Histopathological Correlates of Epileptogenicity as Expressed by Electrocorticographic Spiking and...

Epilepsiu, 39(8):850-856, 1998 Lippincott-Raven Publishers, Philadelphia 0 lnternational League Against Epilepsy

Histopathological Correlates of Epileptogenicity as Expressed by Electrocorticographic Spiking and Seizure Frequency

*¶Felix Rosenow, *Hans 0. Liiders, *Dudley S. Dinner, ?Richard A. Prayson, $Edward Mascha, *Barbara R. Wolgamuth, OYoussef G. Comair, and “Gregory Bennett

Departments of Neurology, *Pathology, TBiostatistics, and $Epidemiology and $Neurosurgery, The Cleveland Clinic Foundation; “Department of Neurosurgery, Buffalo, New York, U.S.A. and ¶Department of Neurology, Philipps-University, Marburg, Germany

Summary: Purpose: To study the correlation between histopathology and epileptogenicity, as measured by seizure frequency and electrocorticography (EcoG), in patients with cortical dysplasia (CD) as compared with control patients with gangliogliomas or gliomas.

Methods: The influence of the histopathological classification and the presence of balloon cells in CD on the frequency and extension of five predefined patterns of ECoG spiking, seizure frequency, age of seizure onset and 6-month postoperative outcome were analyzed in 32 patients with focal epilepsy undergoing presurgical evaluation with chronically implanted subdural electrodes.

Results: Comparison of patients with CD, gangliogliomas, and gliomas showed that the seizure frequency was greatest in patients with CD and ECoG spiking and was most extensive in patients with gangliogliomas. The onset of epilepsy was earlier in patients with CD and with gangliogliomas. None of these differences was significant. However, in patients with CD, the

presence of balloon cells was associated with significantly greater seizure frequency (p = 0.009), and a significantly greater number of electrodes recording continuous frequent spiking (p = 0.03). The presence of continuous very frequent spiking correlated with the duration of the epilepsy and the number of seizures recorded during monitoring. No significant correlation was detected between histopathology, seizure frequency, or ECoG activity and postoperative outcome, which was relatively favorable in patients with balloon cells.

Conclusions: CD refers to a variety of histopathological patterns associated with different epileptogenicity. In CD, increased clinical and ECoG epileptogenicity correlates with the presence of balloon cells. This finding confirms that balloon cells should be considered in the histopathological classification of CD. The predefined ECoG were not specific for any of the histopathologies investigated. Key Words: Cortical dysplasia-Glioma-Ganglioglioma-Electrocorticography- Focal epilepsy.

Cortical dysplasia (CD) is a frequent cause of medi- cally resistant focal epilepsy. However, findings suggestive of CD have also been reported in 2% of 50 normal volunteers on magnetic resonance imaging (MRI) scans (1) and “severe migrational disturbances” were observed in 1.7% of 7,374 normal subjects in a large post- mortem series (2). In addition, epilepsies responsive to antiepileptic drug (AED) monotherapy have been reported in patients with CD (3). Therefore, similar to other lesions, the epileptogenicity of dysplastic neuronal tissues varies greatly. Likewise, the spectrum of histopathological changes in CD is wide (4). The presence of so-called ‘‘balloon cells,” i.e. large cells with eccentric nuclei and abundant eosinophilic cytoplasm of indeter- minate histogenesis, in the context of a disruption of the

Acepted March 24, 1998. Address correspondence and reprint requests to Dr. med. F. Rosenow at

Department of Neurology, University of Marburg, Rudolf-Bultmann-Str. 8, 35033 Marburg, Germany.

normal cortical lamination has been implicated as a histopathological marker of epileptogenicity of CD ever since their description by Taylor et al. in 1971 (5). Bal- loon cells have been used in histopathological grading of CD, indicating the most severe form (4,6-8). A correlation of their presence with a poor surgical outcome was suggested (6). Patients with focal CD were recently reported to display significantly higher epileptogenicity, as expressed by electrocorticographic (ECoG) spiking, than controls, who mainly had low-grade gliomas (9). How- ever, the question of whether epileptogenicity is increased in CD in general or is dependent on the presence of certain histopathological features such as balloon cells has not been addressed. Therefore, we compared the epileptogenicity, as expressed by ECoG spiking and seizure frequency, of patients with CD with two control groups- patients with gangliogliomas and patients with gliomas- and studied the influence of balloon cells and marginal heterotopia on epileptogenicity in the patients with CD.

