Pachygyria

Focal cortical dysplasia (FCD) is often associated with severe partial epilepsy. In such cases, interictal frequent rhythmic bursting epileptiform activity (FBREA) on both scalp electroencephalography (EEG) and electrocorticography (ECoG) is generally accepted to be identical to the ictal epileptiform activity. We used magnetoencephalography (or Magnetic Source Imaging (MSI)) to determine the epileptogenic zone in a 6-year-old patient with histopathologically proven FCD and normal magnetic resonance imaging (MRI). MSI was used to localize the sources of both ictal activity and FRBEA, which was then compared with ECoG findings. The intracranial sources of both types of activity co-localized in the left inferior frontal and superior temporal gyri. The location and extent of the epileptogenic area determined by MSI was essentially identical to that determined directly through extra-operative ECoG. In the absence of structural abnormalities detectable on MRI, the noninvasive method of MSI provided valuable information regarding the location and extent of the primary epileptogenic area. This was critical for pre-surgical planning regarding placement of intracranial electrodes and for risk-benefit evaluation. [Neurol Res 2002; 24: 525-530]

Keywords: Focal cortical dysplasia; magnetoencephalography; electrocorticography; epileptogenicity; epilepsy surgery

INTRODUCTION

Several investigators have reported on the electrophysiological manifestations of focal cortical dysplasia (FCD)1-9. A common electrophysiological correlate of FCD consists of frequent rhythmic bursting epileptiform activity (FRBEA) that is more prominent on invasive electrocorticography (ECoG) than on the surface EEG interictally3,10 Given that FCD is often associated with very subtle structural abnormalities not detectable on MRI, pre-surgical planning relies on the localization of paroxysmal activity preceding seizures on ECoG recorded from chronically implanted electrodes. Although there are indications that FRBEA originates from the same region as ictal discharges, studies on the morphology and intracranial origin of the former by magnetoencephalography (MEG, otherwise known as Magnetic Source Imaging (MSI)) are rare. Establishing the relative utility of interictal FRBEA and ictal paroxysmal discharges is an important step if MEG is to be used for the pre-surgical localization of the primary epileptogenic zone in FCD4-6,11,12. The accuracy of MSI in the localization of neuronal populations that show briefly elevated levels of activity, such as those producing epileptiform discharges, can be very high (i.e., in the order of 2-3 mm)13. MSI evaluations typically rely only on interictal activity.

The present study provided the opportunity, firstly to examine the utility of interictal bursting activity, observed in both MEG and ECoG, for identifying the epileptogenic zone in FCD, and secondly, to assess the localization accuracy of MSI, by comparing the MEG-- based source locations of ictal and interictal discharges, with the localization of corresponding events obtained directly through extraoperative ECoG.

PROCEDURES

Case description

The patient was a 6-year-old, right-handed girl who was born full term. She had no perinatal problems and showed normal development up to the age of 2 years, when she was referred to a neurologist because of repeated complex partial seizures, lasting for 10-15 sec. The clinical semiology consisted of staring episodes with alteration in her levels of consciousness and right-sided facial twitching. Her seizures were initially infrequent, but over the last three months had increased dramatically. She typically had 5-10 per day, and occasionally up to 40 per day, even with aggressive medical treatment. In light of her refractory seizure disorder, she underwent a pre-surgical evaluation. Neurological examination was normal with the exception of mild bilateral facial weakness and a prominent oral motor apraxia.

An MRI was entirely normal and did not reveal any of the abnormalities often present in FCD, such as regional signal intensity changes, pachygyria or microgyria on T1 - and T2-weighted scans, or on fluid attenuated inversion recovery (FLAIR) images.

MEG recording

MEG recording was performed pre-operatively for localization of the sources of interictal epileptiform activity and somatosensory mapping. Spontaneous MEG was recorded with a 148 channel whole-head magnetometer (Magnes WH2500, 4-D Neuroimaging, San Diego, CA, USA) in a magnetically shielded room. Simultaneous EEG was recorded, with gold disc electrodes, using a bipolar montage (Neurofax, NihonKohden, Tokyo, Japan) from 21 scalp locations, placed according to the International 10-20 system. The MEG recordings were digitized at a sampling rate of 508 Hz. The on-line bandpass filter was set between 1-100 Hz. For optimal interictal analysis offline filtering was performed with a bandpass between 3 and 70 with a 60 Hz notch filter. The principles underlying MEG generation, recording, and source localization are reviewed elsewhere14-18.

