A novel technique of detecting MRI‐negative lesion in focal symptomatic epilepsy: Intraoperative ShearWave Elastography

Focal symptomatic epilepsy is the most common form of epilepsy that can often be cured with surgery. A small proportion of patients with focal symptomatic epilepsy do not have identifiable lesions on magnetic resonance imaging (MRI). The most common pathology in this group is type II focal cortical dysplasia (FCD), which is a subtype of malformative brain lesion associated with medication‐resistant epilepsy. We present a patient with MRI‐negative focal symptomatic epilepsy who underwent invasive electrode recordings. At the time of surgery, a novel ultrasound‐based technique called ShearWave Elastography (SWE) was performed. A 0.5 cc lesion was demonstrated on SWE but was absent on B‐mode ultrasound and 3‐T MRI. Electroencephalography (EEG), positron emission tomography (PET), and magnetoencephalography (MEG) scans demonstrated an abnormality in the right frontal region. On the basis of this finding, a depth electrode was implanted into the lesion. Surgical resection and histology confirmed the lesion to be type IIb FCD. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

A comprehensive clinico‐pathological and genetic evaluation of bottom‐of‐sulcus focal cortical dysplasia in patients with difficult‐to‐localize focal epilepsy

Aims. We comprehensively studied the clinical presentation, stereo‐EEG and MRI findings, histopathological diagnosis, and brain somatic mutations in a retrospective series of drug‐resistant patients with difficult‐to‐localize epilepsy due to focal cortical dysplasia at the bottom of a sulcus (BOS‐FCD). Methods. We identified 10 patients with BOS‐FCD from the Cleveland Clinic epilepsy surgery database submitted for intracranial video‐EEG monitoring. Brain MRI, including voxel‐based morphometric analysis and surgical tissue submitted for histopathology, was reviewed. Paraffin tissue samples from five patients were made available for targeted next‐generation sequencing. Postsurgical follow‐up was available in nine patients. Results. BOS‐FCD was identified in the superior frontal sulcus in six patients, inferior frontal sulcus in one patient, central sulcus in one patient, and intraparietal sulcus in two patients. All patients had stereotyped seizures. Intracranial EEG recordings identified ictal onset at the BOS‐FCD in all 10 patients, whereas ictal scalp EEG had a localizing value in only six patients. Complete resection was achieved by lesionectomy or focal corticectomy in nine patients. Histopathologically, six patients had FCD type IIb and three had FCD type IIa. Next‐generation sequencing analysis of DNA extracted from lesion‐enriched (micro‐dissected) tissue from five patients with FCD type II led to the identification of a germline frameshift insertion in DEPDC5, introducing a premature stop in one patient. Eight out of nine patients with available follow‐up were completely seizure‐free (Engel Class IA) after a mean follow‐up period of six years. Conclusion. Our results confirm previous studies classifying difficult‐to‐localize BOS‐FCD into the emerging spectrum of FCD ILAE type II mTORopathies. Further studies with large patient numbers and ultra‐deep genetic testing may help to bridge the current knowledge gap in genetic aetiologies of FCD.     

Electro- and magneto-encephalographic spike source localization of small focal cortical dysplasia in the dorsal peri-rolandic region

ObjectiveSmall focal cortical dysplasia (FCD) may be ambiguous or overlooked on magnetic resonance (MR) imaging. Source localization of EEG and magnetoencephalography (MEG) spikes was evaluated to confirm the diagnosis of small FCD.MethodsThis study included 6 epilepsy patients with a single small lesion on MR imaging suggesting FCD within a single gyrus among 181 consecutive epilepsy patients admitted to our epilepsy monitoring unit over 27 months. Stereotypical interictal spikes were detected on simultaneous EEG and MEG recordings and the onset-related source of averaged spikes was estimated.ResultsAll 6 patients had unique clinical characteristics as follows: leg sensori-motor seizures in 5 patients and eye version in 1 patient; a small MR imaging lesion suggesting FCD in the dorsal peri-rolandic region, which had been overlooked until our evaluation; and both EEG and MEG dipoles were estimated adjacent to the MR imaging lesion.ConclusionsSource localization of EEG and MEG spikes can confirm the diagnosis of FCD based on a single small MR imaging lesion, which was overlooked by previous examination of MR images.SignificanceExamination of MR images should be based on spike source localization as well as seizure semiology to identify subtle MR imaging abnormalities.     

