Recent Advances in Epilepsy Surgery and Achieving Best Outcomes Using High-Frequency Oscillations, Diffusion Tensor Imaging, Magnetoencephalography, Intraoperative Neuromonitoring, Focal Cortical Dysplasia, and Bottom of Sulcus Dysplasia

BOSD: bottom of sulcus dysplasia DTI: diffusion tensor imaging EEG: electroencephalography FCD: focal cortical dysplasia HFO: high-frequency oscillations IONM: intraoperative neuromonitoring MEG: magnetoencephalography MEP: motor evoked potential MRI: magnetic resonance imaging The management of lesional epilepsy in neurosurgery is a fruitful and highly rewarding field of endeavor. The epilepsy neurosurgeon will care for a wide variety of patients with disease conditions that lend themselves to direct neurosurgical intervention and subsequent improved patient outcomes. These conditions include tumors such as astrocytoma, oligodendroglioma, dysembryoplastic neuroepithelial tumors, and ganglioglioma; vascular malformations including arteriovenous malformations, cavernomas, and Sturge Weber syndrome; malformative lesions, which are quite common, especially in pediatric neurosurgery, including cortical dysplasia, tuberous sclerosis, neuronal migration, and hemimegalencephaly; cysts of the brain including neuroglial and arachnoid cysts; infectious etiologies including bacterial, viral, and parasitic disorders; mesial temporal sclerosis; posttraumatic epilepsy; and Rasmussen encephalitis (Table 1). In this presentation, we discuss the many recent advances that have been made to enable the epilepsy neurosurgeon to achieve best outcomes for patients. These advances have included neuroimaging and procedural techniques that have paved the way towards reliable, consistent, and improved outcomes (Figure 1) and are discussed in the subsequent sections below. At our institution, the standard consent form includes language to allow us to use images and information for research purposes like case reports. In addition, our institution does not require Institutional Review Board approval for case reports.FIGURE 1: Examples of recent advances in epilepsy surgery.MAGNETOENCEPHALOGRAPHY Magnetoencephalography (MEG) has been used for many years to identify and localize the seizure focus in the brains of patients with epilepsy.1-5 MEG works on the fundamental principle that in response to an electrical current, a magnetic field is generated according to the “right-hand rule” in physics, perpendicular to the orientation of the electric field (Figure 2). MEG has the best spatial resolution in millimeters and temporal resolutions in milliseconds of all imaging modalities including functional magnetic resonance imaging (MRI), computed tomography scan, positron emission tomography scan, and single-photon emission computed tomography scanning. At our institution, we have been using MEG since 1998 to investigate children with intractable epilepsy who are candidates for epilepsy surgery. We have previously characterized the correlation between magnetic spike sources using MEG-guided neuronavigation, and outcomes for epilepsy surgery.1,2 Our results indicate that MEG spikes can be classified into tight clusters of more than 20 spike sources within a 1 cm distance, small clusters which are characterized by 6 to 19 spike sources within a 1 cm distance; scatters where there are dispersed spike source separation; and the absence of spike sources altogether.1FIGURE 2: In response to an electrical current, a magnetic field is generated according to the “right-hand rule” in physics. Minute magnetic field disturbances are detected by superconducting quantum interference devices. These disturbances can then be localized onto an MRI scan providing exquisite spatial and temporal resolution of neurological function, and epileptogenic activity.TABLE 1: Lesional Conditions in Epilepsy SurgeryOne of the main issues with the interpretation of MEG data is that MEG represents an interictal phenomenon. That said, on occasion, as in the cases of children with Rasmussen encephalitis, an ictal MEG can be obtained (Figure 3). Recently, we have described the use of MEG-guided resection of epileptogenic lesions in children where MEG spike clusters are identified and removed with neuronavigation and neuromonitoring.3 These patients have done extremely well after surgery, by and large, and in these cases, we have obviated the need for invasive subdural grid monitoring. Over the years, we have determined that MEG is particularly helpful for characterizing the location of epileptogenic lesions in proximity to the Rolandic cortex (Figure 4).4,5 The repertoire of functional applications of MEG continues to grow, and we have shown that MEG can also be used to help map the visual cortex in efforts to preserve the visual fields where lesions abut against the calcarine cortex or visual pathways (Figure 5).FIGURE 3: Left panel: 6-yr-old boy who presented with explosive onset of seizures emanating from the