Surgical Management and Long-Term Seizure Outcome After Surgery for Temporal Lobe Epilepsy Associated with Cerebral Cavernous Malformations

Original Article

Surgical Management and Long-Term Seizure Outcome After Surgery for Temporal Lobe Epilepsy Associated with Cerebral Cavernous Malformations Peng-Fan Yang1, Jia-Sheng Pei1, Yan-Zeng Jia2, Qiao Lin2, Hui Xiao3, Ting-Ting Zhang4, Zhong-Hui Zhong2

OBJECTIVE: Operative strategies for cerebral cavernous malformation (CCM)-associated temporal lobe epilepsy and timing of surgical intervention continue to be debated. This study aimed to establish an algorithm to evaluate the efficacy of surgical intervention strategies, to maximize positive surgical outcomes and minimize postsurgical neurologic deficits.

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METHODS: 47 patients having undergone operation for CCM-associated temporal lobe epilepsy were retrospectively reviewed. They had received a diagnostic series for seizure localization, including long-term video electroencephalography (vEEG), high-resolution magnetic resonance imaging (MRI), and positron emission tomographye computed tomography (PET-CT). In patients with mesial temporal lobe CCMs, the involved structures (amygdala, hippocampus, or parahippocampal gyrus) were resected in addition to the lesions. Patients with neocortical epileptogenic CCM underwent extended lesionectomy guided by intraoperative electrocorticography; further performance of amygdalohippocampectomy depended on the extent of hippocampal epileptogenicity.

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RESULTS: The study cohort contained 28 patients with drug-resistant epilepsy (DRE), 12 with chronic epilepsy (CE), and 7 with sporadic seizure (SS). Normal temporal lobe metabolism was seen in 7/7 patients of the SS group. Hypometabolism was found in all patients with chronic

disease except for those with posterior inferior and middle temporal gyrus cavernous malformations (CMs). Of the 31 patients with superficial neocortical CCM, 7 had normal PET without hippocampal sclerosis, 14 had ipsilateral temporal lobe hypometabolism without hippocampal sclerosis, and 10 had obvious hippocampal sclerosis and hypometabolism. Seizure freedom in DRE, CE, and SS was 82.1%, 75%, and 100%, respectively. A significant difference was found between lesion laterality and postoperative seizure control; the rate was lower in left-sided cases because of less aggressive resection. CONCLUSIONS: Our study demonstrates that the data from the presurgical evaluation, particularly regarding CM location, responsiveness to antiepileptic drugs, and temporal lobe metabolism, are crucial parameters for choosing surgical approaches to CCM-associated temporal lobe epilepsy. By this operative strategy, patients may receive maximized seizure control and minimized postsurgical neurologic sequelae.

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Key words Cerebral cavernous malformation - Epilepsy surgery - Seizure outcome - Temporal lobe -

Abbreviations and Acronyms AED: Antiepileptic drug AH: Amygdalohippocampectomy AMTL: Anterior mesial temporal lobectomy CE: Chronic epilepsy CM: Cavernous malformation CT: Computed tomography CCM: Cerebral cavernous malformation DRE: Drug-resistant epilepsy ECoG: Electrocorticography EEG: Electroencephalography EL: Extended lesionectomy

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INTRODUCTION

S

upratentorial cerebral cavernous malformations (CCMs) are regarded as highly epileptogenic lesions if they involve the cortex,1 but the mechanisms underlying epileptogenicity are

FCD: Focal cortical dysplasia FDG-PET: 18F-fluorodexyglucose positron emission tomography IQ: Intelligence quotient MRI: Magnetic resonance imaging SS: Spontaneous seizures vEEG: Video electroencephalography

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Departments of 1Neurosurgery, 2Epileptology, 3Medical Imaging, and 4Pathology, Fuzhou General Hospital, Fujian Medical University, Fuzhou, China To whom correspondence should be addressed: Peng-Fan Yang, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2017). https://doi.org/10.1016/j.wneu.2017.11.067 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.

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ORIGINAL ARTICLE PENG-FAN YANG ET AL.

SURGERY FOR TEMPORAL LOBE EPILEPSY ASSOCIATED WITH CEREBRAL CAVERNOUS MALFORMATIONS

Figure 1. Flow chart of inclusion of patients in the study. CCM, cerebral cavernous malformation; PET-CT, positron emission tomography computed tomography.

still not fully understood. Asymptomatic, repeated microhemorrhages into the surrounding brain parenchyma through leaky endothelial junctions,2,3 subsequently followed by perifocal hemosiderosis and gliosis, have been considered the major cause of a chronic epileptic state.4,5 It has been established that extended lesionectomy (EL), with removal of CCMs and the adjacent epileptogenic cortex, consistently contributes to good long-term outcomes in patients whose CCMs are located in the extratemporal lobe.6-12 Around 10% to 20% of all CCMs occur in the temporal lobe,13,14 and this region has been considered more epileptogenic than other supratentorial locations.15 The mesial structures have a particular tendency to develop independent epileptogenic foci after continuous exposure to seizure activity, especially when the CCMs involve or are close to the mesial temporal structures.16,17 However, it is difficult to exactly assess the severity of epileptogenesis emerging from the mesial temporal structures. In addition, there is also some concern regarding the necessity of additionally resecting the mesial structures; even though such a measure is capable of improving the seizure outcomes, it may also potentiate the risk of neuropsychiatric side effects. Therefore, some suggest a 2-step approach whereby a lesionectomy (sparing the hippocampus) is performed first, followed by more extensive resections for those that fail at the first stage.2,5,18 There is no universally accepted method that can be applied to the assessment and surgical treatment of patients with epileptogenic temporal CMs. In April 2004, our epilepsy center began to be equipped with high-resolution magnetic resonance imaging (MRI) and PET-CT systems. After several years of clinical research, we refined a noninvasive presurgical anatomo-electro-clinical evaluation workup. The aim of this study was to develop a 1step surgical algorithm capable of maximizing the chance of seizure freedom, minimizing postsurgical neurologic deficit, and obviating the need for reoperation. We analyzed the presurgical evaluation data, operative strategies, pathologic findings, and seizure control outcomes in a consecutive series of surgically treated adult patients with epilepsy associated with solitary temporal lobe CCMs in an attempt to make explicit all factors considered in decision making for optimal operative management.

