Influence of magnetic source imaging for planning intracranial EEG in epilepsy.

BACKGROUND: Magnetic source imaging (MSI) is used routinely in epilepsy presurgical evaluation and in mapping eloquent cortex for surgery. Despite increasing use, the diagnostic yield of MSI is uncertain, with reports varying from 5% to 35%. To add benefit, a diagnostic technique should influence decisions made from other tests, and that influence should yield better outcomes. We report preliminary results of an ongoing, long-term clinical study in epilepsy, where MSI changed surgical decisions. METHODS: We determined whether MSI changed the surgical decision in a prospective, blinded, crossover-controlled, single-treatment, observational case series. Sixty-nine sequential patients diagnosed with partial epilepsy of suspected neocortical origin had video-EEG and imaging. All met criteria for intracranial EEG (ICEEG). At a surgical conference, a decision was made before and after presentation of MSI. Cases where MSI altered the decision were noted. RESULTS: MSI gave nonredundant information in 23 patients (33%). MSI added ICEEG electrodes in 9 (13%) and changed the surgical decision in another 14 (20%). Based on MSI, 16 patients (23%) were scheduled for different ICEEG coverage. Twenty-eight have gone to ICEEG, 29 to resection, and 14 to vagal nerve stimulation, including 17 where MSI changed the decision. Additional electrodes in 4 patients covered the correct: hemisphere in 3, lobe in 3, and sublobar ictal onset zone in 1. MSI avoided contralateral electrodes in 2, who both localized on ICEEG. MSI added information to ICEEG in 1. CONCLUSION: Magnetic source imaging (MSI) provided nonredundant information in 33% of patients. In those who have undergone surgery to date, MSI added useful information that changed treatment in 6 (9%), without increasing complications. MSI has benefited 21% who have gone to surgery.

Magnetic source imaging localizes epileptogenic zone in children with tuberous sclerosis complex.

The authors assessed whether magnetoencephalography/magnetic source imaging (MEG/MSI) identified epileptogenic zones in patients with tuberous sclerosis complex (TSC). In six TSC children with focal seizures, ictal video-EEG predicted the region of resection with 56% sensitivity, 80% specificity, and 77% accuracy (p = 0.02), whereas interictal MEG/MSI fared better (100%, 94%, and 95%, respectively; p < 0.0001). Interictal MEG/MSI seems to identify epileptogenic zones more accurately in children with TSC and focal intractable epilepsy.

Hidden Markov modelling of spike propagation from interictal MEG data.

For patients with partial epilepsy, automatic spike detection techniques applied to interictal MEG data often discover several potentially epileptogenic brain regions. An important determination in treatment planning is which of these detected regions are most likely to be the primary sources of epileptogenic activity. Analysis of the patterns of propagation activity between the detected regions may allow for detection of these primary epileptic foci. We describe the use of hidden Markov models (HMM) for estimation of the propagation patterns between several spiking regions from interictal MEG data. Analysis of the estimated transition probability matrix allows us to make inferences regarding the propagation pattern of the abnormal activity and determine the most likely region of its origin. The proposed HMM paradigm allows for a simple incorporation of the spike detector specificity and sensitivity characteristics. We develop bounds on performance for the case of perfect detection. We also apply the technique to simulated data sets in order to study the robustness of the method to the non-ideal specificity-sensitivity characteristics of the event detectors and compare results with the lower bounds. Our study demonstrates robustness of the proposed technique to event detection errors. We conclude with an example of the application of this method to a single patient.

Automated interictal spike detection and source localization in magnetoencephalography using independent components analysis and spatio-temporal clustering.

