scholarly journals Excitatory GABAergic signalling is associated with acquired benzodiazepine resistance in status epilepticus

2018 ◽  
Author(s):  
Richard J. Burman ◽  
Joshua S. Selfe ◽  
John Hamin Lee ◽  
Maurits van den Burg ◽  
Alexandru Calin ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Epileptiform Activity ◽  
Brain Slices ◽  
Medical Emergency ◽  
Dependent Manner ◽  
High Concentration ◽  
Cellular Mechanisms ◽  
Epileptiform Discharges ◽  
Threatening Condition ◽  
Eeg Recordings

AbstractStatus epilepticus (SE) is defined as a state of unrelenting seizure activity. Generalised convulsive SE is associated with a rapidly rising mortality rate, and thus constitutes a medical emergency. Benzodiazepines, which act as positive modulators of chloride (Cl-) permeable GABAA receptors, are indicated as first-line treatment, but this is ineffective in many cases. We found that 48% of children presenting with SE were unresponsive to benzodiazepine treatment, and critically, that the duration of SE at the time of treatment is an important predictor of non-responsiveness. We therefore investigated the cellular mechanisms that underlie acquired benzodiazepine resistance, using rodent organotypic and acute brain slices. Removing Mg2+ ions leads to an evolving pattern of epileptiform activity, and eventually to a persistent state of repetitive discharges that strongly resembles clinical EEG recordings of SE. We found that diazepam loses its antiseizure efficacy and conversely exacerbates epileptiform activity during this stage of SE-like activity. Interestingly, a low concentration of the barbiturate phenobarbital had a similar exacerbating effect on SE-like activity, whilst a high concentration of phenobarbital was effective at reducing or preventing epileptiform discharges. We then show that the persistent SE-like activity is associated with a reduction in GABAA receptor conductance and Cl- extrusion capability. We explored the effect on intraneuronal Cl- using both gramicidin, perforated-patch clamp recordings and Cl- imaging. This showed that during SE-like activity, reduced Cl- extrusion capacity was further exacerbated by activity-dependent Cl- loading, resulting in a persistently high intraneuronal Cl-. Consistent with these results, we found that optogenetic stimulation of GABAergic interneurons in the SE-like state, actually enhanced epileptiform activity in a GABAAR dependent manner. Together our findings describe a novel potential mechanism underlying benzodiazepine-resistant SE, with relevance to how this life-threatening condition should be managed in the clinic.

Cellular Mechanisms Underlying Antiepileptic Effects of Low- and High-Frequency Electrical Stimulation in Acute Epilepsy in Neocortical Brain Slices In Vitro

2007 ◽  
Vol 97 (3) ◽  
pp. 1887-1902 ◽  
Author(s):  
Yitzhak Schiller ◽  
Yael Bankirer
Keyword(s):  
Electrical Stimulation ◽  
High Frequency ◽  
Brain Slices ◽  
Low Frequency ◽  
High Frequency Stimulation ◽  
Dependent Manner ◽  
Cellular Mechanisms ◽  
Epileptiform Discharges ◽  
Frequency Stimulation