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PATIENTS AND METHODS Standard Protocol Approvals, Registrations, and Patient Consent The study was approved by the institutional review board of Fuzhou General Hospital. Written informed consent was obtained from all patients. Patients Between April 2004 and December 2014, a total of 151 consecutive patients underwent surgery in our comprehensive epilepsy center for the treatment of CCMs-associated epilepsy. Among them, 58 received diagnoses of temporal lobe CCMs and received temporal lobe CCM-associated epilepsy surgery. As shown in Figure 1, the inclusion criteria of this study were specified as follows: adult patients (1) with temporal lobe epilepsy (indicated by video electroencephalography [vEEG] examination, seizure diary, or both) and solitary temporal CCMs (radiographically proven by MRI), (2) having undertaking PET-CT scanning, (3) with pathologically confirmed diagnosis of the resected temporal lesion as CCMs, and (4) undergoing minimum postoperative follow-up for 24 months. Six patients younger than 18 years of age were excluded. Four patients harboring other CCMs in extratemporal areas and 1 patient harboring 2 temporal CCMs were excluded from the analysis. In the end, 47 patients were included. Among those patients, 3 types of epilepsy were defined: (1) drug-resistant epilepsy (DRE), characterized by seizures for a minimum duration of 2 years despite adequate treatment with at least 2 different, appropriate antiepileptic drugs (AEDs); (2) chronic epilepsy (CE), characterized by persistent seizures without matching the criteria of DRE; and (3) sporadic seizures (SS), characterized by single or multiple seizures during 1 year. Data Collection Information was gathered pertaining to the patients’ gender, handedness, age at seizure onset, age at surgery, seizure type and frequency, vEEG monitoring data, history of AED therapy, preoperative and postoperative neurologic function, preoperative MRI findings (including location and size [maximum diameter] of CCMs and radiographic evidence of hippocampal sclerosis),

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ORIGINAL ARTICLE PENG-FAN YANG ET AL.

SURGERY FOR TEMPORAL LOBE EPILEPSY ASSOCIATED WITH CEREBRAL CAVERNOUS MALFORMATIONS

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F-fluorodexyglucose positron emission tomography (18FDG-PET) images, neurocognitive testing results, seizure focus laterality, extent of resection, pathologic diagnosis, and postoperative seizure control outcomes. Institutional Review Board approval for the study was obtained (No. 2016-10-18). Preoperative Evaluation All patients underwent a standard workup: (1) high-resolution 1.5-T or 3-T MRI including T2 weighted imaging (T2WI) and susceptibility-weighted imaging sequences, (2) long-term vEEG monitoring, (3) interictal 18FDG-PET (examination of metabolic changes in brain), (4) functional MRI (assessment of speech dominance and location for patients with middle or superior temporal gyrus CCMs), and (5) detailed neuropsychologic testing with the Wechsler Adult Intelligence Scale (Chinese version, including verbal intelligence quotient [VIQ], performance intelligence quotient [PIQ], and full intelligence quotient [FIQ] scores). Algorithm of Surgical Strategy The operative strategy was based on clinical semiology, electrophysiology, anatomic location of the CCMs, and evidence of brain metabolic alterations as revealed by interictal 18FDG-PET. Neuronavigation was used when necessary. When the CMs directly invaded the mesial temporal structures (hippocampus, amygdala, or parahippocmapal gyrus), the involved structure was resected in addition to the lesion, totally or partially according to factors including epilepsy duration, hippocampal deformity on MRI, and degree of hypometabolism on PET-CT. When the CMs were located in the superficial temporal neocortex such as the anterior and lateral temporal lobes, and there was no radiographic evidence of hippocampal sclerosis, EL (resection of the cavernous malformation and perilesional tissue with abnormal appearance on direct intraoperative visualization) alone was done with the assistance of intraoperative electrocorticography (ECoG) if not contraindicated by functional data. When the CMs were located in the superficial temporal neocortex, and there was obvious radiographic evidence of hippocampal sclerosis, EL was followed by anterior mesial temporal lobectomy (AMTL) or amygdalohippocampectomy (AH). When the CMs were located between the superficial temporal neocortex and the deep mesiotemporal structures, other factors were considered in the decision whether or not to resect the hippocampus and amygdala, such as preoperative duration of epilepsy, structure of hippocampus, degree of hypometabolism on PET, and effects of prior AEDs treatment modalities. For the most “challenging” patient subgroup with superficial temporal neocortex CCM-related epilepsy of long disease duration and poor responsiveness to AEDs but yet a “structurally normal” hippocampus, the extent of resection was decided mainly according to the extent of hippocampal hypometabolism. Outcome Evaluation All patients were followed up postoperatively once by the end of the third month and yearly thereafter (minimum time, 24 months). Seizure outcome was classified as complete freedom from seizures since surgery, that is, Engel class I, or not seizurefree (Engel class II-IV). The standard postoperative AED protocol consisted of continuation of patients’ preoperative AED regimen for a minimum of 2 years postoperatively. Based on the related

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results, the types and doses of AED agents were modified (maintained, reduced, or stopped). Neuropathology Surgical specimens from all patients were fixed in formaldehyde overnight and embedded into paraffin. Macroscopic and histopathologic examinations were performed by experienced neuropathologists. Neuropathologic staining constituted at least hematoxylin & eosin, Prussian blue, and Elastica van Gieson for assessment of CCMs and neuronal nuclei antigen immunohistochemistry for evaluation of focal cortical dysplasia (FCD, for lateral temporal lobe specimen). Statistical Analysis Variables including sex, age at seizure onset, epilepsy duration, lesion location, size of CCM, type of seizures, presence or absence of DRE, presence or absence of hippocampal sclerosis, PET hypometabolism, type of surgery (extent of resection), and presence or absence of FCD were studied in a univariate analysis to assess their association with seizure outcomes, which were categorized as a binary variable: Engel class I versus Engel class IIeIV. We used the Student t test and the Fisher exact test for continuous and categoric variables, respectively. P values of <0.05 were considered statistically significant. RESULTS Demographic Data Our study population consisted of 47 patients, 27 of whom were male (57.42%). The mean age at seizure onset was 24.7 years (range, 6e40 years). The mean duration of epilepsy was 9.9 years (range, 0.6e27.9 years). The mean age at surgery was 34.3 years (range, 19e51 years). Epilepsy Type/Seizure Semiology Of the 47 patients, 28 (59.6%) were classified as having DRE, 12 (25.5%) had CE, and 7 (14.9%) had SS (Table 1). Patients with CE had the lowest mean age at seizure onset, whereas those with DRE had the greatest symptom duration. Thirty-four patients (72.3%) had unilateral epileptic discharges, 11 (23.4%) had bilateral discharges, and 2 (4.3%) had no discharges on interictal electroencephalography (EEG), respectively. Of the 36 patients who experienced habitual seizures during vEEG monitoring, 29 (80.5%) had unilateral temporal epileptic discharges on ictal EEG, 2 (5.6%) had bilateral discharges, and 1 (2.8%) had contralateral discharges. In 4 (11.1%) patients, ictal EEG revealed no definite epileptic focus. Analyzing EEG with ictal clinical semiology documented by vEEG or seizure diary, the seizure types were classified as follows: focal aware seizure in 3 patients, focal impaired awareness seizure in 21 patients, and focal to bilateral tonic-clonic seizure in 23 patients. CCMs Localization and PET Data Right temporal lobe lesions were seen in 25 (53.2%) patients. CCMs were located in the neocortex in 34 (72.3%) patients, among whom 31 and 3 CCMs, respectively, were shown to affect the superficial neocortex (21 lateral temporal neocortex and 10 temporal pole) (Figures S1 and S4) and the fusiform gyrus. The mesial

