nine of 12 patients showing disappearance of such ECoG abnormalities did not have an excellent' (Engel class I) outcome, and the disappearance of interictal spiking on ECoG did not predict a seizure-free outcome. The value of I/CEDs in defining the epileptogenic zone thus remains unclear. In fascinating reports, ECoG studies in some patients with SZ actually guided resections away from the visualized MCD to electrically more active regions, with, in all cases, more than 80% reduction in seizure frequency for at least a year of follow-up (Leblanc et al., 1991; Landy et al., 1992).

Chronic intracranial recordings may show independent epileptiform activity in MCD and other regions, spreading activity from other epileptogenic tissue (e.g. coexistent HS) and changes emanating from normal-appearing regions (e.g. Francione et al., 1994; Dubeau et al., 1995; Munari et al., 1996; Kothare et al., 1998; Bautista et al., 1999). Bautista and colleagues raise the possibility that chronic interictal recordings might better predict outcome than other measures in extratemporal epilepsy, on the basis that even modern neuroimaging methods might not reveal all the pathology present, and that this might be better revealed using intracranial recording (Bautista et al., 1999). They acknowledge the weakness of such methods, however. Chronic intracranial recordings, ECoG and subdural EEG suffer from limited spatial sampling: they can only provide information from recorded regions, not from unsampled areas. Thus, in the report of Li and colleagues, intracranial electrode studies were in fact deceptive, leading to temporal resections, whereas presumed epileptogenic MCD heterotopia were rarely recorded from and were usually left unresected, leading to a failure to render any patients seizure-free in their series (Li et al., 1997). These findings suggest the presence, in some cases, of more than one epileptogenic focus. Thus, widespread ECoG abnormalities were associated in one report with a worse postoperative seizure outcome (Hirabayashi et al., 1991). The individual contribution of ECoG to evaluation is therefore difficult to assess. It is far from clear that ECoG alone can fully define the epileptogenic zone in MCD. The findings overall suggest that different pathologies may need to be considered separately. These issues will be discussed further below. The possible influence of anaesthesia on ECoG has not been discussed, but is a complex and potentially confounding issue.

### The role of MRI

MRI has revolutionized the detection of MCD and has obvious potential in identifying the true extent of MCD (Shorvon, 1997) and of its resection. However, it is difficult to judge the impact of modern MRI techniques on outcome, as few studies address this question specifically. Some studies state that completeness of resection was judged using postoperative imaging (Palmini et al., 1991; Montes et al., 1995). There are reports of complete excision according to MRI not being associated with a seizure-free outcome (e.g. Spreafico et al., 1998b), attributed variously to inaccuracy in method of quantitating lesion resection' (Palmini et al., 1991) or the presence of MRI-occult pathology (Palmini et al., 1995; Aykut-Bingol et al., 1998).

In a preliminary report of the most comprehensive series (from the Cleveland Clinic) (Edwards et al., 1998; E. Wyllie, personal communication), extent of completeness of resection was judged by comparison of pre- and postoperative MRI data. A seizure-free outcome was achieved in 58% with complete resection and in 27% of those with incomplete resection. This is the first large series using modern MRI methods to report on outcome with respect to completeness of resection in MCD. The benefit to patients of a favourable outcome including possibly rare, non-disabling seizures cannot be denied, and it is of great interest that some patients with multilobar involvement became seizure-free. However, long-term follow-up is essential. In particular, it would appear that there remain patients (42% in this report) with apparently complete resection as judged by MRI who failed to become seizure-free, and it is from this group that most stands to be learnt. Whereas the postoperative findings in this group will be of interest, it remains possible that even standard high-resolution MRI may fail to reveal the entire extent of MCD, so that perceived complete resection is, in fact, not necessarily complete resection of all the pathology present.

### PET and SPECT

There is little doubt that PET can identify MCD (Duncan, 1997); this has been histologically verified in many instances (e.g. Chugani et al., 1993; Wyllie et al., 1996a). In paediatric practice, PET may have a clinical role, revealing abnormalities that are otherwise difficult to detect, and leading to successful surgical intervention in a number of cases (Chugani et al., 1993; Wyllie et al., 1996a). MRI was reported to be normal in many of these cases, though it is not clear to what extent this would still be the case if state-of-the-art high-resolution scanners were employed. It is possible that PET will continue to be useful in infants because of the pattern of myelination in the immature brain.

In adults, there has been very little work demonstrating the utility of PET in presurgical evaluation. Most patients studied by PET have not proceeded to surgery. In a recent large series (Ryvlin et al., 1998), both flumazenil and fluorodeoxyglucose (FDG) PET were normal in two patients with minute or subcortical MCD, and both showed multilobar involvement in a case with FCD who was seizure-free over a 2-year follow-up after a simple lesionectomy'. In two other unoperated patients with mesial occipital MCD, both flumazenil and FDG PET results were concordant with MRI and intracranial studies.

SPECT has been shown to aid in the localization of the seizure focus in presurgical evaluation for epilepsy surgery (e.g. Cross et al., 1997). Although patterns of cerebral blood flow have been well documented in MTLE (Newton et al., 1992), studies may not be so reliable in extratemporal epilepsy, particularly if the injection is not truly ictal (Newton et al., 1995). It may be more difficult to achieve ictal injections in extratemporal epilepsy because there may not be an aura of useful length and the seizures themselves may be shorter. It is imperative that such studies are performed with concomitant video-EEG monitoring, as any delay in injection may mean the results show seizure spread rather than seizure onset (O'Brien et al., 1998).

Few patients with MCD have been studied. Series to date concentrate more on localization of seizure onset than on underlying pathology. However, where data are available, seizures arising from MCD usually demonstrate an area of hyperperfusion concordant with the lesion following an ictal injection (Aihara et al., 1997; Kuzniecky et al., 1997). In a series of 55 SPECT scans from 51 children undergoing evaluation for epilepsy surgery at the Great Ormond Street Hospital for Children (H. Cross, personal communication), of 11 with MCD confirmed histologically (nine demonstrated on MRI, one focal atrophy and one normal MRI), all demonstrated EEG focus-concordant lobar or multilobar hyperperfusion on ictal/postictal SPECT compared with interictal SPECT. Interictal scans alone demonstrated hypoperfusion in a smaller number of cases, with a tendency for wider areas of abnormality to be seen compared with ictal scans. These findings suggest ictal SPECT may be a useful tool in the presurgical evaluation of children with MCD. It may be particularly useful if MRI is normal or inconclusive, ictal hyperperfusion and interictal hypoperfusion raising the possibility of MCD. In extratemporal epilepsy, SPECT may provide a guide to invasive monitoring. Data available from SPECT may be enhanced by the use of computerized subtraction and MRI-coregistration techniques (SISCOM; O'Brien et al., 1998). SPECT data must be examined in conjunction with data from other investigations, with an awareness of the spatial resolution of SPECT. SPECT is a complementary method, helping to define the epileptogenic zone rather than being of critical importance. In the series of O'Brien and colleagues, three patients with MCD are reported (O'Brien et al., 1998); in two, SISCOM results were concordant with MRI, but were discordant with correctly localizing scalp EEG and MRI in another. As with all new methods, it is not always clear what the results mean and whether they identify the epileptogenic zone or reflect epiphenomena.

### Summary of current investigational methods

No current technique defines the epileptogenic zone in MCD reliably enough to guarantee a successful surgical outcome, echoing Engel's general statement (Engel, 1996). Even with the best current guide, high-resolution structural imaging with intraoperative ECoG, it is evident that complete resection, though probably necessary for a good outcome, is not always sufficient for such an outcome. Consideration of some aspects of the biology of MCD may explain the inability of current methods to delineate the epileptogenic zone.

## The biology of MCD

A biological limitation to surgical resection has long been apparent. This is the overlap between MCD and normally functioning brain tissue. Total disruption of function normally ascribed to a given cortical region is often found (Brown et al., 1993; Calabrese et al., 1994). However, specific function normally ascribed to an affected region may persist in modified fashion. A patient with gross bilateral posterior MCD (Fig. 1) had normal visual fields and function, as far as could be determined. Raymond and colleagues recorded (distorted) somatosensory evoked potentials in five of 13 patients with MCD affecting the appropriate central regions (Raymond et al., 1997). Leblanc and colleagues demonstrated that electrocortical stimulation over a dysgenetic posterior temporal gyrus led to interference with speech (Leblanc et al., 1995). Duchowny and colleagues found overlapping language representation and MCD (Duchowny et al., 1996). The complexities of the mixture of normal and abnormal neurons within MCD (Preul et al., 1997), of neuronal connections, and of the timing of maldevelopment with respect to synaptogenesis and functional commitment, may explain why cortical function is not always reallocated to other regions. ECoG, with stimulation, is currently the best means of identifying eloquent cortex in vivo, and in cases where MCD abuts such cortex, ECoG may delimit the boundaries of resection. Clearly, this biological feature of some cases of MCD cannot be overcome by current surgical techniques. In addition, the structural substrate of the normal function (and indeed, the epileptogenesis) may be more locally dispersed than usual, confounding investigation dependent on changes in spatial density of information (e.g. functional MRI). When MCD is responsible for convulsive or focal motor status epilepticus, eloquent cortex may need to be sacrificed to stop seizures, even at the cost of a hemiplegia (Desbiens et al., 1993).

However, in many cases such biological limits do not apply, yet seizure-freedom is not obtained, even with complete resection of the epileptogenic zone. The question then arises: what evidence is there that MCD are intrinsically epileptogenic and contain the epileptogenic zone? While useful in assembling patients with developmental causes of refractory epilepsy, it must be remembered that a variety of conditions are included in the blanket term MCD'. Each type needs separate consideration.

## Varieties of MCD—correlation with clinical studies

There are many types of MCD. In some cases, the observed pathology does not fall neatly into one type and more than one category of MCD may coexist. For each category, the following aspects of biology may be addressed: animal models, intrinsic epileptogenicity, occult changes and dual pathology, and implications of genetic findings.