As part of the analysis of the interictal paroxysmal activity, we calculated the equivalent current dipole (ECD) location, orientation and moment for each event. ECDs were computed at successive 2 msec intervals during the temporal evolution of the spike, using data from a set of 37 neighboring MEG sensors that contained both extrema of the magnetic flux distribution associated with each event. ECD solutions were considered acceptable if they met the following criteria:

1. A correlation coefficient of at least 0.98 (ensuring that the solution accounted for 96% or more of the observed magnetic flux distribution associated with each event).

2. A root mean square (RMS) of magnetic flux across all 37 channels of 400 fT or more.

3. A dipole moment (Q) under 400 nAm. An ECD sorting program was also applied for selecting the ECD with the best correlation coefficient for each event. This procedure results in a tighter cluster of ECDs, by retaining only the 'best' (i.e., presumably more reliable) solution for each event, from a series of contiguous ECDs that are likely to be modeling the same source19. More details on MEG data analyses can be found in a previous report from our group17,18.

Before the MRI scan was performed, three skin markers were placed at fiducial points on the patient's head (the nasion, the left and the right external meati). The location of the same fiducial points was also recorded, at the beginning of the MEG recording session, relative to the magnetometer sensor, thus establishing a common spatial reference for the transposition of 3-D coordinates between MEG and MRI data, as previously described

Electrocorticography

With the patient under general anesthesia, a left fronto-temporo-parietal craniotomy was performed. No gross abnormalities were apparent in the exposed cortex. A 64-contact subdural grid was placed over the fronto-parieto-temporal area. In addition, two six-- contact subdural strip electrodes were placed over left basal temporal areas. Long-term video-EEG monitoring was performed with these electrodes for a period of five days in order to capture a representative sample of paroxysmal activity associated with clinical seizures.

RESULTS

Magnetoencephalography

Frequent, large amplitude magnetic and electrical bursting epileptiform activity was noted predominantly over the left posterior frontal area on MEG and were recorded simultaneously on the surface EEG. The discharge trains occurred more frequently on MEG (Figure 1). Source localization of each burst of discharges was performed during three noncontiguous time windows, ranging in duration between 400 and 800 msec:

1. A window encompassing the onset of each burst.

2. A randomly selected window during the course of the burst.

3. A window capturing the last portion of each spike train.

ECD sources computed during each of the three time periods for a total of 72 discharge bursts overlapped anatomically, forming a large cluster of sources in the left inferior frontal and superior temporal lobes, extending into adjacent sensorimotor regions (Figure 2).

During the MEG recording session, ictal activity was registered for 20 sec before it developed into right sided facial twitching. Figure 3 shows that MEG paroxysmal discharges were more obvious and more frequent than EEG discharges. Reliable localization of ECD sources was successful at several time points during the ictal pattern just before it spread. The estimated sources of ictal activity were found near the center of FRBEA source clusters (Figure 2).

Electrocorticography

Ictal activity during the course of 13 recorded seizures showed a wide electrode distribution. In contrast, the distribution of activity at seizure onset was focal and confined to six electrode contacts (Figures 2 and 4). This region corresponded closely with the ictal focus derived from MEG. Further, the same contacts that defined the primary epileptogenic area also showed FRBEA interictally (Figure 1). This region was essentially coextensive with the distribution of the ECD cluster associated with magnetic rhythmic discharge bursts. However, the area that appeared to be generating interictal activity was larger than the ictal focus and this was true for both ECoG and MEG-derived localization data.

Surgery and post-operative course

Following the extra-operative video-EEG monitoring the patient underwent a repeat craniotomy under general anesthesia. At first, the presumed epileptogenic area, in the inferior frontal and superior temporal lobes, as determined by both ictal MEG and extra-operative ECoG, was resected. Histopathology of the resected tissue revealed giant neurons and balloon cells. Intraoperative ECoG recordings continued to show paroxysmal activity overlapping with part of the sensorimotor cortex superior to the resected area. Multiple subpial transection (MST) was performed in this region, instead of a corticectomy. All paroxysmal activity disappeared immediately after the MST. The patient's post-operative course was uneventful with the exception of a mild transient weakness in her right upper extremity.

At the most recent follow-up seven months after surgery the patient continues to be seizure-free and receives a single antiepileptic drug21. Her neurological examination is now normal, and her oral motor apraxia resolved when she stopped having daily seizures. She attends school and is performing at grade level.

