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Summary: Purpose: Malformations due to abnormal cortical development (MCDs) are common pathologic substrates of medically intractable epilepsy. The in situ epileptogenicity of these lesions as well as its relation to histopathologic changes remains unknown. The purpose of this study was to correlate the cellular patterns of MCDs with the expression of focal cortical epileptogenicity as assessed by direct extraoperative electrocorticographic (ECoG) recordings by using subdural grids.
Methods: Fifteen patients with drug-resistant focal epilepsy due to pathologically confirmed MCD who underwent subdural electrode placement for extraoperative seizure localization and cortical mapping between 1997 and 2000 were included in the study. Areas of interictal spiking and ictal-onset patterns were identified and separated during surgery for further pathologic characterization (cellular and architectural). Three pathologic groups were identified: type I; architectural disorganization with/without giant neurons, type IIA; architectural disorganization with dysmorphic neurons, and type IIB; architectural disorganization, dysmorphic neurons, and balloon cells (BCs). The focal histopathologic subtypes of MCDs in cortical tissue resected were then retrospectively correlated with in situ extraoperative ECoG patterns.
Results: Cortical areas with histopathologic subtype IIA showed significantly higher numbers of slow repetitive spike pattern in comparison with histopathologic type I (p = 0.007) and normal pathology (p = 0.002). The ictal onset came mainly from cortical areas with histopathologic type IIA (nine of 15 patients). None of the seizures originated from neocortical areas that showed BC-containing MCD (type IIB).
Conclusions: This study shows that areas containing BCs are less epileptogenic than are closely located dysplastic regions. These results suggest a possible protective effect of BCs or a severe disruption in the neuronal networks in BCs containing dysplastic lesions. Further studies are needed to elucidate the nature and the potential role(s) of balloon cells in MCD-induced epileptogenicity.
Malformations due to abnormal cortical development (MCDs) are frequent causes of medically intractable epilepsy that is amenable to surgical resection. But the presence of MCD is not always associated with a history of epilepsy (1,2). Pathologic studies on human brain tissues surgically resected from patients with a history of drug-resistant focal epilepsy identified various architectural and cellular changes (1–4). The main histologic hallmark of MCD is the presence of columnar and laminar disorganization that can be intermixed with various cellular abnormalities that include dysmorphic neurons, giant neurons, and balloon cells (BCs). Recent studies on patients who underwent surgical resection for the treatment of drug-resistant epilepsy suggested characteristic clinical, imaging, and electrocorticographic (ECoG) patterns that are correlated with the presence or absence of BCs (large cells with eccentric nuclei and opalescent cytoplasm). Patients with BC-containing MCDs had an earlier age at seizure onset, more frequent seizures, and worse postoperative outcome (5–9). Moreover, BC-containing MCDs are characterized by signal increase on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) sequence (10). With histopathologic data acquired from patients who had direct ECoG recordings and underwent en bloc surgical resection, Rosenow et al. (1998) showed a significant increase in the number of spikes in BC-containing MCD as compared with MCD that was devoid of BCs (9). However, no in situ and direct correlations were made between the interictal EcoG spiking and the various histopathologic patterns that are usually found in the same patient (11,12).
In this study, we directly correlated the different histopathologic subtypes of MCDs with the frequency and patterns of interictal spiking and ictal EcoG patterns acquired in patients who underwent prolonged extraoperative ECoG recordings by using subdural electrode recordings.
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- MATERIALS AND METHODS
Our study is the first to demonstrate a direct in situ correlation between various types of MCDs and both interictal and ictal epileptic patterns in patients who underwent cortical resection for the treatment of medically intractable focal epilepsy. Our results show a differential expression of in situ epileptogenicity in selected types of MCDs. Ictal-onset patterns were not found in BC-containing regions (type IIB) despite the presence of severe cortical architectural disorganization and a high number of dysmorphic neurons. The most severe interictal and ictal in situ changes were seen in MCDs that are characterized by the presence of dysmorphic cells and architectural disorganization (type IIA).
