Biomedical subjects

J C Sackellares

Publications and source records attributed to J C Sackellares.

At least 19 recordsLinked to original sources

PubMed2005

Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures.

OBJECTIVE: To evaluate the efficacy and tolerability of adjunctive lamotrigine in primary generalized tonic-clonic (PGTC) seizures in a randomized, double-blind, placebo-controlled trial. METHODS: Patients with a diagnosis of epilepsy with PGTC seizures who were receiving one or two antiepileptic drugs at study entry were eligible. Patients with partial seizures were excluded on the basis of seizure history and screening EEGs. The study comprised a baseline phase, an escalation phase during which study medication was titrated to a target dose, and a 12-week maintenance phase during which doses of lamotrigine/placebo and concomitant antiepileptic drugs were maintained. RESULTS: Of the 121 randomized patients ages 2 to 55 years, 117 (58 lamotrigine, 59 placebo) entered the escalation phase and received study medication. During the escalation and maintenance phases combined, median percent reduction in PGTC seizure frequency was 66.5% with lamotrigine compared with 34.2% with placebo (p = 0.006). The corresponding numbers for lamotrigine and placebo were 60.6% and 32.8% (p = 0.038) during the escalation phase and 81.9% and 43.0% (p = 0.006) during the maintenance phase. During the maintenance phase, 72% of lamotrigine-treated patients compared with 49% of placebo-treated patients experienced a > or = 50% reduction in frequency of PGTC seizures (p = 0.014). A similar pattern of results was observed for all generalized seizures. The most common drug-related adverse events were dizziness (5% lamotrigine, 2% placebo), somnolence (5% lamotrigine, 2% placebo), and nausea (5% lamotrigine, 3% placebo). CONCLUSIONS: Adjunctive lamotrigine is effective in the treatment of primary generalized tonic-clonic seizures and has a favorable tolerability profile.

Adolescent↗

PubMed2005

Long-term prospective on-line real-time seizure prediction.

OBJECTIVE: Epilepsy, one of the most common neurological disorders, constitutes a unique opportunity to study the dynamics of spatiotemporal state transitions in real, complex, nonlinear dynamical systems. In this study, we evaluate the performance of a prospective on-line real-time seizure prediction algorithm in two patients from a common database. METHODS: We previously demonstrated that measures of chaos and angular frequency, estimated from electroencephalographic (EEG) signals recorded at critical sites in the cerebral cortex, progressively converge (i.e. become dynamically entrained) as the epileptic brain transits from the asymptomatic interictal state to the ictal state (seizure) (Iasemidis et al., 2001, 2002a, 2003a). This observation suggested the possibility of developing algorithms to predict seizures well ahead of their occurrences. One of the central points in those investigations was the application of optimization theory, specifically quadratic zero-one programming, for the selection of the critical cortical sites. This current study combines that observation with a dynamical entrainment detection method to prospectively predict epileptic seizures. The algorithm was tested in two patients with long-term (107.54h) and multi-seizure EEG data B and C (Lehnertz and Litt, 2004). RESULTS: Analysis from the 2 test patients resulted in the prediction of up to 91.3% of the impending 23 seizures, about 89+/-15min prior to seizure onset, with an average false warning rate of one every 8.27h and an allowable prediction horizon of 3h. CONCLUSIONS: The algorithm provides warning of impending seizures prospectively and in real time, that is, it constitutes an on-line and real-time seizure prediction scheme. SIGNIFICANCE: These results suggest that the proposed seizure prediction algorithm could be used in novel diagnostic and therapeutic applications in epileptic patients.

Brain Mapping↗

PubMed2005

Performance of a seizure warning algorithm based on the dynamics of intracranial EEG.

