Ultrasonographic features of focal cortical dysplasia and their relevance for epilepsy surgery

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OBJECTIVE

Surgery has proven to be the best therapeutic option for drug-refractory cases of focal cortical dysplasia (FCD)–associated epilepsy. Seizure outcome primarily depends on the completeness of resection, rendering the intraoperative FCD identification and delineation particularly important. This study aims to assess the diagnostic yield of intraoperative ultrasound (IOUS) in surgery for FCD-associated drug-refractory epilepsy.

METHODS

The authors prospectively enrolled 15 consecutive patients with drug-refractory epilepsy who underwent an IOUS-assisted microsurgical resection of a radiologically suspected FCD between January 2013 and July 2016. The findings of IOUS were compared with those of presurgical MRI postprocessing and the sonographic characteristics were analyzed in relation to the histopathological findings. The authors investigated the added value of IOUS in achieving completeness of resection and improving postsurgical seizure outcome.

RESULTS

The neurosurgeon was able to identify the dysplastic tissue by IOUS in all cases. The visualization of FCD type I was more challenging compared to FCD II and the demarcation of its borders was less clear. Postsurgical MRI showed residual dysplasia in 2 of the 3 patients with FCD type I. In all FCD type II cases, IOUS allowed for a clear intraoperative visualization and demarcation, strongly correlating with presurgical MRI postprocessing. Postsurgical MRI confirmed complete resection in all FCD type II cases. Sonographic features correlated with the histopathological classification of dysplasia (sonographic abnormalities increase continuously in the following order: FCD IA/IB, FCD IC, FCD IIA, FCD IIB). In 1 patient with IOUS features atypical for FCD, histopathological investigation showed nonspecific gliosis.

CONCLUSIONS

Morphological features of FCD, as identified by IOUS, correlate well with advanced presurgical imaging. The resolution of IOUS was superior to MRI in all FCD types. The appreciation of distinct sonographic features on IOUS allows the intraoperative differentiation between FCD and non-FCD lesions as well as the discrimination of different histological subtypes of FCD. Sonographic demarcation depends on the underlying degree of dysplasia. IOUS allows for more tailored resections by facilitating the delineation of the dysplastic tissue.

ABBREVIATIONS AED = antiepileptic drug; ECoG = electrocorticography; EEG = electroencephalography; FCD = focal cortical dysplasia; ILAE = International League Against Epilepsy; IOUS = intraoperative ultrasound.

Abstract

OBJECTIVE

Surgery has proven to be the best therapeutic option for drug-refractory cases of focal cortical dysplasia (FCD)–associated epilepsy. Seizure outcome primarily depends on the completeness of resection, rendering the intraoperative FCD identification and delineation particularly important. This study aims to assess the diagnostic yield of intraoperative ultrasound (IOUS) in surgery for FCD-associated drug-refractory epilepsy.

METHODS

The authors prospectively enrolled 15 consecutive patients with drug-refractory epilepsy who underwent an IOUS-assisted microsurgical resection of a radiologically suspected FCD between January 2013 and July 2016. The findings of IOUS were compared with those of presurgical MRI postprocessing and the sonographic characteristics were analyzed in relation to the histopathological findings. The authors investigated the added value of IOUS in achieving completeness of resection and improving postsurgical seizure outcome.

RESULTS

The neurosurgeon was able to identify the dysplastic tissue by IOUS in all cases. The visualization of FCD type I was more challenging compared to FCD II and the demarcation of its borders was less clear. Postsurgical MRI showed residual dysplasia in 2 of the 3 patients with FCD type I. In all FCD type II cases, IOUS allowed for a clear intraoperative visualization and demarcation, strongly correlating with presurgical MRI postprocessing. Postsurgical MRI confirmed complete resection in all FCD type II cases. Sonographic features correlated with the histopathological classification of dysplasia (sonographic abnormalities increase continuously in the following order: FCD IA/IB, FCD IC, FCD IIA, FCD IIB). In 1 patient with IOUS features atypical for FCD, histopathological investigation showed nonspecific gliosis.

CONCLUSIONS

Morphological features of FCD, as identified by IOUS, correlate well with advanced presurgical imaging. The resolution of IOUS was superior to MRI in all FCD types. The appreciation of distinct sonographic features on IOUS allows the intraoperative differentiation between FCD and non-FCD lesions as well as the discrimination of different histological subtypes of FCD. Sonographic demarcation depends on the underlying degree of dysplasia. IOUS allows for more tailored resections by facilitating the delineation of the dysplastic tissue.

Epilepsy affects more than 50 million people worldwide.54 Approximately one-third of patients show inadequate seizure control with antiepileptic drugs (AEDs).31,32 In children, focal cortical dysplasia (FCD) is the most frequent underlying pathology, accounting for more than 50% of cases.4 FCD was first described by Taylor et al. in 197150 and its classification has since undergone several modifications.37,40,49 In 2011, the first international consensus classification was released, differentiating 3 main categories of FCD and 9 subtypes,5 which have been widely used ever since.39 In FCD-associated epilepsy, seizure onset usually occurs in early childhood39,42,53 and the clinical course is often severe, with high seizure frequency, high rates of status epilepticus, and poor AED response.18 FCDs often escape detection on conventional MRI.9,13,27,30 However, recent technological advances, particularly MRI postprocessing techniques such as morphometric analysis,23,24,52 curvilinear reformatting,25 and quantitative FLAIR analysis20 increasingly allow for FCD detection and, consequently, for resection.

Surgery is the most promising intervention to achieve seizure control in FCD-associated drug-resistant epilepsy. The reported postsurgical freedom from seizures ranges widely—between 33% and 90%,9,10,12,15,21,22,47–49,51 depending to a great extent on presurgical candidate selection. The identification of the precise extent of the dysplastic cortical region and, consequently, its complete resection has proven to be the single most important prognostic factor for postsurgical seizure freedom.12,15,26,29,41,43 Seizures may originate from the center as well as the periphery of the FCD, and the regions of most severe dysplasia do not necessarily overlap with the regions of highest epileptogenicity. Thus, complete FCD resection, as opposed to a resection of the central part of the lesion or of its most dysplastic areas, is crucial for surgical success.6 Intraoperative tools currently used to define lesion borders include electrocorticography (ECoG), neuronavigation, and intraoperative MRI, as well as visual and tactile information. However, all of these tools have their intrinsic limitations.