OBJECTIVE: Magnetoencephalography (MEG) dipole localization of epileptic spikes is useful in epilepsy surgery for mapping the extent of abnormal cortex and to focus intracranial electrodes. Visually analyzing large amounts of data produces fatigue and error. Most automated techniques are based on matching of interictal spike templates or predictive filtering of the data and do not explicitly include source localization as part of the analysis. This leads to poor sensitivity versus specificity characteristics. We describe a fully automated method that combines time-series analysis with source localization to detect clusters of focal neuronal current generators within the brain that produce interictal spike activity. METHODS: We first use an ICA (independent components analysis) method to decompose the multichannel MEG data and identify those components that exhibit spike-like characteristics. From these detected spikes we then find those whose spatial topographies across the array are consistent with focal neural sources, and determine the foci of equivalent current dipoles and their associated time courses. We then perform a clustering of the localized dipoles based on distance metrics that takes into consideration both their locations and time courses. The final step of refinement consists of retaining only those clusters that are statistically significant. The average locations and time series from significant clusters comprise the final output of our method. RESULTS AND SIGNIFICANCE: Data were processed from 4 patients with partial focal epilepsy. In all three subjects for whom surgical resection was performed, clusters were found in the vicinity of the resectioned area. CONCLUSIONS: The presented procedure is promising and likely to be useful to the physician as a more sensitive, automated and objective method to help in the localization of the interictal spike zone of intractable partial seizures. The final output can be visually verified by neurologists in terms of both the location and distribution of the dipole clusters and their associated time series. Due to the clinical relevance and demonstrated promise of this method, further investigation of this approach is warranted.

A model for frequency dependence of conductivities of the live human skull.

A mathematical model (sigma(omega) approximately equal to A omega alpha, where, sigma is identical with conductivity, omega = 2 pi f is identical with applied frequency (Hz), A (amplitude) and alpha (unit less) is identical with search parameters) was used to fit the frequency dependence of electrical conductivities of compact, spongiosum, and bulk layers of the live and, subsequently, dead human skull samples. The results indicate that the fit of this model to the experimental data is excellent. The ranges of values of A and alpha were, spongiform (12.0-36.5, 0.0083-0.0549), the top compact (5.02-7.76, -0.137-0.0144), the lower compact (2.31-10.6, 0.0267-0.0452), and the bulk (7.46-10.6, 0.0133-0.0239). The respective values A and alpha for the respective layers of the dead skull samples were (40.1-89.7, -0.0017-0.0287), (5.53-14.5, -0.0296 - -0.0061), (4.58-15.9, -0.0226-0.0268), and (12.7-25.3, -0.0158-0.0132).

Magnetoencephalography-directed surgery in patients with neocortical epilepsy.