During the past decade, several studies have demonstrated experimental evidence that temporal lobe seizures are preceded by changes in dynamical properties (both spatial and temporal) of electroencephalograph (EEG) signals. In this study, we evaluate a method, based on chaos theory and global optimization techniques, for detecting pre-seizure states by monitoring the spatio-temporal changes in the dynamics of the EEG signal. The method employs the estimation of the short-term maximum Lyapunov exponent (STL(max)), a measure of the order (chaoticity) of a dynamical system, to quantify the EEG dynamics per electrode site. A global optimization technique is also employed to identify critical electrode sites that are involved in the seizure development. An important practical result of this study was the development of an automated seizure warning system (ASWS). The algorithm was tested in continuous, long-term EEG recordings, 3-14 days in duration, obtained from 10 patients with refractory temporal lobe epilepsy. In this analysis, for each patient, the EEG recordings were divided into training and testing datasets. We used the first portion of the data that contained half of the seizures to train the algorithm, where the algorithm achieved a sensitivity of 76.12% with an overall false prediction rate of 0.17h(-1). With the optimal parameter setting obtained from the training phase, the prediction performance of the algorithm during the testing phase achieved a sensitivity of 68.75% with an overall false prediction rate of 0.15h(-1). The results of this study confirm our previous observations from a smaller number of patients: the development of automated seizure warning devices for diagnostic and therapeutic purposes is feasible and practically useful.

Adult↗

PubMed2003

A new approach towards predictability of epileptic seizures: KLT dimension.

This paper proposes a measure of complexity of the epileptic electroencephalogram (EEG) based on the dimensionality of the Karhunen-Loeve Transform (KLT) in the time domain. We estimate the KLT dimensionality by assuming the same observation noise level in the EEG during the interictal period (between the seizures) as the one during an epileptic seizure (ictal period). Utilizing an optimality criterion based on the T-index [1] and the predictability time, derived from the created KLT dimensionality profiles, we show that 10 out of 15 seizures in one patient with temporal lobe epilepsy were predictable with an average predictability time of about 36 minutes.

Algorithms↗

PubMed2003

Predictability of epileptic seizures: a comparative study using Lyapunov exponent and entropy based measures.

In this paper, a comparative study involving measures from the theory of chaos, namely the short-term largest Lyapunov exponent, Shannon and Kullback-Leibler entropies from information theory, has been carried out in terms of their predictability of temporal lobe epileptic seizures. These three measures are estimated from electroencephalographic (EEG) recordings with sub-dural and in-depth electrodes from various brain locations in patients with temporal lobe epilepsy. Techniques from optimization theory are applied to select optimal sets of electrodes whose dynamics is then followed over time. Results from analysis of multiple seizures in two epileptic patients with these measures are presented and compared in terms of their ability to identify pre-ictal dynamical entrainment well ahead of seizure onset time.

Algorithms↗

PubMed2001

Status epilepticus and tiagabine therapy: review of safety data and epidemiologic comparisons.

PURPOSE: To determine whether an increased risk of status epilepticus (SE) and complex partial status epilepticus (CPSE) is associated with tiagabine (TGB) therapy. METHODS: Thirteen cases in which an EEG, performed on patients with altered mental status taking TGB, was reported to demonstrate spike-and-wave discharges (SWDs) were reviewed by a panel of experts. In addition, all cases of suspected SE from TGB clinical trials were reviewed. The occurrence of SE in four epidemiologic cohorts from Rochester, Minnesota, Turku, Finland, Bronx, New York, and New Haven, Connecticut was analyzed as an external comparison. RESULTS: Review of the 13 cases with reported SWDs found that the majority had had prior EEGs with similar findings, and only three were thought to have electrographic evidence of SE. There was no difference in the frequency of SE or CPSE in the placebo-controlled clinical trials between the TGB-treated (1.0% SE, 0.8% CPSE) and placebo-treated (1.5% SE, 1.5% CPSE) groups. The 5% frequency of SE and 3% frequency of CPSE in the TGB-treated patients in the long-term safety studies, which included 2,248 patients, were very similar to the rates of occurrence of SE and CPSE in the four external cohorts. The major risk factor for the occurrence of SE and CPSE in all groups was a prior episode of SE (p < 0.0001). CONCLUSIONS: Over a 3-year period, SE will occur in 5-10% of patients with epilepsy not in remission. At highest risk are those who have had a prior episode of SE. Treatment with TGB in recommended doses does not increase the risk of SE in patients with partial seizures.