Intraoperative ultrasound (IOUS) is a promising tool for intraoperative anatomical guidance, particularly regarding the demarcation of lesion borders, thereby enabling more complete resection. The efficacy of IOUS in surgery for FCD-associated drug-resistant epilepsy has been indicated by Miller et al. in a case report in 200835 and in a retrospective 5-patient series in 2011,36 as well as by Lee et al. in a case report in 201433 (Table 1). Our study aimed to extend previous research in this field by systematically and prospectively assessing the diagnostic yield of IOUS in surgery for FCD-associated drug-resistant epilepsy in a larger cohort. For this purpose, we compared IOUS findings with those of presurgical postprocessed MRI, and we analyzed IOUS features in relation to the histologically confirmed FCD subtype. We investigated the added value of IOUS in improving completeness of resection and, thus, postsurgical seizure outcomes.

TABLE 1.

Overview of available literature regarding the use of IOUS in patients with FCD

Authors & YearTotal CasesFCD TypeIOUSSz Outcome (Engel class)
IdentificationClear DemarcationFeatures   
Miller et al., 20081IIBYesYesClear HEI
Miller et al., 20115IAYesNoFaint HEII
IBNoNoNoneII  
IIB*YesYesClear HEI  
IIYesYesClear HEII  
IIYesYesClear HEII  
Lee et al., 20141IIAYesYesClear HEI

HE = hyperechogenicity; Sz = seizure.

Same case as in Miller et al., 2008.

Methods

Patient Selection

We prospectively enrolled 15 consecutive patients with drug-resistant focal epilepsy associated with a radiologically suspected FCD who underwent epilepsy surgery in our institution between January 2013 and July 2016. All patients received comprehensive presurgical evaluation according to a standard protocol in the Swiss Epilepsy Center at Klinik Lengg in Zurich, the University Hospital Zurich, and/or the University Children’s Hospital Zurich and were referred for surgical treatment by an interdisciplinary case management board. All patients and/or their parents gave their written informed consent for the participation in this study. The study was approved by the local ethics committee.

Presurgical Evaluation

Demographics and Epilepsy Course

Systematically and prospectively collected data included demographics (sex, age at surgery); epilepsy history (age at epilepsy onset, duration of epilepsy to surgery, seizure classification according to the International League Against Epilepsy [ILAE] 201719 system); seizure frequency at surgery; presurgical AED treatment; prior epilepsy surgery; presurgical neurological and neuropsychological deficits; and psychiatric comorbidities.

EEG Studies

All patients underwent long-term scalp electroencephalography (EEG), including ictal recordings. In addition, 9 patients underwent invasive EEG in a preceding, separate surgery, with subdural grid and strip electrodes and/or with stereotactically implanted depth electrodes. Invasive electrode positions were visualized in 3D format according to the postimplantation MRI.28

Preoperative MRI

MRI was visually reviewed regarding the classification and extent of lesions, including the presence of a secondary pathology. In addition, MRI postprocessing techniques (morphometric analysis,24 curvilinear reformatting,25 and quantitative FLAIR analysis20) were applied to improve FCD detection and delineation. These tools serve to highlight MRI abnormalities suspicious for FCD—such as abnormal gyral patterns, abnormally wide and/or deep sulci, increased cortical thickness, and blurring of the gray-white-matter junction, as well as abnormal cortical or subcortical signal intensity, including the transmantle sign. These criteria were based on current literature regarding MRI features of FCDs.2,9,13,25,30

Surgery and Intraoperative Guidance

Neuronavigation (Stealth Station; Medtronic) was used in all cases. For this purpose, the localization of the lesion, as indicated by postprocessed MRI, was transferred as a bright marker into a 3D T1-weighted image, which in turn was loaded into the neuronavigation system. After craniotomy and dura mater opening, IOUS was applied, allowing for anatomical orientation, morphological comparison to preoperative imaging, and delineation of the lesion. For this high-resolution intraoperative imaging we used an iU22 Ultrasound System with a real-time L15–7 intraoperative probe (7–15 MHz extended frequency with a phased linear array of 128 elements including a 23-mm effective aperture length, probe tip measure 11 × 31 mm; Philips).8 Intraoperative ECoG was performed in all cases. Thus, the final extent of resection finding was based on the postprocessed preoperative MRI, IOUS, and intraoperative ECoG.

Histopathological Evaluation

Resection specimens were analyzed by the Department of Neuropathology, University Hospital Zurich. To increase diagnostic certainty, an additional histopathological evaluation was performed in the European FCD Reference Center in Erlangen. FCDs were categorized according to the ILAE classification system.3

Follow-Up

Clinical and EEG follow-up was scheduled at 3, 6, and 12 months after surgery and then yearly in cases of seizure control or at appropriate intervals in cases of seizure recurrence. MRI was performed 3 months after surgery to assess for potential residual dysplasia, including postprocessing evaluations as well as coregistration with presurgical MRI. Epilepsy course, AED tapering, and neurological deficit were noted. The classification of postsurgical seizure outcome was performed according to the Engel classification system.16

Data Analysis

Due to the small sample size, statistical analysis is provided in a descriptive manner.

Results

Demographics and Epilepsy Course

Seven female (47%) and 8 male (53%) patients were included in our study. The demographic data and the presurgical epilepsy course are given in Table 2. Epilepsy onset occurred at a mean of 3.5 years (SD 4.1, range 0.5–15 years), the mean duration from epilepsy to surgery was 12.4 years (SD 13.4, range 0.5–40 years), and the mean age at surgery was 16.7 years (SD 14.5, range 1–44 years). All but 3 patients were experiencing daily seizures at the time of surgery despite multiple AED trials. None of the patients had previously undergone epilepsy surgery. All but one of our patients presented with focal neurological deficit, neuropsychological impairment, or psychiatric comorbidities prior to surgery.

TABLE 2.

