GABAergic networks jump‐start focal seizures

Abnormally enhanced glutamatergic excitation is commonly believed to mark the onset of a focal seizure. This notion, however, is not supported by firm evidence, and it will be challenged here. A general reduction of unit firing has been indeed observed in association with low‐voltage fast activity at the onset of seizures recorded during presurgical intracranial monitoring in patients with focal, drug‐resistant epilepsies. Moreover, focal seizures in animal models start with increased γ‐aminobutyric acid (GABA)ergic interneuronal activity that silences principal cells. In vitro studies have shown that synchronous activation of GABA_A receptors occurs at seizure onset and causes sizeable elevations in extracellular potassium, thus facilitating neuronal recruitment and seizure progression. A paradoxical involvement of GABAergic networks is required for the initiation of focal seizures characterized by low‐voltage fast activity, which represents the most common seizure‐onset pattern in focal epilepsies.     

Noninvasive dynamic imaging of seizures in epileptic patients

Epileptic seizures are due to abnormal synchronized neuronal discharges. Techniques measuring electrical changes are commonly used to analyze seizures. Neuronal activity can be also defined by concomitant hemodynamic and metabolic changes. Simultaneous electroencephalogram (EEG)‐functional MRI (fMRI) measures noninvasively with a high‐spatial resolution BOLD changes during seizures in the whole brain. Until now, only a static image representing the whole seizure was provided. We report in 10 focal epilepsy patients a new approach to dynamic imaging of seizures including the BOLD time course of seizures and the identification of brain structures involved in seizure onset and discharge propagation. The first activation was observed in agreement with the expected location of the focus based on clinical and EEG data (three intracranial recordings), thus providing validity to this approach. The BOLD signal preceded ictal EEG changes in two cases. EEG‐fMRI may detect changes in smaller and deeper structures than scalp EEG, which can only record activity form superficial cortical areas. This method allowed us to demonstrate that seizure onset zone was limited to one structure, thus supporting the concept of epileptic focus, but that a complex neuronal network was involved during propagation. Deactivations were also found during seizures, usually appearing after the first activation in areas close or distant to the activated regions. Deactivations may correspond to actively inhibited regions or to functional disconnection from normally active regions. This new noninvasive approach should open the study of seizure generation and propagation mechanisms in the whole brain to groups of patients with focal epilepsies. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Intracranial EEG Substrates of Scalp Ictal Patterns from Temporal Lobe Foci

Summary: Purpose: To determine the intracranial EEG features responsible for producing the various ictal scalp rhythms, which we previously identified in a new EEG classification for temporal lobe seizures. Methods: In 24 patients, we analyzed simultaneous intracranial and surface ictal EEG recordings (64 total channels) obtained from a combination of intracerebral depth, subd-ural strip, and scalp electrodes. Results: Four of four patients with Type 1 scalp seizure patterns had mesial temporal seizure onsets. However, discharges confined to the hippocampus produced no scalp EEG rhythms. The regular 5- to 9-Hz subtemporal and temporal EEG pattern of Type 1a seizures required the synchronous recruitment of adjacent inferolateral temporal neocortex. Seizure discharges confined to the mesiobasal temporal cortex produced a vertex dominant rhythm (Type 1c) due to the net vertical orientation of dipolar sources located there. Ten of 13 patients with Type 2 seizures had inferolateral or lateral, temporal neocortical seizure onsets. Initial cerebral ictal activity was typically a focal or regional, low voltage, fast rhythm (20–40 Hz) that was often associated with widespread background flattening. Only an attenuation of normal rhythms was reflected in scalp electrodes. Irregular 2- to 4-Hz cortical ictal rhythms that commonly followed resulted in a comparably slow and irregular scalp EEG pattern (Type 2a). Type 2C seizures showed regional, periodic, 1– to 4-Hz sharp waves following intracranial seizure onset. Seven patients had Type 3 scalp seizures, which were characterized by diffuse slowing or attenuation of background scalp EEG activity. This resulted when seizure activity was confined to the hippocampus, when there was rapid seizure propagation to the contralateral temporal lobe, or when cortical ictal activity failed to achieve widespread synchrony. Conclusions: Type 1, 2, and 3 scalp EEG patterns of temporal lobe seizures are not a reflection of cortical activity at seizure onset. Differences in the subsequent development, propagation, and synchrony of cortical ictal discharges produce the characteristic scalp EEG rhythms.     

