Ictal propagation of high frequency activity is recapitulated in interictal recordings: effective connectivity of epileptogenic networks recorded with intracranial EEG.

Seizures are increasingly understood to arise from epileptogenic networks across which ictal activity is propagated and sustained. In patients undergoing invasive monitoring for epilepsy surgery, high frequency oscillations have been observed within the seizure onset zone during both ictal and interictal intervals. We hypothesized that the patterns by which high frequency activity is propagated would help elucidate epileptogenic networks and thereby identify network nodes relevant for surgical planning. Intracranial EEG recordings were analyzed with a multivariate autoregressive modeling technique (short-time direct directed transfer function--SdDTF), based on the concept of Granger causality, to estimate the directionality and intensity of propagation of high frequency activity (70-175 Hz) during ictal and interictal recordings. These analyses revealed prominent divergence and convergence of high frequency activity propagation at sites identified by epileptologists as part of the ictal onset zone. In contrast, relatively little propagation of this activity was observed among the other analyzed sites. This pattern was observed in both subdural and depth electrode recordings of patients with focal ictal onset, but not in patients with a widely distributed ictal onset. In patients with focal ictal onsets, the patterns of propagation recorded during pre-ictal (up to 5 min immediately preceding ictal onset) and interictal (more than 24h before and after seizures) intervals were very similar to those recorded during seizures. The ability to characterize epileptogenic networks from interictal recordings could have important clinical implications for epilepsy surgery planning by reducing the need for prolonged invasive monitoring to record spontaneous seizures.

Tolerability and efficacy of oral loading of levetiracetam.

OBJECTIVE: Nonsedating antiepileptic drugs (AEDs) that can be initiated rapidly are desirable in a variety of clinical situations. Levetiracetam (LEV) is a newer AED, with a recently approved parenteral formulation, that can be initiated at doses effective in controlling seizures. We investigated whether oral loading of levetiracetam is well tolerated and facilitates stabilization and discharge of patients in epilepsy monitoring units (EMU). METHODS: Adult patients in the EMU at two centers were identified who received 1,500 mg of LEV in a single dose. This was an observational study of these patients where LEV was thought to be an appropriate component of the therapeutic regimen. Patients were either LEV naive or had been off all LEV for at least 3 days. LEV maintenance was begun 12 hours later at doses of 500 to 1,000 mg twice a day. RESULTS: A total of 37 adult patients (20 female) were identified. There were no spontaneous complaints of side effects. Upon questioning, 33 patients (89%) denied side effects. The remaining 4 patients (11%) reported transient irritability, imbalance, tiredness, or lightheadedness. Eleven patients (mean weight = 85.0 Kg) had mean LEV serum concentration of 31.5 microg/mL after 1 hour, 23 (mean weight 85.7 Kg) had mean concentration of 30.77 microg/mL after 2 hours, five (mean weight 84.3 Kg) had mean concentration of 12.1 microg/mL after 12 hours, and two (mean weight 94 Kg) had mean concentration of 7.4 microg/mL after 14 hours. No seizures occurred within 24 hours of loading. All patients were able to be discharged 3 to 30 hours after loading. CONCLUSIONS: In the population surveyed, oral loading with levetiracetam was well-tolerated and rapidly yielded serum concentrations thought to decrease seizure frequency. This regimen facilitated discharge from the epilepsy monitoring units.

Gabor atom density as a measure of seizure complexity.

The Gabor atom density (GAD) is a measure of complexity of a signal. It is based on the time-frequency decomposition obtained by the matching pursuit (MP) algorithm. The GAD/MP method was applied to EEG data recorded from intracranial electrodes in patients with intractable complex partial seizures. GAD shows that epileptic seizures, which are reflections of increased neuronal synchrony, are also periods of increased and changing signal complexity. The GAD/MP method is well suited to analyzing these signals from seizures characterized by rapid dynamical changes. The period of organized rhythmic activity exhibits lower complexity than that seen during other phases of the seizure.

Evaluation of the patient with epilepsy.

Accurate evaluation of the patient with epilepsy is the first step toward developing an effective treatment regimen. Many problems can occur when patients who have had seizures are not assessed properly. A seizure may be caused by conditions other than epilepsy. If epilepsy is the cause, knowing the type of seizure and identifying epilepsy syndromes as early as possible is vital. An incorrect diagnosis can leave the patient with uncontrolled disease, leading to debilitating morbidity that in most cases can be treated effectively. Patients who would be good candidates for surgical intervention benefit by being identified early to prevent long periods, perhaps years, with uncontrolled disease. Understanding the type of seizure or epilepsy syndrome also determines the type of antiepileptic drugs that should be selected. Early, accurate evaluation and diagnosis are 2 of the most important aspects of treatment.