Demographic and clinical data according to histological result in 15 patients with FCD-associated epilepsy

Histological TypeSexAge at Op (yrs)Age at Epilepsy Onset (yrs)Duration of Epilepsy (yrs)*Sz Classification (ILAE 2017)Preop Sz Frequency (Szs/wk)Preop Neurological Abnormalities
FO-aFO-ia2° TCSEFNPP     
FCD IAM1679YesNoNoNo0.5NoYesNo
FCD IBF44440YesYesYesNo21YesYesYes
FCD ICM40.53.5YesYesNoNo14NoYesYes
FCD IIAM1578YesYesNoNo0.5NoYesNo
FCD IIAM380.537.5YesYesYesNo14NoYesNo
FCD IIAM10.50.5YesYesYesYes7NoYesNo
FCD IIAF15411YesYesYesNo10YesYesNo
FCD IIAF30.52.5NoYesNoNo8NoYesNo
FCD IIBM34331YesYesYesYes14YesYesYes
FCD IIBM33825NoYesYesNo21NoYesNo
FCD IIBF291514NoYesYesNo7NoYesYes
FCD IIBF10.50.5YesNoNoNo56NoYesNo
FCD IIBF64.51.5YesYesNoNo7NoNoNo
FCD IIBF725NoYesYesNo1NoYesYes
GliosisM40.53.5YesYesNoNo70NoYesNo

F = focal; FO-a = focal onset, aware; FO-ia = focal onset, impaired awareness; NP = neuropsychological; P = psychiatric; SE = status epilepticus; 2° TC = focal to bilateral tonic clonic.

Duration at time of surgery.

Presurgical Evaluation

Topographical and morphological features of the suspected dysplastic areas are presented for all patients in Table 3 and for illustrative cases in Figs. 13. Blurring of the gray-white-matter junction was the most consistent feature pointing to FCD in our cohort. Radiologically, dual pathology was found in a single patient, who presented with left hippocampal sclerosis in addition to a suspected left mesiotemporal FCD. It should be noted, however, that histopathological investigation did not confirm FCD, only showing nonspecific gliosis in this case.

TABLE 3.

Imaging features and outcome according to histological result in 15 patients with FCD-associated epilepsy

Histological TypeTopographyMRI MorphologyIOUS MorphologyClear Margins on IOUSResidual EDs on iECoGPostop Residual FCDSz Outcome* (Engel class)
SideLobeGyri/Sulcigwmj-bICTA-G/ST2-cT2-scTMSHE-cHE-gwmjHE-scICT 
FCD IARtParietalIPSYesNoNoNoNoNo++NoNoYesIA
FCD IBRtParietalCS/post-CSYesNoNoNoNoNo++NoYesYesIA
FCD ICRtTemporalTP/amyg/HHYesYesNoNoYesNo++++YesNoIB
FCD IIALtFrontalSFS/F1YesYesYesYesYesYes++++++++YesNoNoIA
FCD IIALtParietalPost-CSYesYesYesYesYesYes++++++YesNoNoIIB
FCD IIARtFrontalF1YesYesYesYesYesYes+++++++++YesNoNoIA
FCD IIALtFrontalPre-CSYesYesYesYesYesYes+++++++YesNoNoIA
FCD IIARtTemporalTPYesYesYesYesYesNo+++++++YesNoNoIA
FCD IIBRtFrontalF1 (mS)YesYesYesYesYesYes++++++++++YesNoNoIIB
FCD IIBRtFrontalPre-CSYesYesYesYesNoNo++++++++++++YesNoNoIA
FCD IIBLtTemporalITS/T3YesYesYesYesYesYes+++++++++++YesYesNoIA
FCD IIBLtFrontalIFSYesYesYesYesYesNo+++++++++YesNoNoIID
FCD IIBLtFrontalF1 (mS)YesYesYesYesYesYes+++++++++++YesNoNoIA
FCD IIBLtFrontalF1 (mS)YesYesYesYesYesNo++++++++++++YesNoNoIA
GliosisLtTemporalTP/Fu/LTOSYesNoNoYesYesNo+NoNoNAIVB

A-G/S = atypical gyration/sulcation; amyg = amygdala; CS = central sulcus; EDs = epileptiform discharges; Fu = fusiform (lateral temporo-occipital gyrus); F1 = superior frontal gyrus; gwmj-b = gray-white-matter junction blurring; HE-c = cortical HE; HE-gwmj = HE at the gray-white-matter junction; HE-sc = subcortical HE; HH = head of hippocampus; ICT = increased cortical thickness; iECoG = intraoperative ECoG; IFS = inferior frontal sulcus; IPS = intraparietal sulcus; ITS = inferior temporal sulcus; LTOS = lateral temporo-occipital sulcus; mS = medial sulcus; NA = not applicable; SFS = superior frontal sulcus; TMS = transmantle sign; TP = temporal pole; T2-c = cortical T2 hyperintensity; T2-sc = subcortical T2 hyperintensity; T3 = inferior temporal gyrus; −, +, ++, +++ = degree of HE.

At last follow-up.

† Questionable residual FCD.

FIG. 1.
FIG. 1.

Examples of pre-, intra-, and postoperative imaging in a patient with type IA FCD in the depth of the right intraparietal sulcus. Preoperative MRI with postprocessing (example sequence shown) allowed us to identify an area of subtle blurring of the gray-white-matter junction suspicious for the presence of FCD. Despite very discrete signal alterations on preoperative MRI, IOUS allowed us to depict the dysplastic area with high resolution by showing hyperechogenicity in the cortex and the underlying gray-white-matter junction. Topographical and morphological features correlated well to preoperative imaging. However, a sharp demarcation of the altered area was not possible, resulting in subtotal resection, with residual dysplasia seen with coregistration between pre- and postoperative MRI.

FIG. 2.
FIG. 2.

Examples of pre-, intra-, and postoperative imaging in a patient with type IIA FCD in the depth of the superior precentral sulcus. Preoperative MRI with postprocessing (example sequence shown) revealed subtle cortical and subcortical T2-weighted and FLAIR hyperintensity, discrete increase in cortical thickness, and blurring of the gray-white-matter junction. On IOUS, this area suspicious for FCD could be easily identified by the marked hyperechogenicity of a thickened cortex, hyperechogenic, blurred gray-white-matter junction, and increased signal of the adjacent subcortical white matter, with high topographical-morphological correlation to preoperative imaging. Sharp demarcation of FCD borders by IOUS allowed us to perform complete resection without residual dysplasia on coregistration between pre- and postoperative MRI.