Interneuron activity leads to initiation of low‐voltage fast‐onset seizures

Seizures in temporal lobe epilepsy can be classified as hypersynchronous and low‐voltage fast according to their onset patterns. Experimental evidence suggests that low‐voltage fast‐onset seizures mainly result from the synchronous activity of γ‐aminobutyric acid–releasing cells. In this study, we tested this hypothesis using the optogenetic control of parvalbumin‐positive interneurons in the entorhinal cortex, in the in vitro 4‐aminopyridine model. We found that both spontaneous and optogenetically induced seizures had similar low‐voltage fast‐onset patterns. In addition, both types of seizures presented with higher ripple than fast ripple rates. Our data demonstrate the involvement of interneuronal networks in the initiation of low‐voltage fast‐onset seizures. Ann Neurol 2015;77:541–546     

Interictal to ictal transition in human temporal lobe epilepsy: insights from a computational model of intracerebral EEG.

In human partial epilepsies and in experimental models of chronic and/or acute epilepsy, the role of inhibition and the relationship between the inhibition and excitation and epileptogenesis has long been questioned. Besides experimental methods carried out either in vitro (human or animal tissue) or in vivo (animals), pathophysiologic mechanisms can be approached by direct recording of brain electrical activity in human epilepsy. Indeed, in some clinical presurgical investigation methods like stereoelectroencephalography, intracerebral electrodes are used in patients suffering from drug resistant epilepsy to directly record paroxysmal activities with excellent temporal resolution (in the order of 1 millisecond). The study of neurophysiologic mechanisms underlying such depth-EEG activities is crucial to progress in the understanding of the interictal to ictal transition. In this study, the authors relate electrophysiologic patterns typically observed during the transition from interictal to ictal activity in human mesial temporal lobe epilepsy (MTLE) to mechanisms (at a neuronal population level) involved in seizure generation through a computational model of EEG activity. Intracerebral EEG signals recorded from hippocampus in five patients with MTLE during four periods (during interictal activity, just before seizure onset, during seizure onset, and during ictal activity) were used to identify the three main parameters of a model of hippocampus EEG activity (related to excitation, slow dendritic inhibition and fast somatic inhibition). The identification procedure used optimization algorithms to minimize a spectral distance between real and simulated signals. Results demonstrated that the model generates very realistic signals for automatically identified parameters. They also showed that the transition from interictal to ictal activity cannot be simply explained by an increase in excitation and a decrease in inhibition but rather by time-varying ensemble interactions between pyramidal cells and local interneurons projecting to either their dendritic or perisomatic region (with slow and fast GABAA kinetics). Particularly, during preonset activity, an increasing dendritic GABAergic inhibition compensates a gradually increasing excitation up to a brutal drop at seizure onset when faster oscillations (beta and low gamma band, 15 to 40 Hz) are observed. These faster oscillations are then explained by the model feedback loop between pyramidal cells and interneurons targeting their perisomatic region. These findings obtained from model identification in human temporal lobe epilepsy are in agreement with some results obtained experimentally, either on animal models of epilepsy or on the human epileptic tissue.     

Perioral reflex myoclonias: a controlled study in patients with JME and focal epilepsies

PURPOSE: Perioral reflex myoclonias (PORM) are obvious, frequent, but often unobserved focal seizures in different epileptic syndromes and the leading seizure type in reading epilepsy. PORMs remain often undiagnosed because the patients are not aware that these are epileptic seizures and fail to report them. Their semiology is not fundamentally different in various epileptic syndromes. METHODS: We studied the frequency of PORM in patients with juvenile myoclonic epilepsy (JME) compared with patients with focal epilepsies. Twenty-five patients with JME were investigated with a standardized neuropsychological test program and compared with 25 matched patients with focal epilepsies. Statistical significance was calculated by using Fisher's exact test. RESULTS: We found significant differences between the groups regarding both frequency of PORM and activation of epileptic discharges. These observations seem to indicate that PORM, like praxis-induced seizures, are typical traits in JME. CONCLUSIONS: PORM are more frequent in JME compared with focal epilepsies. The distinction between focal and generalized epileptic ictogenesis may be less clear than is traditionally believed.     