850

HISTOPATHOLOGY AND EPILEPTOGENICITY 851

PATIENTS AND METHODS

Thirty-two patients with focal epilepsy undergoing presurgical video-EEG monitoring between 1991 and 1996 with chronically implanted subdural grid arrays (Fig. 1) were studied. Three groups were defined by histopathological and MRI criteria: patients with CD (n = 17), gangliogliomas (n = 7), and gliomas (n = 8). Patients with dysembryoplastic neuroepithelial tumors (DNET), hamartomas, and ‘‘double pathology” were excluded. Patients in whom histopathological examination demonstrated white matter neuronal heterotopia as the only abnormality were also excluded because MRI showed evidence of CD or vascular lesions in 4 of 8 such patients. The average age at onset of the epilepsy was 9.5 years (range 0.2-37 years), and at the time of subdural recording was 21.2 years (range 1.2-45 years). The patients had an average of 77.9 (range 2450) seizures a month. The monitoring lasted 7.6 days on the average (range 2-14), and an average of 11 (range 0-32) seizures were recorded during that time.

Subdural electrodes ECoG data were derived from chronically implanted

subdural electrode grids and strips (Fig. 1). Their place- ment was guided by one or more of the following: the distribution of interictal and ictal epileptiform discharges recorded during previous noninvasive video-EEG monitoring, the localization of lesions defined by MRI andlor positron emission tomography (PET), the need to iden- tify eloquent cortex in the vicinity of planed resections, and the specific questions, arising from the available data, which lead to the indication for a subdural evaluation. On the average 2.8 (range 1-5 subdural grids and strips with an average of 57.9 (range 37-92) electrodes were implanted. Their position was assessed by lateral and anteroposterior (AP) skull radiographs and by com-

FIG. 1. Lateral skull radiograph-ray showing a typical place- ment of chronically implanted subdural grid and strip electrodes. In this case, 40 electrodes were placed.

puted tomography (CT) or, when platinum electrodes were used, by MRI.

ECoG During a pilot study of 6 patients with CD, five ECoG

patterns of interictal activity were defined (Fig. 2) to quantify spike frequency and the persistence of spiking:

1. Frequent spiking (25 spiked10 s) la. Continuous frequent spiking (ECoG spiking pat-

2. Very frequent spiking (220 spikes/lO s) 2a. Continuous very frequent spiking (ECoG spiking

3. Bursts of fast activity ( a10 Hz for a 2 s)

tern 1 for 2 3 0 s).

pattern 2 for 230 s)

Spikes had to have at least twice the amplitude of the background activity and bursts of fast activity had to be paroxysmal.

The presence of these patterns and the number of electrodes recording each of them was determined by a board-certified clinical neurophysiologist from the first 10 min of interictal ECoG recording digitally saved for the patients. The 10 min consisted of separate samples, usually 2 min long, which were selectively saved during the monitoring because they were representative of the pathological interictal activity. For statistical analysis, the absolute number of electrodes recording each of the five ECoG patterns was used. Because the average number of electrodes implanted in the different groups dif- fered significantly, the proportion of the implanted electrodes recording each pattern was also analyzed. Because this led to no changes in the observed significant correlations, only the absolute number of electrodes is referred to herein.

Clinical data The age of onset of the epilepsy and the number of

seizures per month in the year before monitoring, as clinical measures of epileptogenicity, were determined from the monitoring reports. Each patient’s sex, age at monitoring, and the number of seizures during the monitoring were also analyzed. To compare outcome after surgery, the variable of occurrence of postoperative seizures in the first 6 postoperative months, excluding the first postoperative week, was used. Furthermore, the influence of lobar involvement on outcome was assessed.