right hemisphere. His MEG depicts a large spike cluster (yellow dots) in the Rolandic region indicative of his underlying condition, Rasmussen's encephalitis. Right panel: the neurosurgical treatment of Rasmussen's encephalitis includes hemispherectomy. Coronal MRI scan showing postoperative results after right peri-insular hemispherotomy.FIGURE 4: Twelve-year-old female with intractable epilepsy. As an infant, she suffered a traumatic brain injury resulting in significant encephalomalacia of the right parieto-occipital lobes. Left axial MR images show extensive nature of the encephalomalacia. Right axial and sagittal MR iamges show a spike cluster at the junction of the traumatic encephalomalacia and the normal Rolandic cortex (red arrows). She underwent image-guided resection of this MEG spike cluster, and is currently seizure-free. Invasive subdural grid monitoring could be avoided using this technique.FIGURE 5: Twelve-year-old male with occipital seizures. Left panel (upper) shows a low signal intensity lesion in the occipital lobe (white arrow); lower image shows intraoperative ultrasound demarcating the lesion prior to resection. Right panel (upper) shows the visual evoked field (VEF) as calculated by MEG; lower image shows the postoperative sagittal MRI once the lesion was resected. Using image guidance, the lesion could be resected and the visual fields could be largely preserved by avoiding the VEF during tumor resection. The tumor proved to be a ganglioglioma.INTRAOPERATIVE NEUROMONITORING Intraoperative neuromonitoring (IONM) is of value in identifying neuroanatomical pathways at risk using direct stimulation of the primary motor, somatosensory, language, and visual pathways, and the cranial nerves. By continuous monitoring of these pathways, neurosurgeons can minimize risk to the patient, and preserve neurological function after surgery. A critical element to successful IONM is timely dialog between the neurophysiology technician and the neurosurgeon. As soon as intraoperative changes are noted, this information must be conveyed to the neurosurgeon who can react to the alterations by taking assessment of the operative field. Over the years, we have utilized these IONM techniques in a myriad of ways to assist with epilepsy surgery.5-7 Such monitoring techniques also include the use of pediatric awake craniotomy and intraoperative stimulation mapping.8 As with other institutions, we have reliably used phase reversals to identify the central sulcus, direct motor stimulation to identify the primary motor or supplementary motor cortex, and direct subcortical stimulation to identify the descending cortical spinal tracts. We have taken full advantage of the monopolar “trains of 5” discharge technique, and electroencephalography (EEG) to identify stimulus-induced after discharges. Our technique of direct motor cortex mapping is highlighted in Table 2, which compares and contrasts the traditional “Penfield technique” with the train of 5 technique.9TABLE 2: Direct Motor Cortex Mapping TechniquesAn example of how motor evoked potentials (MEPs) can be used to alert the neurosurgeon to take into account the actions in the operating room is shown in Figure 6. Here, surgery was being conducted until such time that the MEPs were noted to be altered to the tibialis anterior and the abductor hallucis longus. This proved to be due to excessive brain retraction on the nearby Rolandic cortex. With the release of the retraction, the MEPs recovered completely in a short period of time.FIGURE 6: The advantages of IONM and MEPs with alert and recovery of function. During craniotomy, excessive retraction forces were being applied to the corticospinal tract such that the tibialis anterior (TA) and abductor hallucis (AH) muscles stopped receiving signals using trains of 5 continuous neuromonitoring. With release of the brain retractors, normal function resumed, and the patient awakened without a neurological deficit.The benefit of subcortical stimulation during neurosurgical resection of epileptogenic foci is shown in Figure 7. In this case, a patient with intractable epilepsy and extensive polymicrogia abutting the cortical spinal tract could be monitored for integrity of the descending corticospinal tract using subcortical stimulation while the cortical malformation was being excised.FIGURE 7: Eight-year-old girl with intractable epilepsy emanating from the left hemisphere from extensive polymicrogyria. The degree of brain malformation is outlined in red, and highlighted (red arrows). The position of the corticospinal tract (CST) is shown (yellow descending bars). With resection of the cortical malformation, a subcortical stimulator can be used to help document the relative position of the CST so as to avoid injury to it.HIGH-FREQUENCY OSCILLATIONS The normal background rhythm of the brain on EEG is between 20 and 40 Hz. High-frequency oscillations (HFOs) represent oscillations in the ripple