Intrinsic epileptogenicity of focal cortical dysplasia as revealed by magnetoencephalography and electrocorticography

Focal cortical dysplasia (FCD) is often associated with severe partial epilepsy. In this study, we performed magnetoencephalography (MEG) and electrocorticogrsphy (ECoG) on four patients with FCD-associated epilepsy to confirm the 'intrinsic' epileptogenicity of FCD. In all patients, we determined the three-dimensional locations of the magnetic sources of the interictal paroxysmal activities by a single dipole model, and then the estimated dipole localization was superimposed on the magnetic resonance image. The dipole clusters were located in the T2-prolonged lesions, namely in the FCD lesions themselves. All patients underwent surgery for their medically intractable epilepsy, and the acute and/or chronic ECoG were thereafter recorded. Either frequent or continuous paroxysmal activities were recorded from the ECoG electrodes which were placed over the surface of the FCD lesion, while few paroxysmal activities were observed on the normal appearing adjacent cortex. Intraoperative depth recordings were performed in a patient with the needle electrode inserted into the FCD lesion and they revealed these paroxysmal foci to be located not on the cortical surface but at a depth of 15 mm from the cortical surface where both abnormal giant neurons and bizarre large eosinophilic cells (so-called balloon cells) were also prominently observed on the postoperative histological sections. Following a lesionectomy combined with the removal of the underlying white matter, three patients demonstrated a favorable seizure outcome. Our findings thus suggest the FCD lesions to be highly and intrinsically epileptogenic lesions.     

Seizure‐Induced Inflammation in Focal Cortical Dysplasia Resulting in Imaging Progression That Simulates Neoplasia

A 5‐year‐old girl with previously well‐controlled partial epilepsy secondary to focal cortical dysplasia (FCD) developed an increase in seizure frequency. Two months later, magnetic resonance showed a substantial alteration in lesion imaging characteristics. The lesion was resected. FCD was confirmed but inflammatory changes were also present. We propose that chronic inflammation was induced by unremitting seizure activity and suggest that inflammation may be implicated as a basis for alteration in the imaging characteristics of FCD.     

Widespread frontal lobe cortical dysplasia or partial hemimegalencephaly: a continuum of the spectrum

Focal cortical dysplasia (FCD) type II and hemimegalencephaly (HME) are currently considered as a continuum of pathology, the most important distinction being the extent or the size/volume of the lesion. While partial HME involving the posterior cortex has been well described, we present an unusual case with a dysplastic lesion of the whole frontal lobe. A 17‐year‐old boy had focal seizures from the age of nine years. Apart from diminished right‐hand dexterity, his neurological and cognitive status were unremarkable. The course of his epilepsy exhibited a relapsing‐remitting pattern, with prolonged periods of remission. Imaging showed dysplastic left frontal lobe (including paracentral lobule) thickened cortex with an abnormal gyration pattern resembling polymicrogyria, as well as dystrophic calcifications and hypodensity scattered throughout the white matter. This patient represents an intermediate case within the FCD type II/HME spectrum. Localization of the lesion in the frontal lobe as well as clinical characteristics (childhood onset, relapsing‐remitting epilepsy, without hemiparesis and overt cognitive impairment) are more consistent with FCD type II, while a range of MRI features is shared between HME and FCD type II.     