Epileptic seizures are characterized by changing signal complexity.

OBJECTIVE: Epileptic seizures are brief episodic events resulting from abnormal synchronous discharges from cerebral neuronal networks. The traditional methods of signal analysis are limited by the rapidly changing nature of the EEG signal during a seizure. Time-frequency analyses, however, such as those produced by the matching pursuit (MP) method can provide continuous decompositions of recorded seizure activity. These accurate decompositions can allow for more detailed analyses of the changes in complexity of the signal that may accompany seizure evolution. METHODS: The MP algorithm was applied to provide time-frequency decompositions of entire seizures recorded from depth electrode contacts in patients with intractable complex partial seizures of mesial temporal onset. The results of these analyses were compared with signals generated from the Duffing equation that represented both limit cycle and chaotic behavior. RESULTS: Seventeen seizures from 12 different patients were analyzed. These analyses reveal that early in the seizure, the most organized, rhythmic seizure activity is more complex than limit cycle behavior, and that signal complexity increases further later in the seizure. CONCLUSIONS: Increasing complexity routinely precedes seizure termination. This may reflect progressive desynchronization.

Levetiracetam psychosis in children with epilepsy.

PURPOSE: Levetiracetam is a new anticonvulsant (AED) with a novel mechanism of action. Although it is generally well tolerated with a good cognitive profile, irritability and hostility have been reported in some adults taking levetiracetam. Observations in children are limited; levetiracetam is not yet approved by the Food and Drug Administration for use in children. METHODS: In four young patients, acute psychosis developed within days to months of initiation of levetiracetam for seizures. RESULTS: A 5-year-old girl began having visual hallucinations of spiders in her room 14 days after starting levetiracetam. A 13-year-old boy began having auditory hallucinations, insomnia, and screaming behavior 3 months after initiation of levetiracetam. A 16-year-old girl became acutely agitated, hyperreligious, and had persecutory delusions within 7 days of starting levetiracetam. A 17-year-old girl had auditory hallucinations telling her to sing and yell after 30 days of taking the drug. All four children had dramatic improvement within days of either discontinuing or decreasing the dose of levetiracetam. The three adolescents had historical findings consistent with mild behavioral problems before initiating levetiracetam, and all four patients had prior cognitive deficits. CONCLUSIONS: Reversible treatment-emergent psychosis associated with levetiracetam therapy was observed in four children and adolescents. Whether rapid initiation or prior neurobehavioral problems predispose to this side effect is not established.

Future antiepileptic drug development.

The last decade has seen an explosion in the number of antiepileptic drugs approved. Despite these advances, however, there are still other basic mechanisms of epilepsy that could be the targets of new agents. This article discusses some of these novel sites for possible antiepileptic drug action in the context of the available data supporting the various mechanisms. While not all of these investigations will be translated into clinically useful agents, there is still great unrealized potential for the development of new and novel antiepileptic compounds.

An autoregressive method for the measurement of synchronization of interictal and ictal EEG signals.

We propose a new measure of synchronization of multichannel ictal and interictal EEG signals. The measure is based on the residual covariance matrix of a multichannel autoregressive model. A major advantage of this measure is its ability to be interpreted both in the framework of stochastic and deterministic models. A preliminary analysis of EEG data from three patients using this measure documents the expected increased synchronization during ictal periods but also reveals that increased synchrony persists for prolonged periods (up to 2 h or more) in the postictal period.

The effect of vesnarinone on TNF alpha production in human peripheral blood mononuclear cells and microglia: a preclinical study for the treatment of multiple sclerosis.

Vesnarinone (OPC-8212) is a synthetic quinolinone derivative with inotropic and immunomodulatory effects. Vesnarinone has been shown to inhibit tumor necrosis factor-alpha (TNF alpha) produced by mitogen stimulated macrophages, and to inhibit phosphodiesterase (PDE) type III in cardiac muscle. TNF alpha and interferon-gamma (IFNgamma) have been implicated in the pathogenesis of autoimmune diseases, and both cytokines are targets for therapeutic intervention. IFNgamma can enhance autoimmune disease through direct effects, and indirectly by priming macrophages to produce TNF alpha. In this study, we demonstrate that while vesnarinone enhances basal TNF alpha levels, it inhibits TNF alpha production in peripheral blood mononuclear cells from multiple sclerosis (MS) patients and healthy donors stimulated with lipopolysaccharide (LPS) or primed with IFNgamma and stimulated with suboptimal doses of LPS. In addition, vesnarinone inhibited TNF alpha production in primary adult human microglial cultures. However, in contrast to rolipram, another TNF alpha inhibiting agent, vesnarinone failed to inhibit TNF alpha production by myelin basic protein specific T-cell lines. As oral TNF inhibitors are currently being considered in the USA for clinical application in MS, the implications of our findings on the development of vesnarinone for treatment of MS are discussed.