### FCD

In surgical series, FCD is undoubtedly the most common MCD. Current clinical opinion that as much of the lesion should be excised as possible is poorly supported for FCD. Most of the cases included in Table 1 do not comment on completeness of resection. There are cases which have become seizure-free despite histologically proven incomplete resection of visualized abnormality (Sisodiya et al., 2000), and cases not seizure-free despite completeness of resection according to the criteria used.

Experimental evidence favours intrinsic epileptogenicity in human FCD. Ferrer and colleagues (Ferrer et al., 1992), Spreafico and colleagues (Spreafico et al., 1998a) Ying and colleagues (Ying et al., 1998), and Mikuni and colleagues (Mikuni et al., 1999) have all demonstrated specific histopathological changes in human FCD compatible with increased excitability. Epileptiform EEG changes have been recorded from brain shown subsequently to contain FCD (e.g. Palmini et al., 1995), even when such FCD is not visible to the naked eye (Leblanc et al., 1995; Rosenow et al., 1998; Bautista et al., 1999), and resected human FCD maintained in vitro has been shown to generate the equivalent of epileptic activity (Mattia et al., 1995). In one case, intralesional EEG demonstrated epileptiform activity within FCD; in this interesting report, magnetic source imaging localized dipoles within the FCD in three of four cases (Morioka et al., 1999). In the other case, multiple dipoles were calculated, some of which lay outside the visualized abnormality. This patient did not become seizure-free after resection of the visualized abnormality, even with guidance by ECoG and depth electrode study.

Of all the MCD considered, the case for intrinsic epileptogenicity of MCD is best supported for FCD. Completeness of excision is thus likely to be important for seizure-freedom. However, not all FCD cases completely excised become seizure-free (Palmini et al., 1995). Overall, with no comment possible on the extent of resection, at best 38% of cases of FCD become seizure-free with surgery (see Table 1). Taylor and colleagues suggested that this may be because potentially epileptogenic FCD is distributed and may be non-contiguous: it may well be that other, if less ostentatious, areas of cortical dysplasia have been left behind. This possibility is supported by the fact that even within the limits of the resected lobes the abnormality was sometimes disseminated rather than confined to a single patch. The degree, therefore, to which the brain as a whole may be affected remains uncertain' (Taylor et al., 1971). Whether this is the explanation for surgical failure in all cases is unclear, but merits exploration. Postoperative study of cases that have not become seizure-free is therefore vital.

Animal models of FCD are imprecise representations of the human condition. In one of the best models, excitability changes compatible with intrinsic epileptogenesis have been demonstrated (Redecker et al., 1998). However, these workers were also able to demonstrate in some cases identical excitability changes in surrounding histologically normal cortex, suggesting that cortical dysplastic lesions induce long-term functional alterations in structurally normal brain regions'. If such regions are normal on imaging and inspection and not studied by ECoG, or are suppressed by more active regions, then poor outcome might be explained, even when the visible abnormality and regions harbouring abnormal ECoG activity are excised. The biology of FCD may thus overcome current means of determining the epileptogenic zone.

### Periventricular nodular heterotopia

There is direct evidence for periventricular nodular heterotopia (PNH) intrinsic epileptogenicity in humans undergoing invasive electrical recordings (Dubeau et al., 1995; Li et al., 1997; Kothare et al., 1998; Spreafico et al., 1998b). This is underpinned by structural evidence of an imbalance between excitation and inhibition within nodules and of their connectivity to extranodular structures (Jensen and Killackey, 1984; Colacitti et al., 1998; Hannan et al., 1999). However, nodules are rarely localized (Raymond et al., 1994a), so that complete excision is rarely feasible. In addition, occult structural abnormalities in the overlying cortex have been described both histologically and on imaging and these may be of epileptogenic significance (Spreafico et al., 1998a; Hannan et al., 1999). Males in particular may have widespread cortical changes (Sisodiya et al., 1999). PNH is also the commonest MCD associated with the overt presence of more than one class of epileptogenic substrate, or dual pathology' (Raymond et al., 1994b; Cendes et al., 1995). The recent discovery of an X-linked gene thought responsible for familial bilateral PNH (Fox et al., 1998) compounds these issues, as other neurons may also be affected by the same mutation, especially in males. On these grounds, apart from females with visually isolated, completely resectable PNH, the theoretical chances of rendering a patient with PNH seizure-free surgically must be small. This is supported by the literature, notwithstanding that PNH have only recently been easily diagnosed on neuroimaging. In the largest series, epileptogenic activity was recorded from coexistent HS using intracranial electrodes, leading to temporal lobectomy in nine patients (Li et al., 1997). This was uniformly unsuccessful, the best result being obtained when the majority of the PNH was also excised. This provides perhaps the clearest example of dual pathologies, both being capable of epileptogenesis, explaining persistent seizures. Though probably widely applicable, this principle is rarely so dramatically demonstrated. The limitation of intracerebral recordings is highlighted by these findings; de facto, coverage is limited and results may be deceptive or incomplete.

### Subcortical heterotopia

Subcortical heterotopias (SH) are less common MCD. SH may occur in many forms, and may be so extensive or bilateral, as to preclude surgery altogether. SH may be associated with both PNH and abnormalities of overlying cortex (Barkovich et al., 1994; Guerrini et al., 1996). A priori, this suggests focal resection is likely to be ineffective. There are few adequately reported cases in the literature. Intralesional recordings have demonstrated epileptogenic activity arising within SH (Francione et al., 1994), although acute recordings have not always found this (Preul et al., 1997). Histology suggests an imbalance between excitation and inhibition (Hannan et al., 1999). Obviously incomplete excision of SH is associated with a poor outcome (Dubeau et al., 1995; Preul et al., 1997), whereas complete excision, as guided by intracerebral EEG, may lead to seizure-freedom (Francione et al., 1994). Recently, an animal model of bilateral laminar SH, which in humans may also be of genetic aetiology (Gleeson et al., 1999; Pilz et al., 1999), has been generated and termed tish (telencephalic internal structural heterotopia) (Lee et al., 1997). Neurons within the band heterotopia are known to be connected (Schottler et al., 1998), and tish mice have spontaneous seizures. Electrical recordings have not been reported. Given the poverty of human literature, further study of such models may give more insight into the epileptogenic characteristics of such malformed brains and, in particular, offer the chance of widespread examination of both structural and functional aspects, and the testing of hypotheses regarding seizure generation and propagation in SH.

### PMG and SZ

There are few published cases of surgical treatment of epilepsy in polymicrogyric MCD. Brodtkorb and colleagues report on excision of a region of PMG (completeness or otherwise of excision not stated) (Brodtkorb et al., 1998). Over the 10-month follow-up period, seizures continued unchanged, as did a unique and unchanged scalp EEG picture, leading the authors to speculate whether the histologically abnormal, resected MCD was indeed the source of the seizures. In a hemispherectomized child, non-contiguous, distant occult MCD has also been demonstrated (M. V. Squier, personal communication), further confirming the phenomenon of widespread pathology in many MCD.

In an animal model of PMG, it is the surrounding apparently normal-appearing cortex, rather than the malformed cortex, that is epileptogenic, as shown by transection experiments (Jacobs et al., 1999). Analysis of more distant areas of the brain in these models was not reported. Thus, PMG seems to mark a brain that has suffered an insult and may help localize a visually occult epileptogenic region, but may not itself be epileptogenic. A poor outcome with resection of the MRI-visible abnormality should therefore not be entirely surprising.

SZ is among the rarest of MCD. It is characterized by a cleft extending through the thickness of the cortex, lined by PMG. Its aetiology may be genetic (Brunelli et al., 1996). There are currently no functional animal models of SZ, but by inference from PMG, SZ may not be intrinsically epileptogenic. Other areas of the brain may be histologically abnormal (Packard et al., 1997). It is intriguing that of the few cases reported in the literature, in most the cleft itself was not completely excised. In four cases, significantly improved seizure control was achieved by excision of adjacent epileptogenic tissue identified by ECoG or extraoperative intracranial studies (Leblanc et al., 1991; Landy et al., 1992); another case remained seizure-free for 5 years after extralesional temporal lobectomy (Silbergeld and Miller, 1994). In another case (Maehara et al., 1997), the lips of the cleft were excised under ECoG guidance and a seizure-free outcome achieved over the 1-year follow-up period.

Therefore, visible PMG and SZ may point to, rather than contain, the critical part of the epileptogenic zone. However, even with local exploration using ECoG, the entire extent of the MCD may not be revealed and other means are still required to identify this extent.

### LIS

There are few reports in the literature of focal surgery for LIS or pachygyria. LIS is usually too extensive an abnormality, associated with too severe a phenotype, to allow focal resection. No data are available from in vivo depth recordings from LIS and animal models have not been studied from this viewpoint (Majkowski, 1983). Given the recent discovery of genetic mutations underlying LIS (Reiner et al., 1993; Gleeson et al., 1999; Pilz et al., 1999), suggesting widespread neuronal involvement by the mutation, it would not be surprising if epileptogenicity, or at least widespread secondary connectional involvement, were widespread. Pathophysiological parallels with other MCD are therefore likely.

### HM

Debate continues about the nosology of HM. Histologically, the underlying MCD can usually be classified under one or more of the above categories. It is likely that the same strictures apply with respect to epileptogenesis. Abnormalities are more widespread. Hence, surgical treatment is usually by hemispherectomy. This is usually only contemplated in the presence of hemiparesis. Although the contralateral hemisphere usually appears normal, the presence of independent epileptiform changes over this hemisphere preoperatively is held by some to suggest the presence of additional pathology, manifest by a poorer outcome (Smith et al., 1991); others, however, do not find this (Carmant et al., 1995; Döring et al., 1999).

In at least one case of HM, MCD was found in an apparently normal contralateral hemisphere (Jahan et al., 1997). Most HM contain MCD for which this phenomenon has been reported. Further correlative studies are clearly required, as are means of detecting subtle MCD in the contralateral hemisphere.