DISCUSSION

Focal cortical dysplasia is commonly associated with partial seizures3,6,7,10, and complete removal of the epileptogenic zone can lead to significant clinical improvement10. However, given that the suspected epileptogenic zone often contains only microscopic abnormalities not detectable on MRI pre-operatively or by macroscopic examination of the exposed cortex7,22-26, it is difficult to determine the precise location and extent of the area to be resected10,23,27. At present, invasive electrophysiological recordings of ictal epileptiform discharges is the method of choice for pre-surgical planning in FCD. Noninvasive mapping techniques, like MSI which is in principle very accurate in localizing intracranial sources of neurophysiological activity13,16,28, could be particularly useful in the preoperative evaluation of FCD patients, provided that the following requirements are met:

1 . A sufficient sample of epileptiform activity is collected during the MEG recordings to permit reliable localization of these events.

2. This activity is generated within the primary epileptogenic zone.

3. The cortex generating these events is coextensive with the primary epileptogenic zone.

MSI relies primarily upon recordings of interictal epileptiform events that may not be constantly present in a given patient, and altogether absent in some patients. It is also possible that the cortical areas that generate interictal spikes and sharp waves (irritable zone) are not identical to the primary epileptogenic zone. Usually, the irritable zone is more extensive and may include a greater number of anatomically distinct cortical regions than the epileptogenic zone29. Although this may be quite common when the epileptiform activity available for a given patient consists of isolated, intermittent spikes and sharp waves, bursts of spikes occurring at a rate of 10 events per second or faster may provide a more reliable index of abnormal activity produced by the primary epileptogenic area3,10. Such bursts are a common occurrence in patients with FCD and may represent an intermediate stage between ictal and interictal state10. In fact, rhythmic spike discharges often precede the onset of ictal activity in some patients with FCD 2,6,10. Experimental studies are in agreement with these observations, showing increased excitatory events and reduced inhibitory influence generating longlasting seizure-like discharges . Our data clearly support this view, by showing that the area defined by the sources of FRBEA on MEG and the topography of similar events on extraoperative ECoG, was essentially identical to the primary epileptogenic region as determined by both ictal MEG and ECoG. This finding successfully addressed the first principal focus of the present investigation as outlined in the Introduction. The region that showed persistent, recurring epileptiform activity as indicated by the anatomical consistency of source localization during the temporal course of each spike burst coincided spatially with the extent of the cortex that contained microscopic abnormalities characterized by both prominent abnormal giant neurons and balloon cells on post-operative histological examination 32,33. This finding further supports the notion, indicating by extra-operative ECoG and acute depth electrode monitoring2,3,10, that epileptogenicity in FCD is intrinsic. Given that regional cortical pathology is (as in the case presented here) often not detectable on MRI, our data highlight the potential utility of MSI as a noninvasive tool for determining the location and extent of the epileptogenic zone in patients with FCD, provided that recordings of a sufficient sample of rhythmic epileptiform events, and subsequent reliable localization of their intracranial sources are feasible.

Our study is the first investigation that directly assessed the validity and accuracy of MSI-based localizations of both ictal and interictal epileptiform activity in FCD with reference to the `gold standard' in clinical practice, electrocorticography through chronically implanted subdural electrodes. It should be noted, however, that by using a single ECD model for source localization, the ictal onset zone was depicted by MSI as a single point, that was located near the geometric center of the ECoG ictal focus, in agreement with previous reports,15,34,35.

ACKNOWLEDGEMENTS

We wish to thank Ms Michele E. Fitzgerald for critical reading of this manuscript. We also thank Mr Eric Y. Caballero, 4-D Neuroimaging, Ms Pamela S. Zanek and Mr Mohammad Ayub, Epilepsy Monitoring Unit, Memorial Hermann Children's Hospital, for their technical assistance. This work was supported by NIH Grant R01 NS37941 to Andrew C. Papanicolaou.

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Hideaki Ishibashi*, Panagiotis G. Simos*, James W. Wheless^^^, James E. Baumgartner(sec), Howard L. Kim^^, Eduardo M. Castillo*, Robert N. Davis* and Andrew C. Papanicolaou*

*Department of ^Neurosurgery, ^^Department of Neurology, (sec)Department of Pediatrics, Department of Pediatric Surgery (Neurosurgery), Vivian L Smith Center for Neurologic Research, Texas Comprehensive Epilepsy Program, The University of Texas Health Science Center at Houston, Houston, TX, USA

Correspondence and reprint requests to: Hideaki Ishibashi, MD, PhD, Department of Neurosurgery, University of Texas, Houston Medical School, 1333 Moursund St., Suite HI 114, Houston, TX 77030, USA. [Hideaki. Ishibashi@uth.tmc.edu] Accepted for publication May 2002.

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