Adolescent↗

PubMed2001

Impaired motor function in patients with psychogenic pseudoseizures.

PURPOSE: To evaluate motor speed and grip strength in patients with well-documented psychogenic pseudoseizures. METHODS: We analyzed manual motor speed and grip strength in a group of 40 patients with confirmed psychogenic pseudoseizures (without evidence of concomitant epilepsy) and a group of 40 normal controls matched for handedness and gender, and of comparable age. The two groups were compared with respect to manual motor performance with the dominant hand, nondominant hand, and asymmetry between the dominant and nondominant hands. For the patient sample, we reviewed the neurologic history. RESULTS: Patients with pseudoseizures performed more poorly than controls with both dominant and nondominant hands. In addition, pseudoseizure patients failed to demonstrate the dominant-hand advantage observed in the normal control subjects on both tasks. The patient group had a high incidence of head trauma and other antecedent neurologic risk factors, and the proportion of left-handers was 3 times higher than expected. CONCLUSIONS: Bilaterally reduced motor speed and grip strength, reduced intermanual performance asymmetry, the high percentage of left-handers, and historical evidence of antecedent insults to the brain indicate that frontal lobe impairment may be common in patients with psychogenic pseudoseizures.

Adult↗

PubMed2001

Topiramate titration and tolerability.

OBJECTIVE: To evaluate the tolerability and efficacy of two titration rates for topiramate initiated as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization, in a multicenter, double-blindtrial. METHODS: After a two-week baseline phase, 188 patients were randomized to either a 50/50 titration schedule (initial dosage 50 mg/d increased in 50-mg/d increments at weekly intervals; n = 95) or to a 100/200 titration schedule (initial dosage 100 mg/d increased by 100-200 mg/d at weekly intervals; n = 93). The maximum dosage of 400 mg/d was therefore achieved in eight weeks or three weeks, respectively. RESULTS: Compared with the 100/200 titration rate, the 50/50 titration rate significantly reduced the cumulative incidence of treatment-emergent adverse events (TEAEs) leading to changes in topiramate therapy (ie., dosage reductions, interruptions or discontinuations of therapy) (p = 0.048) and significantly reduced treatment interruptions or withdrawals due to TEAEs (p = 0.040). Mild or moderate effects involving the central nervous system were the most frequent adverse events. At the final visit, therapeutic responses were comparable in the 50/50 and 100/200 titration groups: median percent seizure reduction was 42% vs. 33%, proportion of patients with 250% seizure reduction was 42% vs. 38%, and proportion of patients with no seizures during double-blind treatment was 14% vs. 10%, respectively. Seizure frequency was substantially reduced from baseline during topiramate titration. At day 22, with the 50/50 titration group receiving 150 mg/d and the 100/200 titration group receiving 400 mg/d, the mean percent seizure reduction was 51% and 54%, respectively. CONCLUSIONS: Gradual initiation of topiramate therapy can significantly enhance patient tolerability without delaying therapeutic response.

Adolescent↗

PubMed1999

Intellectual and neuropsychological features of patients with psychogenic pseudoseizures.

Psychogenic pseudoseizures typically are thought to reflect emotional disturbances. Studies have suggested that patients with psychogenic pseudoseizures may also have impaired neuropsychological function. We examined intellectual and neuropsychological performance in a large sample of patients with well-documented psychogenic pseudoseizures. Patients with pseudoseizures only (Pure group) and patients with both pseudoseizures and epilepsy (Mixed group) were included. For the total sample, the WAIS-R IQ scores were quite variable. Full Scale and Performance IQ ranged from deficient to very superior. The Full Scale IQ was in the low average or borderline range in 41.5% of patients. A striking finding was the high incidence of impaired performance on the Halstead-Reitan Neuropsychological Battery in both the Pure and Mixed groups. Considering the neuropsychological variables for which published cut-off scores are available, more than 50% of the total sample (as well as the Pure and Mixed groups) scored in the impaired range on more than half the measures. The Halstead Impairment Index, which reflects the overall level of neuropsychological performance, was in the impaired range (0.5-1.0) in 63% of the sample. Given the high incidence of accidents and physical trauma reported by our patients, we postulate that head trauma might be responsible for neuropsychological impairment in an appreciable number of the patients in this sample.