局灶性脑皮质发育不良致难治性癫痫病理分型和手术疗效分析

目的 探讨难治性癫痫术后局灶性脑皮质发育不良(FCD)不同病理分型与术后疗效的相巨关系.方法 回顾性分析54例经手术治疗后,病理证实为FCD的药物难治性癫痫患者的临床资料,分析病理分型与手术预后的关系.结果 轻型组(FCD Ⅰ A)24例,重型组(FCD Ⅰ B+ⅡA+ⅡB)30例.术后有效率:轻型组96%,重型组70%,总有效率82%.结论 随着FCD病理改变程度的逐渐加重,手术后疗效越来越差,FCD可能是影响药物难治性癫痫术后疗效的一个重要因素.     

Role of MRI in patient selection for surgical treatment of intractable epilepsy in infancy

Epilepsy surgery is an effective treatment in selected patients with localization-related intractable epilepsy. The success of epilepsy surgery is in part dependent upon identification of a lesion on MRI. In infants, the surgical epileptogenic substrates include focal cortical dysplasia (FCD), hemimegalencephaly, tuberous sclerosis complex, Sturge Weber syndrome, hypoxic-ischemic or cerebrovascular injury and low-grade tumor. The sensitivity of MRI in identifying the epileptogenic substrate is influenced by the nature of the epileptogenic substrate, MRI technique and expertise of the interpreting physician. The MRI features of some lesions such as FCD may differ in infants compared to children and adults; the white matter adjacent to FCD may demonstrate lower T2 and higher T1 signal in some infants due to premature myelination, while in others, the white matter demonstrates higher T2 or lower T1 signal due to demyelination, dysmyelination or gliosis, similar to children and adults. The appearances of some lesions, such as FCD, may change with time, due to brain maturation or seizure related changes. MRI for patients with localization-related intractable epilepsy should have high-resolution, multiplanar and multisequence. In infants, volumetric T1 and high-resolution T2 imaging are recommended. FLAIR and proton density sequences are less helpful in infants due to lack of myelin in the white matter. The physician interpreting the scan should be familiar with the imaging appearances of epileptogenic substrates and may need to review the scan more than once if a lesion is not seen on initial inspection.     

Epilepsy surgery in the first months of life: a large type IIb focal cortical dysplasia causing neonatal drug‐resistant epilepsy

Focal cortical dysplasia is a common cause of medically refractory epilepsy in infancy and childhood. We report a neonate with seizures occurring within the first day of life. Continuous video‐EEG monitoring led to detection of left motor seizures and a right frontal EEG seizure pattern. Brain MRI revealed a lesion within the right frontal lobe without contrast enhancement. The patient was referred for epilepsy surgery due to drug resistance to vitamin B6 and four antiepileptic drugs. Lesionectomy was performed at the age of two and a half months, and histopathological evaluation confirmed the diagnosis of focal cortical dysplasia type IIb (FCD IIb). The patient is free of unprovoked seizures without medication (Engel Class I) and is normally developed at 36 months after surgery. The case study demonstrates that FCD IIb may cause seizures within the first day of life and that epilepsy surgery can be successfully performed in medically intractable patients with a clearly identifiable seizure onset zone within the first three months of life. Although radical surgery such as hemispherectomy and multi‐lobar resections are over‐represented in early infancy, this case also illustrates a favourable outcome with a more limited resection in this age group.     

Focal Cortical Dysplasias: clinical implication of neuropathological classification systems