Approximately 30% of epilepsy patients suffer from drug-resistant epilepsy. Direct electrical stimulation of the epileptogenic zone is a potential new treatment modality for this devastating disease. In this study, we investigated the effect of two electrical stimulation paradigms, sustained low-frequency stimulation and short trains of high-frequency stimulation, on epileptiform discharges in neocortical brain slices treated with either bicuculline or magnesium-free extracellular solution. Sustained low-frequency stimulation (5–30 min of 0.1- to 5-Hz stimulation) prevented both interictal-like discharges and seizure-like events in an intensity-, frequency-, and distance-dependent manner. Short trains of high-frequency stimulation (1–5 s of 25- to 200-Hz stimulation) prematurely terminated seizure-like events in a frequency-, intensity-, and duration-dependent manner. Roughly one half the seizures terminated within the 100-Hz stimulation train ( P < 0.01 compared with control), whereas the remaining seizures were significantly shortened by 53 ± 21% ( P < 0.01). Regarding the cellular mechanisms underlying the antiepileptic effects of electrical stimulation, both low- and high-frequency stimulation markedly depressed excitatory postsynaptic potentials (EPSPs). The EPSP amplitude decreased by 75 ± 3% after 10-min, 1-Hz stimulation and by 86 ± 6% after 1-s, 100-Hz stimulation. Moreover, partial pharmacological blockade of ionotropic glutamate receptors was sufficient to suppress epileptiform discharges and enhance the antiepileptic effects of stimulation. In conclusion, this study showed that both low- and high-frequency electrical stimulation possessed antiepileptic effects in the neocortex in vitro, established the parameters determining the antiepileptic efficacy of both stimulation paradigms, and suggested that the antiepileptic effects of stimulation were mediated mostly by short-term synaptic depression of excitatory neurotransmission.

scholarly journals Epileptiform Discharges With In-Vivo-Like Features in Slices of Rat Piriform Cortex With Longitudinal Association Fibers

2001 ◽  
Vol 86 (5) ◽  
pp. 2445-2460 ◽  
Author(s):  
Rezan Demir ◽  
Lewis B. Haberly ◽  
Meyer B. Jackson
Keyword(s):  
Seizure Activity ◽  
Epileptiform Activity ◽  
Piriform Cortex ◽  
Brain Slices ◽  
Epileptiform Discharges ◽  
Local Circuitry ◽  
Association Fibers ◽  
Discharge Propagation

Brain slices serve as useful models for the investigation of epilepsy. However, the preparation of brain slices disrupts circuitry and severs axons, thus complicating efforts to relate epileptiform activity in vitro to seizure activity in vivo. This issue is relevant to studies in transverse slices of the piriform cortex (PC), the preparation of which disrupts extensive rostrocaudal fiber systems. In these slices, epileptiform discharges propagate slowly and in a wavelike manner, whereas such discharges in vivo propagate more rapidly and jump abruptly between layers. The objective of the present study was to identify fiber systems responsible for these differences. PC slices were prepared by cutting along three different nearly orthogonal planes (transverse, parasagittal, and longitudinal), and epileptiform discharges were imaged with a voltage-sensitive fluorescent dye. Interictal-like epileptiform activity was enabled by either a kindling-like induction process or disinhibition with bicuculline. The pattern of discharge onset was very similar in slices cut in different planes. As described previously in transverse PC slices, discharges were initiated in the endopiriform nucleus (En) and adjoining regions in a two-stage process, starting with low-amplitude “plateau activity” at one site and leading to an accelerating depolarization and discharge onset at another nearby site. The similar pattern of onset in slices of various orientations indicates that the local circuitry and neuronal properties in and around the En, rather than long-range fibers, assume dominant roles in the initiation of epileptiform activity. Subtle variations in the onset site indicate that interneurons can fine tune the site of discharge onset. In contrast to the mode of onset, discharge propagation showed striking variations. In longitudinal slices, where rostrocaudal association fibers are best preserved, discharge propagation resembled in vivo seizure activity in the following respects: propagation was as rapid as in vivo and about two to three times faster than in other slices; discharges jumped abruptly between the En and PC; and discharges had large amplitudes in superficial layers of the PC. Cuts in longitudinal slices that partially separated the PC from the En eliminated these unique features. These results help clarify why epileptiform activity differs between in vitro and in vivo experiments and suggest that rostrocaudal pyramidal cell association fibers play a major role in the propagation of discharges in the intact brain. The longitudinal PC slice, which best preserves these fibers, is ideally suited for the study their role.

scholarly journals Intensive Care Management of Multiorgan Dysfunction and Hypoxic Brain Injury Secondary to Refractory Status Epilepticus