Our results are in agreement with those reported by Munari et al. (15) by using depth EEG recordings. In one of the two cases reported by these authors, the ictal-onset area was mainly recorded from the cortical area surrounding the lesion that was shown to contain BCs on histopathologic examination (15). These results are in apparent disagreement with a recent report on the epileptogenicity of cortical dysplasias (16). With retrospective analyses of resected tissue from patients with medically intractable focal epilepsy who underwent stereotactic depth EEG monitoring (SEEG) over a long period that preceded CT or MRI scanning, Chassoux et al. (16) reported recording of epileptogenicity from BC-containing lesions. The majority of the patients included in that study had BCs (24 patients of a total of 28 patients: 85.7%) as compared with other series reporting on a smaller proportion of MCDs with BCs (5,9). The methods of the two studies are significantly different: (a) We performed a prospective study that included patients with high-resolution MRI and direct electrode-anatomic correlations, whereas the recent report is based on a retrospective review of resected samples with no preoperative MRI correlates on most of the patients; (b) we assayed epileptogenicity by using surface cortical recordings (subdural grids), whereas the epileptogenicity in the report by Chassoux et al. was assessed by depth electrodes.
Our group previously reported on an increased epileptogenicity in patients with BC-containing dysplastic lesions (9). In the previous study, direct correlations between the in situ histopathologic changes and ECoG findings were not made through an intraoperative identification of various areas as defined by imaging and/or ECoG findings. In the current study, we report on the direct correlations between various histopathologic subtypes (that may be present in the same patient) and in situ ECoG patterns. Therefore interictal activities that may be generated in non–BC-containing but dysplastic lesions may have been attributed to BC-containing MCDs.
Our findings support the previous concept of the presence of intrinsic epileptogenicity in some forms of MCDs. The high degree of in situ epileptogenicity of focal MCDs has been observed in previous studies from a large number of patients with intractable epilepsy who underwent invasive/direct cortical EEG recordings (7,8). Moreover, patients with focal MCDs have high seizure frequency and increased incidence of status epilepticus (6–9,17). By using direct intraoperative ECoG recordings, Palmini et al. (8) demonstrated the selective occurrence of distinct in situ occurrence of ictal or continuous epileptogenic discharges (I/CEDs) in focal cortical dysplasias as compared with control epileptic pathologies (such as tumors or arteriovenous malformations). Our results extend these findings, as we show that the expression of in situ epileptogenicity in focal MCDs is differentially correlated with specific types of histopathologic neocortical changes.
With the same methods, we recently showed that BC-containing dysplastic lesions are nonfunctional on direct cortical electrical stimulation, and they show significant FLAIR increased signal on MRI (12). The lack of cortical eloquent function in BC-containing regions could be secondary to severe architectural disorganization and subsequent disruption of the neuronal circuits in those cortical areas. The same mechanism(s) may underlie the decreased in situ epileptogenicity, as the build-up of neuronal synchrony is impaired despite the presence of hyperexcitable dysmorphic neurons. Cellular and architectural studies are needed to elucidate the possible mechanism(s) of lack of function and epileptogenicity in the BC-containing MCDs.
The role and function of BCs in the setting of MCDs is not yet known. Previous studies showed that these large opalescent cells with multinuclear and eccentric nuclei have neuronal and glial characteristics (5). We recently acquired preliminary evidence on the presence of an increased protein density of glutamate-clearance mechanisms (glutamate transporters and glutamine synthetase) within the BCs and in BC-containing regions (Najm et al., unpublished data). These glutamate-clearance mechanisms may be limiting the spread of epileptogenicity in these lesions. Studies to confirm these findings and to assess their significance are under way at our laboratory.
Our study shows that some interictal epileptic patterns may predict the pathologic characteristics and the location of ictal-onset zones. According to our findings, certain patterns of interictal epileptiform activities correlated with specific histopathologic subtypes (as proposed by Palmini and Lüders) (14). Cortical areas that were characterized by architectural disorganization and the presence of dysmorphic neurons (subtype IIA) showed higher prevalence of slow repetitive spiking as compared with type I regions. The areas that showed slow repetitive spiking often overlapped with ictal-onset zones in areas containing dysmorphic neurons (subtype IIA).
Further studies are needed to validate these results through the analyses of postsurgical seizure outcome and to establish the basic pathophysiologic mechanism(s) responsible for decreased epileptogenicity in the BC-containing regions.