Focal Cortical Dysplasias (FCDs) are highly epileptogenic brain lesions and are a frequent cause for drug-resistant focal epilepsies in humans. FCDs present with variable histopathological patterns, including architectural, cytoarchitectural or white matter abnormalities. Pathomechanisms compromising neuroblast proliferation, migration, or differentiation are likely to play a role in the etiology of FCD variants. FCDs were subsumed, therefore, into the broad spectrum of malformations of cortical development. The most frequent subtype comprises FCD Type II, which in general occurs as isolated lesion in extratemporal location and is histopathologically characterized by dysmorphic neurons (Type IIA) and balloon cells (Type IIB). Neuroimaging hallmarks include hyperintense T2-signaling and a “transmantle sign”. Electrophysiological recordings show peculiar interictal spike patterns and complete surgical resection results in favorable seizure control. In contrast, FCD Type I can be identified in young children with severe epilepsy and psychomotor retardation. Parietal, temporal, and occipital lobes may be involved in seizure generation, although neuroimaging often reveals normal contrast intensities. Surgical resection strategies ameliorate seizure frequencies in many children, whereas complete seizure relief can be achieved only in rare cases. According to the currently used FCD classification system, the same histopathological FCD Type I variant can be diagnosed as associated lesion in the large cohort of epilepsy patients with hippocampal sclerosis, low-grade glio-neuronal tumors, vascular malformations, or glial scarring. MRI is often not helpful to detect the dysplastic cortical areas. In addition, there is no specific electrophysiological pattern for an associated dysplastic lesion. Surgical resection of the epileptogenic area results, however, in favorable seizure control. These findings argue for a revised neuropathological classification system that distinguishes isolated versus associated FCD variants to obtain a better correlation with electro-clinical findings and prediction of postsurgical seizure control.     

Focal cortical dysplasia: prevalence, clinical presentation and epilepsy in children and adults

Focal cortical dysplasias (FCD) are defined as circumscribed malformations of cortical development. They result from an impairment of neuronal proliferation, migration and differentiation. In the diagnosis of focal epilepsy FCD prevalence ranges between 5% and 25%, depending on patient collective and imaging techniques. Several 'cryptogenic' epilepsies may be caused by FCD but have not been diagnosed because of the lack of high-quality magnetic resonance imaging assessment. Retrospective analysis of patients who have undergone epilepsy surgery can be biased because of the fact that they represent a mere subset of potential FCD diagnoses. Epilepsy typically manifests within the first years of life, but has been documented up to the age of 60 years. Cognitive impairment commonly accompanies early onset. Epilepsy is often refractory to antiepileptic drug (AED) treatment. Clinical observations and pathophysiological findings illustrate intrinsic epileptogenicity. Upregulation of drug transporter proteins has been found in FCD tissue. There is no specific drug treatment in FCD, as any AED used in focal epilepsy could prove effective. A sequential AED therapy should be designed individually and take side effects as well as developmental progresses into consideration. Fifty to sixty-five percent of FCD patients are rendered seizure-free after surgery. Presurgical evaluation should be initiated after two unsuccessful AED trials. Both risks and potential benefits regarding seizure control and developmental impairment need to be considered on an individual basis when deciding between surgical intervention and conservative treatment. Current knowledge on epilepsy course and psychomotor development in FCD is limited in the absence of qualified long-term studies combining imaging with cognitive evaluation.     

Limited resection of focal cortical dysplasia and associated epileptogenic cortex may lead to positive surgical outcome

A drug-resistant epilepsy patient with premotor type IIb focal cortical dysplasia is described with a positive postoperative outcome following partial resection of the lesion and epileptogenic zone. Presurgical fMRI of the sensorimotor areas showed haemodynamic responses over the posterior border of the lesion and ictal EEG-fMRI revealed activation of both the primary sensorimotor strip and premotor lesion area. Almost continuous 1-2 Hz interictal spiking was recorded during a chronic ECoG study over the primary sensorimotor cortex. Following partial resection of the lesion, an acute ECoG revealed marked reduction of epileptic activity over the sensorimotor area. Post-operatively, seizure control was significantly improved (class IV ILAE outcome). Although partial FCD resections predict a worse postoperative outcome, individual patients may still respond favourably. The type of lesion, resected portion, and histopathology may be included among factors related to successful outcome.     