### Microdysgenesis

That microdysgenesis (MD) is a pathological condition underlying some epilepsies has been popularized by Meencke (reviewed in Meencke and Veith, 1992). However, there is continuing uncertainty about its precise definition and significance (e.g. Lyon and Gastaut, 1985). Undoubtedly, abnormalities of cortical architecture that are more subtle than FCD do exist, manifest, for example, by an abnormal clustering of neurons, but difficulties in stereologically valid estimation of neuronal densities have hindered detection of MD. MD is usually reported in association with other pathologies, especially HS, making determination of its individual role difficult. This area is in need of clarification, particularly as MD may be the pathology underlying widespread or distributed additional pathology in other forms of MCD.

Thus, with the exception of PMG and SZ, most MCD are intrinsically epileptogenic, the MCD lying within the epileptogenic zone. For most MCD, however, pathology spreads beyond the visible MCD. In many cases, dysfunction may also be widespread: the epileptogenic zone is more extensive than the visualized MCD.

## Distributed epileptogenesis

Epileptogenesis is a complex and incompletely understood process. Despite decades of study, the basis of epileptogenesis, even in HS, remains unclear. Undoubtedly, the sclerosed hippocampus itself is involved in the disease process. Hippocampal resection is associated with cessation of seizures in some 70% of patients, but this does not imply that epileptogenesis and the epileptogenic zone are contained entirely within the diseased hippocampus. Indeed, the diversity of aurae, varieties of autonomic and psychomotor ictal manifestations, and possibly widespread neuropsychological deficits, all argue against a strictly localized disease process (e.g. Fish et al., 1993a; Dupont et al., 1998; Baxendale et al., 1999). Moreover, neuroimaging studies have shown a variety of subtle abnormalities in addition to atrophy of the hippocampus itself: additional extrahippocampal temporal, extratemporal, basal ganglia and ipsilateral hemispheric changes have all been reported (Sisodiya et al., 1997; DeCarli et al., 1998; Lee et al., 1998). The presence of these unsuspected additional changes may be associated with a poorer outcome after surgery (Sisodiya et al., 1997). These additional changes may be secondary or associated with the underlying primary disease process. There is, of course, the possibility that at least some component of HS itself may be developmental rather than acquired in origin (Fernandez et al., 1998; VanLandingham et al., 1998), and that the visualized hippocampal atrophy is just the most visible part of a more widespread abnormality (Baulac et al., 1998).

Therefore, at least in some patients with HS, dysfunction that includes epileptogenesis may be distributed. Gloor hypothesized that persistent experiential aurae after temporal lobectomy might be due to distributed matrices' capable of maintaining the substance of an aura even after resection of part of a network responsible for its generation (Gloor, 1990). From stimulation studies in patients undergoing preoperative intracranial recordings, Fish and colleagues confirmed that the same aura could be generated by stimulation in disparate sites (Fish et al., 1993a). That seizures might also be generated similarly was not discussed but remains possible. A network of neurons distributed non-contiguously in the brain might be involved in the generation of seizures. However, despite circumstantial evidence, there is little direct proof. Surprisingly little is written about postoperative findings in patients who fail to become seizure-free after surgery.

It is tempting to link surgical failure blamed on a distributed epileptogenic zone with widespread structural abnormalities. Mesial temporal resection might be sufficient to inactivate a distributed epileptogenic zone in most cases, but in others the amount of the distributed network resected may not be sufficient to inactivate a more distributed epileptogenic zone. Time, too, may be a variable. Resection may remove enough of the epileptogenic zone to render a patient seizure-free for a certain period, but given sufficient time, the remainder of a distributed epileptogenic zone may be able to reorganize itself causing recrudescence (Berkovic et al., 1995). The epileptogenic zone ought to be thought of as having both spatial and temporal dimensions.

In some cases of HS there is obvious spatially distributed pathology: dual pathology. In general it is known, when lesions are present, that their removal is fundamental to a successful outcome (e.g. Fish et al., 1991). For dual pathology cases, removal of one may not be sufficient to render that patient seizure-free (Cascino et al., 1993; Li et al., 1997, 1999); removal of both abnormalities, where possible, is a better option (Li et al., 1999). Raymond and colleagues identified localized areas of MCD in 15% of patients using MRI or histological evidence of HS (Raymond et al., 1994b). In 25% of patients with MRI-identified MCD, significant hippocampal asymmetry has been found (Cendes et al., 1995). Ho and colleagues, studying patients with temporal lobe MCD, demonstrated a very high proportion (87%) of patients with either unilateral or bilateral dual pathologies (Ho et al., 1998). The possibility of dual pathology necessitates hippocampal measurements in all patients with MCD being evaluated for epilepsy surgery.

In terms of generating seizures, the distinction between overt dual pathology' and occult widespread pathology is purely semantic. Distributed occult MCD in addition to overt MCD might thus account for poor seizure outcome. This returns to the issue of what actually constitutes the epileptogenic zone in MCD. The most parsimonious operative definition is that the epileptogenic zone in MCD is that region of excision which leads to freedom from seizures over a defined period of follow-up. The latter addition to the definition is important: some patients who are initially seizure-free may develop seizures without a second precipitating factor after some years. The dynamic and distributed properties of epileptogenesis in MCD may be reflected in some results of tests currently used to identify the epileptogenic zone, manifest as non-concordant or widespread abnormalities at one time (e.g. Raymond et al., 1995a; Sisodiya et al., 1995; Richardson et al., 1996, 1998; O'Brien et al., 1998; Ryvlin et al., 1998; Morioka et al., 1999) or changing abnormalities over time (e.g. Raymond et al., 1995b; Palmini et al., 1997; Döring et al., 1999; Sisodiya et al., 2000). The epileptogenic zone in MCD may also be a changing spatiotemporal entity, possibly with different behaviour for different MCD.

This possibility is illustrated by a case of MCD treated surgically for refractory epilepsy. MRI had shown an abnormality in the right parietal cortex. Maximal interictal and ictal activity on scalp EEG recordings was noted at P4. Subdural grid recordings showed widespread frequent spike discharges; recordings during habitual seizures showed unifocal early electrographic changes preceding clinical change in all cases. Resection was performed under corticographic guidance. The superior and inferior parietal lobules, angular gyrus, superior cuneus, and superior and middle occipital gyri were removed. Histology of the resected 4 × 1 cm specimen showed FCD. Postoperatively, seizures of identical semiology recurred after 6 days and continued over the 5 years of follow-up. On EEG, 6 days after resection, a definite reduction in the spike discharge was noted over the previously active focus. Some time over the course of the following year, a new very active focus had developed, with phase-reversal over the mid-central area (T4 and C4), a clear shift noted despite the limited spatial resolution of scalp EEG. Some months later the focus had shifted inferiorly, and 2 years after surgery a single discrete focus could no longer be discerned. Seizure semiology did not change significantly over this period (R. Kennett, personal communication).

The rapid recurrence of seizures, despite excision of cortex with abnormal ECoG activity, suggests that a distributed epileptogenic zone already existed in this patient, perhaps manifest by the multifocal preoperative subdural interictal recordings. Seizure semiology did not change, suggesting that these distributed areas were acting in concert. The most active area, coterminous with the MRI abnormality, seemed to have enslaved the network. Excision of the most active area released the rest of the network. Similar phenomena may underlie rapid cortical plasticity (e.g. Ziemann et al., 1998). The postulated networks may function in a hierarchical fashion, such that a dominant pacemaker' is able to entrain the rest of the network, as suggested by Awad and colleagues (Awad et al., 1991). The human cardiac conducting system is, of course, an excellent example of this behaviour. In summary, for many types of MCD, at any one time the complete epileptogenic zone may be more widespread than the visualized abnormality, even if the most active part of the epileptogenic zone (the `pacemaker') is for most of the time contained within the visualized abnormality. The structural basis of such systems may be the widespread histological change reported in some MCD (see above).

If the epileptogenic zone in MCD is a distributed spatiotemporal entity, how can its components be identified? How also can the proportion of the epileptogenic zone that needs to be removed to stop seizures be determined? To date, the presence of persistent epileptogenic MCD tissue has been assumed in cases of surgical failure (e.g. Taylor et al., 1971; Awad et al., 1991; Palmini et al., 1991; Aykut-Bingol et al., 1998; Mukahira et al., 1998). Widespread histological examination of the brain is rarely feasible, as resections are of necessity minimized. Subtle MCD may be seen only at a synaptic level and thus not detected by routine histological study (Huttenlocher, 1974). Only in a few cases has there been histological proof of extensive abnormalities and this is usually by chance (Jahan et al., 1997). Intracranial EEG study, another possible tool for the detection of occult pathology (Bautista et al., 1999), also cannot be applied to large areas of the brain. In most cases, it is not possible to show histologically that other MCD is present or that other epileptiform dysfunction is present. Other means of examining the brain are required.

There are many ways of examining the whole extent of the cortex preoperatively. Some methods may allow detection of a potentially distributed epileptogenic zone. The widespread nature of scalp EEG changes in a high proportion of patients with MCD has been discussed. Although a few papers suggest that widespread changes are associated with a poor outcome, a thorough analysis, for example, on all the cases in Table 1, is not currently possible, but would seem worthwhile. New tools for the determination of potential coherence of multifocal interictal and ictal changes are becoming available, both for the temporal (Martinerie et al., 1998) and spatial aspects of distribution (e.g. objective quantitative neuroimaging methods). Detailed analysis of single cases may show that such phenomena do exist and stimulate more extensive study. The spatial resolution of scalp EEG may be enhanced by the use of multi-channel systems. Ideally, EEG or functional imaging would be performed after reversible presurgical inactivation of the postulated focus alone. This cannot currently be achieved, but intracarotid amylobarbital tests offer the chance of studying with EEG other parts of postulated networks, without the influence of the dominant lesion and other brain regions supplied by either the middle or posterior cerebral arteries. Neuroimaging methods alone may demonstrate widespread changes and rarely these have been shown to be of biological relevance (e.g. Chugani et al., 1993). The recent development of in vivo imaging of interictal epileptiform activity may provide further information (Krakow et al., 1999), especially if data are continuously acquired and analysed, bearing the possibility of distributed malfunction in mind. Magnetic source imaging may provide another means of examining distributed hierarchical networks (Morioka et al., 1999), especially if preconceived models of focal onset are not used to study real data. Although many of these methods are not widely available, a period of comprehensive evaluation in a cohort of patients might establish which test is most discriminatory in specific types of MCD. Sugimoto and colleagues report that in some cases, reoperation for MCD may improve outcome (Sugimoto et al., 1999); it may be that additional investigative methods can be used on cases that have failed to become seizure-free with a view to more complete excision of epileptogenic pathology.