Histopathological classification For the purpose of histopathological classification a

mean of 9.9 slides (range 1-28) of 30 patients were reviewed by a neuropathologist (R.A.P.) who was unaware of the ECoG and clinical data. For 2 patients, histologic slides were not available for review, but the diagnosis of CD had been made by personnel in the same department using the same classification. The microscopic slides reviewed represented the total of the submitted tissue in 7

Epilepsia, Vol. 39, No. 8, 1998

852 F. ROSENO W ET AL.

Frequent Spikes (2 5 I 10 seconds) = Pattern I

A 1 0 - P 8 +-

Continuous Frequent Spikes 11 5 I 10 seconds for a 30 seconds) = Pattern I n

A i e- ~p q--& Y

Very Frequent Spikes (a 20 I 10 seconds) = Pattern II FIG. 2. The five patterns of electrocorticographic activity defined during a pilot study of 6 patients with cortical dysplasia are shown in sections of 10 or 30 s.

A l O - P E

Continuous Very Frequent Spikes {r 20 I 10 seconds for 'e 30 seconQ) = Pattern I I a

cases, half or more of it in 19 cases and less than half in 2 cases (unknown in 3 cases). Samples studied com- pletely were usually smaller and were represented, on the average by 5.75 reviewed slides. Samples studied incom- pletely were usually larger and represented by in average 12.2 reviewed slides. In patients with balloon cells, an average of 5.4 slides was reviewed, and in patients with CD but no evidence of balloon cells an average of 12.4 slides was reviewed. There was no significant correlation between patient groups, the number of slides, and the amount of tissue they represented.

For histopathological classification of neuronal migration disorders, the presence of the following histopathological patterns was determined: (a) balloon cells (Fig. 3), (b) molecular layer neurons, (c) cortical disorganiza- tion, (d) gyral fusion/polymicrogyria, (e) cluster form, (f)

marginal heterotopia, (g) persistent superficial granular cell layer, (h) gray matter heterotopia and (i) white matter neuronal heterotopia. These were defined (and modi- fied) according to the proposal of Mischel et al. (8) and as described previously (10). Of these patterns, only balloon cells and molecular layer neurons occurred suffi- ciently often to allow statistical analysis of their correlation with epileptogenicity. Statistical analysis

The parameters described were used for statistical analysis. Two group comparisons were performed: Ini- tially, patients were divided into three histopathologically defined subgroups: patients with CD (n = 17), gangliogliomas (n = 7), and gliomas (n = 8, including 3 oligoastrocytomas, 2 low-grade astrocytomas, 1 oligo- gendroglioma and 1 anaplastic mixed glioma).

FIG. 3. Several large balloon cells.

Epilepsio, Vol. 39, No. 8. 1998


In the patient group with CD the influence of histopathological evidence of balloon cells and of molecular layer neurons on ECoG spiking and the clinical parameters was analyzed separately. Furthermore, the correlations between seizure frequency and ECoG spiking, between these two parameters and outcome at 6 months after operation, and between lobar involvement and outcome were investigated. Groups were compared on cat- egorical variables by a likelihood-ratio chi-square test or Fisher’s exact test. Fisher’s exact test was used when the expected sample size in any cell of a cross-tabulation between the two variables was <5 or the observed cell count was 0. Groups were compared on the mean of continuous variables with either a t test (if two groups) or analysis of variance (ANOVA; if more than two groups). If the data appeared not to be normally distributed, the nonparametric Wilcoxon rank-sum test (if two groups) or Kruskal-Wallis test (1 1) (if more than two groups) was performed. To assess the relationship between two continuous or ordinally scaled variables, the nonparametric Spearman correlation coefficient was calculated. For each test, an overall significance level of 0.05 was used.

In comparing the three histopathologically defined subgroups, the overall test for differences (ANOVA or Kruskal-Wallis) was first performed, for which a p-value is reported. A multiple comparison procedure was then performed to test for all six painvise differences; this was Tukey’ s multiple comparison procedure for ANOVA variance (12) and Dunn’s multiple comparison procedure for the Kruskal-Wallis test (13). p-Values are not available for specific pairwise comparisons using these pro- cedures. Groups were considered statistically significant at overall significance levels of 0.05.