Application of the directed transfer function method to mesial and lateral onset temporal lobe seizures.

The directed transfer function (DTF) method is a multichannel analysis based on an autoregressive model that detects flow of seizure activity. This report extends the application of the DTF method to compare patterns of flow of seizures with different sites of origin. Analysis of a seizure originating from mesial temporal structures is compared with a seizure originating from lateral temporal neocortex; both complex partial seizures were recorded with intracranial electrodes that combine subdural grid arrays and depth electrodes. The DTF method has the potential to determine patterns of flow of activity, including periods when visual analysis of the intracranial ictal EEG may not allow for definitive source localization. The extension of the DTF analyses into integrated DTF (IDTF) formats is also illustrated. When activity of a relatively discrete frequency can be identified, the IDTF analysis facilitates display of patterns of flow of this selected activity.

Time-frequency analysis using the matching pursuit algorithm applied to seizures originating from the mesial temporal lobe.

OBJECTIVES: The ability to analyze patterns of recorded seizure activity is important in the localization and classification of seizures. Ictal evolution is typically a dynamic process with signals composed of multiple frequencies; this can limit or complicate methods of analysis. The recently-developed matching pursuit algorithm permits continuous time-frequency analyses, making it particularly appealing for application to these signals. The studies here represent the initial applications of this method to intracranial ictal recordings. METHODS: Mesial temporal onset partial seizures were recorded from 9 patients. The data were analyzed by the matching pursuit algorithm were continuous digitized single channel recordings from the depth electrode contact nearest the region of seizure onset. Tine frequency energy distributions were plotted for each seizure and correlated with the intracranial EEG recordings. RESULTS: Periods of seizure initiation, transitional rhythmic bursting activity, organized rhythmic bursting activity and intermittent bursting activity were identified. During periods of organized rhythmic bursting activity, all mesial temporal onset seizures analyzed had a maximum predominant frequency of 5.3-8.4 Hz with a monotonic decline in frequency over a period of less than 60 s. The matching pursuit method allowed for time-frequency decomposition of entire seizures. CONCLUSIONS: The matching pursuit method is a valuable tool for time-frequency analyses of dynamic seizure activity. It is well suited for application to the non-stationary activity that typically characterizes seizure evolution. Time-frequency patterns of seizures originating from different brain regions can be compared using the matching pursuit method.

Subdural grid implantation for intracranial EEG recording: CT and MR appearance.

PURPOSE: Subdural grid arrays are used when seizure activity cannot be located by ictal scalp recordings and when functional cortical mapping is required before surgery. This study was performed to determine and compare the CT and MR imaging appearance of subdural EEG grids and to identify the types and frequency of associated complications. METHODS: We retrospectively reviewed the medical records and imaging studies of 51 consecutive patients who underwent 54 craniotomies for subdural EEG grid implantation with either stainless steel or platinum alloy contacts between June 1988 and September 1993. Twenty-two patients had both CT and MR examinations, 27 patients had CT only, and five patients had MR imaging only. All studies were assessed for image quality and degradation by the implanted EEG grids, for intra- and extraaxial collections, and for mass effect, with differences of opinion resolved by consensus. RESULTS: Subdural EEG grids caused extensive streak artifacts on all CT scans (corresponding directly to grid composition) and mild to moderate magnetic susceptibility artifacts on MR images. Sixteen associated complications were detected among the 54 patients imaged, including four significant extraaxial hematomas, four subfalcine or transtentorial herniations, two tension pneumocephali, two extraaxial CSF collections, two intraparenchymal hemorrhages, and one case each of cerebritis and brain abscess. In all but four cases, the detected complications were not clinically apparent and did not require specific treatment. There were no residual sequelae. CONCLUSION: Because of extensive streak artifacts, CT showed only gross complications, such as herniation and grid displacement by extraaxial collections. MR imaging artifacts were more localized, allowing superior evaluation of subdural EEG grid placement and associated complications.

Nonepileptic posttraumatic seizures.

