Review: The international consensus classification of Focal Cortical Dysplasia - a critical update 2018.

The Diagnostic Methods commission of the International League against Epilepsy (ILAE) released a first international consensus classification of Focal Cortical Dysplasia (FCD) in 2011. Since that time, this FCD classification has been widely used in clinical diagnosis and research (more than 740 papers cited in Pubmed between 1/1/2012 and 7/1/2017). Herein, we review the new data that will inform and revise the FCD classification. Many recent papers described molecular-genetic characteristics in FCD type II including multiple mutations in the mTOR pathway. In addition, the electro-clinico-imaging phenotype and surgical outcomes of FCD type II (in particular type IIb) were further defined and validated. These results pave the way for the design of an integrated clinico-pathological and genetic classification system, as recently recommended by the WHO for the classification of malignant brain tumours. On the other hand, little new information was acquired on FCD types I and III. Focal cortical dysplasia type I subtypes are still lacking a comprehensive description of clinical phenotypes, reproducible imaging characteristics, and specific molecular/genetic biomarkers. Associated FCD III subtypes also became rare in published literature. Despite temporal lobe epilepsy being the most common focal epilepsy in adults, we have not identified neurophysiological, imaging, histopathological and/or genetic biomarkers to reliably classify FCD III with or without hippocampal sclerosis. In respect of pathogenesis, FCD adjacent to a non-developmental, postnatally acquired lesion is difficult to explain and perhaps does not exist. This update may help foster shared efforts towards a better understanding of FCD, potential future updates of classification and novel targeted treatments.

Re-review of MRI with post-processing in nonlesional patients in whom epilepsy surgery has failed.

Management of MRI-negative patients with intractable focal epilepsy after failed surgery is particularly challenging. In this study, we aim to investigate whether MRI post-processing could identify relevant targets for the re-evaluation of MRI-negative patients who failed the initial resective surgery. We examined a consecutive series of 56 MRI-negative patients who underwent resective surgery and had recurring seizures at 1-year follow-up. T1-weighted volumetric sequence from the pre-surgical MRI was used for voxel-based MRI post-processing which was implemented in a morphometric analysis program (MAP). MAP was positive in 15 of the 56 patients included in this study. In 5 patients, the MAP+ regions were fully resected. In 10 patients, the MAP+ regions were not or partially resected: two out of the 10 patients had a second surgery including the unresected MAP+ region, and both became seizure-free; the remaining 8 patients did not undergo further surgery, but the unresected MAP+ regions were concordant with more than one noninvasive modality in 7. In the 8 patients who had unresected MAP+ regions and intracranial-EEG before the previous surgery, the unresected MAP+ regions were concordant with ictal onset in 6. Our data suggest that scrutiny of the presurgical MRI guided by MRI post-processing may reveal relevant targets for reoperation in nonlesional epilepsies. MAP findings, when concordant with the patient's other noninvasive data, should be considered when planning invasive evaluation/reoperation for this most challenging group of patients.

Effects of dual pathology on cognitive outcome following left anterior temporal lobectomy for treatment of epilepsy.

The objective of this retrospective study was to determine if dual pathology [DUAL - focal cortical dysplasia (FCD) and mesial temporal sclerosis (MTS)] in patients with left temporal lobe epilepsy is associated with greater risk for cognitive decline following temporal lobectomy than single pathology (MTS only). Sixty-three adults (Mage=36.5years, female: 52.4%) who underwent left anterior temporal lobectomy for treatment of epilepsy (MTS=28; DUAL=35) completed preoperative and postoperative neuropsychological evaluations. The base rate of dual pathology was 55.5%. Repeated measures ANOVAs yielded significant 2-way interactions (group×time) on most measures of language and memory with generally moderate effect sizes. Specifically, patients with MTS only demonstrated postoperative declines, while those with dual pathology remained unchanged or improved. Results suggest that dual pathology may be associated with better cognitive outcome following epilepsy surgery than MTS alone, possibly reflecting limited functionality of the resected tissue or intrahemispheric reorganization of function in the context of a developmental lesion.

Role of cortisol in mood and memory in patients with intractable temporal lobe epilepsy.