FIG. 3.
FIG. 3.

Examples of pre-, intra-, and postoperative imaging in a patient with type IIB FCD of the superior frontal gyrus in the region of the medial sulcus. Preoperative MRI with postprocessing (example sequence shown) revealed cortical and subcortical T2-weighted and FLAIR hyperintensity, marked increase in cortical thickness, and pronounced blurring of the gray-white-matter junction. With high topographical-morphological correlation to preoperative imaging, IOUS revealed an area of heavily increased cortical thickness and marked hyperechogenicity in the cortex, at both the gray-white-matter junction and subcortically. Lesion borders could be clearly identified. Coregistration between pre- and postoperative MRI showed no residual dysplasia.

Intraoperative Ultrasound

IOUS showed signal abnormalities in the region of suspected FCD in all cases. These sonographic abnormalities presented a high anatomical correlation with the features suspicious for FCD on preoperative MRI (Figs. 13), whereas IOUS resolution was superior to MRI in all cases. In addition, the sonographic features of the lesions correlated well with histopathological findings (Fig. 4). In all but one patient, IOUS showed specific and circumscribed signal abnormalities: histopathological investigation confirmed FCD. In a single patient, IOUS showed diffuse signal alterations with a blurry cortical and subcortical hyperechogenicity: histopathological studies revealed only nonspecific gliosis.

FIG. 4.
FIG. 4.

Examples showing sonographic morphology of the different FCD subtypes versus nonspecific gliosis.

In cases with specific and circumscribed signal abnormalities corresponding to histologically verified FCD, the degree of cortical and subcortical signal alterations correlated to the underlying degree of dysplasia; i.e., to the FCD subtype. In the 3 cases of FCD type I, the dysplastic cortical areas showed discrete hyperechogenicity with a blurred border toward the underlying white matter, albeit without any white matter changes. In FCD type I, the dysplastic area was thus identifiable, but the precise demarcation of its borders was challenging. FCD types IA and IB presented with almost identical features in IOUS, whereas FCD type IC was characterized by a higher degree of cortical hyperechogenicity. FCD type II presented with more pronounced sonographic abnormalities, including marked cortical hyperechogenicity, increased cortical thickness, blurred and hyperechogenic gray-white-matter junction, and variably increased white matter signal. These changes were more prominent in FCD type IIB. In FCD type II, the dysplastic area was not only identifiable, but the precise demarcation of its borders was facilitated by these pronounced signal changes. IOUS findings are given in Table 3.

Intraoperative Electrocorticography

Intraoperative ECoG following the sonographically guided resection revealed residual epileptic discharges in only 2 cases (Table 3). In one of these patients, further ECoG-guided resection was limited by the localization of the epileptic discharges within the primary motor area. In the second case the residual epileptic activity in ECoG led to an extension of the previous resection; in repeat ECoG, no unequivocal epileptic discharges were noted.

Intraoperative and Immediate Postoperative Course

The mean duration of the surgical procedure was 226 minutes (SD 54.5 minutes, median 210 minutes, range 165–355 minutes). No surgical complications such as intra- or postoperative hematoma, stroke, or wound infection were noted. Fourteen patients had an uneventful postoperative course, whereas 1 patient suffered from mild postoperative paresis and hyposensibility in the left lower extremity after removal of a right postcentral FCD adjacent to the central sulcus. This neurological deficit was considerably improved at last follow-up.

Follow-Up

At last follow-up (between 18 and 60 months—mean 35.9, SD 11.3, median 35 months), 10 of 15 (67%) patients were completely seizure free (Engel IA) (Table 3), 1 had only simple partial nondisabling seizures, and 3 more had rare disabling seizures (Engel II). The patient with nonspecific gliosis showed no worthwhile improvement (Engel IVB).

Seizure outcome varied considerably between different FCD types. Two of the 3 patients with FCD type I were completely seizure free after surgery (Engel IA), whereas the other one had only simple partial nondisabling seizures after surgery (Engel IB). Residual dysplastic cortex at the resection border was identified in the 2 patients with FCD type I (1 with FCD type IA, 1 with FCD type IB) who achieved seizure freedom. Eight of the 11 patients with FCD type II were completely seizure free after surgery (Engel IA), and the other 3 had rare disabling seizures (Engel II). No residual dysplastic cortex was identified in any of the patients with FCD type II.

Discussion

To the best of our knowledge, this is the largest case series of IOUS utilization in epilepsy surgery, particularly in the context of FCD-associated drug-resistant epilepsy. The size of our cohort enables us to draw some reliable conclusions regarding the feasibility and added value of IOUS application in the resection of FCD.

FCD is one of the main underlying substrates in drug-resistant partial epilepsy, especially in children.5 Resection is the most promising therapeutic option, with incomplete resection of the dysplastic cortex posing a major risk for seizure recurrence.12,17,26,29 Therefore, the optimal pre- and intraoperative definition of the lesion border and its resection are the key for surgical success. Dedicated MRI sequences, including MRI postprocessing techniques, markedly improved preoperative detection. However, intraoperative tools to guide FCD resection are limited. Direct visual and tactile information is generally poor in the case of FCD compared to other lesions such as brain tumors.33,35 Furthermore, neuronavigation accuracy is limited by its low overall resolution and by the risk of brain shift.1,11,14,33,35 Intraoperative MRI has been reported to be useful,7,46 but its application is restricted by the limited availability, high costs, associated delay of surgery, low resolution,38 and absence of postprocessing techniques. Even though ECoG is of high value during FCD resection, it gives only 2D functional—and not anatomical—information, with a variable relation to the dysplastic region.34 IOUS, on the contrary, is widely available and inexpensive. It has the advantage of being safe as well as quickly and repetitively applicable. IOUS interrupts the surgical procedure for only some seconds, in comparison to other intraoperative techniques such as acquisition of intraoperative MRI. It delivers real-time information, independent of brain shift, and provides 3D lesion visualization. Despite the many advantages of IOUS, only 3 studies, each reporting 1–5 cases,33,35,36 have addressed the use of IOUS for FCD delineation in epilepsy surgery (Table 1).

