Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.

OBJECTIVE: To evaluate a trial of immunotherapy as an aid to diagnosis in suspected autoimmune epilepsy. METHOD: We reviewed the charts of 110 patients seen at our autoimmune neurology clinic with seizures as a chief complaint. Twenty-nine patients met the following inclusion criteria: (1) autoimmune epilepsy suspected based on the presence of ≥ 1 neural autoantibody (n = 23), personal or family history or physical stigmata of autoimmunity, and frequent or medically intractable seizures; and (2) initiated a 6- to 12-week trial of IV methylprednisolone (IVMP), IV immune globulin (IVIg), or both. Patients were defined as responders if there was a 50% or greater reduction in seizure frequency. RESULTS: Eighteen patients (62%) responded, of whom 10 (34%) became seizure-free; 52% improved with the first agent. Of those receiving a second agent after not responding to the first, 43% improved. A favorable response correlated with shorter interval between symptom onset and treatment initiation (median 9.5 vs 22 months; p = 0.048). Responders included 14/16 (87.5%) patients with antibodies to plasma membrane antigens, 2/6 (33%) patients seropositive for glutamic acid decarboxylase 65 antibodies, and 2/6 (33%) patients without detectable antibodies. Of 13 responders followed for more than 6 months after initiating long-term oral immunosuppression, response was sustained in 11 (85%). CONCLUSIONS: These retrospective findings justify consideration of a trial of immunotherapy in patients with suspected autoimmune epilepsy. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with suspected autoimmune epilepsy, IVMP, IVIg, or both improve seizure control.

Spatio-temporal source localization and Granger causality in ictal source analysis.

We have proposed a new ictal source analysis approach by combining a spatio-temporal source localization approach, and causal interaction estimation technique. The FINE approach is used to identify neural electrical sources from spatio-temporal scalp-EEGs. The Granger causality estimation uses source waveforms estimated by FINE to characterize the causal interaction between the neural electrical sources in order to distinguish primary sources, which initiate ictal events, from secondary sources, which are caused by propagation. In the present study, we applied the proposed analysis approach to an epilepsy patient with symptomatic MRI lesions. It is found that the primary ictal source is within the visible lesion, which gave the consistent presurgical evaluation as MRI for this patient.

The relationship between quantitative T2 relaxometry and memory in nonlesional temporal lobe epilepsy.

PURPOSE: We investigated the relationship between preoperative quantitative magnetic resonance imaging (MRI) T2 relaxometry and volumetry of the hippocampi and pre- and postoperative verbal memory in temporal lobectomy patients who had nonlesional temporal lobe epilepsy. METHODS: Pre- and postoperative memory data based on the Logical Memory (LM) subtest of the Wechsler Memory Scale-Revised (WMS-R) and the 30-min delayed recall trial of the Rey Auditory Verbal Learning Test (AVLT) were obtained from 26 left and 15 right temporal lobectomy patients. Coronal MRI T2 maps were generated for these 41 temporal lobectomy patients as well as 61 control patients. Hippocampal T2 relaxation times and hippocampal volumes, converted to z scores using control group data, were correlated with neuropsychological performance in the patients. RESULTS: In left temporal lobe-onset patients, high T2 in the left hippocampal body predicted higher LM performance after surgery. Asymmetrically high T2 in the left hippocampal body (i.e., the right-minus-left difference), compared with the right hippocampal body, also predicted higher LM performance after surgery. In right temporal lobe-onset patients, high T2 in the left hippocampal body predicted relatively lower AVLT performance after surgery. Multiple regression analysis in left temporal-onset patients revealed that high T2 in the left hippocampal body together with higher preoperative LM performance predict higher postoperative LM performance. CONCLUSIONS: Our findings suggest that elevated (i.e., abnormal) hippocampal T2 signal is associated with memory ability (or hippocampal functional capacity) independent of MRI-determined hippocampal atrophy. Therefore, our findings support the use of quantitative T2 relaxometry as an independent predictor of verbal memory outcome in both left and right TLE patients who are candidates for temporal lobectomy.