OBJECTIVE: This study prospectively examined the relationships among late night salivary cortisol (NSC) levels and depressive symptoms, memory performance, and hippocampal volumes in patients with medically intractable temporal lobe epilepsy (TLE) and the potential mediating effects of cortisol in the relationships between these variables. METHODS: Participants included 24 adults with well-characterized medically refractory TLE (right = 11; left = 12; bitemporal = 1). All patients provided saliva samples and completed measures of mood, anxiety, and memory (objective and subjective). MRI-based volumetric analyses of the hippocampi were also conducted. RESULTS: As hypothesized, cortisol was found to be negatively related to several memory measures such that patients with higher cortisol levels demonstrated lower memory performance. However, unexpectedly, cortisol was not related to current symptoms of depression or anxiety, subjective memory ratings, or hippocampal volumes. Consistent with previous findings in the literature, a number of other relationships among the study variables were observed (objective memory and hippocampal volume; subjective memory and mood/anxiety). Results of mediator analyses suggested that cortisol does not mediate the relationship between depression and memory dysfunction or the relationship between depression and hippocampal atrophy. CONCLUSIONS: While cortisol may play a role in memory performance in patients with TLE, it does not fully explain the relationship between depression and mesial temporal dysfunction, likely reflecting the complex and multifactorial relationships among these variables. Results confirm the relationship between memory performance and structural brain integrity and provide further support for a role of depression in subjective memory complaints.

Voxel-based morphometric MRI post-processing in MRI-negative focal cortical dysplasia followed by simultaneously recorded MEG and stereo-EEG.

We aim to report on the usefulness of a voxel-based morphometric MRI post-processing technique in detecting subtle epileptogenic structural lesions. The MRI post-processing technique was implemented in a morphometric analysis program (MAP), in a 30-year-old male with pharmacoresistant focal epilepsy and negative MRI. MAP gray-white matter junction file facilitated the identification of a suspicious structural lesion in the right frontal opercular area. The electrophysiological data by simultaneously recorded stereo-EEG and MEG confirmed the epileptogenicity of the underlying subtle structural abnormality. The patient underwent a limited right frontal opercular resection, which completely included the area detected by MAP. Surgical pathology revealed focal cortical dysplasia (FCD) type IIb. Postoperatively the patient has been seizure-free for 2 years. This study demonstrates that MAP has promise in increasing the diagnostic yield of MRI reading in challenging patients with "non-lesional" MRIs. The clinical relevance and epileptogenicity of MAP abnormalities in patients with epilepsy have not been investigated systematically; therefore it is important to confirm their pertinence by performing electrophysiological recordings. When confirmed to be epileptogenic, such MAP abnormalities may reflect an underlying subtle cortical dysplasia whose complete resection can lead to seizure-free outcome.

ApoE-epsilon4 is associated with reduced memory in long-standing intractable temporal lobe epilepsy.

OBJECTIVE: To investigate the relationship between the apolipoprotein (ApoE) epsilon4 allele and memory performance (verbal and nonverbal) in patients with medically intractable temporal lobe epilepsy (TLE) who underwent temporal lobectomy. METHODS: Presurgical and postsurgical memory performance was examined in 87 adult patients with TLE (epsilon4 = 22; non-epsilon4 = 65) to determine whether the expression of ApoE-epsilon4 may be associated with memory performance in this population and to examine how this relationship may be affected by duration of epilepsy. RESULTS: There was a significant interaction between ApoE-epsilon4 status and duration of epilepsy such that epsilon4 carriers with a long duration of epilepsy demonstrated the poorest memory performance on both verbal and nonverbal measures. This relationship was observed both before and after temporal lobectomy, with little change in test performance over time. CONCLUSIONS: The ApoE-epsilon4 allele interacts with longstanding seizures to affect memory performance, both verbal and nonverbal, in patients with medically intractable temporal lobe epilepsy.

Predictors of outcome after temporal lobectomy for the treatment of intractable epilepsy.

To assess short- and long-term seizure freedom, the authors reviewed 371 patients who underwent anterior temporal lobectomy to treat pharmacoresistant epilepsy. The mean follow-up duration was 5.5 years (range 1 to 14.1 years). Fifty-three percent of patients were seizure free at 10 years. The authors identified multiple predictors of recurrence. Results of EEG performed 6 months postoperatively correlated with occurrence and severity of seizure recurrence, in addition to breakthrough seizures with discontinuation of antiepileptic drugs.