Our study confirms the added value of IOUS for FCD detection, identification, and delineation. Sonographic visualization showed high correlation with preoperative MRI, including advanced postprocessing techniques. IOUS resolution was superior to MRI in all cases. Furthermore, sonographic features were shown to correlate to the underlying histopathological findings. First, this allows for a differentiation between FCD and non-FCD lesions (e.g., gliosis, characterized by diffuse nonorganized hyperechogenicity), which may have a direct impact on surgical strategy (e.g., intended extent or completeness of resection). Second, IOUS allows surgeons to estimate the underlying FCD type, due to the strong correlation between the severity of signal abnormalities and the degree of dysplasia (sonographic abnormalities increase continuously in the following order: FCD IA/IB, FCD IC, FCD IIA, FCD IIB). FCD type I, histologically defined by isolated dyslamination, showed only discrete cortical hyperechogenicity and blurring of the gray-white-matter junction. These features were similar in FCD type IA and IB, whereas they were more pronounced in the case of FCD type IC. This is in line with the histological properties of FCD types IA and IB, which are characterized by isolated radial or tangential dyslamination, whereas type IC combines these characteristics. Type II FCDs, histologically defined by the additional presence of dysmorphic neurons within the dysplastic area, showed more extensive sonographic abnormalities than with FCD I. The cortex appeared thickened and more hyperechogenic, the blurring of the gray-white-matter junction was more obvious, and there was some degree of subcortical hyperechogenicity. FCD IIB lesions (i.e., those containing balloon cells) displayed these features in an even more pronounced manner than type IIA. The clear sonographic visualization of FCD type II allowed for sharp demarcation of lesion borders in every case. Our results are in line with the reports from Miller and colleagues35,36 and Lee et al.33 Miller et al. described 3 cases of FCD type IIB characterized by marked hyperechogenicity and 1 of FCD type IA with faint hyperechogenicity. In contrast to our results, sonographic visualization was not possible in an FCD type IB in this study.36 The case of FCD IIA reported by Lee et al. was sonographically characterized by homogeneous hyperechogenicity.

In our study, the extent of resection correlated with the demarcation of lesion margins on IOUS, which again matched the degree of dysplasia. IOUS allowed for complete resection in all FCD type II cases, whereas there was some marginal residual dysplasia in 2 cases (FCD IA and IB). Reported postsurgical seizure freedom rates in patients with FCD range from 33% to 90%.9,10,12,15,21,22,47–49,51 The size and heterogeneity of our cohort does not allow for definitive statements regarding seizure outcome. However, the 71% Engel IA outcome is particularly favorable. Surgery in FCD type II has previously been associated with superior seizure outcome as compared to FCD type I,4,44,45 highlighting the challenges in the surgical approach for FCD type I. The inferior postsurgical outcome in patients with FCD type I—without IOUS—may be explained by the more difficult visualization with MRI, because cortical cellular density is only minimally altered in these FCD types.39 Patients with FCD type I in our series, however, had a favorable seizure outcome, despite the residual dysplasia. One possible explanation is that IOUS, by its high resolution, allows the surgeon to visualize and resect the regions of biologically relevant dysplasia in FCD type I, balancing the outcome between the different FCD subtypes.

This study shows the high potential of IOUS as a readily available neurosurgical tool in surgery for FCD-associated drug-resistant epilepsy, due to the excellent morphological resolution and close relation of the sonographic features to the histological degree of dysplasia. However, our findings should be interpreted with care, considering the following limitations. First, despite the reported higher resolution of IOUS, the role of MRI—and especially of postprocessing techniques—remains important and MRI cannot be replaced by IOUS. MRI is still the modality guiding the presurgical evaluation by identifying the potential epileptogenic lesion and determining the extent of resection. Second, IOUS interpretation remains subjective, and is highly dependent on the judgment and the experience of the investigator as well as on the apparatus and its settings. Third, the histopathological limitations of the 2011 classification3 should be mentioned: the differentiation of FCD I subtypes is increasingly considered arbitrary;39 they reportedly lack a clinical, imaging, or molecular phenotype. Despite the fact that the detected discrete sonographic differences between type IA/IB and IC represent such an imaging phenotype, the relevance of this differentiation remains unclear. The subdivision of FCD II into IIA and IIB has also been questioned.39 Sonographically, we identified these subtypes as different entities; however, the main distinction clearly remains between types I and II. Finally, limitations are posed by the small size of our cohort, which includes many different histological subtypes, precluding statistical analysis. Further research in larger cohorts and a prospective randomized design will be needed to make clear statements regarding the prognostic value of IOUS and its effect on residual dysplasia and seizure outcome.

Conclusions

This is the largest study to date investigating the yield of IOUS in surgery for FCD-associated drug-resistant epilepsy. Morphological features identified by IOUS show a high correlation with advanced preoperative imaging and may provide a superior resolution in some cases. The distinct sonographic features allow for the intraoperative distinction between FCD and non-FCD lesions as well as between the different histological subtypes of FCD. The sharpness of sonographic demarcation depends on the underlying degree of dysplasia. IOUS facilitates the completeness of resection by clearly delineating the dysplastic area.

Acknowledgments

We kindly thank the Prof. Dr. I. Blümcke and his team from the European FCD Reference Center in Erlangen for histopathological reference analysis.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Akeret, Krayenbühl. Acquisition of data: Akeret. Analysis and interpretation of data: Akeret, Bellut. Drafting the article: Akeret. Critically revising the article: Bellut, Huppertz, Ramantani, König, Serra, Regli, Krayenbühl. Reviewed submitted version of manuscript: Bellut, Ramantani, Krayenbühl. Statistical analysis: Akeret. Administrative/technical/material support: Akeret. Study supervision: Krayenbühl.