The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission

Purpose: Focal cortical dysplasias (FCD) are localized regions of malformed cerebral cortex and are very frequently associated with epilepsy in both children and adults. A broad spectrum of histopathology has been included in the diagnosis of FCD. An ILAE task force proposes an international consensus classification system to better characterize specific clinicopathological FCD entities. Methods: Thirty‐two Task Force members have reevaluated available data on electroclinical presentation, imaging, neuropathological examination of surgical specimens as well as postsurgical outcome. Key Findings: The ILAE Task Force proposes a three‐tiered classification system. FCD Type I refers to isolated lesions, which present either as radial (FCD Type Ia) or tangential (FCD Type Ib) dyslamination of the neocortex, microscopically identified in one or multiple lobes. FCD Type II is an isolated lesion characterized by cortical dyslamination and dysmorphic neurons without (Type IIa) or with balloon cells (Type IIb). Hence, the major change since a prior classification represents the introduction of FCD Type III, which occurs in combination with hippocampal sclerosis (FCD Type IIIa), or with epilepsy‐associated tumors (FCD Type IIIb). FCD Type IIIc is found adjacent to vascular malformations, whereas FCD Type IIId can be diagnosed in association with epileptogenic lesions acquired in early life (i.e., traumatic injury, ischemic injury or encephalitis). Significance: This three‐tiered classification system will be an important basis to evaluate imaging, electroclinical features, and postsurgical seizure control as well as to explore underlying molecular pathomechanisms in FCD.     

ILAE focal cortical dysplasia type IIIc in the ictal onset zone in epileptic patients with solitary meningioangiomatosis

“Solitary” meningioangiomatosis (MA) is a rare, benign, hamartomatous lesion of the cerebral cortex and frequently leads to epilepsy. However, the source of the epileptogenicity in meningioangiomatosis remains controversial. We report two surgically‐treated meningioangiomatosis cases with medically intractable epilepsy. In both cases, chronic subdural electrocorticogram (ECoG) recordings identified the ictal onset zone on apparently normal cortex, adjacent to and/or above the meningioangiomatosis lesion, not on the meningioangiomatosis lesion itself. The ictal onset zone was resected, along with the MA lesion, and good seizure outcome was achieved. Histological examination of the ictal onset zone revealed the presence of ILAE focal cortical dysplasia (FCD) type IIIc. Our case studies suggest that in the surgical management of epilepsy with meningioangiomatosis, it is important to identify undetected, but epileptogenic, ILAE FCD Type IIIc, using preoperative multimodal examinations, including chronic ECoG recordings.     

Focal cortical dysplasia with calcification: a case report

Case report Focal cortical dysplasia (FCD) with calcification is rare. We presented a 13-year-old epileptic patient with FCD and calcification in the left frontal lobe. At age 24, the FCD lesion and the surrounding epileptogenic cortex and underlying subcortex were removed after chronic subdural electrode recording. Histological examination showed that the calcified lesion was not independent of the FCD lesion but located in the subcortical area of the FCD lesion. A neoplastic nature was ruled out for the lesion. Discussion The pathophysiological mechanism involved in the coexistence of FCD and calcification is discussed.     

Three-dimensional brain surface visualization for epilepsy surgery of focal cortical dysplasia

Focal cortical dysplasia (FCD) causes medically intractable seizures in 5–10% of adult epilepsy patients, but patients can become seizure free through surgical resection. The authors present the utility of three-dimensional surface visualization (3DSV) that expands on existing imaging datasets to highlight surface vasculature as a tool for achieving more successful resections in patients with FCD. In this prospective series of six patients, preoperative 3DSV was performed for planning the surgical approach to the lesion and for intraoperative guidance. Reconstructions involved volume rendering of a contrast-enhanced dataset to visualize surface venous vasculature. Postoperatively, five of the six patients had complete resections, with one patient having a subtotal resection due to proximity to crucial vasculature. We report that 3DSV is a useful tool for surgical planning, since topographical relationships between lesion location and surface vasculature landmarks are less likely to change with surgical progress.     