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SURGERY FOR TEMPORAL LOBE EPILEPSY ASSOCIATED WITH CEREBRAL CAVERNOUS MALFORMATIONS

Table 1. Demographic Data Group

All Patients

DRE

CE

SS

47

28

12

7

8/4

4/3

Total number Gender, M/F

27/20

15/13

Mean age at onset (years)

24.96  8.2

25.54  8.5

20.58  6.0 30.14  7.1

Mean age at surgery (years)

36.02  9.1

39.54  8.5

30.25  7.8 31.86  7.3

Mean duration of 11.04  9.3 14.00  10.4 symptoms (years)

9.67  3.8

1.61  0.9

DRE, drug-resistant epilepsy; CE, chronic epilepsy; SS, sporadic seizures.

temporal structures were affected in 13 patients: hippocampusparahippocampal complex in 5, hippocampi in 3, parahippocampal gyri in 2, and amygdala in 3. Normal metabolism of the temporal lobe was seen in 7 of 7 patients in the SS group, except for focal hypometabolism of CMs. Hypometabolism was seen in all the patients with long-term duration but in 3 CE patients with posterior inferior temporal gyrus CMs and posterior middle temporal gyrus CMs, respectively. Of the 31 patients with CCM of the superficial neocortex, 7 (4 SS and 3 CE) had no hippocampal sclerosis and normal PET, 14 (3 CE and 11 DRE) had no sclerosis (Figures S2 and S3) but ipsilateral temporal hypometabolism (Figures S6-S8), and 10 (1 CE and 9 DRE) had obvious hippocampal sclerosis and hypometabolism. Of the 3 patients with fusiform CCMs, 2 had obvious hippocampal sclerosis and hypometabolism; the third had no sclerosis but moderate hypometabolism. Surgical Management The CMs of all patients were resected in this study, but pure lesionectomy was not done in any case. Eighteen patients underwent operation with the assistance of neuronavigation. As

shown in Table 2, in 13 patients the temporal CMs had directly invaded the hippocampus, the amygdala, or the parahippocampal gyrus, and therefore the affected structures were resected (being completely resected in 6 of 6 patients with DRE and 4 of 4 patients with CE, and partially resected in 3 of 3 patients with SS). Of the 31 patients with superficial neocortical CMs, EL (of cavernoma and hemosiderin-stained brain) alone was done in 13 cases: 4/4 SS, 5/7 CE, and 4/20 DRE. They had radiographically normal hippocampus, with isometabolism or regional hypometabolism in the temporal lobe. AMTL or AH was performed in addition to EL (Figure S5) in 18 cases (2/7 CE and 16/20 DRE) (with obvious hippocampal sclerosis in 10 DRE; MRI-PETþ in 2 CE and 6 DRE). Intraoperative ECoG was routinely used for detecting superficial neocortical locations, but the results did not lead to alterations of the surgical plan. One patient with SS and left superior temporal gyrus CM underwent incomplete rim resection because of eloquent cortex limitations. Among the 3 patients whose CCMs were located in the fusiform gyrus, EL combined with AH was done in 2/2 patients with DRE and with obvious hippocampal sclerosis on MRI and hypometabolism on PET. The third patient had dominantside CMs and radiographically normal hippocampus, but PET-CT examination showed moderate hypometabolism. Intraoperative visualization revealed abnormal hemosiderin staining extended to the hippocampal-parahippocmapal region, which somewhat tough on palpation. Given the clinical semiology of mesial temporal lobe epilepsy and CE, this patient was treated with lesionectomy and selective hippocampectomy (i.e., sparing the amygdala). In sum, with respect to the patients with neocortical CMs, the proportions of the additional hippocampectomy in the SS, CE, and DRE groups were 0/4, 3/8, and 18/22, respectively. Pathologic Results Forty-seven patients were confirmed as having CMs by gross and histopathologic examination. Of the 34 patients with neocortical lesions, 21 underwent hippocampal resection, and all the hippocampal specimens were subjected to histopathologic analysis. Five patients had minor degrees of hippocampal sclerosis (Figure S9), whereas 13 patients had obvious hippocampal sclerosis (inclusive

Table 2. Hippocampal MRI and Ipsilateral PET with Respect to CCM Localization Abnormal Hippocampal MRI and Abnormal Ipsilateral PET

Normal Hippocampal MRI but Abnormal Ipsilateral PET

Normal Hippocampal MRI and Normal Ipsilateral PET

(SS/CE/DRE)

(SS/CE/DRE)

(SS/CE/DRE)

21 (0/5/16)

16 (0/4/12)

10 (7/3/0)

6 (0/2/4)

4 (0/2/2)

3 (3/0/0)

12 (0/1/11)

15 (0/4/11)

7 (4/3/0)

10 (0/1/9)

14 (0/3/11)

7 (4/3/0)

2 (0/0/2)

1 (0/1/0)

0 (0/0/0)

Location Total Mesial temporal CM Temporal neocortex CM Superficial neocortex Deep neocortex (fusiform gyrus)

Abnormal hippocampal MRI ¼ hippocampal sclerosis; abnormal ipsilateral PET ¼ ipsilateral temporal lobe hypometabolism. Temporal neocortex CMs comprise superficial neocortex and deep neocortex (fusiform gyrus). MRI, magnetic resonance imaging; PET, positron emission tomography; CCM, cerebral cavernous malformation; SS, sporadic seizures; CE, chronic epilepsy; DRE, drug-resistant epilepsy; CM, cavernous malformation.