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    Colombo NTassi LGalli CCitterio ALo Russo GScialfa G: Focal cortical dysplasias: MR imaging, histopathologic, and clinical correlations in surgically treated patients with epilepsy. AJNR Am J Neuroradiol 24:7247332003

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    Dorward NLAlberti OVelani BGerritsen FAHarkness WFKitchen ND: Postimaging brain distortion: magnitude, correlates, and impact on neuronavigation. J Neurosurg 88:6566621998

  • 15

    Edwards JCWyllie ERuggeri PMBingaman WLüders HKotagal P: Seizure outcome after surgery for epilepsy due to malformation of cortical development. Neurology 55:111011142000

  • 16

    Engel J JrVan Ness PCRasmussen TBOjemann LM: Outcome with respect to epileptic seizures in Engel J Jr (ed): Surgical Treatment of the Epilepsiesed 2. New York: Raven Press1993 pp 609621

  • 17

    Fauser SEssang CAltenmüller DMStaack AMSteinhoff BJStrobl K: Long-term seizure outcome in 211 patients with focal cortical dysplasia. Epilepsia 56:66762015

  • 18

    Fauser SHuppertz HJBast TStrobl KPantazis GAltenmueller DM: Clinical characteristics in focal cortical dysplasia: a retrospective evaluation in a series of 120 patients. Brain 129:190719162006

  • 19

    Fisher RS: The New Classification of Seizures by the International League Against Epilepsy 2017. Curr Neurol Neurosci Rep 17:482017

  • 20

    Focke NKSymms MRBurdett JLDuncan JS: Voxel-based analysis of whole brain FLAIR at 3T detects focal cortical dysplasia. Epilepsia 49:7867932008

  • 21

    Guerrini RDuchowny MJayakar PKrsek PKahane PTassi L: Diagnostic methods and treatment options for focal cortical dysplasia. Epilepsia 56:166916862015

  • 22

    Harvey ASMandelstam SAMaixner WJLeventer RJSemmelroch MMacGregor D: The surgically remediable syndrome of epilepsy associated with bottom-of-sulcus dysplasia. Neurology 84:202120282015

  • 23

    House PMLanz MHolst BMartens TStodieck SHuppertz HJ: Comparison of morphometric analysis based on T1- and T2-weighted MRI data for visualization of focal cortical dysplasia. Epilepsy Res 106:4034092013

  • 24

    Huppertz HJGrimm CFauser SKassubek JMader IHochmuth A: Enhanced visualization of blurred gray-white matter junctions in focal cortical dysplasia by voxel-based 3D MRI analysis. Epilepsy Res 67:35502005

  • 25

    Huppertz HJKassubek JAltenmüller DMBreyer TFauser S: Automatic curvilinear reformatting of three-dimensional MRI data of the cerebral cortex. Neuroimage 39:80862008

  • 26

    Kim DWLee SKChu KPark KILee SYLee CH: Predictors of surgical outcome and pathologic considerations in focal cortical dysplasia. Neurology 72:2112162009

  • 27

    Kim YHKang HCKim DSKim SHShim KWKim HD: Neuroimaging in identifying focal cortical dysplasia and prognostic factors in pediatric and adolescent epilepsy surgery. Epilepsia 52:7227272011

  • 28

    Kovalev DSpreer JHonegger JZentner JSchulze-Bonhage AHuppertz HJ: Rapid and fully automated visualization of subdural electrodes in the presurgical evaluation of epilepsy patients. AJNR Am J Neuroradiol 26:107810832005

  • 29

    Krsek PMaton BJayakar PDean PKorman BRey G: Incomplete resection of focal cortical dysplasia is the main predictor of poor postsurgical outcome. Neurology 72:2172232009

  • 30

    Krsek PPieper TKarlmeier AHildebrandt MKolodziejczyk DWinkler P: Different presurgical characteristics and seizure outcomes in children with focal cortical dysplasia type I or II. Epilepsia 50:1251372009

  • 31

    Kwan PArzimanoglou ABerg ATBrodie MJAllen Hauser WMathern G: Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51:106910772010

  • 32

    Kwan PBrodie MJ: Early identification of refractory epilepsy. N Engl J Med 342:3143192000

  • 33

    Lee CCLin CFYu HYHung SCShih YHHsu SPC: Applications of intraoperative ultrasound in epilepsy surgery for focal cortical dysplasia. J Med Ultrasound 22:43462014

  • 34

    Lüders HAwad IBurgess RWyllie EVan Ness P: Subdural electrodes in the presurgical evaluation for surgery of epilepsy. Epilepsy Res Suppl 5:1471561992

  • 35

    Miller DKnake SBauer SKrakow KPagenstecher ASure U: Intraoperative ultrasound to define focal cortical dysplasia in epilepsy surgery. Epilepsia 49:1561582008

  • 36

    Miller DKnake SMenzler KKrakow KRosenow FSure U: Intraoperative ultrasound in malformations of cortical development. Ultraschall Med 32 (Suppl 2):E69E742011

  • 37

    Mischel PSNguyen LPVinters HV: Cerebral cortical dysplasia associated with pediatric epilepsy. Review of neuropathologic features and proposal for a grading system. J Neuropathol Exp Neurol 54:1371531995

  • 38

    Mittal SBlack PM: Intraoperative magnetic resonance imaging in neurosurgery: the Brigham concept. Acta Neurochir Suppl 98:77862006

  • 39

    Najm IMSarnat HBBlümcke I: Review: The international consensus classification of focal cortical dysplasia—a critical update 2018. Neuropathol Appl Neurobiol 44:18312018

  • 40

    Palmini ANajm IAvanzini GBabb TGuerrini RFoldvary-Schaefer N: Terminology and classification of the cortical dysplasias. Neurology 62 (6 Suppl 3):S2S82004

  • 41

    Ramantani GKadish NEMayer HAnastasopoulos CWagner KReuner G: Frontal lobe epilepsy surgery in childhood and adolescence: predictors of long-term seizure freedom, overall cognitive and adaptive functioning. Neurosurgery 83:931032018

  • 42

    Ramantani GKadish NEStrobl KBrandt AStathi AMayer H: Seizure and cognitive outcomes of epilepsy surgery in infancy and early childhood. Eur J Paediatr Neurol 17:4985062013

  • 43

    Ramantani GStathi ABrandt AStrobl KSchubert-Bast SWiegand G: Posterior cortex epilepsy surgery in childhood and adolescence: predictors of long-term seizure outcome. Epilepsia 58:4124192017

  • 44

    Ramírez-Molina JLDi Giacomo RMariani VDeleo FCardinale FUscátegui-Daccarett AM: Surgical outcomes in two different age groups with focal cortical dysplasia type II: any real difference? Epilepsy Behav 70 (Pt A):45492017

  • 45

    Rowland NCEnglot DJCage TASughrue MEBarbaro NMChang EF: A meta-analysis of predictors of seizure freedom in the surgical management of focal cortical dysplasia. J Neurosurg 116:103510412012