Localization of the epileptic focus by low-resolution electromagnetic tomography in patients with a lesion demonstrated by MRI.

Patients with medically intractable partial epilepsy and well-defined symptomatic MRI lesions were studied using phase-encoded frequency spectral analysis (PEFSA) combined with low-resolution electromagnetic tomography (LORETA). Ten patients admitted to the epilepsy monitoring unit with MRI-identified lesions and intractable partial epilepsy were studied using 31-electrode scalp EEG. The scalp electrodes were located in three-dimensional space using a magnetic digitizer and coregistered with the patient's MRI. PEFSA was used to obtain a phase-encoded scalp map for the ictal frequencies. The ictal generators were obtained from the scalp map using LORETA. In addition, the generators of interictal epileptogenic spikes were identified using time-domain LORETA. The LORETA generators were rostral to the MRI lesion in 87% (7/8) of patients with temporal lobe lesions, but all were located in the mesial temporal lobe in concordance with the patients' MRI lesions. In patients with frontal lobe epilepsy, the ictal generators at the time that the spectral power was maximal localized to the MRI lesions. Eight of 10 patients had interictal spikes, of which 4 were bilateral independent temporal lobe spikes. Only generators of the interictal spikes that were ipsilateral to seizure onset correlated with the ictal generators. LORETA combined with PEFSA of the ictal discharge can localize ictal EEG discharges accurately and improve correlation with brain anatomy by allowing coregistration of the ictal generator with the MRI. Analysis of interictal spikes was less useful than analysis of the ictal discharge.

Cortical potentials at the frequency of absolute wrist velocity become phase-locked during slow sinusoidal tracking movements.

A 1-Hz rhythmic event-related potential was recorded at the scalp during performance of a 0.5-Hz tracking task. At cortical motor areas, negative peaks occurred 10-20 ms after peak tracking speeds. Analysis of single sweeps suggested that EEG phase was reset at initiation of the tracking motion and then maintained a constant relationship to wrist speed until task completion. Frequency analysis indicated that rhythm appearance in the averaged potential was predominantly due to phase-locking, because there was no tracking-related increase in 1 Hz amplitude within individual sweeps. While tracking, phase-locking was present over bilateral parieto-occipital and frontal regions, with a slight predominance at the contralateral frontal region. When subjects observed the target motion, phase-locking was localized to parieto-occipital regions. We suggest mental processes such as visual processing, visuomotor coordination and real-time motor planning are reflected in the pacing of localized cortical potential fluctuations.

Clinical neurophysiologic findings in patients with rapidly progressive familial parkinsonism and dementia with pallido-ponto-nigral degeneration.

OBJECTIVE: To present clinical electrophysiologic studies performed on the pallido-ponto-nigral degeneration (PPND) family linked to chromosome 17q21-22. METHODS: Nine patients from this kindred were studied with 11 electroencephalograms (EEGs), 4 electroencephalographic background frequency analysis (BFA) studies, 4 electromyographic recordings (EMGs) including nerve conduction studies (NCSs), 4 electromyographic multichannel surface recordings (MSRs), one pattern visual evoked potential (VEP) study and one median nerve somatosensory evoked potential (SEP) study. RESULTS: EEGs revealed normal findings early in the disease and diffuse slowing which became more prominent with disease progression. BFA studies demonstrated rapid decrease in mean parietal frequencies with disease progression. EMGs and NCSs showed no abnormalities. MSRs revealed action myoclonus and a dystonic process. Long loop reflexes were absent in resting hand muscles. VEPs and SEPs were normal. CONCLUSIONS: Clinical neurophysiologic studies were consistent with a cortical and subcortical degenerative process. With clinical deterioration, there is a progressive decline in the mean parietal frequency and background rhythms. Tremor studies were consistent with action myoclonus and a dystonic process and did not show parkinsonian features of resting tremor or agonist-antagonist cocontraction. There was no evidence of peripheral nerve involvement or slowing in central sensory pathways. Electrophysiologic findings are characteristic for this illness.