Adult↗

PubMed1999

Measuring the coherence of intracranial electroencephalograms.

OBJECTIVE: Previous coherence studies of human intracranial electroencephalograms (EEGs) can be faulted on two methodological issues: (1) coherence estimates in a majority were formed from a very small number of independent sample spectra, and (2) the statistical significance of coherence estimates was either not reported or was poorly evaluated. Coherence estimator performance may be poor when a small number of independent sample spectra are employed, and the coupling of poor estimation and statistical testing can result in inaccuracy in the measurement of coherence. The performance characteristics of the coherence estimator and statistical testing of coherence estimates are described in this manuscript. METHODS: The bias, variance, probability density functions, and confidence intervals of the estimate of magnitude squared coherence (MSC); and power analysis for the test of zero MSC were developed from the exact analytic form of the probability density function of the estimate of MSC for Gaussian random processes. The coherence of a single epoch of background EEG, recorded from a patient with intractable seizures, was evaluated with different parameter values to aid in the exposition of the concepts developed here. RESULTS: The statistical characteristics of WOSA coherence estimates are a function of a single estimator parameter, the number of independent sample spectra employed in the estimation. Bias and variance are high, confidence intervals may be large, and the probability of Type II errors is high if a small number of independent sample spectra are employed. A considerable improvement in measurement accuracy is possible with careful selection of estimator parameter values. CONCLUSIONS: Coherence measurement accuracy can be improved over previous applications by attention to estimator performance and accurate statistical testing of coherence estimates.

Adult↗

PubMed1999

Muscarinic receptor loss and preservation of presynaptic cholinergic terminals in hippocampal sclerosis.

PURPOSE: Prior single-photon emission tomography studies showed losses of muscarinic acetylcholine receptor (MAChR) binding in patients with refractory mesial temporal lobe epilepsy. Experimental animal studies demonstrated transient losses of MAChR due to electrically induced seizures originating in the amygdala. However, the relations between cholinergic synaptic markers, seizures, and underlying neuropathology in human temporal lobe epilepsy are unknown. We tested the hypotheses that human brain MAChR changes are attributable to hippocampal sclerosis (HS), and that HS resembles axon-sparing lesions in experimental animal models. METHODS: We measured MAChR binding-site density, an intrinsic neuronal marker, within the hippocampal formation (HF) in anterior temporal lobectomy specimens from 10 patients with HS and in 10 autopsy controls. Binding-site density of the presynaptic vesicular acetylcholine transporter (VAChT) was measured as a marker of extrinsic cholinergic afferent integrity. MAChR and VAChT results were compared with neuronal cell counts to assess their relations to local neuronal losses. RESULTS: Reduced MAChR binding-site density was demonstrated throughout the HF in the epilepsy specimens compared with autopsy controls and correlated in severity with reductions in cell counts in several HF regions. In contrast to MAChR, VAChT binding-site density was unchanged in the epilepsy specimens compared with autopsy controls. CONCLUSIONS: Reduction in MAChR binding in HS is attributable to intrinsic neuronal losses. Sparing of afferent septal cholinergic terminals is consistent with the hypothesis that an excitotoxic mechanism may contribute to the development of HS and refractory partial epilepsy in humans.

Adult↗

PubMed1998

An active-control trial of lamotrigine monotherapy for partial seizures.