OBJECT: Magnetoencephalography (MEG) and magnetic source (MS) imaging are techniques that have been increasingly used for preoperative localization of epileptic foci and areas of eloquent cortex. The use of MEG examinations must be carefully balanced against the high cost and technological investments required to perform these studies, particularly when less expensive alternative localization methods are available. To help elucidate the value of MEG, the authors have critically reviewed their experience with whole-head MEG in the case management of patients undergoing epilepsy surgery. METHODS: The authors identified 23 patients with suspected focal epilepsy who underwent whole-head MEG and MS imaging at Huntington Memorial Hospital and, subsequently, underwent invasive intracranial electrode monitoring and electrocorticography (ECoG) to localize the zone of seizure origin for surgical resection. The results of the MS imaging were retrospectively stratified into three groups by the number of interictal spikes recorded during a 4-hour recording session: Class I (no spikes), Class II (< or = five spikes), and Class III (> or = six spikes). Class III was further subdivided according to the clustering density of the interictal spikes: Class IIIA represents a mean distance between interictal spikes of 4 mm or greater (that is, diffusely clustered) and Class IIIB represents a mean distance between interictal spikes of less than 4 mm (that is, densely clustered). The authors analyzed these groups to determine to what extent the results of MS imaging correlated with the ECoG-determined zone of seizure origin. In addition, they assessed whether the MS imaging study provided critical localization data and correlated with surgical outcome following resection. A statistical analysis of these correlations was also performed. Of the 40 patients studied, 23 underwent invasive monitoring, including 13 with neocortical epilepsy, four with mesial temporal lobe epilepsy, and six with suspected neocortical epilepsy that could not be clearly localized by ECoG. Depth electrodes were used in nine cases, subdural grids in nine cases, depth electrodes followed by subdural grids and strips in four cases, and intraoperative ECoG in one case. Electrocorticography was able to localize the zone of seizure origin in 16 (70%) of 23 cases. In 11 (69%) of the 16 cases in which ECoG was able to localize the zone of seizure origin, the interictal spikes on the MS images were classified as Class IIIB (densely clustered) and regionally correlated to the MS imaging-determined localization in all cases (that is, the same lobe). In contrast, no Class IIIB cases were identified when ECoG was unable to localize the zone of seizure origin. This difference showed a trend toward, but did not achieve, statistical significance (p < 0.23), presumably because of the relatively small number of cases available for analysis. In three cases (all Class IIIB), MS imaging was used to guide invasive electrodes to locations that otherwise would not have been targeted and provided unique localization data, not evident from other imaging modalities, that strongly influenced the surgical management of the patient. The classification of findings on MS images into subgroups and subsequent statistical analysis generated a model that predicted that Class IIIB MS imaging data are likely to provide reliable information to guide surgical placement of electrodes, but all other data groups do not provide localization information that is reliable enough to guide surgical decision making. CONCLUSIONS: Magnetic source imaging can provide unique localization information that is not available when other noninvasive methods are used. Magnetic source imaging appears most useful for cases of neocortical epilepsy. In particular, when an MS imaging study revealed six or more interictal spikes that were densely clustered in a single anatomical location, the MS image was highly correlated with the zone of seizure origin identified by ECoG. In these cases the MS imaging data may be useful to guide placement of intracranial electrodes.

Conductivities of three-layer live human skull.

Electrical conductivities of compact, spongiosum, and bulk layers of the live human skull were determined at varying frequencies and electric fields at room temperature using the four-electrode method. Current, at higher densities that occur in human cranium, was applied and withdrawn over the top and bottom surfaces of each sample and potential drop across different layers was measured. We used a model that considers variations in skull thicknesses to determine the conductivity of the tri-layer skull and its individual anatomical structures. The results indicate that the conductivities of the spongiform (16.2-41.1 milliS/m), the top compact (5.4-7.2 milliS/m) and lower compact (2.8-10.2 milliS/m) layers of the skull have significantly different and inhomogeneous conductivities. The conductivities of the skull layers are frequency dependent in the 10-90 Hz region and are non-ohmic in the 0.45-2.07 A/m2 region. These current densities are much higher than those occurring in human brain.

Dipole localization of human induced focal afterdischarge seizure in simultaneous magnetoencephalography and electrocorticography.

Localizations were compared for the same human seizure between simultaneously measured MEG and iEEG, which were both co-registered to MRI. The whole-cortex neuromagnetometer localized a dipole in a sphere phantom, co-registered to the MEG sensor array, with an error of 1.4 mm. A focal afterdischarge seizure was induced in a patient with partial epilepsy, by stimulation at a subdural electrocorticography (ECoG) electrode with a known location, which was co-registered to the MRI and to the MEG sensor array. The simultaneous MEG and ECoG during the 30-second seizure was measured and analyzed using the single, moving dipole model, which is the localization model used clinically. The dipole localizations from simultaneous whole cortex 68-channel MEG and 64-channel ECoG were then compared for the repetitive spiking at six different times during the seizure. There were two main regions of MEG and ECoG activity. The locations of these regions were confirmed by determining the location clusters of 8,000 dipoles on ECoG at consecutive time points during the seizure. The mean distances between the stimulated electrode location versus the dipole location of the MEG and versus the dipole location of the ECoG were each about one (1) centimeter. The mean distance between the dipole locations of the MEG versus the dipole locations of the ECoG was about 2 cm. These errors were compared to errors of MEG and ECoG reported previously for phantoms and for somatosensory evoked responses (SER) in patients. Comparing the findings from the present study to those from prior studies, there appeared to be the expected stepwise increase in mean localization error progressing from the phantom, to the SER, to the seizure.