Neuropathological work-up of focal cortical dysplasias using the new ILAE consensus classification system - practical guideline article invited by the Euro-CNS Research Committee

FCDs are increasingly recognized in patients with drug-resistant epilepsies, and many patients benefit from tailored resection strategies. Yet, postsurgical seizure control cannot be sufficiently predicted and specification of FCD variants remains difficult during presurgical monitoring. The International League against Epilepsy (ILAE) has published a new consensus classification system for focal cortical dysplasias (FCDs). Based on a review of imaging data, electroclinical features and postsurgical seizure control correlation with neuropathological findings specify three clinico-pathological FCD subtypes: FCD Type I is characterized by aberrant radial (FCD Type Ia) or tangential lamination of the neocortex (FCD Type Ib) affecting one or multiple lobes. FCD Type II is characterized by cortical dyslamination and dysmorphic neurons without (Type IIa) or with balloon cells (Type IIb). It is important to note, that these types should not be associated with any other structural brain lesion (isolated FCD). In contrast, a new FCD Type III is introduced, which occurs in combination with hippocampal sclerosis (FCD Type IIIa), or with epilepsy-associated tumors (FCD Type IIIb). FCD Type IIIc is found adjacent to vascular malformations, whereas FCD Type IIId can be diagnosed in association with other epileptogenic lesions obtained in early life (i.e., traumatic injury, ischemic injury or encephalitis). Histopathological features are very similar to those observed in FCD Type I, but likely present postnatal development and maturation failures acquired by the principal lesion. This first international consensus classification may encourage neuropathologists to focus their attention onto this important histopathological group. Addressing more precisely defined clinico-pathological entities will also help to clarify underlying pathomechanisms and, thereby, improve treatment strategies for patients with difficult-to-treat epilepsies.     

Multiple focal cortical dysplasias presenting with intractable epilepsy: case report]

A 14-year-old female, who had intractable epilepsy associated with multiple focal cortical dysplasias (FCD), was reported. She developed intractable epilepsy at the age of 7 and was diagnosed as having frontal lobe epilepsy based on the seizure semiology and interictal EEG. MRI revealed multiple lesions in the right frontal, bilateral occipital and left parietal lobes. EEG demonstrated that ictal discharge was preceded by spike on the right frontal region and FDG-PET showed hypometabolic area in the right frontal lobe. Chronic subdural electrode recordings from the right frontal lobe indicated that ictal onset zone was located around the right frontal lesion, especially frontal tip and base, and these areas including the lesion were resected. Postoperatively, residual seizure was noted although seizure frequency was decreased. It is well known that, postoperatively, satisfactory seizure outcome can be obtained in patients with FCD. However, further investigation in terms of surgical indication and strategies for multiple FCD should be needed.     

Neuroimaging of Focal Cortical Dysplasia

Focal cortical dysplasia (FCD) is a common cause of pharmacoresistant epilepsy that is amenable to surgical resective treatment. The identification of structural FCD by magnetic resonance imaging (MRI) can contribute to the detection of the epileptogenic zone and improve the outcome of epilepsy surgery. MR epilepsy protocols that include specific T1 and T2 weighted, and fluid-attenuated inversion recovery (FLAIR) sequences give complementary information about the characteristic imaging features of FCD; focal cortical thickening, blurring of the gray-white junction, high FLAIR signal, and gyral anatomical abnormalities. Novel imaging techniques such as magnetic resonance spectroscopy (MRS), magnetization transfer imaging (MTI), and diffusion tensor imaging (DTI) can improve the sensitivity of MR to localize the anatomical lesion. Functional/metabolic techniques such as positron emission tomography (PET), ictal subtraction single photon emission computed tomography (SPECT), functional MRI (fMRI), and magnetic source imaging (MSI) have the potential to visualize the metabolic, vascular, and epileptogenic properties of the FCD lesion, respectively. Identification of eloquent areas of cortex, to assist in the surgical resection plan, can be obtained non-invasively through the use of fMRI and MSI. Although a significant number of FCD lesions remain unidentified using current neuroimaging techniques, future advances should result in the identification of an increasing number of these cortical malformations.