Localising and lateralising value of ictal piloerection.

BACKGROUND: Piloerection is a rare clinical symptom described during seizures. Previous reports suggested that the temporal lobe is the ictal onset zone in many of these cases. One case series concluded that there is a predominant left hemispheric representation of ictal cold. The aim of this study is to evaluate the localising and lateralising value of pilomotor seizures. METHODS: Medical records of patients who underwent video electroencephalogram (EEG) monitoring at the Cleveland Clinic between 1994 and 2001 were reviewed for the presence of ictal piloerection. The clinical history, physical and neurological examination, video EEG data, neuroimaging data, cortical stimulation results, and postoperative follow ups were reviewed and used to define the epileptogenic zone. Additionally, all previously reported cases of ictal piloerection were reviewed. RESULTS: Fourteen patients with ictal piloerection were identified (0.4%). Twelve out of 14 patients had temporal lobe epilepsy. In seven patients (50%), the ictal onset was located in the left hemisphere. Four out of five patients with unilateral ictal piloerection had ipsilateral temporal lobe epilepsy as compared with the ipsilateral side of pilomotor response. Three patients became seizure free after left temporal lobectomy for at least 12 months of follow up. An ipsilateral left leg pilomotor response with simultaneously recorded after-discharges was elicited in one patient during direct cortical stimulation of the left parahippocampal gyrus. CONCLUSIONS: Ictal piloerection is a rare ictal manifestation that occurs predominantly in patients with temporal lobe epilepsy. Unilateral piloerection is most frequently associated with ipsilateral focal epilepsy. No hemispheric predominance was found in patients with bilateral ictal piloerection.

MR imaging in epilepsy.

The advent of MR imaging techniques has immensely improved the ability to evaluate and manage patients with epilepsy. The principles of various MR techniques, the pertinent MRI neuro-anatomic features, and computer based 3D reconstruction post processing methods are discussed. Newer MR-based techniques such as magnetic resonance spectroscopy (MRS) and diffusion weighted imaging (DWI) and their applications and potential usefulness in the evaluation of patients with medically intractable epilepsy are also reviewed.

Nerve rootlets to be sectioned for spasticity resolution in selective dorsal rhizotomy.

BACKGROUND: The goal of this study is to confirm the efficacy of the protocol for selective dorsal rhizotomy (SDR). In this protocol, rootlets to be sectioned are selected by palpable responses elicited by intraoperative electrical stimulation, without detailed electromyographic classifications. METHODS: Thirty-six children with spasticity due to cerebral palsy underwent SDR according to our protocol. Priority was given to sectioning rootlets that showed palpable clonic or bilateral responses, which were considered abnormal, over sectioning rootlets that merely had hyperactive responses to intraoperative stimulation. The results of intraoperative monitoring and sectioning amount were analyzed by physical evaluation. RESULTS: Significant improvements were obtained in passive range of motion and muscle tone of the lower extremities. The total percentages of rootlets with abnormal and hyperactive responses at L3 and S1 were bilaterally correlated with preoperative spasticity of the hip adductors and the plantar flexors, respectively. When rootlets with hyperactive responses were excluded from the correlation analysis, no bilateral correlation was observed. From the correlation analyses between the improvement in the physical evaluation and the amount of nerve sectioned, it was concluded that a greater improvement in muscle tone in all examined muscles, except the hamstrings, could be obtained if larger amounts of nerve roots were sectioned. CONCLUSION: The number of rootlets with palpable abnormal and hyperactive responses elicited by intraoperative stimulation reflects the preoperative spasticity of multiple muscles. This implies that only selecting rootlets with palpable responses can be reliable. Because more sectioning leads to better spasticity resolution, our protocol should be reviewed to increase the percentage of rootlets sectioned with hyperactive responses, especially for innervated levels of severely affected muscles.

Epileptogenicity correlated with increased N-methyl-D-aspartate receptor subunit NR2A/B in human focal cortical dysplasia.