Scalp-recorded EEG localization in MRI volume data.

Scalp-recorded EEG is a noninvasive and widely available tool for studying normal and dysfunctional human neurophysiology with unsurpassed temporal resolution. However, scalp-recorded EEG data is difficult to correlate with anatomy, and most current display and neural source estimation algorithms are based on unrealistic spherical or elliptical models of the head. It is possible to measure the positions of electrodes on the patient's scalp, and to register those electrode positions into the space of a high-resolution MRI volume, and to then use the patient-specific anatomy as the basis for display and estimation of neural sources. We use a surface matching algorithm to register digitized electrode and scalp surface coordinates to a three-dimensional MRI volume. This study uses fiducial markers in phantom and volunteer studies to quantitatively estimate the accuracy of the electrode registration method. Our electrode registration procedure is accurate to 2.21 mm for a realistic head phantom and accurate to 4.16 mm on average for five volunteers. This level of accuracy is considered within acceptable limits for clinical applications.

Spatial filtering of multichannel electroencephalographic recordings through principal component analysis by singular value decomposition.

Principal component analysis (PCA) by singular value decomposition (SVD) may be used to analyze an epoch of a multichannel electroencephalogram (EEG) into multiple linearly independent (temporally and spatially noncorrelated) components, or features; the original epoch of the EEG may be reconstructed as a linear combination of the components. The result of SVD includes the components, expressible as time series waveforms, and the factors that determine how much each component waveform contributes to each EEG channel. By omission of some component waveforms from the linear combination, a new EEG can be reconstructed, differing from the original in useful ways. For example, artifacts can be removed and features such as ictal or interictal discharges can be enhanced by suppressing the remainder of the EEG. We developed a variation of this technique in which the factors that reconstruct the modified EEG from the original are stored as a matrix. This matrix is applied to multichannel EEG at successive times to create a new EEG continuously in real time, without redoing the time-consuming SVD. This matrix acts as a spatial filter with useful properties. We successfully applied this method to remove artifacts, including ocular movement and electrocardiographic artifacts. Removal of myogenic artifacts was much less complete, but there was significant improvement in the ability to visualize underlying activity in the presence of myogenic artifacts. The major limitations of the method are its inability to completely separate some artifacts from cerebral activity, especially when both have similar amplitudes, and the possibility that a spatial filter may distort the distribution of activities that overlap with the artifacts being removed.

Long-term electroencephalographic monitoring for diagnosis and management of seizures.

Long-term electroencephalographic (EEG) monitoring is the process of recording an EEG for a prolonged period in order to document epileptic seizures or other episodic disturbances of neurologic function. Indications for long-term EEG monitoring include diagnosis of a seizure disorder (epilepsy), classification of seizure types in patients with epilepsy, and localization of the epileptogenic region of the brain. Methods used for long-term EEG monitoring include prolonged analog or digital EEG, prolonged analog or digital ambulatory EEG, and prolonged analog or digital video-EEG monitoring with telemetry. Each of these methods has distinct advantages and disadvantages, particularly relative to storage, retrieval, and manipulation of data. Long-term EEG monitoring is useful in the management of patients with epilepsy and in the diagnosis of a seizure disorder. For most patients, inpatient long-term EEG monitoring is best performed in a specialized epilepsy-monitoring unit, which can provide a safe environment and both educational and psychosocial support. The choice of the most appropriate method of long-term monitoring for a specific clinical situation is best made by an epileptologist or a neurologist at an epilepsy center.

The effect of reference-electrode choice on the spatial resolution of topographical potential maps in the discrimination of deep cerebral sources.