range (80-150 Hz), or fast ripple range (>200 Hz). HFOs are best detected by invasive subdural grid monitoring. They are thought to represent the synchronous firing of abnormally bursting principle cells localized to discrete neuronal clusters.10-12 It is now known that the presence of EEG HFOs precede the onset of clinical seizures. In addition, it has been determined that the resection of cortical regions expressing HFOs are associated with improved seizure outcome.13 Recently, we have developed a strategy to illustrate, in real time, the propagation of a seizure focus across the surface of the brain using video animation technology.10,13,14 This strategy has been particularly helpful when discussing surgical plans with patients and families prior to embarking on the final resection after invasive subdural grid monitoring. Over the years, we have published numerous papers on the utility of HFOs in identifying the seizure onset zone, and in achieving excellent seizure outcomes.10-15 However, there are some limitations to using HFOs in epilepsy surgery. These include the fact that the neuronal mechanisms underlying HFOs is unknown; the normal cerebral cortex itself can exhibit HFOs on occasion; the precise manner in which HFOs cause seizures is undetermined; and long-term outcome data are lacking in this regard. DIFFUSION TENSOR IMAGING Diffusion tensor imaging (DTI) is a relatively recent advance in neuroimaging that is based on the restriction of diffusivity of water molecules. The diffusion anisotropy is influenced by the degree of myelination density of fiber packing and fiber diameter. Using fractional anisotropy, color vector maps and directionality of white matter tracts can be determined. We have recently reported on the use of DTI studies in characterizing seizures recurrences after hemispherectomy. In this study, DTI data provided information regarding persistent connectivities between the 2 hemispheres leading to targeted surgery that could be performed to enable patients to become seizure-free after repeat disconnection.16 Some examples of the advantages of using DTI in planning epilepsy resections are shown in Figure 8.FIGURE 8: Examples of DTI in epilepsy surgery. Upper panels, left: sagittal MRI and DTI showing small area of cortical dysplasia (pink) anterior to the CST (yellow). Middle: coronal MRI and DTI showing cingulate-gyrus-based lesion (pink) mesial to the CST (yellow); the lesion proved to be a ganglioglioma. Right: sagittal MRI and DTI showing area of encephalomalacia (pink) posterior to the CST (yellow). Lower panels, left: axial MRI and DTI showing large area of polymicrogyria (pink) overlapping with Rolandic region and CST (yellow). Middle: 3-D rendering of MRI and DTI axial based, showing tumor (pink) just lateral to the CST (yellow). Right: axial MRI and DTI showing left ganglioglioma adjacent to fibers of the visual fields (yellow).BOTTOM OF SULCUS DYSPLASIA Improvement in neuroimaging techniques has allowed the visualization of subtle cortical malformations in the brain that predispose to epilepsy. One of these is the so-called bottom of sulcus dysplasia (BOSD). Typically, the pathology of BOSD is focal cortical dysplasia (FCD) type II. It is indeed interesting that these small and subtle lesions, which are difficult to identify on MRI, can cause profound epileptogenic disturbances (Figures 9A and 9B). We have recently published on the use of MEG and characterizing the localization of FCD at the bottom of the sulcus.17 Our experience with BOSD is similar to others in that the resection of these lesions is associated with good to excellent seizure outcome.FIGURE 9: A, BOSD case examples. The MRI image from these different examples of cases of children with intractable epilepsy demonstrate BOSD in all cases, as outlined in yellow. Reproduced with permission from Nakajima et al,17 © John Wiley and Sons. B, Seventeen-year-old male with BOSD embedded within the Rolandic region and the left CST. He presented with intractable epilepsy. A subdural grid was placed spanning the Rolandic region, with depth electrodes inserted into the lesion using frameless stereotaxy. Once it was determined that the epilepsy was coming from the BOSD, an intersulcal approach was taken to removing the lesion from directly behind the primary motor cortex. Following resection of the lesion which proved to be FCD, the patient has been seizure-free.ILLUSTRATIVE CASES Case 1 A 4-yr-old girl with intractable right focal motor seizures had failed numerous anticonvulsants. She had a left Rolandic lesion on MRI scanning, and a functional MRI was equivocal for language at her age (Figure 10). She underwent left invasive subdural grid monitoring. A combination of subdural strip and depth electrodes were placed with neuronavigation. During extraoperative monitoring, her seizures were localized to the suspected area of FCD. An analysis of the HFOs showed definitively that the lesion on