The “Connectivity Epileptogenicity Index ” (cEI), a method for mapping the different seizure onset patterns in StereoElectroEncephalography recorded seizures

ObjectiveLocalization of epileptogenic brain regions is a crucial aim of pre-surgical evaluation of patients with drug-resistant epilepsy. Several methods have been proposed to identify the seizure onset zone, particularly based on the detection of fast activity. Most of these methods are inefficient to detect slower patterns of onset that account for 20–30% of commonly observed Stereo-Electro-Encephalography (SEEG) patterns. We seek to evaluate the performance of a new quantified measure called the Connectivity Epileptogenicity Index (cEI) in various types of seizure onset patterns.MethodsWe studied SEEG recorded seizures from 51 patients, suffering from focal drug-resistant epilepsy. The cEI combines a directed connectivity measure (“out-degrees”) and the original epileptogenicity index (EI). Quantified results (Out-degrees, cEI and EI) were compared to visually defined seizure onset zone (vSOZ). We computed recall (sensitivity) and precision (proportion of correct detections within all detections) with vSOZ as a reference. The quality of the detector was quantified by the area under the precision-recall curve.ResultsBest results (in terms of match with vSOZ) were obtained for cEI. For seizures with fast onset patterns, cEI and EI gave comparable results. For seizures with slow onset patterns, cEI gave a better estimation of the vSOZ than EI.ConclusionsWe observed that cEI discloses better performance than EI when seizures starts with slower patterns and equal to EI in seizures with fast onset patterns.SignificanceThe cEI is a promising new tool for epileptologists, that helps characterizing the seizure onset zone in sEEG, in a robust way despite variations in seizure onset patterns.     

Dynamics underlying interictal to ictal transition in temporal lobe epilepsy: insights from a neural mass model

We propose an approach that combines a neural mass model and clinical intracranial electroencephalographic (iEEG) recordings to explore the potential pathophysiological mechanisms (at the neuronal population level) of ictogenesis. Thirty iEEG recordings from 10 temporal lobe epilepsy (TLE) patients around seizure onset were investigated. Physiologically meaningful parameters [average excitatory (A_e), slow (B), and fast (G) inhibitory synaptic gain] were identified during interictal to ictal transition. Four ratios (A_e/G, A_e/B, A_e/(B + G), and B/G) were derived from these parameters, and their evolution over time was analyzed. The excitation/inhibition ratio increased around seizure onset and decreased before seizure offset, indicating the impairment and re‐emergence of excitation/inhibition balance around seizure onset and before seizure offset, respectively. Moreover, the slow inhibition may have an earlier effect on excitation/inhibition imbalance. We confirm the decrease in excitation/inhibition ratio upon seizure termination in human temporal lobe epilepsy, as revealed by optogenetic approaches both in vivo in animal models and in vitro. The increase in excitation/inhibition ratio around seizure occurrence could be an indicator to detect seizures.     

Temporal lobe epileptiform activity following systemic administration of 4‐aminopyridine in rats

Purpose: The K⁺ channel blocker 4‐aminopyridine (4AP) induces epileptiform synchronization in brain slices maintained in vitro without interfering with γ‐aminobutyric acid (GABA)_A receptor–mediated inhibition and, actually, even enhancing it. The hypothesis that similar electrographic epileptiform patterns occur in vivo following systemic 4AP injection was tested here. Methods: Sprague‐Dawley rats (n = 13) were implanted with bipolar electrodes aimed at the hippocampal CA3 region, entorhinal cortex, subiculum, dentate gyrus, and amygdala. They were then injected with a single dose of 4AP (4–5 mg/kg, i.p.), and video‐monitoring/electroencephalography (EEG) recordings were performed. Key Findings: 4AP induced convulsive or nonconvulsive seizures in 12 of 13 rats, along with generalized fascicular twitching, wet‐dog shakes, and myoclonic jerks. On EEG, we observed in 7 (58.3%) of 12 animals long‐lasting interictal spikes from the subiculum before the occurrence of the first seizure. Once seizures had started, interictal spikes occurred in all areas with no fixed site of origin. Most seizures (41/60, 68.3%) were characterized by a low‐voltage fast‐activity onset pattern and were convulsive (48/60, 80%). 4AP also induced highly rhythmic theta (6–11 Hz) oscillations in CA3 and entorhinal cortex before seizure occurrence. Significance: Our study shows that systemic 4AP administration in vivo can enhance theta oscillations and induce slow interictal spikes and low‐voltage fast‐onset seizures similar to those reported in brain slices. We propose that these effects may reflect, at least in part, enhanced GABA_A receptor–mediated inhibition as reported in in vitro studies.     