  • 46

    Schwartz THMarks DPak JHill JMandelbaum DEHolodny AI: Standardization of amygdalohippocampectomy with intraoperative magnetic resonance imaging: preliminary experience. Epilepsia 43:4304362002

  • 47

    Siegel AMCascino GDMeyer FBMarsh WRScheithauer BWSharbrough FW: Surgical outcome and predictive factors in adult patients with intractable epilepsy and focal cortical dysplasia. Acta Neurol Scand 113:65712006

  • 48

    Sisodiya SM: Surgery for malformations of cortical development causing epilepsy. Brain 123 (Pt 6):107510912000

  • 49

    Tassi LColombo NGarbelli RFrancione SLo Russo GMai R: Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain 125:171917322002

  • 50

    Taylor DCFalconer MABruton CJCorsellis JA: Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 34:3693871971

  • 51

    Tripathi MSingh MSPadma MVGaikwad SBal CSTripathi M: Surgical outcome of cortical dysplasias presenting with chronic intractable epilepsy: a 10-year experience. Neurol India 56:1381432008

  • 52

    Wagner JWeber BUrbach HElger CEHuppertz HJ: Morphometric MRI analysis improves detection of focal cortical dysplasia type II. Brain 134:284428542011

  • 53

    Widdess-Walsh PKellinghaus CJeha LKotagal PPrayson RBingaman W: Electro-clinical and imaging characteristics of focal cortical dysplasia: correlation with pathological subtypes. Epilepsy Res 67:25332005

  • 54

    World Health Organization: Epilepsy fact sheet. WHO.int. February 8 2018 (http://www.who.int/news-room/fact-sheets/detail/epilepsy) [Accessed July 11 2018]

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Correspondence Kevin Akeret: University Hospital Zurich, Switzerland. kevin.akeret@gmx.ch.

ACCOMPANYING EDITORIAL DOI: 10.3171/2018.6.FOCUS18329.

INCLUDE WHEN CITING DOI: 10.3171/2018.6.FOCUS18221.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Examples of pre-, intra-, and postoperative imaging in a patient with type IA FCD in the depth of the right intraparietal sulcus. Preoperative MRI with postprocessing (example sequence shown) allowed us to identify an area of subtle blurring of the gray-white-matter junction suspicious for the presence of FCD. Despite very discrete signal alterations on preoperative MRI, IOUS allowed us to depict the dysplastic area with high resolution by showing hyperechogenicity in the cortex and the underlying gray-white-matter junction. Topographical and morphological features correlated well to preoperative imaging. However, a sharp demarcation of the altered area was not possible, resulting in subtotal resection, with residual dysplasia seen with coregistration between pre- and postoperative MRI.

  • View in gallery

    Examples of pre-, intra-, and postoperative imaging in a patient with type IIA FCD in the depth of the superior precentral sulcus. Preoperative MRI with postprocessing (example sequence shown) revealed subtle cortical and subcortical T2-weighted and FLAIR hyperintensity, discrete increase in cortical thickness, and blurring of the gray-white-matter junction. On IOUS, this area suspicious for FCD could be easily identified by the marked hyperechogenicity of a thickened cortex, hyperechogenic, blurred gray-white-matter junction, and increased signal of the adjacent subcortical white matter, with high topographical-morphological correlation to preoperative imaging. Sharp demarcation of FCD borders by IOUS allowed us to perform complete resection without residual dysplasia on coregistration between pre- and postoperative MRI.

  • View in gallery

    Examples of pre-, intra-, and postoperative imaging in a patient with type IIB FCD of the superior frontal gyrus in the region of the medial sulcus. Preoperative MRI with postprocessing (example sequence shown) revealed cortical and subcortical T2-weighted and FLAIR hyperintensity, marked increase in cortical thickness, and pronounced blurring of the gray-white-matter junction. With high topographical-morphological correlation to preoperative imaging, IOUS revealed an area of heavily increased cortical thickness and marked hyperechogenicity in the cortex, at both the gray-white-matter junction and subcortically. Lesion borders could be clearly identified. Coregistration between pre- and postoperative MRI showed no residual dysplasia.

  • View in gallery

    Examples showing sonographic morphology of the different FCD subtypes versus nonspecific gliosis.

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Colombo NTassi LGalli CCitterio ALo Russo GScialfa G: Focal cortical dysplasias: MR imaging, histopathologic, and clinical correlations in surgically treated patients with epilepsy. AJNR Am J Neuroradiol 24:7247332003

14

Dorward NLAlberti OVelani BGerritsen FAHarkness WFKitchen ND: Postimaging brain distortion: magnitude, correlates, and impact on neuronavigation. J Neurosurg 88:6566621998

15

Edwards JCWyllie ERuggeri PMBingaman WLüders HKotagal P: Seizure outcome after surgery for epilepsy due to malformation of cortical development. Neurology 55:111011142000

16

Engel J JrVan Ness PCRasmussen TBOjemann LM: Outcome with respect to epileptic seizures in Engel J Jr (ed): Surgical Treatment of the Epilepsiesed 2. New York: Raven Press1993 pp 609621

17

Fauser SEssang CAltenmüller DMStaack AMSteinhoff BJStrobl K: Long-term seizure outcome in 211 patients with focal cortical dysplasia. Epilepsia 56:66762015

18

Fauser SHuppertz HJBast TStrobl KPantazis GAltenmueller DM: Clinical characteristics in focal cortical dysplasia: a retrospective evaluation in a series of 120 patients. Brain 129:190719162006

19

Fisher RS: The New Classification of Seizures by the International League Against Epilepsy 2017. Curr Neurol Neurosci Rep 17:482017

20

Focke NKSymms MRBurdett JLDuncan JS: Voxel-based analysis of whole brain FLAIR at 3T detects focal cortical dysplasia. Epilepsia 49:7867932008

21

Guerrini RDuchowny MJayakar PKrsek PKahane PTassi L: Diagnostic methods and treatment options for focal cortical dysplasia. Epilepsia 56:166916862015

22

Harvey ASMandelstam SAMaixner WJLeventer RJSemmelroch MMacGregor D: The surgically remediable syndrome of epilepsy associated with bottom-of-sulcus dysplasia. Neurology 84:202120282015