MRI was the seizure-onset zone. She was taken to surgery using continuous trains of 5 neuromonitoring, and the lesion was excised, proving to be FCD type II. Interestingly, despite intact monitoring throughout the procedure, she awakened with mild dysphasia and a right hemiparesis. Thankfully, these deficits improved rapidly back to normal within 1 wk of hospitalization. She is seizure-free now more than 2 yr after surgery.FIGURE 10: Case 1: composite MR imaging and DTI images of area of FCD in the left parietal cortex of a 4-yr-old child who underwent subdural grid monitoring, and excision of the lesion (pink) which proved to be FCD. The integrity of the CST could be maintained using trains of 5 intraoperative neuromonitoring stimulation.Case 2 A 10-yr-old male with a premotor lesion on MRI was suspected as having BOSD. He had failed multiple anticonvulsant medications (Figure 11). He underwent invasive subdural monitoring at which time strip and depth electrodes were placed (Figure 12). The depth electrodes were placed directly into the lesion using frameless stereotaxy. After 4 d of extraoperative recordings, his seizures were found to originate from the lesion. The lesion was then approached transcortically leaving the depth electrodes in Situ to follow them into the area of the lesion, at which time the grey matter abnormality was excised in its entirety (Figure 13). Continuous trains of 5 neuromonitoring were stable throughout the procedure. The lesion proved to be FCD type II. After surgery, he has been seizure-free for 18 mo.FIGURE 11: Case 2: composite imaging of 10-yr-old male with intractable epilepsy from mesial right frontal lesion (pink, white arrow) anterior to the CST (yellow). The patient underwent invasive monitoring with depth electrodes placed using frameless stereotaxy into the lesion. The depth electrodes were then used to accurately pinpoint the lesion at the time of resection of the lesion, and to remove it completely. It proved to be FCD, and the patient has been seizure-free for 1 yr.FIGURE 12: Intraoperative screensave targeting using depth electrodes from case depicted in Figure 10. Placement of the depth electrodes provides a pathway for subsequently identifying and successfully removing such small BOSD lesions.FIGURE 13: At the time of resection for the case described in Figure 10, the intraoperatively placed depth electrodes help to facilitate localization and resection of the lesion in its entirety.Case 3 A 4-yr-old male was found to have intractable epilepsy and right lower extremity sensory seizures with a subtle lesion on MRI scan (Figure 14). By DTI, the lesion was abutting the left corticospinal tract medially (Figure 15). Both depth electrodes and intrahemispheric strip electrodes were placed. Extraoperative monitoring proved that the lesion was the source of the epilepsy. The lesion was then targeted using an interhemispheric approach and neuronavigation under continuous trains of 5 neuromonitoring. The lesion involving the cingulate gyrus was then excised. Postoperatively, there were no seizures, and the final diagnosis was ganglioglioma. He has been seizure-free for 6 mo.FIGURE 14: Axial MRI of 7-yr-old male with intractable epilepsy and mesial lesion (pink) abutting the CST (yellow).FIGURE 15: The lesion from Figure 13 was resected using an interhemispheric approach with neuronavigation and IONM. It proved to be a ganglioglioma, and the patient has been seizure-free since its resection.CONCLUSION Advances in epilepsy surgery have occurred progressively with the improvement in neuroimaging techniques such as DTI, MEG, and the identification of FCD in BOSDs. Abnormalities that are found on MRI are then linked to frameless stereotaxy, neuronavigation platforms that facilitate neurosurgical resection. We have found that the information from both surface and depth electrode recordings are summative, and particularly helpful in designing the best epilepsy surgery map. We have been able to characterize regions of safe resections even within eloquent brain regions such as the Rolandic region and Broca's area. Advances in seizure onset detection using HFO ripples and fast ripples have helped us to further characterize the epileptogenic zone better than we could before these techniques were available. Finally, it should be stressed that we can use awake craniotomy and intraoperative neuromonitoring even in young children with epilepsy to affect the best seizure outcomes possible. As mentioned at the outset, the field of epilepsy surgery is a rich and rewarding one. Future advances will only help to improve patient safety and outcomes beyond our current levels of expertise and understanding. Disclosures This work was supported by funds provided by the Jack Beqaj and Wylie Family Funds in Epilepsy Surgery at the Hospital for Sick Children. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

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