Intracranial EEG with Very Low Frequency Activity Fails to Demonstrate an Advantage Over Conventional Recordings

PURPOSE: Conventional scalp and intracranial EEG is recorded within a limited band of frequencies (0.3-70 Hz) based on the premise that clinically relevant cerebral activity occurs within this frequency range. Ikeda et al. recently demonstrated focal very low frequency activity (VLFA), <0.3 Hz, at seizure onset for both intra- and extracranial recordings. The purpose of this investigation was prospectively to study VLFA during seizures in intracranial recordings to determine whether activity in this frequency range provides useful information regarding localization of seizure onset and spread. METHODS: Patients undergoing intracranial electrode implantation were studied by using a high-pass filter of 0.01 Hz. The timing, location, and pattern of seizure onset were first determined by using a digital high-pass filter of 0.3 Hz (conventional seizure onset). Seizures were then reviewed without digital filters and the presence of VLFA recorded, along with its timing and location. RESULTS: Forty-seven seizures were recorded in four patients. VLFA was not observed in 29 seizures and, in one other case, VLFA occurred simultaneous with movement. Of seizures with VLFA (n = 17), the timing and location of VLFA were not consistent with those of conventional seizure onset or propagation. CONCLUSIONS: Our study failed to demonstrate any clinical advantage of intracranial telemetry recordings with a high-pass filter of 0.01 Hz over conventional recordings with regard to determining the timing and location of seizure onset and propagation.     

Seizure-induced miosis

Ictal autonomic pupillary dilation is common; however, miosis is rare. We describe a case of focal seizures secondary to cortical dysplasia presenting with bilateral pupillary miosis, rendered seizure free by resective surgery. The seizure-onset zone was localized within the left middle parietal gyrus by intracranial electrographic recording. Seizure onset was coincident with focal left centroparietal fast spike activity on electroencephalography (EEG). A large region of the left frontocentral cortical dysplasia was demonstrated on magnetic resonance imaging (MRI). Complete resection of the area of cortical dysplasia and additional cortical regions of ictal activity, identified using intracranial EEG, rendered the patient seizure free.     

Multimodal imaging reveals the role of γ activity in eating-reflex seizures

In reflex epilepsies, alteration of γ oscillations may mediate transition between interictal and ictal states. Here, we explored a patient having seizures triggered by syrup intake. From intracranial electroencephalography combined with functional MRI, the overlap of the gustatory cortex and of the preictal and ictal onset zones, as defined by early gamma changes, motivated the successful resective surgery of the middle short gyrus of the right insula. This case provides a rare demonstration from human gamma activity that the route to seizure may be supported by the interplay between physiological and epileptogenic networks.     

Local disruption of glial adenosine homeostasis in mice associates with focal electrographic seizures: A first step in epileptogenesis?

Astrogliosis and associated dysfunction of adenosine homeostasis are pathological hallmarks of the epileptic brain and thought to contribute to seizure generation in epilepsy. The authors hypothesized that astrogliosis-an early component of the epileptogenic cascade-might be linked to focal seizure onset. To isolate the contribution of astrogliosis to ictogenesis from other pathological events involved in epilepsy, the authors used a minimalistic model of epileptogenesis in mice, based on a focal onset status epilepticus triggered by intra-amygdaloid injection of kainic acid. The authors demonstrate acute neuronal cell loss restricted to the injected amygdala and ipsilateral CA3, followed 3 weeks later by focal astrogliosis and overexpression of the adenosine-metabolizing enzyme adenosine kinase (ADK). Using synchronous electroencephalographic recordings from multiple depth electrodes, the authors identify the KA-injected amygdala and ipsilateral CA3 as two independent foci for the initiation of non-synchronized electrographic subclinical seizures. Importantly, seizures remained focal and restricted to areas of ADK overexpression. However, after systemic application of a non-convulsive dose of an adenosine A(1) -receptor antagonist, seizures in amygdala and CA3 immediately synchronized and spread throughout the cortex, leading to convulsive seizures. This focal seizure phenotype remained stable over at least several weeks. We conclude that astrogliosis via disruption of adenosine homeostasis per se and in the absence of any other overt pathology, is associated with the emergence of spontaneous recurrent subclinical seizures, which remain stable over space and time. A secondary event, here mimicked by brain-wide disruption of adenosine signaling, is likely required to turn pre-existing subclinical seizures into a clinical seizure phenotype.     