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ORIGINAL ARTICLE PENG-FAN YANG ET AL.

SURGERY FOR TEMPORAL LOBE EPILEPSY ASSOCIATED WITH CEREBRAL CAVERNOUS MALFORMATIONS

Table 3. Postsurgical Seizure Control Location Total number (left/right)

Engel I Engel II Engel III Engel IV 39 (17/22) 3 (2/1)

4 (2/2)

1 (1/0)

Mesial temporal CM

11

2

0

0

Temporal neocortex CM

28

1

4

1

Superficial neocortex

25

1

4

1

Deep neocortex (fusiform gyrus)

3

0

0

0

Temporal neocortex CMs comprise superficial neocortex and deep neocortex (fusiform gyrus). CM, cavernous malformation.

of 2 patients whose PET results revealed moderate hypometabolism although the MRI results were basically normal). Nevertheless, 3 of the 21 patients undergoing hippocampal resection were unable to receive definite diagnoses because of insufficient amount of obtained specimens. Of the 31 patients having temporal superficial cortex CCMs, merely 23 patients underwent FCD analysis for the sake of avoiding operational risk; excessive excision of the adjacent parenchyma, which potentially elevates surgical jeopardy, would have to be performed in the remaining patients if we wanted to acquire a sufficient amount of welloriented sections of the surrounding cortex for FCD assessment. Consequently, no FCD was identified in 4/4 SS patients. As for the 2 groups with symptoms of long duration, adjacent FCD was identified in 8 of the 19 patients: type Ia (Figures S10-S12) in 5 and type Ib in 3. Moreover, balloon cells were not identified in any of the patients. Using the recently proposed International League Against Epilepsy classification, these lesions would all be classified as FCD type IIIc.4 In patients with FCD, 6 underwent superficial cortex lesionectomy combined with AH. Notably, 1 CE patients with left posterior middle temporal gyrus CM was also included. Taking into account the possible cognitive risk after a large resection of the CM and the anterior mesial and lateral temporal lobes, the posterior rim was resected conservatively in this patient. However, the specimen did not show the edge of the FCD, possibly because of the residual seizure onset zone. The seizure outcome in this patient was Engel class II. Postoperative Follow-Up and Seizure Control Outcome The average follow-up period was 63 months (range, 24e133 months), during which no patients were lost. The efficiency of seizure control was ranked according to Engel (Table 3): Engel class I seizure control was observed in 39 (83.0%) of the total patients at the last follow-up, class II in 3 (6.4%), class III in 4 (8.5%), and class IV in 1 (2.1%). In this combined neocortical cohort, the percentages of Engel class I seizure outcomes in patients in the neocortical and mesial CM groups were, respectively, 82.3% (28/34) and 84.6% (11/13). The Fisher exact test showed no significant association between radiographic lesion locations (neocortical vs. mesial) and postoperative seizure free outcomes (P ¼ 0.29). In the neocortical CM group, 3 fusiform patients attained Engel class I after EL combined with AH or hippocampectomy. Thirteen of the remaining 31 superficial CM patients reserved the hippocampus and attained 4

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suboptimal outcomes (also belonging to the 6 MRI-PETþ patients); 18 of the remaining patients underwent additional AH, but only 2 patients (inclusive of 1 with incomplete resection of adjacent FCD) attained suboptimal outcomes. Of the 15 MRI-PETþ patients with a long-term seizure duration, seizure freedom was attained in 8 of the 9 patients with additional hippocampectomy and in 2 of the 6 patients without additional hippocampectomy. Statistically, whether an epileptogenic hippocampus was resected or not did not significantly affect postoperative seizure-free rates (P ¼ 0.60). There was also a difference in seizure outcome in the mesial CM group according to the extent of hippocampectomy: 2 patients (1 DRE and 1 CE) attained suboptimal outcomes because of insufficient resection of the posterior part of the hippocampusparahippocampal complex. Interestingly, 3 SS patients achieved seizure freedom (Engel class I) after insufficient resection. Univariate analysis showed no statistically significant difference between age at seizure onset and postoperative seizure control. When the duration of epilepsy was evaluated as a continuous variable using the Mann-Whitney U test, there was a negative significant association between duration of epilepsy and seizurefree outcomes (P ¼ 0.15). Patients who presented with new-onset seizures (7 patients) had a better seizure-free outcome than were those with diagnoses of long-term seizure disorder. Seizure freedom rates in the SS, CE, and DRE groups were 100%, 75%, and 82.1%, respectively. Altogether, the seizure freedom rate of the CE cohort, which underwent less aggressive resections, was lower than that of the DRE cohort. Similarly, the seizure freedom rate in the patients with left-sided disease who underwent less aggressive resection (77.3%, 17/22) was comparatively lower than that in the patients with right-sided disease (88.0%, 22/25), suggesting that the extent of conservative resection was associated with the prognosis for seizure control.

Intelligence Quotient Testing: VIQ, PIQ, and FIQ Table 4 lists the intelligence quotient (IQ) patients of the subjects before surgery, 3 months after surgery, and 24 months after surgery, respectively. Before this study, no patients in the SS group had received declined IQ scores. By contrast, 29% of the CE and DRE groups were shown to display impaired cognition. At the 24-month follow-up visit, there was a significant increase in PIQ and FIQ scores in the patients as a whole, especially in those with a right temporal focus. In the right-sided cohort, the VIQ scores remained stable between the preoperative state and the 3-month postoperative follow-up visit. Although this score had a slight increase at the 24-month follow-up visit, there was no statistical significance in comparison with the preoperative state. Postoperatively, patients with left temporal disease had a nonsignificant tendency to have lower VIQ scores. In the neocortical CM cohort, no patients revealed VIQ decrease after EL. There was an obvious decrease in VIQ scores in 1/13 patients belonging to the mesial CM cohort (left 1/5) and 4/34 patients in the neocortical CM cohort (left 4/17). The 5 patients with an obvious decrease in VIQ were all MRI-PETþ patients whose hippocampus was resected because of subtle hippocampal sclerosis. The VIQ scores returned to near the preoperative level at the 24-month follow-up visit in 3/5 patients, and VIQ decrease remained in 2/5 patients.