The operational significance of additional abnormalities shown by these tests could only be determined by correlation with prolonged outcome measures. Perhaps only a proportion of patients with MCD can ever be helped by surgery, if, for example, the distribution of changes is too widespread for current surgical methods to tackle. In this case, the purpose of further study must be to identify the third of patients who will actually benefit from surgery. If newer surgical methods are developed, such studies might also help to direct their application. The importance of prolonged follow-up is clear. A central registry of cases might fulfil this need, facilitating assiduous reporting that need not depend on either follow-up at a tertiary referral facility or limited reporting opportunities.

## Conclusion

Overall, some 41% of patients with MCD, especially FCD, may be rendered seizure-free over a 2-year follow-up period by resective surgery (Table 1). This figure incorporates a broad sweep of studies, old and new; some newer studies suggest that this figure may be more of the order of 50% (e.g. Duchowny et al., 1998; Edwards et al., 1998; Keene et al., 1998; Eriksson et al., 1999). A proportion of patients may also be helped significantly, even if they are not rendered seizure-free, although seizure-freedom must remain the gold standard. Therefore, surgery should be considered seriously in patients with refractory epilepsy due to MCD detected on MRI.

Undoubtedly, however, careful presurgical evaluation is essential. Not all MCD are the same. Attempts should be made to make a presurgical diagnosis, because this may have implications both for further investigation and prognostication. In some cases, the visualized lesion may simply be a marker of more extensive abnormality. In other cases, genetic studies may reveal an underlying diathesis, allowing both more careful classification and an indication of the likely extent of cerebral involvement. Developments in imaging technology may assist in diagnosis and in determination of the possible extent of underlying abnormality. All patients with MCD being considered for surgery should have preoperative EEG, MRI and PET studies (and if possible, SPECT, functional MRI and magnetoencephalography), with quantitative analysis. Extralesional regions should be studied in all cases. Intraoperatively, the exact role of ECoG in MCD surgery still needs to be defined. All cases should also be studied postoperatively, at least with EEG and MRI, so that excision may be quantified. Prolonged follow-up is of paramount importance.

Based on this review, the following guidelines might be posited. (i) For lesions that are thought to be FCD, limited subcortical and/or periventricular heterotopia without HS, excision of as much of the visualized lesion and as much ECoG-detected abnormality as possible should take place, within limits placed by encroaching eloquent cortex. (ii) For PMG and SZ, ECoG is especially important in guiding resection, as the visualized abnormality itself may not harbour the most active part of the epileptogenic zone. (iii) All patients with MCD being considered for surgery should have hippocampal mensuration. (iv) In the presence of overt dual pathology, such as HS, careful consideration needs to be given to the multiple contributions to the epileptogenic zone that are probably made by both pathologies; focal resection may include both pathologies. (v) The existence of additional, subtle, widespread components of the epileptogenic zone needs to be borne in mind; new methods for the detection of spatiotemporally distributed networks need to be developed and assessed.

Surgery may be a crude instrument and we must hope that better understanding of MCD will lead to the development of better treatments, but in the meantime, it may be the best means currently at our disposal to improve the quality of life for people with refractory epilepsy due to MCD. Its further study is essential for this purpose.

Table 1

Outcome of surgery for MCD: review of adequate literature published since 1971

Minimum duration of follow-up Numbers All MCD pathologies FCD only or main pathology FCD
Series only Series and single cases Series only Series and single cases
Seizure-free is Engel class I or equivalent (Engel et al., 1993). Series defined as reports with at least two patients. Series and reports included: Taylor et al., 1971; Lindsay et al., 1987; Bruton, 1988; Hopkins et al., 1991; Leblanc et al., 1991; Palmini et al., 1991, 1995; al Rodhan et al., 1992; Landy et al., 1992; Salanova et al., 1992, 1995; Verity et al., 1992; Chugani et al., 1993; Desbiens et al., 1993; Fish et al., 1993b; Hirabayashi et al., 1993; Kuzniecky et al., 1993, 1995, 1997; Rintahaka et al., 1993; Khanna et al., 1994; Silbergeld and Miller, 1994; Taha et al., 1994; Bass et al., 1995; Carmant et al., 1995; Dubeau et al., 1995; Laskowitz et al., 1995; Montes et al., 1995; Pedespan et al., 1995; Raymond et al., 1995a; Saint Martin et al., 1995; Guerrini et al., 1996; Olivier et al., 1996; Pinard et al., 1996; Wyllie et al., 1996a, b, 1998; Barkovich et al., 1997; Kilpatrick et al., 1997; Li et al., 1997, 1999; Maehara et al., 1997; Shaver et al., 1997; Chan et al., 1998; Jambaque et al., 1998; Keene et al., 1998; Mukahira et al., 1998; O'Brien et al., 1998; Ryvlin et al., 1998; Sandok and Cascino, 1998; So, 1998; Spreafico et al., 1998b; Swartz et al., 1998; Szabo et al., 1999; Bastos et al., 1999; Bautista et al., 1999; Caraballo et al., 1999; Eriksson et al., 1999; Gleissner et al., 1999; Li et al., 1999; Mathern et al., 1999; Morioka et al., 1999; Sugimoto et al., 1999; Thom et al., 1999; Whitney et al., 1999; Hashizume et al., 2000. Cases with dual pathology are included.
1 year All 353 373 204 218
Seizure-free (%) 152 (43%) 168 (45%)  77 (38%)  88 (40%)
2 years All 197 214  98 113
Seizure-free (%)  80 (41%)  92 (43%)  35 (36%)  44 (39%)
Minimum duration of follow-up Numbers All MCD pathologies FCD only or main pathology FCD
Series only Series and single cases Series only Series and single cases
Seizure-free is Engel class I or equivalent (Engel et al., 1993). Series defined as reports with at least two patients. Series and reports included: Taylor et al., 1971; Lindsay et al., 1987; Bruton, 1988; Hopkins et al., 1991; Leblanc et al., 1991; Palmini et al., 1991, 1995; al Rodhan et al., 1992; Landy et al., 1992; Salanova et al., 1992, 1995; Verity et al., 1992; Chugani et al., 1993; Desbiens et al., 1993; Fish et al., 1993b; Hirabayashi et al., 1993; Kuzniecky et al., 1993, 1995, 1997; Rintahaka et al., 1993; Khanna et al., 1994; Silbergeld and Miller, 1994; Taha et al., 1994; Bass et al., 1995; Carmant et al., 1995; Dubeau et al., 1995; Laskowitz et al., 1995; Montes et al., 1995; Pedespan et al., 1995; Raymond et al., 1995a; Saint Martin et al., 1995; Guerrini et al., 1996; Olivier et al., 1996; Pinard et al., 1996; Wyllie et al., 1996a, b, 1998; Barkovich et al., 1997; Kilpatrick et al., 1997; Li et al., 1997, 1999; Maehara et al., 1997; Shaver et al., 1997; Chan et al., 1998; Jambaque et al., 1998; Keene et al., 1998; Mukahira et al., 1998; O'Brien et al., 1998; Ryvlin et al., 1998; Sandok and Cascino, 1998; So, 1998; Spreafico et al., 1998b; Swartz et al., 1998; Szabo et al., 1999; Bastos et al., 1999; Bautista et al., 1999; Caraballo et al., 1999; Eriksson et al., 1999; Gleissner et al., 1999; Li et al., 1999; Mathern et al., 1999; Morioka et al., 1999; Sugimoto et al., 1999; Thom et al., 1999; Whitney et al., 1999; Hashizume et al., 2000. Cases with dual pathology are included.
1 year All 353 373 204 218
Seizure-free (%) 152 (43%) 168 (45%)  77 (38%)  88 (40%)
2 years All 197 214  98 113
Seizure-free (%)  80 (41%)  92 (43%)  35 (36%)  44 (39%)
Table 2

Outcome by age at surgery: adequately documented cases only (series and single reports)

Minimum duration of follow-up Numbers Age (years)
<1 1–16 >16
Results are given for all MCD pathologies; seizure-free is Engel class I only.
1 year All 25 122 120
Seizure-free (%) 14 (56)  56 (45)  36 (30)
2 year All 14  49  56
Seizure-free (%)  8 (57)  20 (40)  20 (36)
Minimum duration of follow-up Numbers Age (years)
<1 1–16 >16
Results are given for all MCD pathologies; seizure-free is Engel class I only.
1 year All 25 122 120
Seizure-free (%) 14 (56)  56 (45)  36 (30)
2 year All 14  49  56
Seizure-free (%)  8 (57)  20 (40)  20 (36)
Table 3

Outcome by location of surgery: adequately documented cases only (series and single reports)

Minimum duration of follow-up Numbers All MCD pathologies FCD only or main pathology FCD
Temporal* Extratemporal Hemispherectomy Temporal* Extratemporal Hemispherectomy
Seizure-free is Engel class I only. *Some component of surgery involved temporal lobe (exact extent may be undefined); included in this category are patients who had partial resections initially but went on to have hemispherectomy.
1 year All 124 152 60 78 127 13
Seizure-free (%)  40 (32)  53 (35) 35 (58) 33 (42)  43 (34)  5 (38)
2 years All  59  67 43 40  42
Seizure-free (%)  19 (32)  23 (34) 25 (58) 14 (35)  16 (38)  2 (25)
Minimum duration of follow-up Numbers All MCD pathologies FCD only or main pathology FCD
Temporal* Extratemporal Hemispherectomy Temporal* Extratemporal Hemispherectomy
Seizure-free is Engel class I only. *Some component of surgery involved temporal lobe (exact extent may be undefined); included in this category are patients who had partial resections initially but went on to have hemispherectomy.
1 year All 124 152 60 78 127 13
Seizure-free (%)  40 (32)  53 (35) 35 (58) 33 (42)  43 (34)  5 (38)
2 years All  59  67 43 40  42
Seizure-free (%)  19 (32)  23 (34) 25 (58) 14 (35)  16 (38)  2 (25)
Fig. 1

Vertical view (occipital pole at top of picture) of surface rendering of high-resolution MRI scan of patient with gross bilateral posterior macrogyria. The underlying diagnosis is probably pachygyria based on detailed analysis of the unreconstructed images.