Although scalp potential distributions do not uniquely determine the location and configuration of neural generators, they are important because they provide the necessary conditions that any hypothesized sources must satisfy and suggest a basis for testing alternate source hypotheses. One problem that could confound the correct interpretation of scalp potentials is the choice of reference electrode. Changing the reference may make activity patterns and waveform components appear and disappear (Pascual-Marqui et al. (1988) Int. J. Neurosci., 43: 237-249). The cortical imaging technique (CIT), a method for approximating potential fields on the cortical surface, was used to test the effects of the choice of reference electrode on these fields. Simulated and empirical evoked potential scalp-recorded referential data were mathematically analyzed for the case in which the reference (linked-ears) was arbitrarily assumed to be at zero potential, and the case in which the reference was the 'average' electrode, the arithmetic mean of all of the scalp-recorded voltages in the referential montage. The results for the two references were similar. This is encouraging because potential measurements relative to a point at infinity (zero potential) are never available and the assumption that any actual reference used for a recording is at zero potential is therefore suspect.

Routine EEG and temporal lobe epilepsy: relation to long-term EEG monitoring, quantitative MRI, and operative outcome.

PURPOSE: To investigate the relation among routine EEG, long-term EEG monitoring (LTM), quantitative magnetic resonance imaging (MRI), and surgical outcome in temporal lobe epilepsy (TLE). METHODS: We evaluated 159 patients with intractable TLE who underwent an anterior temporal lobectomy between 1988 and 1993. The epileptogenic temporal lobe was determined by ictal LTM. A single awake-sleep outpatient EEG with standard activating procedures was performed before LTM. EEGs were analyzed by a blinded investigator. RESULTS: MRI scans showed unilateral medial temporal atrophy (109 patients) or symmetrical hippocampal volumes (50 patients). The surgically excised epileptogenic brain tissue revealed mesial temporal sclerosis, gliosis, or no histopathologic alteration. Routine EEG revealed temporal lobe epileptiform discharges in 123 patients. Routine EEG findings correlated with the temporal lobe of seizure origin (p < 0.0001) and the results of MRI volumetric studies (p < 0.0001). Interictal epileptiform discharges were seen only during LTM in 24 patients. Routine EEG was disconcordant with interictal LTM in another 20 patients. MRI-identified unilateral medial temporal lobe atrophy was a strong predictor of operative success (p < 0.0001). There was no significant relation between the routine EEG findings and operative outcome (p > 0.20). CONCLUSIONS: Results of this study modified our approach in patients with TLE. Interictal epileptiform discharges localized to one temporal lobe on serial routine EEGs or during LTM may be adequate to identify the epileptogenic zone in patients with MRI-identified unilateral medial temporal lobe atrophy.

Interelectrode coherences from nearest-neighbor and spherical harmonic expansion computation of laplacian of scalp potential.

Interchannel coherence is a measure of spatial extent of and timing relationships among cerebral electroencephalogram (EEG) generators. Interchannel coherence of referentially recorded potentials includes components due to volume conduction and reference site activity. The laplacian of the potential is reference independent and decreases the contribution of volume conduction. Interchannel coherences of the laplacian should, therefore, be less than those of referentially recorded potentials. However, methods used to compute the laplacian involve forming linear combinations of multiple recorded potentials, which may inflate interchannel coherences. WE compared 3 methods of computing the laplacian: (1) modified Hjorth (4 equidistant neighbors to each electrode), (2) Taylor's series (4 nonequidistant neighbors), and (3) spherical harmonic expansion (SHE). Average interchannel coherence introduced by computing the laplacian was less for nearest-neighbor methods (0.0207 +/- 0.0766) but still acceptable for the SHE method (0.0337 +/- 0.0865). Average interchannel coherence for simulated EEG (random data plus a common 10 Hz signal) was less for laplacian than for referential data because of removal of the common referential signal. Interchannel coherences of background EEG and partial seizure activity were less with the laplacian (any method) than with referential recordings. Laplacians calculated from the SHE do not demonstrate excessively large interchannel coherences, as have been reported for laplacians from spherical splines.