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93 IQ, intelligence quotient; CM, cavernous malformation; VIQ, verbal intelligence quotient; PIQ, performance intelligence quotient; FIQ, full intelligence quotient.

76.50  23.33

97

86.00  12.73 75.00  25.46

92 95

74.50  23.33 83.00  9.90

98 93

72.50  24.79

89

80.50  13.44 82.00  8.49 81.00  15.56 Left

Right

Deep neocortex (fusiform gyru)

88

93.25  19.39 90.19  18.94 Right

89

94.13  18.27 97.13  18.65

92.94  18.81

94.20  18.97

Temporal neocortex CM

90.12  18.34

90.81  18.49

90.13  19.19

95.94  19.83

92.38  18.56

93.38  19.22

94.06  17.69

89.13  15.54

97.12  18.06

95.60  18.07

93.29  18.61

87.20  14.64 86.47  16.40

92.53  17.98 96.06  19.21

95.27  18.76 82.80  15.67

90.29  18.60 90.71  17.91

DISCUSSION

86.73  15.83

Right

Postoperative Complications There were no operative or perioperative morbidities or mortality. No severe speech problems were identified. No patients were reported to have visual field defect after the surgery, but postoperative visual field examination showed mild contralateral upper quadrantanopia in both eyes of 7 patients.

Left

89.53  16.15

87.65  16.22 94.47  17.49 85.06  16.88 93.82  18.19 81.59  16.27 88.47  15.76 92.76  18.33 86.06  15.43 Left

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Superficial neocortex

87.75  10.29 91.38  11.64

85.76  15.63

87.20  20.78 90.40  21.04

86.50  11.07

83.60  21.08 88.80  19.84

90.38  12.39 82.00  12.40

80.00  21.48

87.75  14.34 81.25  13.37

83.88  13.45

89.40  18.54 83.60  22.56

Right

Mesial temporal CM

Left

86.20  21.15

83.88  12.83

92.04  15.77

84.60  20.28

87.55  16.81 93.55  7.90

95.28  16.26

85.50  16.27

90.28  17.30 90.60  16.11

84.73  17.38 92.68  18.21

94.24  17.27 87.64  17.06

81.23  17.03

91.28  17.38 87.28  17.14 Right

88.52  16.65

92.00  17.98 85.50  16.71 Left Total

Location

PIQ

87.95  16.60

PIQ PIQ

SURGERY FOR TEMPORAL LOBE EPILEPSY ASSOCIATED WITH CEREBRAL CAVERNOUS MALFORMATIONS

VIQ

FIQ

VIQ

3 Months After Operation Before Operation

Table 4. IQ Scores of Patients Before Surgery, 3 Months After Surgery, and 24 Months After Surgery

FIQ

VIQ

24 Months After Operation

FIQ

PENG-FAN YANG ET AL.

We present one of the largest single-center cohorts of surgically treated patients with solitary temporal CCMs and CCM-associated temporal lobe epilepsy. Of 47 patients who underwent 1-stage resective epilepsy surgery after noninvasive presurgical anatomoelectro-clinical evaluation, 41 patients had excellent postoperative seizure control outcomes (Engel class I) at a minimum follow-up time of 24 months, with Engel class I rate of 100%, 75%, and 82.1% in SS patients, CE patients, and DRE patients, respectively. The details of their presurgical evaluation, operative treatment, pathologic findings, and postoperative seizure control outcomes were analyzed to address a still open question about optimal operative strategies for these lesions. As for extratemporal lobe epileptic CCMs, seizure freedom can most often be achieved by complete removal of the CCMs and the tissues immediately surrounding them6-12; however, for temporal lobe CCMs, apart from EL, seizure freedom requires the removal of any epileptic tissues within the mesial temporal structures.17,19 Therefore, it is critical to carry out detailed assessments of the possible risks associated with the neurologic and cognitive sequelae (particularly taking place in the dominant temporal lobe) and potential benefits with respect to improved therapeutic effects resulting from extended resection. However, in clinical practice, it is difficult to exactly assess both the epileptogenicity of the mesial temporal structures and the necessity of resecting the mesial structures for better seizure control. Although extraoperative intracranial EEG, such as stereo EEG recordings and mapping, helps a lot with addressing these difficulties, such an approach is both invasive and expensive.5 On the other hand, certain patients, although having displayed moderate epileptogenicity in hippocampal structures, still show a good response to AED treatment. Accordingly, preserving the hippocampus might be a reasonable option that avoids cognitive decline and other neurologic disorders. To avert unnecessary hippocampal resection, some reports have suggested a 2-step operation strategy: treating temporal CCMs initially with lesionectomy, followed by further treatment with AH if no improvement occurs.2,18 In developing countries such as China, surgical safety, expense, and convenience are the important factors that affect patients’ willingness to receive a potentially efficacious operative plan. Regarding CCM-associated temporal lobe epilepsy, which is relatively easier to diagnose and orientate, we propose to perform noninvasive presurgical evaluation as far as possible. In this regard, we have developed a 1-stage surgical strategy for the treatment of temporal lobe epilepsy patients with concordant clinical semiology, which is based on EEG, MRI, and PET analyses. In such a series, the pivotal factor that determines whether or not to further perform AH after EL is the anatomic relationship between epileptogenic CCMs and the mesiotemporal structures. The mesiotemporal structures encroached on by the CCMs were

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ORIGINAL ARTICLE PENG-FAN YANG ET AL.