RESULTS

Comparison of the three sub-groups showed epilepsy to have onset twice as early in patients with CD and gangliogliomas as in patients with gliomas. The mean seizure frequency of patients with CD was four times as great as in patients with gangliogliomas and twice as great as in patients with gliomas (Fig. 4).

Frequent spiking was noted in all patients. All other ECoG patterns were more common in the patients with gangliogliomas, followed by those with CD. The number of electrodes recording a certain pattern (i.e., its extension) was always highest in the ganglioglioma group (Fig. 5) . The percentage of patients who were seizure- free for 6 months postoperatively was highest in the ganglioglioma group (66.7%), followed by the glioma group (50%) and the CD group (47.1%). None of these differences was statistically significant.

In patients with CD, the presence of balloon cells was associated with a significantly greater seizure frequency (p = 0.009) (Fig. 6) and a significantly higher number of

FIG. 4. Comparison of three histopathologically defined groups (clinical data): age of onset of epilepsy, average seizure frequency per month in the year before monitoring, and percentage of patients with no seizures during the first 6 postoperative months (excluding the first week after operation).

electrodes recording continuous frequent spiking (p =

0.03) (Fig. 7). These differences remained significant when the relative proportion of implanted electrodes recording this pattern was compared. The number of implanted electrodes was significantly higher in patients with balloon cells (p = 0.004).

The mean age at onset of epilepsy was lower in patients with balloon cells, but this difference was not significant. Surprisingly, patients with CD and balloon cells more commonly were seizure-free for 6 months (80%) than were those without balloon cells (33.3%) (Fig. 6). The presence of molecular layer neurons on histopathology had no effect on the clinical or ECoG data. Bursts of paroxysmal fast activity (pattern 3) were infrequent and did not correlate with histopathology or clinical parameters. No correlation was detected between seizure frequency or ECoG spiking and postoperative outcome. Furthermore, lobar involvement did not correlate with a 6-month postoperative seizure-free outcome. For the en- tire group of 32 patients, the presence of continuous very frequent spiking (pattern 2a) on ECoG correlated with duration of epilepsy (p = 0.043) and the number of seizures recorded during the monitoring (p = 0.017).

FIG. 5. Comparison of three histopathologically defined groups (electrocorticogram data): percentage of patients with “continuous frequent spikes” (>5 spikesilo s for 330 s) and average number of the electrodes per patient recording continuous frequent spiking.


F. ROSENOW ET AL.

8 0 - 70 - 60 - 50 - 40 - 30 - 20 - 10 - 0 7

854

250 -

200 -

150 -

100 -

50 -

rn CD, Balloon Cells

CD, no Balloon Cells

P=0.03

age of onset seiruredmonth %seizure free at 6 month

FIG. 6. Comparison of patients with cortical dysplasia with and without balloon cells (clinical data): age of onset of epilepsy, average seizure frequency per month in the year before monitoring, and percentage of patients with no seizures during the first 6 postoperative months (excluding the first week after operation).

DISCUSSION

ECoG measures of epileptogenicity To be able to analyze the large amount of ECoG data,

we graded ECoG spiking into five patterns reflective of the frequency and persistence of the ECoG spikes. The number of subdural electrodes recording these patterns was used to quantify the extension of ECoG spiking. The presence and extension of these patterns were used as measures of ECoG epileptogenicity. Objective defini- tions of these measures decreased the influence of sub- jective judgment and allowed reproducibility of our study. Using these criteria, we noted a significant correlation in patients with CD between the presence of balloon cells and epileptogenicity as measured by ECoG. Furthermore, longer duration of the epilepsy and greater number of seizures recorded during monitoring correlated with the presence of continuous very frequent spiking on ECoG. However, no significant correlations were noted between ECoG spiking and the three histopathological groups or seizure frequency or postoperative outcome.