OBJECTIVE: We report the results of a double-blind, double-dummy, active-control study designed to evaluate the efficacy and safety of lamotrigine (LTG) administered as monotherapy to adult outpatients with partial seizures. BACKGROUND: The effectiveness of LTG as add-on therapy for partial seizures in adults has previously been established. METHODS: After an 8-week baseline during which patients continued their baseline antiepileptic drug (carbamazepine or phenytoin monotherapy), 156 patients were randomly assigned to receive increasing doses of LTG (target 250 mg b.i.d.) or valproic acid (VPA; target low dose of 500 mg b.i.d.) during the first 4 weeks of an 8-week transition period. Carbamazepine or phenytoin was withdrawn over the next 4 weeks; then patients entered a 12-week monotherapy period. Study drug treatment was discontinued in patients who met predetermined escape criteria for seizure worsening. RESULTS: More patients receiving LTG were successfully maintained on monotherapy compared with patients receiving VPA (56% versus 20%; p < 0.001). The time to meet the escape criteria was also significantly longer in LTG-treated patients (median = 168 days) than in VPA-treated patients (median = 57 days; p = 0.001). The incidence of adverse events during the monotherapy period was lower than during the transition period. Four LTG patients and five VPA patients reported serious adverse events. Two of those patients experienced a rash that led to withdrawal soon after adding LTG to carbamazepine. CONCLUSIONS: We conclude that LTG is effective and well tolerated when administered as monotherapy in adult patients with partial seizures.

Adolescent↗

PubMed1997

Non-linearity in invasive EEG recordings from patients with temporal lobe epilepsy.

Electrographic recordings from depth and subdural electrodes, performed in two patients with seizures of mesial temporal origin, were analyzed for the presence of non-linearities in the signal. The correlation integral, a measure sensitive to a wide variety of non-linearities, was used for detection. Statistical significance was determined by comparison of the original signal to surrogate datasets. Statistically significant non-linearities were present in signals generated by the epileptogenic hippocampus and interictal spike foci in the temporal neocortex. Less prominent non-linearities were found in EEG signals generated by more normal areas of the brain. These results indicate that techniques developed for the study of non-linear systems can be used to characterize the epileptogenic regions of the brain during the interictal period and can elucidate the dynamical mechanisms of the epileptic transition.

Electroencephalography↗

PubMed1997

Analysis of MMPI patterns in patients with psychogenic pseudoseizures.

We performed pattern analysis of the Minnesota Multiphasic Personality Inventory (MMPI) profiles of 55 patients with pseudoseizures in order to establish whether there was any single pattern which would be sufficient to characterize the entire sample. Two published methods of pattern analysis were used. Neither method revealed a single pattern or profile code which could best characterize the sample. The Graham method revealed that the Hysteria and Schizophrenia scales were most likely to be found among the profile leads, followed by the Depression, and to a lesser extent, the Hypochondriasis scales. According to the Friedman method, 30.9% of the records could be classified as 'spike', 'two-point code' or 'three-point code'. The most striking finding of the study is that 40% of the profiles had four or more clinical scale elevations. Furthermore, 91% of those profiles with multiple elevations had elevations on both the neurotic and psychotic scales. This suggests that a substantial proportion of MMPI profiles in this sample are complex, and the clinical picture which they reflect requires a broader scope of psychological analysis beyond that of a single psychological mechanism.

Adult↗

PubMed1997

Personality profiles of patients with pseudoseizures.

Minnesota Multiphasic Personality Inventory profiles were analysed in 55 patients with pseudoseizures (40 patients with pseudoseizures only-pure group, and 15 patients with both pseudoseizures and epilepsy-mixed group). For each of the 10 clinical scales, there were no significant differences between the groups in mean T-score values or the incidence of pathological scores (T-score of 70 or above). In 87.3% of cases in the entire sample (groups combined), at least one clinical scale was elevated in the pathological range. For the combined groups, scales having the highest mean values as well as highest incidence of pathological scores were Schizophrenia, Hysteria and Depression. The mean profile of the entire sample (n = 55) had a two-point code of 8-3 with Schizophrenia and Hysteria as profile peaks. Application of three sets of published criteria for hysteria or conversion yielded markedly different results. This finding underscores the difficulty in evaluating the role of hysteria in pseudoseizures in the absence of a single standard. Mean values and the overall profile of this patient sample were remarkably similar to those found in two previous studies.