SURGERY FOR TEMPORAL LOBE EPILEPSY ASSOCIATED WITH CEREBRAL CAVERNOUS MALFORMATIONS

resected either completely or partially, which depends on several factors (e.g., epilepsy duration, AED responsiveness, and brain hypometabolism) having been indicated in several previous studies.17,19 In cases where the CCMs and the hemosiderin fringe are confined to the superficial temporal neocortex, the mesial temporal structures will not have to be resected unless there is radiographic evidence of hippocampal sclerosis. There are 2 somewhat challenging cases: (1) temporal CCM, which is in close proximity to the mesiotemporal structures but does not substantially invade them; and (2) superficial temporal CCM, which leads to long-term seizures and shows poor AED responsiveness but has a “structurally normal” hippocampus (indicated by MRI analysis). Moreover, metabolic changes in the ipsilateral temporal lobe, as revealed by interictal 18FDG-PET, play an auxiliary role in evaluating the epileptogenicity of the hippocampal structures and its extent. In studying the combination of these factors with others (e.g., AED responsiveness, occupation, risks), we came up with a surgical strategy for deciding the extent of resection. Hippocampal sclerosis is thought to be closely related to neuronal loss and gliosis, which is partially genetics driven and partially secondary to repeated insults from hyperexcitability and recurrent seizure activity originating in the temporal lobe.20 We used a 1.5-T MRI scanner before 2007 and a 3.0-T MRI scanner between 2007 and 2014. The limited resolution of the current clinical protocols precludes direct visualization of hippocampal subfields using MRI.21 There may be false-negative diagnoses of hippocampal sclerosis resulting from the absence of hippocampal atrophy in patients or increased signal on T2W images. However, patients with such subtle hippocampal sclerosis often present positive results under metabolic examination.22-24 Of 34 patients with neocortical CM, 7 patients (4 SS and 3 CE) revealed PET isometabolism and thus did not undergo hippocampectomy; 12 patients with radiographic evidence of hippocampal sclerosis showed a broad distribution of ipsilateral PET hypometabolism in the anterior part of the affected temporal lobes, including the mesial, basal, and lateral temporal areas, and most prominently in the hippocampus. Therefore, they all received AH treatment. The remaining 15 patients, belonging to the long-standing epilepsy (CE and DRE) groups, showed no obvious hippocampal sclerosis but presented comparatively more significant hypometabolism in the above-mentioned areas. Nine of these patients, having received diagnoses of sclerosis of different pathologic degrees, underwent AH. After resection, 8 patients were shown to attain optimal seizure outcomes (i.e., Engel class I). By contrast, of the 6 patients with reserved hippocampus, 4 were shown to attain suboptimal outcomes. These results revealed a significant association between resection of epileptogenic hippocampus and seizure outcomes, which were in accordance with the previous reports.12,25,26 Another cause of extralesional epileptogenicity in CCMs is the possible presence of type I FCD in the cortical area surrounding the lesion. An association of FCD type I with vascular malformations has been classified as FCD type IIIc according to the recently issued classification of FCDs.16 This association has been described previously in 2 case reports.27,28 More recently, Chen et al.29 and Niehussmann et al.30 have described FCD type IIIc in their surgical series, although they reported sharply different incidences (72% and 4.3%, respectively). It remains uncertain whether the

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coexistence of FCD type IIIc and CCM results from a shared or related developmental aberration or whether the focal cortical dysplasia is an acquired alteration secondary to the cavernoma and sustained plasticity and neurogenesis in the postnatal brain. We tried our best to get sufficient adjacent parenchyma excised from the patients with superficial neocortical CCM, allowing for well-oriented sections of the surrounding cortex to enable evaluation of the presence of FCD. Sufficient specimens were obtained in 23/31 patients for FCD study. No FCD was identified adjacent to the cavernous angiomas in 4/4 patients in the SS subgroup. However, FCD type IIIc was identified in 8/19 (42.1%) patients with superficial neocortical CCMs with long-term epilepsy duration. The pathologic ascertainment of overlying cortical dysplasia in 8 (42.1%) of the 19 cavernoma patients with long-term epilepsy duration suggests that this coexistence is more than just a chance, possibly being causative. The reason why and which CCMs cause FCD type IIIc after a long epilepsy duration remain enigmatic and need further study. Regardless of their pathogenetic origin, their synergistic seizurogenic potential renders these epilepsies intractable merely through medication. Accordingly, patients have to undergo surgical operation. In the 6 patients who underwent both AH and resection of the cortical dysplasia (FCD type IIIc) overlying the cavernoma, 5 of them attained seizure freedom possibly because of the complete resection of the cortical dysplasia. As for the 1 patient (with left superior temporal gyrus CM) who still experienced seizures after surgery, pathologic examination revealed incomplete resection of FCD. Owing to misgiving about the much greater extent of temporal resection, incomplete excision of the upper rim of the focus was performed. Nevertheless, we cannot conclusively ascertain that this contributed to the observed suboptimal therapeutic efficacy. In patients with sporadic seizures (short-term epilepsy before surgery), the outcome of seizure control (reaching 100% freedom from seizures) was excellent among others in our study, even though they merely underwent limited resection (i.e., without excision of the hippocampus). In 1 patient, we incompletely resected the rim because we did not expect to interfere with the language area. As for the patients with more longstanding seizure types (i.e., DRE and CE), though receiving EL, lengthy preoperative epilepsy duration and high seizure frequency were observed in correlation with slightly worse seizure outcomes. Unlike certain reports, our findings showed that seizure outcomes in the chronic epilepsy group were the worst, which might be attributable to incomplete resection. The lower rate of “good Engel class grades” for the chronic epilepsy group may result from the fact that operative strategy in those cases was not tailored well enough to the epileptogenic zone because such an epilepsy type did not appear to be very severe. This impression comes from the lack of drug resistance in this seizure subgroup; therefore, a less extensive resection of the mesiotemporal structures and the adjacent neocortex (possibly including secondary epileptogenic foci, such as FCD type IIIc) is usually considered. Conversely, the DRE patients and their relatives usually eagerly hope for relief from seizure, readily accepting more aggressive resection approaches with potentially higher risks of cognitive impairment and neuropsychiatric implications, particularly in the dominant temporal lobe. Accordingly, the doctors should find the balance between the seizure outcome and the option of resection approaches, especially when the foci are located in the dominant temporal lobe.

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The therapeutic efficacy of operation often declines while patients progress from sporadic seizures to chronic epilepsy. As a consequence, many researchers suggest that CCM-associated seizures should be treated with early surgery. However, in clinical practice, a majority of doctors differ about this suggestion. As a matter of fact, nearly all CCM patients presenting with a first seizure will have a relapse within 5 years.31 Especially for the epileptogenic CCMs in temporal lobe, which have a potentially higher risk of developing into drug-resistant epilepsy and are often easy to reach surgically, surgical intervention should be considered early, even after only 1 or more seizures. This also eliminates the risk of bleeding. For young patients who display a greater possibility of stopping medication after surgery, curing them of seizures instead of merely controlling the disease seems to be more meaningful in the improvement of their cognitive abilities and enhancement of their neuropsychological function. Study Limitations The conclusion of this study is derived from a retrospective observation rather than a prospective analysis. To perform a decisive assessment, it would be better to gain a sufficiently large number of specimens; however, we acquired only partial hippocampal and FCD samples because of safety restrictions in some cases. Therefore, we expect, in our future studies, to improve the proposed algorithm and ameliorate the surgical management strategy by increasing the sample size, which theoretically enhances the statistical significance of the results. Moreover, if preoperative intracranial long-term EEG monitoring were carried out in this study to ascertain the focal regions, followed by comparison with the results derived from noninvasive MRI and PET assessments, a more meaningful research achievement would supposedly be obtained.