Palmini et al. (14), studying 26 patients wrth “focal neuronal migration disorders” did not note a significant correlation between the amount of excision of the epileptogenic area, as defined by the presence of intraop-

90 1 PzO.24 I

%of patients # of electrodes with pattern 2a recording

pattern 2a

FIG. 7. Comparison of patients with cortical dysplasia with and without balloon cells (electrocorticogram data): percentage of patients with continuous frequent spikes (>5 spikes/lO s for 230 s) and average number of electrodes per patient recording continuous frequent spiking.

erative ECoG spiking in general and surgical outcome. However, 4 years later, after adding 8 patients to their series and reviewing “at least” 10 min of ECoG recording, they reported three spatially more restricted specific ECoG patterns, i.e., repetitive ECoG seizures, repetitive spike bursts lasting 5-10 s and continuous or quasicon- tinuous spiking, to be present in 67% of these patients as compared with 2.5% of controls (mainly patients with gliomas). The absence of these patterns on postexcision ECoG correlated significantly with a favorable outcome, when univariate analysis (Student’s t test) was performed (9). Therefore, ECoG spiking in general or as measured semiquantitatively as in the present study are not predic- tive of surgical outcome, whereas the specific patterns described by Palmini et al. (9) may be more helpful in this respect.

CD with and without balloon cells In the heterogeneous group of CD, histopathological

correlation of ECoG spiking has not yet been reported in detail. The present study shows that the epileptogenicity of CDs as measured by seizure frequency and ECoG spiking, correlates with the presence of balloon cells on histopathology. Balloon cells are large cells with eccentric nuclei and abundant eosinophilic cytoplasm of inde- terminate histogenesis. They often show binucleation or nuclei of bizarre shape (8). They resemble cells described in tuberous sclerosis (1 5 ) and were first reported in the context of CD by Taylor et al. as “grotesque cells probably of glial origin” (5) . Immunohistochemistry mostly shows the presence of glial marker such as glial fibrillary acidic protein (GFAP) but dual staining both with GFAP and synaptophysin, a neuronal marker, has also been reported (16). This is suggestive of cellular immaturity or ‘‘dedifferentiation’ ’ and indicates a distur- bance during the first trimester of pregnancy (8). The receptor expression of these cells and their involvement in neuronal circuitry is largely unknown. However, in most, if not all, cases they are associated with giant dysplastic neurons, from which they cannot always be easily distinguished (17), and with severe disruption of the normal cortical architecture (8). Therefore, they may be sim- ply the hallmark of the most epileptogenic form of CD, with abnormal intercellular connections resulting in an imbalance between excitation and inhibition. Ferrer et al. (1 8) described a marked decrease in inhibitory, GABA- ergic (parvalbumin or calbindin D-28k immunoreactive) local circuit interneurons in the dysplastic cortex (dis- playing neuronomegaly) of a patient with epilepsia partialis continua. However, similar but less pronounced findings were subsequently reported in patients with neoplasms (19). With regard to the electrophysiologic prop- erties of dysplastic cortex, Mattia et al. (20) reported that single shock stimuli and application of 4-aminopyridine induced seizures in in vitro slices of dysplastic human



neocortex but not in relatively normal cortical slices from a patient with hippocampal sclerosis. Furthermore, Avioli et al. (21) reported that neurons in human dysplastic cortex have an increased tendency to generate ‘ ‘all-or-none paroxysmal depolarization shifts’ ’ sensitive to N-methyl-D-aspartate-receptor antagonism, suggesting an underlying abnormality of synaptic circuitry. The sum of these histopathologic and electrophysiologic proper- ties, all (directly or indirectly) related to balloon cells, may explain the increased epileptogenicity associated with these cells. However, the receptor expression and direct involvement in neuronal circuitry of balloon cells have not been established and require further study.