23

House PMLanz MHolst BMartens TStodieck SHuppertz HJ: Comparison of morphometric analysis based on T1- and T2-weighted MRI data for visualization of focal cortical dysplasia. Epilepsy Res 106:4034092013

24

Huppertz HJGrimm CFauser SKassubek JMader IHochmuth A: Enhanced visualization of blurred gray-white matter junctions in focal cortical dysplasia by voxel-based 3D MRI analysis. Epilepsy Res 67:35502005

25

Huppertz HJKassubek JAltenmüller DMBreyer TFauser S: Automatic curvilinear reformatting of three-dimensional MRI data of the cerebral cortex. Neuroimage 39:80862008

26

Kim DWLee SKChu KPark KILee SYLee CH: Predictors of surgical outcome and pathologic considerations in focal cortical dysplasia. Neurology 72:2112162009

27

Kim YHKang HCKim DSKim SHShim KWKim HD: Neuroimaging in identifying focal cortical dysplasia and prognostic factors in pediatric and adolescent epilepsy surgery. Epilepsia 52:7227272011

28

Kovalev DSpreer JHonegger JZentner JSchulze-Bonhage AHuppertz HJ: Rapid and fully automated visualization of subdural electrodes in the presurgical evaluation of epilepsy patients. AJNR Am J Neuroradiol 26:107810832005

29

Krsek PMaton BJayakar PDean PKorman BRey G: Incomplete resection of focal cortical dysplasia is the main predictor of poor postsurgical outcome. Neurology 72:2172232009

30

Krsek PPieper TKarlmeier AHildebrandt MKolodziejczyk DWinkler P: Different presurgical characteristics and seizure outcomes in children with focal cortical dysplasia type I or II. Epilepsia 50:1251372009

31

Kwan PArzimanoglou ABerg ATBrodie MJAllen Hauser WMathern G: Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51:106910772010

32

Kwan PBrodie MJ: Early identification of refractory epilepsy. N Engl J Med 342:3143192000

33

Lee CCLin CFYu HYHung SCShih YHHsu SPC: Applications of intraoperative ultrasound in epilepsy surgery for focal cortical dysplasia. J Med Ultrasound 22:43462014

34

Lüders HAwad IBurgess RWyllie EVan Ness P: Subdural electrodes in the presurgical evaluation for surgery of epilepsy. Epilepsy Res Suppl 5:1471561992

35

Miller DKnake SBauer SKrakow KPagenstecher ASure U: Intraoperative ultrasound to define focal cortical dysplasia in epilepsy surgery. Epilepsia 49:1561582008

36

Miller DKnake SMenzler KKrakow KRosenow FSure U: Intraoperative ultrasound in malformations of cortical development. Ultraschall Med 32 (Suppl 2):E69E742011

37

Mischel PSNguyen LPVinters HV: Cerebral cortical dysplasia associated with pediatric epilepsy. Review of neuropathologic features and proposal for a grading system. J Neuropathol Exp Neurol 54:1371531995

38

Mittal SBlack PM: Intraoperative magnetic resonance imaging in neurosurgery: the Brigham concept. Acta Neurochir Suppl 98:77862006

39

Najm IMSarnat HBBlümcke I: Review: The international consensus classification of focal cortical dysplasia—a critical update 2018. Neuropathol Appl Neurobiol 44:18312018

40

Palmini ANajm IAvanzini GBabb TGuerrini RFoldvary-Schaefer N: Terminology and classification of the cortical dysplasias. Neurology 62 (6 Suppl 3):S2S82004

41

Ramantani GKadish NEMayer HAnastasopoulos CWagner KReuner G: Frontal lobe epilepsy surgery in childhood and adolescence: predictors of long-term seizure freedom, overall cognitive and adaptive functioning. Neurosurgery 83:931032018

42

Ramantani GKadish NEStrobl KBrandt AStathi AMayer H: Seizure and cognitive outcomes of epilepsy surgery in infancy and early childhood. Eur J Paediatr Neurol 17:4985062013

43

Ramantani GStathi ABrandt AStrobl KSchubert-Bast SWiegand G: Posterior cortex epilepsy surgery in childhood and adolescence: predictors of long-term seizure outcome. Epilepsia 58:4124192017

44

Ramírez-Molina JLDi Giacomo RMariani VDeleo FCardinale FUscátegui-Daccarett AM: Surgical outcomes in two different age groups with focal cortical dysplasia type II: any real difference? Epilepsy Behav 70 (Pt A):45492017

45

Rowland NCEnglot DJCage TASughrue MEBarbaro NMChang EF: A meta-analysis of predictors of seizure freedom in the surgical management of focal cortical dysplasia. J Neurosurg 116:103510412012

46

Schwartz THMarks DPak JHill JMandelbaum DEHolodny AI: Standardization of amygdalohippocampectomy with intraoperative magnetic resonance imaging: preliminary experience. Epilepsia 43:4304362002

47

Siegel AMCascino GDMeyer FBMarsh WRScheithauer BWSharbrough FW: Surgical outcome and predictive factors in adult patients with intractable epilepsy and focal cortical dysplasia. Acta Neurol Scand 113:65712006

48

Sisodiya SM: Surgery for malformations of cortical development causing epilepsy. Brain 123 (Pt 6):107510912000

49

Tassi LColombo NGarbelli RFrancione SLo Russo GMai R: Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome. Brain 125:171917322002

50

Taylor DCFalconer MABruton CJCorsellis JA: Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry 34:3693871971

51

Tripathi MSingh MSPadma MVGaikwad SBal CSTripathi M: Surgical outcome of cortical dysplasias presenting with chronic intractable epilepsy: a 10-year experience. Neurol India 56:1381432008

52

Wagner JWeber BUrbach HElger CEHuppertz HJ: Morphometric MRI analysis improves detection of focal cortical dysplasia type II. Brain 134:284428542011

53

Widdess-Walsh PKellinghaus CJeha LKotagal PPrayson RBingaman W: Electro-clinical and imaging characteristics of focal cortical dysplasia: correlation with pathological subtypes. Epilepsy Res 67:25332005

54

World Health Organization: Epilepsy fact sheet. WHO.int. February 8 2018 (http://www.who.int/news-room/fact-sheets/detail/epilepsy) [Accessed July 11 2018]

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