REFERENCES 1. Menzler K, Chen X, Thiel P, Iwinska-Zelder J, Miller D, Reuss A, et al. Epileptogenicity of cavernomas depends on (archi-) cortical localization. Neurosurgery. 2010;67:918-924. 2. Awad I, Jabbour P. Cerebral cavernous malformations and epilepsy. Neurosurg Focus. 2006;21:e7. 3. Clatterbuck RE, Eberhart CG, Crain BJ, Rigamonti D. Ultrastructural and immunocytochemical evidence that an incompetent bloodbrain barrier is related to the pathophysiology of cavernous malformations. J Neurol Neurosurg Psychiatry. 2001;71:188-192. 4. Bourgeois M, Di Rocco F, Sainte-Rose C. Lesionectomy in the pediatric age. Childs Nerv Syst. 2006;22:931-935.

CONCLUSIONS Hippocampal sclerosis and adjacent FCD may occur secondarily to the occurrence of epileptogenic temporal CCM after a history of prolonged seizure. Two or more epileptogenic factors are able to synergistically contribute to potentiating the severity of epilepsy, rendering them intractable. Therefore, surgical intervention should be considered as early as possible. Apart from clinical data, EEG and high-field MRI and FDG-PET are regular noninvasive approaches to assess the hippocampal epileptogenicity, especially in patients having subtle hippocampal sclerosis without hippocampal atrophy or showing T2 signal changes. Excision of the epileptogenic hippocampus and extent of the excision are of great concern to postoperative outcomes in patients with chronic seizures. The assumption regarding “more extensive resection, better outcome” may well be true when only postoperative seizure outcomes in epileptic patients are considered, but it is questionable in terms of cognitive and neurologic function. To the best of our knowledge, former clinical documents mostly suggested that the extent of lesionectomy be defined on the basis of the results of regular noninvasive examination. In this study, we proposed to determine the extent of lesionectomy, in a more proper way, by combining the conventional examination approaches with PET, which can monitor brain metabolic status. In our opinion, intracranial EEG is comparatively much more invasive, and therefore it is usually not recommended to be applied in the diagnosis of apparent epileptic symptoms and epileptogenic lesions on MRI. In this regard, our study suggests that we take advantage of minimally invasive approaches to settle a complicated problem, even though they may give rise to a similar therapeutic outcome. Altogether, surgical planning should be done prudently depending on the parameters of AED responsiveness and operative risks.

stained brain also is removed. Epilepsia. 2006;47: 563-566. 7. Chang EF, Gabriel RA, Potts MB, Garcia PA, Barbaro NM, Lawton MT. Seizure characteristics and control after microsurgical resection of supratentorial cerebral cavernous malformations. Neurosurgery. 2009;65:31-37 [discussion: 37-38]. 8. Cossu M, Raneri F, Casaceli G, Gozzo F, Pelliccia V, Lo RG. Surgical treatment of cavernoma-related epilepsy. J Neurosurg Sci. 2015; 59:237-253. 9. Hammen T, Romstock J, Dorfler A, Kerling F, Buchfelder M, Stefan H. Prediction of postoperative outcome with special respect to removal of hemosiderin fringe: a study in patients with cavernous haemangiomas associated with symptomatic epilepsy. Seizure. 2007;16:248-253.

5. Siegel AM, Roberts DW, Harbaugh RE, Williamson PD. Pure lesionectomy versus tailored epilepsy surgery in treatment of cavernous malformations presenting with epilepsy. Neurosurg Rev. 2000;23:80-83.

10. von der Brelie C, Malter MP, Niehusmann P, Elger CE, von Lehe M, Schramm J. Surgical management and long-term seizure outcome after epilepsy surgery for different types of epilepsy associated with cerebral cavernous malformations. Epilepsia. 2013;54:1699-1706.

6. Baumann CR, Schuknecht B, Lo Russo G, Cossu M, Citterio A, Andermann F, et al. Seizure outcome after resection of cavernous malformations is better when surrounding hemosiderin-

11. von der Brelie C, Schramm J. Cerebral cavernous malformations and intractable epilepsy: the limited usefulness of current literature. Acta Neurochir (Wien). 2011;153:249-259.

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12. Yeon JY, Kim JS, Choi SJ, Seo DW, Hong SB, Hong SC. Supratentorial cavernous angiomas presenting with seizures: surgical outcomes in 60 consecutive patients. Seizure. 2009;18:14-20. 13. Batra S, Lin D, Recinos PF, Zhang J, Rigamonti D. Cavernous malformations: natural history, diagnosis and treatment. Nat Rev Neurol. 2009;5: 659-670. 14. Kivelev J, Niemela M, Blomstedt G, Roivainen R, Lehecka M, Hernesniemi J. Microsurgical treatment of temporal lobe cavernomas. Acta Neurochir (Wien). 2011;153:261-270. 15. Rocamora R, Mader I, Zentner J, SchulzeBonhage A. Epilepsy surgery in patients with multiple cerebral cavernous malformations. Seizure. 2009;18:241-245. 16. Blumcke I, Thom M, Aronica E, Armstrong DD, Vinters HV, Palmini A, et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia. 2011;52:158-174. 17. Upchurch K, Stern JM, Salamon N, Dewar S, Engel J, Vinters HV, et al. Epileptogenic temporal cavernous malformations: operative strategies and postoperative seizure outcomes. Seizure. 2010;19: 120-128.

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SURGERY FOR TEMPORAL LOBE EPILEPSY ASSOCIATED WITH CEREBRAL CAVERNOUS MALFORMATIONS

18. Ferroli P, Casazza M, Marras C, Mendola C, Franzini A, Broggi G. Cerebral cavernomas and seizures: a retrospective study on 163 patients who underwent pure lesionectomy. Neurol Sci. 2006;26: 390-394.