Even though patients with balloon cells had more seizures and more extensive continuous frequent spiking, they had a relatively good postoperative outcome. A similarly good outcome was reported by Taylor et al. ( 5 ) in their series of patients with relatively focal CD. Palmini et al. (6), on the other hand, reported a poorer postoperative prognosis in patients with grade 111 CD (including those with balloon cells) as compared with patients with grade I and I1 (with no balloon cells). How- ever, postoperative outcome is clearly dependent on several other factors, such as size of the lesion, com- pleteness of resection, and temporal involvement as compared with extratemporal involvement (6), which makes univariate data analysis inappropriate. Therefore, the presence of balloon cells does not appear to be an inde- pendent determinator of postoperative outcome.

Gangliogliomas Gangliogliomas are uncommon benign tumors com-

posed of neoplastic astrocytes and rarely oligodendro- cytes and an atypical ganglion cell component, often evi- denced by binucleate neuronal cells. These tumors usually present with seizures and chronic epilepsy and occur more often in children or young adults (22,23). Usually these tumors display little if any growth (grade I or II), rarely, however, a malignant evolution has been reported (24,25). The tumors have been reported to occur in as- sociation with CD (26) and have been classified as “neoplastic developmental malformations” (4). Thus, they take an intermediate position between static congenital malformative lesions and proliferating neoplasms. In our series, patients with coexisting CD apparent on histopathology were excluded from the study. Therefore, we were surprised to note that in patients with gangliogliomas all ECoG patterns defined above were present as often and had an even wider distribution than in patients with CD. Even though these tumors showed the highest epileptogenicity by ECoG criteria, they were also associated with the lowest seizure frequency. Pilcher et al. (22), who studied 12 patients with intraoperative ECoG reported that the epileptogenic zone was distinct from the region of tumor-involved brain in all patients and was

usually larger. Whereas tumor-involved cortex displayed high-amplitude slow activity, the epileptogenic activity was recorded from the surroundings of the tumors or even remote areas, most often the mesial temporal struc- tures. These findings may explain the degree of the ECoG spiking in our patients. Haglund et al. (27), using immunohistochemistry, compared noninvolved epileptogenic with noninvolved nonepileptogenic neocortex in 4 patients with low-grade gliomas, including gangliogliomas, and reported a decrease of somatostatin- and GABA-immunoreactive neurons in epileptogenic cortex. These changes likely contribute to the epileptogenicity of noninfiltrated neocortex in the vicinity of gangliogliomas. In concordance with other reports (22,23), in the present study patients with gangliogliomas had the best seizure outcome.

Gliomas Gliomas causing epilepsy were associated with the

relatively least amount of ECoG spiking. Only 1 of 8 patients had very frequent spiking (>20 spiked10 s) and bursts of rhythmic ECoG activity were not observed. However, frequent spiking (>5 spiked10 s) was observed in all patients and continuous frequent spiking was observed in 3 of 8. The differences between the glioma group and the other groups were not significant. The specific ECoG patterns reported by Palmini et a. (9) (described above) in CD appear to be more useful than ECoG spiking in general to distinguish between gliomas and dysplasia. Even though the mechanisms underlying the development of epileptogenicity may be similar to those observed in gangliogliomas (27), our findings sug- gest that the cortex adjacent to gliomas is less exten- sively affected. In concordance, complete lesionectomy alone is usually sufficient to obtain initial seizure control in most patients with gliomas (28), whereas patients with gangliogliomas appear to profit from ECoG (22). Unique to this patient group is the possibility of seizure recurrence due to tumor recurrence, decreasing the likelihood of prolonged seizure control.

CONCLUSIONS

In our 32 patients with focal epilepsy, the presence of continuous frequent spiking was not indicative of CD in general, and this diagnosis was not associated with significantly increased epileptogenicity as compared with a diagnosis of glioma or ganglioglioma. Instead, in the patient group with CD, epileptogenicity (as measured by seizure frequency, ECoG spiking frequency and extension) was significantly greater when histopathology showed the presence of balloon cells. CD includes a variety of malformative lesions of the neocortex, which display different degrees of epileptogenicity, depending on histopathology. This finding confirms that balloon cells should be considered in the histopathological clas-


856 F. ROSENOW ET AL.

sification of CD, as previously suggested by other inves- tigators (4,6-8,29).

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