Electrocorticography and temporal lobe epilepsy: relationship to quantitative MRI and operative outcome.

We investigated the relationship between electrocorticography (ECoG), quantitative magnetic resonance imaging (MRI), and surgical outcome in 165 patients with intractable nonlesional temporal lobe epilepsy (NLTLE). A standard mesial temporal resection was performed in all patients. Patients with an operative follow-up < 1 year were excluded from the study. The extent of the lateral temporal neocortex resection (LCR) was guided by ECoG and the side of surgery. The extent of the LCR was not predictive of seizure outcome in patients with or without hippocampal formation atrophy (p > 0.5). Patients undergoing a right anterior temporal lobectomy had a larger LCR (p < 0.0001), but the side of surgery was not of predictive value in determining seizure outcome (p > 0.1). The topography of the acute intracranial spikes did not correlate with operative outcome (p > 0.5) and was independent of hippocampal volumetric studies (p > 0.5). The postexcision ECoG was also shown not to be of prognostic importance (p > 0.5). Our results indicates that the extent of the lateral temporal cortical resection and the ECoG findings are not important determinants of surgical outcome in patients with NLTLE.

Hypoxic effect of exogenous insulin on normal and diabetic peripheral nerve.

Insulin administration can cause or worsen experimental and human diabetic neuropathy ("insulin neuritis"). In this study, we tested the hypothesis that insulin administration impairs tissue oxygenation. We infused insulin under nonhypoglycemic conditions and evaluated its effect on endoneurial oxygen tension, nerve blood flow, and the oxyhemoglobin dissociation curve of peripheral nerve in normal and diabetic rats. Intravenous insulin infusion resulted in a dose-dependent reduction in endoneurial oxygen tension in normal nerves (from 26% at 0.04 U/kg insulin to 55% at 32 U/kg). The nerves of rats with streptozotocin-induced diabetes were resistant, but with control of hyperglycemia this susceptibility to the endoneurial hypoxic effect of insulin returned. The reduction in endoneurial oxygen tension regressed with glycosylated hemoglobin (Y = 53.8-2.7X, where Y = %reduction in endoneurial oxygen tension and X = HbA1; r = 0.87; P = < 0.001). Diabetes or insulin administration resulted in only minimal and physiologically insignificant alterations in the oxygen dissociation curve and 2,3-diphosphoglycerate of sciatic nerve. Instead, insulin administration resulted in a reduction in nerve nutritive blood flow and an increase in arteriovenous shunt flow. When the latter was eliminated by the closure of arteriovenous shunts (infusion of 5-hydroxytryptamine), endoneurial oxygen reverted to normal. These findings indicate a deleterious vasoactive effect of insulin and may explain the development of insulin neuritis.

Mathematical modeling of hydrogen clearance blood flow measurements in peripheral nerve.

The hydrogen clearance technique of blood flow measurement often yields biexponential washout curves. In peripheral nerve, arteriovenous shunt vessels may clear hydrogen gas, causing the fast component of a biexponential curve. We simulated the washout of hydrogen from nerve tissue in the vicinity of a large shunt vessel by modeling the diffusion of hydrogen through tissue to the vessel and its removal by a network of capillaries. We then determined the fast and slow clearance rates and the relative weights or contributions of the fast and slow components and found that they are affected by all of the model parameters.

Alfentanil-induced epileptiform activity in patients with partial epilepsy.