Generalized‐onset seizures with secondary focal evolution

The international seizure classification recognizes that partial‐onset seizures can become secondarily generalized, but generalized‐onset seizures are expected to remain generalized. We report six patients who had recorded seizures with generalized onset, but subsequent evolution into a focal discharge. The clinical seizure onset was generalized absence or myoclonic, and the most common subsequent clinical pattern was prolonged behavioral arrest with mild automatisms, and then postictal confusion. The ictal discharge started with generalized spike‐and‐wave activity and then acquired a focal predominance. Interictal epileptiform activity was generalized. There were no focal magnetic resonance imaging abnormalities. Four patients were misdiagnosed with complex partial seizures. All patients were initially refractory, but three became seizure‐free and three improved after treatment with antiepileptic medications appropriate for absence or myoclonic seizures. Generalized‐onset seizures that acquire focal features are easily misdiagnosed as complex partial. These seizures have a more favorable response to medications effective against generalized absence and myoclonic seizures.     

Spatiotemporal neuronal correlates of seizure generation in focal epilepsy

Purpose: Focal seizures are thought to reflect simultaneous activation of a large population of neurons within a discrete region of pathologic brain. Resective surgery targeting this focus is an effective treatment in carefully selected patients, but not all. Although in vivo recordings of single‐neuron (i.e., “unit”) activity in patients with epilepsy have a long history, no studies have examined long‐term firing rates leading into seizures and the spatial relationship of unit activity with respect to the seizure‐onset zone. Methods: Microelectrode arrays recorded action potentials from neurons in mesial temporal structures (often including contralateral mesial temporal structures) in seven patients with mesial temporal lobe epilepsy. Key Findings: Only 7.6% of microelectrode recordings showed increased firing rates before seizure onset and only 32.4% of microelectrodes showed any seizure‐related activity changes. Surprisingly, firing rates on the majority of microelectrodes (67.6%) did not change throughout the seizure, including some microelectrodes located within the seizure‐onset zone. Furthermore, changes in firing rate before and at seizure onset were observed on microelectrodes located outside the seizure‐onset zone and even in contralateral mesial temporal lobe. These early changes varied from seizure to seizure, demonstrating the heterogeneity of ensemble activity underlying the generation of focal seizures. Increased neuronal synchrony was primarily observed only following seizure onset. Significance: These results suggest that cellular correlates of seizure initiation and sustained ictal discharge in mesial temporal lobe epilepsy involve a small subset of the neurons within and outside the seizure‐onset zone. These results further suggest that the “epileptic ensemble or network” responsible for seizure generation are more complex and heterogeneous than previously thought and that future studies may find mechanistic insights and therapeutic treatments outside the clinical seizure‐onset zone.     

Epileptic spasms without hypsarrhythmia in infancy and childhood: tonic spasms as a seizure type

Epileptic spasms were defined by the International League Against Epilepsy Task Force on Classification and Terminology in 2001 as a specific seizure type. Epileptic spasms without hypsarrhythmia have been described in some series of patients, occurring either in infancy or childhood. More prolonged epileptic spasms without hypsarrhythmia were previously defined as a different seizure type, and referred to as “tonic spasm seizures”. Here, we present a 5‐year‐old boy who started having epileptic spasms without hypsarrhythmia at 8 months of age, effectively treated with oxcarbazepine. With the withdrawal of medication, epileptic spasms returned. Video‐EEG monitoring revealed high‐voltage slow waves superimposed by low‐voltage fast activity, followed by an electrodecremental phase and a burst of asymmetric fast activity, time‐locked to clinical tonic spasm seizures. Brain MRI showed left temporal atrophy with temporal pole grey/white matter junction blurring and ictal PET‐CT showed left basal frontal hypermetabolism. Seizures were refractory to several AEDs and vigabatrin was introduced with seizure cessation. Despite efforts to classify epileptic spasms, these are still considered as part of the group of unknown seizure types. In some cases, a focal origin has been suggested, leading to the term “periodic spasms” and “focal spasms”. In this case, epileptic spasms without hypsarrhythmia, associated with tonic spasms, may be a variant of focal spasms and might be considered as an epileptic syndrome. [Published with video sequence]