PURPOSE: Human cortical dysplasia (CD) is a frequent cause of medically intractable focal epilepsy. The neurotransmitter mechanisms of epileptogenicity in these lesions have been attributed to changes in various glutamate receptor subtypes. Increased N-methyl-D-aspartate (NMDA) receptor (NR) 2A/B coassembled with NR1 subunits has been shown in focal epileptic CD. The purpose of this study is to correlate in situ CD epileptogenicity and the expression of various glutamate receptor subtypes. METHODS: The histopathological, morphological, and immunocytochemical findings in cortical tissue resected from five patients with medically intractable epilepsy and CD were correlated with electroencephalographic data recorded from subdural grids. The NMDA antibodies identified subunits NR1 (splicing variants 1a, 1b, 2a, and 2b) and NR2A/B. RESULTS: Epileptogenic specimens displayed the following common features: (a) widespread histological abnormalities of horizontal and columnar dyslamination, neurons with inverted polarity, and more extensive dendritic changes; (b) significantly higher NR2A/B immunoreactivity in both the dysplastic somata and all their dendritic processes; and (c) no statistically significant change in NR1 subunit expression but a more pronounced staining of the apical dendrites in highly epileptogenic cortex. These abnormalities were either absent or minimal in resected specimens that did not show evidence of severe in vivo epileptogenicity. CONCLUSION: These studies provide direct evidence for a major contribution of the NR2A/B subunit in CD-induced epileptogenicity.

Postictal in situ MRS brain lactate in the rat kindling model.

OBJECTIVE: To determine the temporal and spatial extent of the lactate (Lact) changes as correlated with seizure characteristics and EEG changes in the rat kindling model. BACKGROUND: Prior studies using MRS have detected cerebral Lact postictally in animal models of seizures and in patients with intractable focal epilepsy. METHODS: We performed MRS in sham control rats (n = 4) and in rats stimulated in the right hippocampus at two different stages of the kindling and at three time points after the seizures: <2 hours (n = 8 and 5, stage 0 and stage 5), 2 to 3 hours (n = 5 and 6), and >3 hours (n = 4 and 2). Lact/creatine (Cr) and N-acetylaspartate (NAA)/Cr ratios were measured in six contiguous voxels (three left, three right) covering the hippocampi, anterior and posterior regions, and compared with EEG and ictal behavior. Lact/Cr ratios were measured at a very low level in the sham control rats and in the >3-hour group. RESULTS: In the <2-hour group, Lact/Cr increase was higher in stage-5 rats as compared with stage-0 rats (p = 0.001, unpaired t-test) and sham control rats when all the voxels were considered. Lact/Cr ratios were higher in the stimulated area as compared with all other brain areas in stage-0 rats (p = 0.05, paired t-test) but not in the stage-5 rats. Similar results with more inter-animal variability were measured in the 2- to 3-hour group. NAA/Cr ratios increased significantly after stage-0 kindling in the stimulated hippocampus but not after stage-5 kindling. CONCLUSIONS: Postictal Lact increase as assayed by MRS correlates with EEG and behavioral seizures and suggests that it would be an additional noninvasive technique for seizure localization during the presurgical evaluation of patients with intractable focal epilepsy.

A short episode of seizure activity protects from status epilepticus-induced neuronal damage in rat brain.

Kainic acid (KA)-induced status epilepticus (SE) in adult rats results in extensive neuronal damage throughout the limbic system and the loss of selectively vulnerable neuronal populations, particularly CA3 neurons. We investigated the effects of a short episode of seizure activity on neuronal death elicited by a subsequent prolonged SE episode. A short episode of seizure activity was produced by sub-cutaneous (s.c.) injection of KA followed after 1 h by pentobarbital administration. Twenty-four hours later, KA was administered again, and animals were sacrificed 3 days later. Neuronal damage was estimated by visual analysis of neuronal density. Our results show that a short episode of seizure activity did not produce neuronal damage but almost completely protected vulnerable neurons from KA-induced neuronal damage. These results extend to epileptic tolerance the notion of tolerance previously described in the case of ischemia.

MRS metabolic markers of seizures and seizure-induced neuronal damage.