We performed a retrospective study investigating the effect of alfentanil hydrochloride on electrocorticography (ECoG) in 23 patients with intractable nonlesional partial epilepsy undergoing anterior temporal lobectomies at this institution. Alfentanil is a short-acting, parenteral, opioid analgesic with a rapid onset of action. Opioid drugs have the potential to induce hippocampal electrographic seizures. Pre-excision ECoG was obtained before and after the administration of 50 micrograms/kg of alfentanil. ECoG was performed using subdural strips placed on the lateral temporal surface and in the suprasylvian region and monopolar depth electrodes implanted into the amygdala and hippocampus. The surgically excised temporal lobes revealed cortical gliosis and varying degrees of hippocampal neuronal loss in all patients. A quantitative assessment of the effect of alfentanil on the ECoG was performed by measuring the frequency of interictal spikes. There was a significant increase in the mesial temporal lobe mean spike frequency after the administration of alfentanil (p < 0.001). One patient had an alfentanil-induced mesial temporal lobe electrographic seizure. Alfentanil did not have a significant effect on spike activity in the suprasylvian region (p = 0.500). Further studies will be necessary to determine the specificity of alfentanil activation in patients with partial seizures of temporal lobe origin.

Effects of antiepileptic drug treatment on the background frequency of EEGs in epileptic patients.

The effect of changing antiepileptic drug concentrations within the therapeutic range on the EEGs of epileptic subjects was studied by quantitative EEG analysis. Twenty-seven patients had administration of one or more drugs discontinued on admission to the hospital for prolonged video/EEG monitoring, and drug levels were correlated daily with the simultaneous EEG background. Phenytoin, alone or in combination with other drugs, led to significant changes in the mean EEG background frequency and increased the percentage of power in the theta and delta bands. In the plasma ranges studied, carbamazepine, phenobarbital, and valproic acid did not lead to significant change in the EEG background frequency; however, the number of subjects taking these medications was small.

A data interchange standard for clinical neurophysiology.

A Standard Specification for Transferring Digital Neurophysiological Data Between Independent Computer Systems (Designation E 1467-92) has been developed. The specification defines a common representation of all of the data associated with a complete clinical study, including digitized neurophysiological waveforms, textual annotations and interpretive reports. Patterned after existing, related healthcare data interchange standards, it will facilitate data interchange between neurophysiological instruments, computer systems within the neurophysiology laboratory, other information systems in the hospital, and outside healthcare facilities or research laboratories.

Mathematical modeling of time-dependent oxygen transport in rat peripheral nerve.

We modeled time-dependent transport of oxygen in peripheral nerve. Simulation began with a steady-state oxygen tension field determined by capillary diameter and length, intercapillary distance, blood-flow velocity, oxygen consumption rate, and arterial oxygen tension. One of these parameters was assumed to change rapidly to new constant value, producing time-varying oxygen tensions. A monoexponential or biexponential function characterized the oxygen tension time variation. Rate constants of the slower exponential ranged from 0.017 sec-1 to 0.46 sec-1, implying minimal time lag in response of peripheral nerve oxygen tensions to alterations in blood flow, arterial blood oxygenation, or metabolic demands.

Determination of 10-20 system electrode locations using magnetic resonance image scanning with markers.

We determined locations of 33 scalp electrodes used for electroencephalographic (EEG) recording by placing markers in the positions determined by the 10-20 system and performing magnetic resonance image (MRI) scanning on volunteer subjects. Small Vaseline-filled capsules glued on the scalp with collodion produced easily delineated regions of increased signal on standard MRI head images. Measurements of each capsule's coordinates in 3 dimensions were made from MRI scans. A spherical surface was fitted through the marker positions, giving an average radius and an origin (center of sphere). The coordinate axes were rotated to ensure that electrode Cz was on the z-axis and that the y-axis was oriented in the posterior-anterior direction. Two spherical (angular) coordinates were determined for each electrode. Spherical electrode coordinates for different subjects differed by less than 20 degrees in all cases. An average and standard deviation of the spherical coordinates were calculated for each electrode. Standard deviations of several degrees were obtained. The average spherical coordinates obtained were close to those expected on the basis of applying the 10-20 system of placement to an ideal sphere. These measurements provide data necessary for various analyses of EEG performed to help localize epileptic foci.