Fig. 1

Vertical view (occipital pole at top of picture) of surface rendering of high-resolution MRI scan of patient with gross bilateral posterior macrogyria. The underlying diagnosis is probably pachygyria based on detailed analysis of the unreconstructed images.

I wish to thank Professors D. R. Fish, E. Wyllie, S. D. Shorvon and J. S. Duncan, and Drs H. Cross, S. L. Free, R. Kennett and J. M. Oxbury for their comments and help. This work was supported by the National Society for Epilepsy.

## References

Aihara M, Hatakeyama K, Koizumi K, Nakazawa S. Ictal EEG and single photon emission computed tomography in a patient with cortical dysplasia presenting with atonic seizures.
Epilepsia

1997
;
38
:
723
–7.
al Rodhan NR, Kelly PJ, Cascino GD, Sharbrough FW. Surgical outcome in computer-assisted stereotactic resection of intra-axial cerebral lesions for partial epilepsy.
Stereotact Funct Neurosurg

1992
;
58
:
172
–7.
Ambrosetto G. Treatable partial epilepsy and unilateral opercular neuronal migration disorder.
Epilepsia

1993
;
34
:
604
–8.
Awad IA, Rosenfeld J, Ahl J, Hahn JF, Luders H. Intractable epilepsy and structural lesions of the brain: mapping, resection strategies, and seizure outcome.
Epilepsia

1991
;
32
:
179
–86.
Aykut-Bingol C, Bronen RA, Kim JH, Spencer DD, Spencer SS. Surgical outcome in occipital lobe epilepsy: implications for pathophysiology.
Ann Neurol

1998
;
44
:
60
–9.
Barkovich AJ, Guerrini R, Battaglia G, Kalifa G, N'Guyen T, Parmeggiani A, et al. Band heterotopia: correlation of outcome with magnetic resonance imaging parameters.
Ann Neurol

1994
;
36
:
609
–17.
Barkovich AJ, Kuzniecky RI, Bollen AW, Grant PE. Focal transmantle dysplasia: a specific malformation of cortical development.
Neurology

1997
;
49
:
1148
–52.
Bass N, Wyllie E, Comair Y, Kotagal P, Ruggieri P, Holthausen N. Supplementary sensorimotor area seizures in children and adolescents.
J Pediatr

1995
;
126
:
537
–44.
Bastos AC, Comeau RM, Andermann F, Melanson D, Cendes F, Dubeau F, et al. Diagnosis of subtle focal dysplastic lesions: curvilinear reformatting from three-dimensional magnetic resonance imaging.
Ann Neurol

1999
;
46
:
88
–94.
Baulac M, De Grissac N, Hasboun D, Oppenheim C, Adam C, Arzimanoglou A, et al. Hippocampal developmental changes in patients with partial epilepsy: magnetic resonance imaging and clinical aspects.
Ann Neurol

1998
;
44
:
223
–33.
Bautista RE, Cobbs MA, Spencer DD, Spencer SS. Predication of surgical outcome by interictal epileptiform abnormalities during intracranial EEG monitoring in patients with extrahippocampal seizures.
Epilepsia

1999
;
40
:
880
–90.
Baxendale SA, Sisodiya SM, Thompson PJ, Free SL, Kitchen ND, Stevens JM, et al. Disproportion in the distribution of gray and white matter: neuropsychological correlates.
Neurology

1999
;
52
:
248
–52.
Berkovic SF, McIntosh AM, Kalnins RM, Jackson GD, Fabinyi GC, Brazenor GA, et al. Preoperative MRI predicts outcome of temporal lobectomy: an actuarial analysis.
Neurology

1995
;
45
:
1358
–63.
Brodtkorb E, Nilsen G, Smevik O, Rinck PA. Epilepsy and anomalies of neuronal migration: MRI and clinical aspects.
Acta Neurol Scand

1992
;
86
:
24
–32.
Brodtkorb E, Andersen K, Henriksen O, Myhr G, Skullerud K. Focal, continuous spikes suggest cortical developmental abnormalities. Clinical, MRI and neuropathological correlates.
Acta Neurol Scand

1998
;
98
:
377
–85.
Brown MC, Levin BE, Ramsay RE, Landy HJ. Comprehensive evaluation of left hemisphere type I schizencephaly.
Arch Neurol

1993
;
50
:
667
–9.
Brunelli S, Faiella A, Capra V, Nigro V, Simeone A, Cama A, et al. Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly.
Nat Genet

1996
;
12
:
94
–6.
Bruton CJ. The neuropathology of temporal lobe epilepsy. Oxford: Oxford University Press; 1988.
Calabrese P, Fink GR, Markowitsch HJ, Kessler J, Durwen HF, Liess J, et al. Left hemispheric neuronal heterotopia.
Neurology

1994
;
44
:
302
–5.
Caraballo R, Cersosimo R, Fejerman N. A particular type of epilepsy in children with congenital hemiparesis associated with unilateral polymicrogyria.
Epilepsia

1999
;
40
:
865
–71.
Carmant L, Kramer U, Riviello JJ, Helmers SL, Mikati MA, Madsen JR, et al. EEG prior to hemispherectomy: correlation with outcome and pathology.
Electroencephalogr Clin Neurophysiol

1995
;
94
:
265
–70.
Cascino GD, Jack CR Jr, Parisi JE, Sharbrough FW, Schreiber CP, Kelly PJ, et al. Operative strategy in patients with MRI-identified dual pathology and temporal lobe epilepsy.
Epilepsy Res

1993
;
14
:
175
–82.
Cendes F, Cook MJ, Watson C, Andermann F, Fish DR, Shorvon SD, et al. Frequency and characteristics of dual pathology in patients with lesional epilepsy.
Neurology

1995
;
45
:
2058
–64.
Chan S, Chin SS, Nordli DR, Goodman RR, DeLaPaz RL, Pedley TA. Prospective magnetic resonance imaging identification of focal cortical dysplasia, including the non-balloon cell subtype.
Ann Neurol

1998
;
44
:
749
–57.
Chugani HT, Shewmon DA, Shields WD, Sankar R, Comair Y, Vinters HV, et al. Surgery for intractable infantile spasms: neuroimaging perspectives.
Epilepsia

1993
;
34
:
764
–71.
Colacitti C, Sancini G, Franceschetti S, Cattabeni F, Avanzini G, Spreafico R, et al. Altered connections between neocortical and heterotopic areas in methylazoxymethanol-treated rat.
Epilepsy Res

1998
;
32
:
49
–62.
Cross JH, Boyd SG, Gordon I, Harper A, Neville BG. Ictal cerebral perfusion related to EEG in drug resistant focal epilepsy of childhood.
J Neurol Neurosurg Psychiatry

1997
;
62
:
377
–84.
DeCarli C, Hatta J, Fazilat S, Fazilat S, Gaillard WD, Theodore WH. Extratemporal atrophy in patients with complex partial seizures of left temporal origin.
Ann Neurol

1998
;
43
:
41
–5.
Desbiens R, Berkovic SF, Dubeau F, Andermann F, Laxer KD, Harvey S, et al. Life-threatening focal status epilepticus due to occult cortical dysplasia.
Arch Neurol

1993
;
50
:
695
–700.
Döring S, Cross H, Boyd S, Harkness W, Neville B. The significance of bilateral EEG abnormalities before and after hemispherectomy in children with unilateral major hemisphere lesions.
Epilepsy Res

1999
;
34
:
65
–73.
Dubeau F, Tampieri D, Lee N, Andermann E, Carpeneter S, LeBlanc R, et al. Periventricular and subcortical nodular heterotopia. A study of 33 patients.
Brain

1995
;
118
:
1273
–87.
Duchowny M, Jayakar P, Harvey AS, Resnick T, Alvarez L, Dean P, et al. Language cortex representation: effects of developmental versus acquired pathology.
Ann Neurol

1996
;
40
:
31
–8.
Duchowny M, Jayakar P, Resnick T, Harvey AS, Alvarez L, Dean P, et al. Epilepsy surgery in the first three years of life.
Epilepsia

1998
;
39
:
737
–43.
Duncan JS. Imaging and epilepsy. [Review].
Brain

1997
;
120
:
339
–77.
Dupont S, Semah F, Baulac M, Samson Y. The underlying pathophysiology of ictal dystonia in temporal lobe epilepsy: an FDG-PET study.
Neurology

1998
;
51
:
1289
–92.
Edwards JC, Wyllie E, Ruggieri PM, Dinner DS, Bingaman W, Kotagal P, et al. Seizure outcome after surgery for epilepsy due to cortical dysplasia [abstract].
Neurology

1998
;
50 (4 Suppl 4)
;
A65
.
Eliashiv SD, Dewar S, Wainwright I, Engel J Jr, Fried I. Long-term follow-up after temporal lobe resection for lesions associated with chronic seizures.
Neurology