24. Yang PF, Pei JS, Zhang HJ, Lin Q, Mei Z, Zhong ZH, et al. Long-term epilepsy surgery outcomes in patients with PET-positive, MRInegative temporal lobe epilepsy. Epilepsy Behav. 2014;41:91-97.

19. Vale FL, Vivas AC, Manwaring J, Schoenberg MR, Benbadis SR. Temporal lobe epilepsy and cavernous malformations: surgical strategies and long-term outcomes. Acta Neurochir (Wien). 2015; 157:1887-1895 [discussion: 1895].

25. Jehi LE, Palmini A, Aryal U, Coras R, Paglioli E. Cerebral cavernous malformations in the setting of focal epilepsies: pathological findings, clinical characteristics, and surgical treatment principles. Acta Neuropathol. 2014;128:55-65.

20. McNamara JO. Cellular and molecular basis of epilepsy. J Neurosci. 1994;14:3413-3425.

26. Van Gompel JJ, Rubio J, Cascino GD, Worrell GA, Meyer FB. Electrocorticography-guided resection of temporal cavernoma: is electrocorticography warranted and does it alter the surgical approach? J Neurosurg. 2009;110:1179-1185.

21. Sone D, Sato N, Maikusa N, Ota M, Sumida K, Yokoyama K, et al. Automated subfield volumetric analysis of hippocampus in temporal lobe epilepsy using high-resolution T2-weighed MR imaging. Neuroimage Clin. 2016;12:57-64. 22. Capraz IY, Kurt G, Akdemir O, Hirfanoglu T, Oner Y, Sengezer T, et al. Surgical outcome in patients with MRI-negative, PET-positive temporal lobe epilepsy. Seizure. 2015;29:63-68. 23. Gok B, Jallo G, Hayeri R, Wahl R, Aygun N. The evaluation of FDG-PET imaging for epileptogenic focus localization in patients with MRI positive and MRI negative temporal lobe epilepsy. Neuroradiology. 2013;55:541-550.

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focal cortical dysplasia. Clin Neuropathol. 2013;32: 31-36. 30. Niehusmann P, Becker AJ, Malter MP, Raabe A, Boström A, von der Brelie C. Focal cortical dysplasia type IIIc associates with multiple cerebral cavernomas. Epilepsy Res. 2013;107:190-194. 31. Josephson CB, Leach JP, Duncan R, Roberts RC, Counsell CE, Salman RAS. Seizure risk from cavernous or arteriovenous malformations: prospective population-based study. Neurology. 2011; 76:1548-1554.

27. Giulioni M, Zucchelli M, Riguzzi P, Marucci G, Tassinari CA, Calbucci F. Co-existence of cavernoma and cortical dysplasia in temporal lobe epilepsy. J Clin Neurosci. 2007;14:1122-1124.

Conflict of interest statement: This research was supported by Fujian Provincial Department of Science and Technology (Grant: 2015Y0028).

28. Maciunas JA, Syed TU, Cohen ML, Werz MA, Maciunas RJ, Koubeissi MZ. Triple pathology in epilepsy: coexistence of cavernous angiomas and cortical dysplasias with other lesions. Epilepsy Res. 2010;91:106-110.

Citation: World Neurosurg. (2017). https://doi.org/10.1016/j.wneu.2017.11.067

29. Chen DJ, Severson E, Prayson RA. Cavernous angiomas in chronic epilepsy associated with

1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.

Received 5 August 2017; accepted 14 November 2017

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SURGERY FOR TEMPORAL LOBE EPILEPSY ASSOCIATED WITH CEREBRAL CAVERNOUS MALFORMATIONS

SUPPLEMENTARY DATA Supplementary Figures. Radiologic and histopathologic studies in a 30-year-old woman with a left temporal pole cavernous malformation and drug-resistant epilepsy who underwent left anterior temporal lobectomy and became seizure free.

Supplementary Figure S3. Magnetic resonance imaging fluid attenuated inversion recovery coronal image showing the left hippocampal body without atrophy or signal changes.

Supplementary Figure S1. Magnetic resonance imaging fluid attenuated inversion recovery coronal image through the section of left temporal pole showing the cavernous malformation.

Supplementary Figure S2. Magnetic resonance imaging fluid attenuated inversion recovery coronal image through the left hippocampal head without atrophy or signal changes.

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Supplementary Figure S4. T2-weighted axial magnetic resonance image demonstrating the left temporal pole cavernous malformation.

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ORIGINAL ARTICLE PENG-FAN YANG ET AL.

SURGERY FOR TEMPORAL LOBE EPILEPSY ASSOCIATED WITH CEREBRAL CAVERNOUS MALFORMATIONS

Supplementary Figure S7. Preoperative positron emission tomographic image (coronal image) showing both the left mesial temporal cortex and the lateral cortex metabolism obviously reduced. Supplementary Figure S5. Postoperative magnetic resonance imaging fluid attenuated inversion recovery image 2 weeks after the left anterior temporal lobectomy including the cavernous malformation.

Supplementary Figure S6. Preoperative positron emission tomographic image (coronal image) showing left temporal pole cortex metabolism severely reduced.

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Supplementary Figure S8. Preoperative positron emission tomographic image (axial image) showing both the left mesial temporal cortex and the lateral cortex metabolism obviously reduced.

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SURGERY FOR TEMPORAL LOBE EPILEPSY ASSOCIATED WITH CEREBRAL CAVERNOUS MALFORMATIONS

Supplementary Figure S9. Photomicrograph of hippocampal sclerosis (CA1 area of hippocampal head) (hematoxylin and eosin stain; magnification 100).

Supplementary Figure S10. Low-power view of whole mount of lesion showing sufficient (for focal cortical dysplasia study) cortical tissue immediately surrounding the cavernous malformation containing back-to-back hyalinized vascular channels without intervening brain parenchyma (hematoxylin and eosin stain).

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Supplementary Figure S11. High-power view of lesion showing abnormal radial cortical lamination (focal cortical dysplasia Ia) adjacent to the cavernous malformation. (Neuronal nuclei antigen stained photomicrograph, inset in Figure 10).

Supplementary Figure S12. High-magnification (inset in Figure 10) showing formation of microcolumns of >8 neurons aligned in a vertical direction within layer 3.

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