Conductivities of three-layer human skull.

In this study, electrical conductivities of compact, spongiosum, and bulk layers of cadaver skull were determined at varying electric fields at room temperature. Current was applied and withdrawn over the top and bottom surfaces of each sample and potential drop across different layers was measured using the four-electrode method. We developed a model, which considers of variations in skull thicknesses, to determine the conductivity of the tri-layer skull and its individual anatomical structures. The results indicate that the spongiform and the two compact layers of the skull have significantly different and inhomogeneous conductivities ranging from 0.76 +/- .14 to 11.5 +/- 1.8 milliS/m.

Identification of cerebral acetone by 1H-MRS in patients with epilepsy controlled by ketogenic diet.

Ketogenic diet (KD) is highly effective in controlling epileptic seizures in children. One of the mechanisms postulated, the accumulation of ketone bodies, acetoacetate (AcAc) and/or betahydroxybutyrate (beta-OHB) in the brain, would be detectable by non-invasive proton magnetic resonance spectroscopy (1H-MRS). 1H-MRS was performed in occipital cortical grey matter in 14 epileptics (E); ages 3.8-48.3 years), seven KD and seven without, and 16 healthy age-matched subjects. One E was examined before and after KD. A singlet resonance (sigma = 2.22 ppm), distinct from AcAc (sigma = 2.26 and 3.46 ppm), and identified as acetone was present in all spectra of children on KD (nine spectra in five children; concentration 0.7 +/- 0.2 mM). This resonance was absent from Control and E without diet. AcAc and beta-OHB, which were not detectable in KD brain, were found in urine or blood of all KD. Seizures were well controlled in all E in whom acetone was detected. Two of seven E, both adults, were seizure-free without detectable acetone. Cerebral acetone may contribute to seizure control in KD, but is unlikely to be the sole mechanism.

Multiple source localization using genetic algorithms.

We present a new procedure for localizing simultaneously active multiple brain sources that overlap in both space and time on EEG recordings. The source localization technique was based on a spatio-temporal model and a genetic algorithm search routine. The method was successfully applied to the localization of two dipole sources from several sets of simulated potentials with various signal-to-noise ratios (SNR). The different SNR values resembled evoked responses and epileptic spikes as commonly seen in the laboratory. Results of the simulation studies yielded localization accuracy ranging from 0.01 to 0.07 cm with an SNR of 10; from 0.02 to 0.26 cm with an SNR of 5; and from 0.06 to 0.73 cm when the SNR was equal to 2. Additionally, two sets of simulations were based on the dipole arrangements and time activities of data obtained during electrical stimulation of the median nerve in human subjects. These studies yielded localization accuracy within 0.1 cm. We also studied the localization accuracy of the algorithm using a physical model incorporating potential measurements of two current dipoles embedded in a sphere. In this situation the algorithm was successful in localizing the two simultaneously active sources to within 0.07-0.15 cm.

MEG and ECoG localization accuracy test.

We tested the localization accuracy of magnetoencephalography (MEG) and electrocorticography (ECoG) for a current dipole in a saline filled sphere at depths ranging from 1 to 6 cm at 1 cm intervals. We used standard neuromagnetometer placements and subdural electrode grids, previously employed for patient studies, with precise measurements of sensor and electrode locations with a 3-dimensional spatial digitizer. MEG and ECoG had comparable accuracy with mean errors of 1.5 and 1.8 mm, respectively. It appears that use of the spatial digitizer increases accuracy for both MEG and EGoG localizations. The larger errors in the ECoG with increasing depths could be attributed to under-sampling of the spatial pattern of the field which spreads out with deeper sources. It should be noted that in clinical applications a grid of the dimensions used here would most typically be used for superficial sources on the cortex with depth recordings being preferred for investigations of deep epileptogenic activity. Results are encouraging for continued development of non-invasive MEG methods for further definition of epileptogenic zones in the brain.