1997
;
48
:
1383
–8.
Engel J Jr. Outcome with respect to epileptic seizures. In: Engel J Jr, editor. Surgical treatment of epilepsies. New York: Raven Press; 1987. p. 553–73.
Engel J Jr. Surgery for seizures. [Review].
N Engl J Med

1996
;
334
:
647
–52.
Engel J Jr, Van Ness PC, Rasmussen TB, Ojemann LM. Outcome with respect to epileptic seizures. In: Engel J Jr, editor. Surgical treatment of the epilepsies. 2nd ed. New York: Raven Press; 1993. p. 609–21.
Eriksson S, Malmgren K, Rydenhag B, Jönsson L, Uvebrant P, Nordborg C. Surgical treatment of epilepsy – clinical, radiological and histopathological findings in 139 children and adults.
Acta Neurol Scand

1999
;
99
:
8
–15.
Everitt AD, Birnie KD, Stevens JM, Sander JW, Duncan JS, Shorvon SD. The NSE MRI study: structural brain abnormalities in adult epilepsy patients and healthy controls [abstract].
Epilepsia

1998
;
39 Suppl 6
:
140
.
Fernandez G, Effenberger O, Vinz B, Steinlein O, Elger CE, Dohring W, et al. Hippocampal malformation as a cause of familial febrile convulsions and subsequent hippocampal sclerosis.
Neurology

1998
;
50
:
909
–17.
Ferrer I, Pineda M, Tallada M, Oliver B, Russi A, Oller L, et al. Abnormal local-circuit neurons in epilepsia partialis continua associated with focal cortical dysplasia.
Acta Neuropathol (Berl)

1992
;
83
:
647
–52.
Ferrier CH, Engelsman J, Alarcon G, Binnie CD, Polkey CE. Prognostic factors in presurgical assessment of frontal lobe epilepsy.
J Neurol Neurosurg Psychiatry

1999
;
66
:
350
–6.
Fish D, Andermann F, Olivier A. Complex partial seizures and small posterior temporal or extratemporal structural lesions: surgical management.
Neurology

1991
;
41
:
1781
–4.
Fish DR, Gloor P, Quesney FL, Olivier A. Clinical responses to electrical brain stimulation of the temporal and frontal lobes in patients with epilepsy. Pathophysiological implications.
Brain

1993
;
116
:
397
–414.
Fish DR, Smith SJ, Quesney LF, Andermann F, Rasmussen T. Surgical treatment of children with medically intractable frontal or temporal lobe epilepsy: results and highlights of 40 years' experience.
Epilepsia

1993
;
34
:
244
–7.
Fox JW, Lampenti ED, Eksioglu YZ, Hong SE, Feng Y, Graham DA et al. Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.
Neuron

1998
;
21
:
1315
–25.
Francione S, Kahane P, Tassi L, Hoffman D, Durisotti C, Pasquier B, et al. Stereo-EEG of interictal and ictal electrical activity of a histologically proved heterotopic gray matter associated with partial epilepsy.
Electroencephalogr Clin Neurophysiol

1994
;
90
:
284
–90.
Gilliam F, Wyllie E, Kashden J, Faught E, Kotagal P, Bebin M, et al. Epilepsy surgery outcome: comprehensive assessment in children.
Neurology

1997
;
48
:
1368
–74.
Gleeson JG, Minnerath SR, Fox JW, Allen KM, Luo RF, Hong SE, et al. Characterization of mutations in the gene doublecortin in patients with double cortex syndrome.
Ann Neurol

1999
;
45
:
146
–53.
Gleissner U, Johanson K, Helmstaedter C, Elger CE. Surgical outcome in a group of low-IQ patients with focal epilepsy.
Epilepsia

1999
;
40
:
553
–9.
Gloor P. Experiential phenomena of temporal lobe epilepsy. Facts and hypotheses. [Review].
Brain

1990
;
113
:
1673
–94.
Guerrini R, Dravet C, Raybaud C, Roger J, Bureau M, Battaglia A, et al. Epilepsy and focal gyral anomalies detected by MRI: electroclinico-morphological correlations and follow-up.
Dev Med Child Neurol

1992
;
34
:
706
–18.
Guerrini R, Dravet C, Bureau M, Mancini J, Canapicchi R, Livet MO, et al. Diffuse and localized dysplasias of the cerebral cortex: clinical presentation, outcome, and proposal for a morphologic MRI classification based on a study of 90 patients. In: Guerrini R, Andermann F, Canapicchi R, Roger J, Zifkin BG, Pfanner P, editors. Dysplasias of cerebral cortex and epilepsy. Philadelphia: Lippincott-Raven; 1996. p. 255–69.
Hannan AJ, Servotte S, Katsnelson A, Sisodiya SM, Blakemore C, Squier M, et al. Characterization of nodular neuronal heterotopia in children.
Brain

1999
;
122
:
219
–38.
Hashizume K, Kiriyama K, Kunimoto M, Maeda T, Tanaka T, Miyamoto A, et al. Correlation of EEG, neuroimaging and histopathology in an epilepsy patient with diffuse cortical dysplasia.
Childs Nerv Syst

2000
;
16
:
75
–9.
Hirabayashi S, Binnie CD, Janota I, Polkey CE. Surgical treatment of epilepsy due to cortical dysplasia: clinical and EEG findings.
J Neurol Neurosurg Psychiatry

1993
;
56
:
765
–70.
Ho SS, Kuzniecky RI, Gilliam F, Faught E, Morawetz R. Temporal lobe developmental malformations and epilepsy: dual pathology and bilateral hippocampal abnormalities.
Neurology

1998
;
50
:
748
–54.
Hopkins IJ, Klug GL. Temporal lobectomy for the treatment of intractable complex partial seizures of temporal lobe origin in early childhood.
Dev Med Child Neurol

1991
;
33
:
26
–31.
Huttenlocher PR. Dendritic development in neocortex of children with mental defect and infantile spasms.
Neurology

1974
;
24
:
203
–10.
Jacobs KM, Hwang BJ, Prince DA. Focal epileptogenesis in a rat model of polymicrogyria.
J Neurophysiol

1999
;
81
:
159
–73.
Jahan R, Mischel PS, Curran JG, Peacock WJ, Shields DW, Vinters HV. Bilateral neuropathologic changes in a child with hemimegalencephaly.
Pediatr Neurol

1997
;
17
:
344
–9.
Jambaque I, Mottron L, Ponsot G, Chiron C. Autism and visual agnosia in a child with right occipital lobectomy.
J Neurol Neurosurg Psychiatry

1998
;
65
:
555
–60.
Jay V, Becker LE, Otsubo H, Hwang PA, Hoffman HJ, Harwood-Nash D. Pathology of temporal lobectomy for refractory seizures in children.
J Neurosurg

1993
;
79
:
53
–61.
Jensen KF, Killackey HP. Subcortical projections from ectopic neocortical neurons.
Proc Natl Acad Sci USA

1984
;
81
:
964
–8.
Keene DL, Jimenez C-C, Ventureyra E. Cortical microdysplasia and surgical outcome in refractory epilepsy of childhood.
Pediatr Neurosurg

1998
;
29
:
69
–72.
Khanna S, Chugani HT, Messa C, Curran JG. Corpus callosum agenesis and epilepsy: PET findings.
Pediatr Neurol

1994
;
10
:
221
–7.
Kilpatrick C, Cook M, Kaye A, Murphy M, Matkovic Z. Non-invasive investigations successfully select patients for temporal lobe surgery.
J Neurol Neurosurg Psychiatry

1997
;
63
:
327
–33.
Kothare SV, VanLandingham K, Armon C, Luther JS, Friedman A, Radtke RA. Seizure onset from periventricular nodular heterotopias: depth-electrode study.
Neurology

1998
;
51
:
1723
–7.
Krakow K, Woermann FG, Symms MR, Allen PJ, Lemieux L, Barker GJ, et al. EEG-triggered functional MRI of interictal epileptiform activity in patients with partial seizures.
Brain

1999
;
122
:
1679
–88.
Kuzniecky R, Garcia JH, Faught E, Morawetz RB. Cortical dysplasia in temporal lobe epilepsy: magnetic resonance imaging correlations.
Ann Neurol

1991
;
29
:
293
–8.
Kuzniecky R, Mountz JM, Wheatley G, Morawetz R. Ictal single-photon emission computed tomography demonstrates localized epileptogenesis in cortical dysplasia.
Ann Neurol

1993
;
34
:
627
–31.
Kuzniecky R, Morawetz R, Faught E, Black L. Frontal and central lobe focal dysplasia: clinical, EEG and imaging features.
Dev Med Child Neurol

1995
;
37
:
159
–66.
Kuzniecky R, Gilliam F, Morawetz R, Faught E, Palmer C, Black L. Occipital lobe developmental malformations and epilepsy: clinical spectrum, treatment, and outcome.
Epilepsia

1997
;
38
:
175
–81.
Landy HJ, Ramsay RE, Ajmone-Marsan C, Levin BE, Brown J, Pasarin G, et al. Temporal lobectomy for seizures associated with unilateral schizencephaly.
Surg Neurol

1992
;
37
:
477
–81.
Laskowitz D, Sperling MR, French JA, O'Connor MJ. The syndrome of frontal lobe epilepsy: characteristics and surgical management.
Neurology

1995
;
45
:
780
–7.
Leblanc R, Tampieri D, Robitaille Y, Feindel W, Andermann F. Surgical treatment of intractable epilepsy associated with schizencephaly.
Neurosurgery

1991
;
29
:
421
–9.
Leblanc R, Robitaille Y, Andermann F, Ptito A. Retained language in dysgenic cortex: case report.
Neurosurgery

1995
;
37
:
992
–7.
Lee KS, Schottler J, Collins JL, Lanzino G, Couture D, Rao A, et al. A genetic animal model of human neocortical heterotopia associated with seizures.
J Neurosci