PURPOSE: Proton magnetic resonance spectroscopy (MRS) was used to identify specific in situ metabolic markers for seizures and seizure-induced neuronal damage. Kainic acid (KA)-induced seizures lead to histopathologic changes in rat brain. The protective effect of cycloheximide treatment against neuronal damage caused by KA-induced seizures was studied, using in situ proton MRS imaging technique. METHODS: Rats were pretreated with placebo or cycloheximide 1 h before KA injection. Rat brains (n = 25) were scanned at the level of the hippocampus before, during, and 24 h after seizures. Spectra were recorded and the relative ratios of N-acetylaspartate (NAA), choline (cho), and lactate (Lac) to creatine (Cr) were calculated and compared between groups. RESULTS: A significant increase in Lac ratios was observed in KA-treated rats during and 24 h after seizure onset and this increase was prevented by cycloheximide pretreatment. NAA ratios were significantly higher during the ictal phase following KA treatment and this effect was not affected by cycloheximide pretreatment. Nissl staining confirmed previously reported prevention of KA-induced neuronal loss in CA3 and CA1 areas of the hippocampus by cycloheximide pretreatment. CONCLUSIONS: Our results suggest that in situ Lac increase is a marker of seizure-induced neuronal damage, whereas N-acetylaspartate (NAA) changes during and after status epilepticus may be a reflection of neuronal activity and damage, respectively.

Temporal changes in proton MRS metabolites after kainic acid-induced seizures in rat brain.

PURPOSE: In situ 1H-magnetic resonance spectroscopy (MRS) was used to study temporal metabolic changes in a rat model of temporal lobe epilepsy (TLE) by using kainic acid (KA). METHODS: Rat brains were scanned at the level of the hippocampal body for MRS measurements. Relative ratios of N-acetyl groups (NA: N-acetylaspartate and N-acetylaspartyl glutamate), choline, and lactate (Lac) over creatine (Cr) were calculated. RESULTS: NA/Cr ratios increased significantly during the ictal phase. During the postictal and interictal phases, the NA/Cr ratio decreased. There was a significant and prolonged increase of the lactate/Cr ratio in the hippocampi of rats that started 1 h after the onset of KA-induced seizure activity and persisted up to 24 h after the injection. The prolonged lactate/Cr increase in an area susceptible to neuronal damage (e.g., hippocampus) correlated with the onset of seizure activity but remained elevated thereafter. CONCLUSIONS: The ictal and early postictal increase in lactate ratios may reflect increased cellular activity and metabolism resulting from KA excitotoxicity. Assuming that the changes in NA/Cr ratios are due to NAA increase, we speculate that an activation of the N-acetylaspartylglutamate (NAAG) dipeptidase pathway may explain the ictal increase in NA/Cr ratios. The late postictal decrease in NA/Cr ratios is a reflection of KA-induced neuronal cell loss.

Mesial temporal sclerosis. A clinicopathologic study of 27 patients, including 5 with coexistent cortical dysplasia.

OBJECTIVE: Mesial temporal sclerosis (MTS) is a fairly well-recognized cause of intractable epilepsy. Its coexistence with cortical dysplasia is less commonly described. Herein, we describe the clinical and pathologic features of MTS, including cases in which cortical dysplasia was also identified. DESIGN: Retrospective surgical series of 27 patients. SETTING: Tertiary referral center with a high volume of epilepsy surgery. PATIENTS: Patients with medically intractable epilepsy who underwent hippocampal resections and in whom an unequivocal histologic diagnosis of MTS could be made. RESULTS: The patients studied included 18 males and 9 females ranging in age from 15 to 48 years (mean 32 years). Mesial temporal sclerosis was characterized by severe neuronal loss accompanied by gliosis occurring in the CA1/prosubiculum (27 patients, 100%), focally in the dentate gyrus (12 patients, 44%), and in the CA4 region (11 patients, 41%). Five patients (24%) had coexistent cortical dysplasia with increased molecular layer neurons (five patients), gyral fusion (two patients), diffuse architectural disorganization of the cortex (one patient), and clusters of atypical neurons and glial cells within the cortex (one patient). Twenty-five (93%) of the 27 patients had white matter neuronal heterotopia. Follow-up data were available for each patient (mean 23 months). Twenty-two of the patients are free of seizures postoperatively, including all five with coexistent cortical dysplasia; the five remaining patients have fewer seizures. There appeared to be no difference clinically between patients with MTS and no dysplasia and those with coexistent cortical dysplasia. CONCLUSION: We conclude that (1) MTS most severely involves the CA1/prosubiculum and CA4 regions of the hippocampus (the dentate gyrus may also be focally severely involved); (2) MTS and cortical dysplasia do occasionally exist; and (3) surgical outcome for MTS appears to be independent of coexistent cortical dysplasia.