Comparisons of MEG, EEG, and ECoG source localization in neocortical partial epilepsy in humans.

In order to delineate the characteristics of epileptic spikes, 1946 different spikes were studied in 6 patients with complex partial epilepsy. Non-invasive MEG and EEG source analysis of interictal spikes were contrasted to ECoG localization, surgical outcome and presence of lesions on MRI. Results indicated that: (1) using the most frequent occurring spike topography patterns from a large sample of spikes improved goodness-of-fit values for both MEG and EEG localization, (2) when spike patterns could be appropriately matched on several successive MEG measurements to provide an adequate matrix (3 of 6 subjects), there was excellent agreement between MEG dipole sources and ECoG sources as well as surgical outcome and presence of MRI lesions, (3) EEG source analyses also gave good results but not as consistently as MEG.

Somatosensory evoked fields and potentials following tibial nerve stimulation.

We studied evoked magnetic fields and electrical potentials following stimulation of the tibial nerve in a group of 24 normal subjects. Both magnetic and electrical recordings demonstrated a series of oscillatory patterns consisting of four peaks (two positive and two negative) occurring between 40 and 100 msec. Magnetic field source localization of all four peaks using a dipole-in-a-sphere model indicated that all four peaks emanated from the same cortical surface located within the longitudinal fissure, an area typically associated with somatosensory function.

Quality of life of epilepsy surgery patients as compared with outpatients with hypertension, diabetes, heart disease, and/or depressive symptoms.

Health-related quality of life (HRQOL) of 166 adults who had previously undergone surgical treatment for intractable epilepsy was compared with that of outpatients with hypertension, diabetes, heart disease, and/or depressive symptoms. Eight self-reported HRQOL domains were evaluated and compared by the RAND 36-Item Health Survey 1.0: emotional well-being, social function, role limitations due to emotional problems, energy/fatigue, pain, role limitations due to physical problems, physical function, and general health perceptions. A pictorial item on overall QOL was also administered, for a total of 9 HRQOL domains. With adjustment made for age, gender, education, and comorbid conditions, 55 completely seizure-free patients scored higher (i.e., better health) than patients with hypertension in 6 of 9 domains, higher than diabetic patients in 8 of 9, higher than those with heart disease in all 9, and higher than those with depressive symptoms in all 9 (all p < 0.05). Sixty-seven patients still having seizures with impaired consciousness scored worse than hypertensive patients in 5 domains, worse than diabetic patients in 3, and worse than heart disease patients in 2; for all 3 conditions, these domains included emotional well-being and overall QOL (p < 0.05). These 67 patients, however, scored better than patients with depressive symptoms in all 9 domains, better than those with heart disease in 2, and better than those with diabetes in 1 (all p < 0.05). Forty-four other patients had only simple partial seizures (SPS); their scores were comparable to those of diabetic and heart disease patients on mental and social health scales but were higher ("better") than those of these patients on physical health scales. HRQOL among patients who have undergone "curative" epilepsy surgery is better than that of patients who have hypertension, diabetes, heart disease, or depressive symptoms. Patients who have continued seizures with altered consciousness are worse off in terms of emotional well-being and overall QOL than all other patients, except for those with depressive symptoms.

Surgical treatment of partial epilepsy arising from the insular cortex. Report of two cases.

Despite its documented connections with many limbic structures, the role of the insula in the etiology of partial seizures is poorly understood. Two patients are described in whom lesions of the insula were associated with intractable partial seizures. In the first patient, the seizures involved visceral sensory hallucinations followed by motor automatism. Seizures in the second patient began with somatic sensory hallucinations and then produced visceral motor effects. Both patients were found to have low-grade astrocytomas of the insula. In both instances, resection of the lesion and adjacent insular cortex resulted in a cure of the seizures. These cases are placed within the context of the existing literature on the subject.