1997
;
17
:
6236
–42.
Lee JW, Andermann F, Dubeau F, Bernasconi A, MacDonald D, Evans A, et al. Morphometric analysis of the temporal lobe in temporal lobe epilepsy.
Epilepsia

1998
;
39
:
727
–36.
Li LM, Fish DR, Sisodiya SM, Shorvon SD, Alsanjari N, Stevens JM. High resolution magnetic resonance imaging in adults with partial or secondary generalised epilepsy attending a tertiary referral unit.
J Neurol Neurosurg Psychiatry

1995
;
59
:
384
–7.
Li LM, Dubeau F, Andermann F, Fish DR, Watson C, Cascino GD, et al. Periventricular nodular heterotopia and intractable temporal lobe epilepsy: poor outcome after temporal lobe resection.
Ann Neurol

1997
;
41
:
662
–8.
Li LM, Cendes F, Andermann F, Watson C, Fish DR, Cook MJ, et al. Surgical outcome in patients with epilepsy and dual pathology.
Brain

1999
;
122
:
799
–805.
Lindsay J, Ounsted C, Richards P. Hemispherectomy for childhood epilepsy: a 36-year study.
Dev Med Child Neurol

1987
;
29
:
592
–600.
Lyon G, Gastaut H. Considerations of the significance attributed to unusual cerebral histological findings recently described in eight patients with primary generalized epilepsy.
Epilepsia

1985
;
26
:
365
–7.
Maehara T, Shimizu H, Nakayama H, Oda M, Arai N. Surgical treatment of epilepsy from schizencephaly with fused lips.
Surg Neurol

1997
;
48
:
507
–10.
Majkowski J. Drug effects on afterdischarge and seizure threshold in lissencephalic ferrets: an epilepsy model for drug evaluation.
Epilepsia

1983
;
24
:
678
–85.
Marson AG, Kadir ZA, Chadwick DW. New antiepileptic drugs: a systematic review of their efficacy and tolerability.
BMJ

1996
;
313
:
1169
–74.
Martinerie J, Adam C, Le Van Quyen M, Baulac M, Clemenceau S, Renault B, et al. Epileptic seizures can be anticipated by non-linear analysis.
Nat Med

1998
;
4
:
1173
–6.
Mattia D, Olivier A, Avoli M. Seizure-like discharges recorded in human dysplastic neocortex maintained in vitro.
Neurology

1995
;
45
:
1391
–5.
Meencke H-J, Veith G. Migration disturbances in epilepsy. In: Engel J Jr, Wasterlain C, Cavalheiro EA, Heinemann U, Avanzini G, editors. Molecular neurobiology of epilepsy. Amsterdam: Elsevier; 1992. p. 31–40.
Mikuni N, Nishiyama K, Babb TL, Ying Z, Najm I, Okamoto T, et al. Decreased calmodulin-NR1 co-assembly as a mechanism for focal epilepsy in cortical dysplasia.
Neuroreport

1999
;
10
:
1609
–12.
Minassian BA, Otsubo H, Weiss S, Elliott I, Rutka JT, Snead OC 3rd. Magnetoencephalographic localization in pediatric epilepsy surgery: comparison with invasive intracranial electroencephalography.
Ann Neurol

1999
;
46
:
627
–33.
Montes JL, Rosenblatt B, Farmer JP, O'Gorman AM, Andermann F, Watters GV, et al. Lesionectomy of MRI detected lesions in children with epilepsy.
Pediatr Neurosurg

1995
;
22
:
167
–73.
Morioka T, Nishio S, Ishibashi H, Muraishi M, Hisada K, Shigeto H, et al. Intrinsic epileptogenicity of focal cortical dysplasia as revealed by magnetoencephalography and electrocorticography.
Epilepsy Res

1999
;
33
:
177
–87.
Mukahira K, Oguni H, Awaya Y, Tanaka T, Saito K, Shimizu H, et al. Study on surgical treatment of intractable childhood epilepsy.
Brain Dev

1998
;
20
:
154
–64.
Munari C, Francione S, Kahane P, Tassi L, Hoffmann D, Garrel S, et al. Usefulness of stereo EEG investigations in partial epilepsy associated with cortical dysplastic lesions and gray matter heterotopia. In: Guerrini R, Andermann F, Canapicchi R, Roger J, Zifkin BG, Pfanner P, editors. Dysplasias of cerebral cortex and epilepsy. Philadelphia: Lippincott-Raven; 1996. p. 383–94.
Newton MR, Berkovic SF, Austin MC, Reutens DC, McKay WJ, Bladin PF. Dystonia, clinical lateralization, and regional blood flow changes in temporal lobe seizures.
Neurology

1992
;
42
:
371
–7.
Newton MR, Berkovic SF, Austin MC, Rowe CC, McKay WJ, Bladin PF. SPECT in the localisation of extratemporal and temporal seizure foci.
J Neurol Neurosurg Psychiatry

1995
;
59
:
26
–30.
Norman MG, McGillivray BC, Kalousek DK, Hill A, Poskitt KJ. Congenital malformations of the brain. New York: Oxford University Press; 1995.
O'Brien TJ, So EL, Mullan BP, Hauser MF, Brinkmann BH, Bohen NI, et al. Subtraction ictal SPECT co-registered to MRI improves clinical usefulness of SPECT in localizing the surgical seizure focus.
Neurology

1998
;
50
:
445
–54.
Olivier A, Andermann F, Palmini A, Robitaille Y. Surgical treatment of the cortical dysplasias. In: Guerrini R, Andermann F, Canapicchi R, Roger J, Zifkin BG, Pfanner P, editors. Dysplasias of cerebral cortex and epilepsy. Philadelphia: Lippincott-Raven; 1996. p. 351–66.
Packard AM, Miller VS, Delgado MR. Schizencephaly: correlations of clinical and radiologic features.
Neurology

1997
;
48
:
1427
–34.
Paillas JE, Gastaut H, Sedan R, Bureau M. Long-term results of conventional surgical treatment for epilepsy. Delayed recurrence after a period of 10 years.
Surg Neurol

1983
;
20
:
189
–93.
Palmini A, Andermann F, Olivier A, Tampieri D, Robitaille Y, Andermann E, et al. Focal neuronal migration disorders and intractable partial epilepsy: a study of 30 patients. [Review].
Ann Neurol

1991
;
30
:
741
–9.
Palmini A, Gambardella A, Andermann F, Dubeau F, da Costa JC, Olivier A, et al. Operative strategies for patients with cortical dysplastic lesions and intractable epilepsy. [Review].
Epilepsia

1994
;
35 Suppl 6
:
S57
–71.
Palmini A, Gambardella A, Andermann F, Dubeau F, da Costa JC, Olivier A, et al. Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results.
Ann Neurol

1995
;
37
:
476
–87.
Pedespan JM, Loiseau H, Vital A, Marchal C, Fontan D, Rougier A. Surgical treatment of an early epileptic encephalopathy with suppression-bursts and focal cortical dysplasia.
Epilepsia

1995
;
36
:
37
–40.
Pilz DT, Kuc J, Matsumoto N, Bodurtha J, Bernadi B, Tassinari CA. Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1.
Hum Mol Genet

1999
;
8
:
1757
–60.
Pinard J-M, Delalande O, Dulac O. Hemispherotomy and callosotomy for cortical dysplasia in children. Technique and postoperative outcome. In: Guerrini R, Andermann F, Canapicchi R, Roger J, Zifkin BG, Pfanner P, editors. Dysplasias of cerebral cortex and epilepsy. Philadelphia: Lippincott-Raven; 1996. p. 375–81.
Preul MC, Leblanc R, Cendes F, Dubeau F, Reutens D, Spreafico R, et al. Function and organization in dysgenic cortex.
J Neurosurg

1997
;
87
:
113
–21.
Raymond AA, Fish DR. EEG features of focal malformations of cortical development.
J Clin Neurophysiol

1996
;
13
:
495
–506.
Raymond AA, Fish DR, Stevens JM, Sisodiya SM, Alsanjari N, Shorvon SD. Subependymal heterotopia: a distinct neuronal migration disorder associated with epilepsy. [Review].
J Neurol Neurosurg Psychiatry

1994
;
57
:
1195
–202.
Raymond AA, Fish DR, Stevens JM, Cook MJ, Sisodiya SM, Shorvon SD. Association of hippocampal sclerosis with cortical dysgenesis in patients with epilepsy.
Neurology

1994
;
44
:
1841
–5.
Raymond AA, Fish DR, Sisodiya SM, Alsanjari N, Stevens JM, Shorvon SD. Abnormalities of gyration, heterotopias, tuberous sclerosis, focal cortical dysplasia, microdysgenesis, dysembryoplastic neuroepithelial tumour and dysgenesis of the archicortex in epilepsy. Clinical, EEG and neuroimaging features in 100 adult patients. [Review].
Brain

1995
;
118
:
629
–60.
Raymond AA, Fish DR, Boyd SG, Smith SJ, Pitt MC, Kendall B. Cortical dysgenesis: serial EEG findings in children and adults.
Electroencephalogr Clin Neurophysiol

1995
;
94
:
389
–97.
Raymond AA, Jones SJ, Fish DR, Stewart J, Stevens JM. Somatosensory evoked potentials in adults with cortical dysgenesis and epilepsy.
Electroencephalogr Clin Neurophysiol

1997
;
104
:
132
–42.
Redecker C, Lutzenburg M, Gressens P, Evrard P, Witte OW, Hagemann G. Excitability changes and glucose metabolism in experimentally induced focal cortical dysplasias.
Cereb Cortex

1998
;
8
:
623
–34.
Reiner O, Carrozzo R, Shen Y, Wehnent M, Faustinella F, Dobyns WB, et al. Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats.
Nature

1993
;
364
:
717
–21.
Richardson MP, Koepp MJ, Brooks DJ, Fish DR, Duncan JS. Benzodiazepine receptors in focal epilepsy with cortical dysgenesis.
Ann Neurol