Adult↗

PubMed1997

Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: a double-blind, concentration-response design clinical trial. Depakote Monotherapy for Partial Seizures Study Group.

This is the first randomized, double-blind, parallel-group, multicenter trial that evaluated the efficacy of divalproex sodium monotherapy by comparing seizure frequency in 143 patients with poorly controlled partial epilepsy randomly assigned to high (80 to 150 micrograms/mL; 555 to 1,040 mumol/L) or low (25 to 50 micrograms/mL; 175 to 345 mumol/L) plasma valproate groups. There was a statistically significant reduction from baseline in the 8-week frequency of complex partial (p = 0.001) and secondarily generalized tonic-clonic seizures (p = 0.018) for patients in the high, compared with the low, plasma valproate group. Compared with baseline, there was a 30% median reduction in complex partial seizures for patients in the high group and a 19% increase for those in the low group. The median reduction for secondarily generalized tonic-clonic seizures was 70% for patients in the high group compared with a 22% increase in the low group. Adverse events that occurred significantly more frequently in the high group included tremors, thrombocytopenia, alopecia, asthenia, diarrhea, vomiting, and anorexia. This study demonstrates the efficacy of divalproex sodium as monotherapy for the treatment of partial-onset seizures and supports its role as one of the first-line antiepileptic drug treatments for patients with partial epilepsy.

Adolescent↗

PubMed1997

Gabapentin monotherapy: II. A 26-week, double-blind, dose-controlled, multicenter study of conversion from polytherapy in outpatients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 82/83.

This study evaluated gabapentin monotherapy in 275 patients with medically refractory complex partial or secondarily generalized seizures who were taking one or two antiepileptic drugs (AEDs). Following an 8-week baseline, patients received randomized dosages of gabapentin (600, 1,200, or 2,400 mg/d) during a 26-week double-blind phase comprising 2 weeks gabapentin add-on therapy, an 8-week AED taper, and a 16-week gabapentin monotherapy period. Patients exited the study if they experienced a protocol-defined exit event. Results of outcome measures, including time to exit, completion rate, and mean time on monotherapy, showed no significant differences among dosage groups. Possible reasons for this lack of a dose-response relationship include withdrawal seizures and the limited range of gabapentin dosages studied. Overall, 20% of patients completed the study. Completion rates were higher among patients who had discontinued one AED (23%) than two AEDs (14%), and higher among patients who were not withdrawn from carbamazepine (27%) than among those who were (16%).

Acetates↗

PubMed1995

Temporal lobe central benzodiazepine binding in unilateral mesial temporal lobe epilepsy.

PET-demonstrated decreases in [11C]flumazenil binding occur in anterior mesial temporal structures on the side of epileptogenesis in unilateral mesial temporal lobe epilepsy. We performed quantitative autoradiography on anterior mesial and lateral temporal specimens from 11 subjects with unilateral mesial temporal lobe epilepsy and six neurologically normal controls to identify the predominant in vitro correlates of the decreased [11C]flumazenil binding. In anterior mesial temporal regions exhibiting the greatest neuronal cell loss, decreases in agonist and antagonist binding to type 1 and 2 (central) benzodiazepine binding sites were highly correlated with neuronal cell counts. Cell loss and decreased binding were particularly prominent in the lateral portion of hippocampal region CA1, adjacent to CA2. Lateral temporal central benzodiazepine binding was diffusely increased, achieving statistical significance in cortical laminae V and VI. These findings suggest that the predominant source of PET-demonstrated decreases in [11C]flumazenil binding in mesial temporal epilepsy is hippocampal sclerosis, rather than down-regulation of central benzodiazepine binding sites on surviving hippocampal neurons.

Adult↗