PURPOSE: Epileptic posttraumatic seizures (PTSs) are a well-recognized consequence of head injury (HI), but HI and nonepileptic seizures (NESs) have not been related. We describe a significant subset of patients with NESs who had their seizures attributed to HI. METHODS: We reviewed the records of all patients diagnosed with NES at the University of Maryland Medical Center over a 6-year period (1989-1995) and selected patients with seizures attributed to a head injury occurring < or =3 years before the onset of their seizures. RESULTS: Of 157 patients with video-EEG confirmed NES, 37 (24%) had the onset of their seizures attributed to an HI. Their average age was 34 years (range, 15-56 years); 68% were women. Nonepileptic PTS usually developed within the first year after HI (89%). Convulsive symptoms were present in 54%. Whereas epileptic PTSs characteristically follow severe HI, the majority (78%) of our patients with nonepileptic PTSs sustained only mild HI. Before their HI, 76% of our patients were employed, working in the home, or students, but only 11% could continue those activities after developing nonepileptic PTSs. CONCLUSIONS: Nonepileptic PTSs are frequently mistaken for epileptic PTSs and result in serious disability. The misdiagnosis of nonepileptic PTSs leads to ineffective and inappropriate treatment. Patients with intractable seizures after HIs, particularly mild HIs, should be carefully evaluated for NESs.

Gabapentin monotherapy: I. An 8-day, double-blind, dose-controlled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 88/89.

We evaluated the efficacy and safety of gabapentin administered as monotherapy in an 8-day, randomized, double-blind, dose-controlled, parallel-group, multicenter study comparing dosages of 300 and 3,600 mg/d gabapentin in 82 hospitalized patients whose antiepileptic medications had been discontinued for seizure monitoring. Seizures under study were complex partial seizures with or without secondary generalization. Patients exited the study if they experienced a protocol-defined exit event indicating lack of efficacy. Time to exit was significantly longer (p = 0.0001) and completion rate was significantly higher (53% versus 17%; p = 0.002) for patients receiving 3,600 mg/d gabapentin. Gabapentin was well tolerated by patients in both dosage groups, and no patients exited the study due to adverse events, despite rapid initiation of full dose within 24 hours. These results demonstrate that gabapentin has anticonvulsant activity and is well tolerated when administered as monotherapy in patients with refractory partial seizures.

A simple computer model of excitable synaptically connected neurons.

The space-lumped two-variable neuron model is studied. Extension of the neural model by adding a simple synaptic current allows the demonstration of neural interactions. The production of synchronous burst activity in this simple two-neuron excitatory loop is modeled, including the influence of random background excitatory input. The ability of the neuron model to integrate inputs spatially and temporally is shown. Two refractory periods after stimuli were identified and their role in burst cessation is demonstrated. Our findings show that simple neural units without long-lasting membrane processes are capable of generating long lasting patterns of activity. The results of simulation of simple background activity suggest that an increase in background activity tends to cause decreased activity of the network. This phenomenon, as well as the existence of two refractory periods, allows for burst cessation without inhibition in this simple model.

Complex partial seizure provocation by vasovagal syncope: video-EEG and intracranial electrode documentation.

Vasovagal syncope precipitating an epileptic seizure has only rarely been described. A patient with known intractable complex partial seizures being evaluated for a left anterior temporal lobectomy experienced a typical seizure with mesial temporal onset precipitated by an observed vasovagal episode. This is the first report of a partial epileptic seizure precipitated by vasovagal syncope and the first example of an epileptic seizure induced by syncope in an adult. Video and intracranial depth electrode and subdural grid recordings documented the event.

Human microglia activate lymphoproliferative responses to recall viral antigens.

The capacity of adult human microglia to activate memory T-lymphocyte responses to recall viral antigens in autologous peripheral blood lymphocytes (PBL) was examined using measles and influenza viruses. Microglia and peripheral blood macrophages were isolated form 6 patients who underwent surgical brain biopsies. Microglial cultures readily expressed high levels of HLA class II molecules under basal culture conditions. However, compared to macrophages, microglia appeared to express much lower levels of CD45, a phenotype that has been associated with the ability of rat brain macrophage/microglia to present antigen. PBL were depleted of macrophages (D-PBL) and the efficacy of the depletion was assessed by a reduction in the T-cell response to concanavalin A. D-PBL were reconstituted with macrophages, microglia, or in some cases microglia pretreated with interferon-gamma (IFN gamma). It was observed that microglia were as efficient as macrophages in presenting viral antigens. Pretreatment of microglia with IFN gamma did not enhance further antigen presentation. Oligodendrocytes which lack constitutive or inducible HLA class II molecules failed to present viral antigens. The results have implications of the direct function of microglia as perpetuators and possibly initiators of immune responses to virus infection in the central nervous system compartment.