1996
;
40
:
188
–98.
Richardson MP, Koepp MJ, Brooks DJ, Coull JT, Grasby P, Fish DR, et al. Cerebral activation in malformations of cortical development.
Brain

1998
;
121
:
1295
–304.
Rintahaka PJ, Chugani HT, Messa C, Phelps ME. Hemimegalencephaly: evaluation with positron emission tomography.
Pediatr Neurol

1993
;
9
:
21
–8.
Rosenow F, Luders HO, Dinner DS, Prayson RA, Mascha E, Wolgamuth BR, et al. Histopathological correlates of epileptogenicity as expressed by electrocorticographic spiking and seizure frequency.
Epilepsia

1998
;
39
:
850
–6.
Ryvlin P, Bouvard S, Le Bars D, De Lamerie G, Gregoire MC, Kahane P, et al. Clinical utility of flumazenil-PET versus [18F]fluorodeoxyglucose-PET and MRI in refractory partial epilepsy.
Brain

1998
;
121
:
2067
–81.
Saint Martin C, Adamsbaum C, Robain O, Chiron C, Kalifa G. An unusual presentation of focal cortical dysplasia.
AJNR Am J Neuroradiol

1995
;
16 (4 Suppl)
:
840
–2.
Salanova V, Andermann F, Olivier A, Rasmussen T, Quesney LF. Occipital lobe epilepsy: electroclinical manifestations, electrocorticography, cortical stimulation and outcome in 42 patients treated between 1930 and 1991. Surgery of occipital lobe epilepsy.
Brain

1992
;
115
:
1655
–80.
Salanova V, Andermann F, Rasmussen T, Olivier A, Quesney LF. Parietal lobe epilepsy. [Review].
Brain

1995
;
118
:
607
–27.
Sandok EK, Cascino GD. Surgical treatment for perirolandic lesional epilepsy. [Review].
Epilepsia

1998
;
39 Suppl 4
:
S42
–8.
Schottler F, Couture D, Rao A, Kahn H, Lee KS. Subcortical connections of normotopic and heterotopic neurons in sensory and motor cortices of the tish mutant rat.
J Comp Neurol

1998
;
395
:
29
–42.
Scott C, Fish DR, Smith SJ, Free SL, Stevens JM, Thompson PJ, et al. Presurgical evaluation of patients with epilepsy and normal MRI: role of scalp video-EEG telemetry.
J Neurol Neurosurg Psychiatry

1999
;
66
:
69
–71.
Semah F, Picot MC, Adam C, Broglin D, Arzimanoglou A, Bazin B, et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence?
Neurology

1998
;
51
:
1256
–62.
Shaver EG, Harvey AS, Morrison G, Prats A, Jayakar P, Dean P, et al. Results and complications after reoperation for failed epilepsy surgery in children.
Pediatr Neurosurg

1997
;
27
:
194
–202.
Shinnar S. Prolonged febrile seizures and mesial temporal sclerosis [editorial].
Ann Neurol

1998
;
43
:
411
–2.
Shorvon S. MRI of cortical dysgenesis.
Epilepsia

1997
;
38 Suppl 10
:
13
–18.
Silbergeld DL, Miller JW. Resective surgery for medically intractable epilepsy associated with schizencephaly.
J Neurosurg

1994
;
80
:
820
–5.
Sisodiya SM, Free SL, Stevens JM, Fish DR, Shorvon SD. Widespread cerebral structural changes in patients with cortical dysgenesis and epilepsy.
Brain

1995
;
118
:
1039
–50.
Sisodiya SM, Moran N, Free SL, Kitchen ND, Stevens JM, Harkness WF, et al. Correlation of widespread preoperative magnetic resonance imaging changes with unsuccessful surgery for hippocampal sclerosis.
Ann Neurol

1997
;
41
:
490
–6.
Sisodiya SM, Free SL, Thom M, Everitt AD, Fish DR, Shorvon SD. Evidence for nodular epileptogenicity and gender differences in periventricular nodular heterotopia.
Neurology

1999
;
52
:
336
–41.
Sisodiya SM, Squier MV, Anslow P. Malformation of cortical development. In: Oxbury J, Polkey C, Duchowny M, editors. Intractable focal epilepsy: medical and surgical treatment. London: W.B. Saunders. In press 2000.
Smith SJ, Andermann F, Villemure J-G, Rasmussen TB, Quesney LP. Functional hemispherectomy: EEG findings, spiking from isolated brain postoperatively, and prediction of outcome.
Neurology

1991
;
41
:
1790
–4.
So NK. Mesial frontal epilepsy. [Review].
Epilepsia

1998
;
39 Suppl 4
:
S49
–61.
Spencer SS. MRI and epilepsy surgery [editorial].
Neurology

1995
;
45
:
1248
–50.
Sperling MR, Saykin AJ, Roberts FD, French JA, O'Connor MJ. Occupational outcome after temporal lobectomy for refractory epilepsy.
Neurology

1995
;
45
:
970
–7.
Sperling MR, O'Connor MJ, Saykin AJ, Plummer C. Temporal lobectomy for refractory epilepsy.
JAMA

1996
;
276
:
470
–5.
Sperling MR, Feldman H, Kinman J, Liporace JD, O'Connor MJ. Seizure control and mortality in epilepsy.
Ann Neurol

1999
;
46
:
45
–50.
Spreafico R, Battaglia G, Arcelli P, Andermann F, Dubeau F, Palmini A, et al. Cortical dysplasia: an immunocytochemical study of three patients.
Neurology

1998
;
50
:
27
–36.
Spreafico R, Pasquier B, Minotti L, Garbelli R, Kahane P, Grand S, et al. Immunocytochemical investigation on dysplastic human tissue from epileptic patients.
Epilepsy Res

1998
;
32
:
34
–48.
Steffenburg U, Hedström A, Lindroth A, Wiklund L-M, Hagberg G, Kyllerman M. Intractable epilepsy in a population-based series of mentally retarded children.
Epilepsia

1998
;
39
:
767
–75.
Sugimoto T, Otsubo H, Hwang PA, Hoffman HJ, Jay V, Snead O 3rd. Outcome of epilepsy surgery in the first three years of life.
Epilepsia

1999
;
40
:
560
–5.
Swartz BE, Delgado-Escueta AV, Walsh GO, Rich JR, Dwan PS, DeSalles AA, et al. Surgical outcomes in pure frontal lobe epilepsy and foci that mimic them.
Epilepsy Res

1998
;
29
:
97
–108.
Szabo CA, Wyllie E, Dolske M, Stanford LD, Kotagal P, Comair YG. Epilepsy surgery in children with pervasive developmental disorder.
Pediatr Neurol

1999
;
20
:
349
–53.
Taha JM, Crone KR, Berger TS. The role of hemispherectomy in the treatment of holohemispheric hemimegaloencephaly.
J Neurosurg

1994
;
81
:
37
–42.
Taylor DC, Falconer MA, Bruton CJ, Corsellis JA. Focal dysplasia of the cerebral cortex in epilepsy.
J Neurol Neurosurg Psychiatry

1971
;
34
:
369
–87.
Thom M, Moran NF, Plant GT, Stevens JM, Scaravilli F. Cortical dysplasia with angiodysgenesis and chronic inflammation in multifocal partial epilepsy.
Neurology

1999
;
52
:
654
–7.
VanLandingham KE, Heinz ER, Cavazos JE, Lewis DV. Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions.
Ann Neurol

1998
;
43
:
413
–26.
Verity CM, Strauss EH, Moyes PD, Wada JA, Dunn HG, Lapointe JS. Long-term follow-up after cerebral hemispherectomy: neurophysiologic, radiologic, and psychological findings.
Neurology

1982
;
32
:
629
–39.
Vickrey BG, Hays RD, Rausch R, Engel J Jr, Visscher BR, Ary CM, et al. Outcomes in 248 patients who had diagnostic evaluations for epilepsy surgery.
Lancet

1995
;
346
:
1445
–9.
Walker MC, Sander JW. The impact of new antiepileptic drugs on the prognosis of epilepsy: seizure freedom should be the ultimate goal. [Review].
Neurology

1996
;
46
:
912
–4.
Whitney KD, Andrews PI, McNamara JO. Immunoglobulin G and complement immunoreactivity in the cerebral cortex of patients with Rasmussen's encephalitis.
Neurology

1999
;
53
:
699
–708.
Wyllie E, Baumgartner C, Prayson R, Estes M, Comair Y, Kosalko J, et al. The clinical spectrum of focal cortical dysplasia and epilepsy.
J Epilepsy

1994
;
7
:
303
–12.
Wyllie E, Comair YG, Kotagal P, Raja S, Ruggieri P. Epilepsy surgery in infants.
Epilepsia

1996
;
37
:
625
–37.
Wyllie E, Comair Y, Ruggieri P, Raja S, Prayson R. Epilepsy surgery in the setting of periventricular leukomalacia and focal cortical dysplasia.
Neurology

1996
;
46
:
839
–41.
Wyllie E, Comair YG, Kotagal P, Bulacio J, Bingaman W, Ruggieri P. Seizure outcome after epilepsy surgery in children and adolescents.
Ann Neurol

1998
;
44
:
740
–8.
Ying Z, Babb TL, Comair YG, Bingaman W, Bushey M, Touhalisky K. Induced expression of NMDAR2 proteins and differential expression of NMDAR1 splice variants in dysplastic neurons of human epileptic neocortex.
J Neuropathol Exp Neurol

1998
;
57
:
47
–62.
Zentner J, Hufnagel A, Wolf HK, Ostertun B, Behrens E, Campos MG, et al. Surgical treatment of temporal lobe epilepsy: clinical, radiological, and histopathological findings in 178 patients.
J Neurol Neurosurg Psychiatry

1995
;
58
:
666
–73.
Ziemann U, Hallett M, Cohen LG. Mechanisms of deafferentation-induced plasticity in human motor cortex.
J Neurosci

1998
;
18
:
7000
–7.