2021 ◽  
Vol 2 (4) ◽  
pp. 3
Author(s):  
Sanum Kashif
Keyword(s):  
Status Epilepticus ◽  
Refractory Status Epilepticus ◽  
Medical Emergency ◽  
High Grade Fever ◽  
Refractory Status ◽  
Hypoxic Brain Injury ◽  
Hypoxic Brain ◽  
Threatening Condition ◽  
Life Threatening ◽  
Permanent Brain Damage

Refractory Status Epilepticus (RSE) is a medical emergency that may lead to permanent brain damage or death.Mortality rate is 16-39%. It is the life threatening condition in which continuous fits occur, despite treatmentwith benzodiazepines and one antiepileptic drug.A 25-year-old female, brought in emergency department with high-grade fever and frequent fits. GlasgowComa Scale (GCS) was 3/15 with unstable hemodynamics. Resuscitation started immediately and managed asstatus epilepticus. Patient was in multi organ failure on arrival. On the basis of history and examination, hypoxicbrain injury was diagnosed initially. Later on, refractory status epilepticus (RSE) with multi organ dysfunctionsyndrome (MODS) was diagnosed, after necessary investigations and treatment. Patient was managed as ateam with multidisciplinary approach and after continuous effort of 2 weeks, patient was successfullydischarged to home.

scholarly journals Treatment of refractory status epilepticus with electroconvulsive therapy: Need for future clinical studies

2017 ◽  
Vol 04 (01) ◽  
pp. 098-103 ◽  
Author(s):  
Anindya Ray
Keyword(s):  
Status Epilepticus ◽  
Electroconvulsive Therapy ◽  
Low Cost ◽  
Refractory Status Epilepticus ◽  
Medical Emergency ◽  
Therapeutic Modality ◽  
Future Research ◽  
Systematic Research ◽  
Threatening Condition ◽  
Life Threatening

AbstractStatus epilepticus (SE) is a serious medical emergency. Refractory-SE non-responsive to anesthetic medication is a life threatening condition with very high mortality rate. Proper management of those cases is a big medical challenge. Over the last two decades there are anecdotal reports of successful management of such cases with electroconvulsive therapy (ECT) in 12 patients of different age group with variable pattern of seizures and different etiology. However, there is no systematic research about it. ECT is a well-known safe, easy- to-administer, low-cost therapeutic modality in the field of neuro-psychiatry. Thus its potential to treat refractory-SE which essentially lacks effective management should be evaluated in future research. The objectives of this article are to do a thorough literature review on use of ECT in refractory-SE; mechanism of action of ECT in refractory-SE; and finally formulate a working protocol for future study of using ECT in patients of refractory-SE.

scholarly journals Electrical Status Epilepticus in Sleep: Is this a Focal or Generalized Pattern?

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Raphael R. Almeida ◽  
Ana Carolina Coan ◽  
Marilisa M Guerreiro
Keyword(s):  
Status Epilepticus ◽  
Clinical Data ◽  
Epileptiform Activity ◽  
Rolandic Epilepsy ◽  
Epileptiform Discharges ◽  
Epileptic Syndromes ◽  
Epileptic Discharges ◽  
Genetic Epilepsies ◽  
Rolandic Region ◽  
Correlate Data

Objectives: To evaluate the spatial distribution of the epileptiform activity in electrical status epilepticus in sleep (ESES) and to correlate data from electroencephalograms (EEGs) with clinical and neuroimaging variables. Methods: From 2008 to 2015, 162 reports (1.01%) out of 16,000 EEGs, from 23 patients, showed ESES. We selected one representative EEG per patient. Clinical data was collected retrospectively. Neuroimaging examinations were reviewed. The EEGs were classified as generalized ESES (ESESg) and focal ESES (ESESf) according to the distribution of epileptiform discharges. Results: From the 23 patients, 5 were classified as ESESg and 18 as ESESf. In ESESf, there was a prevalence of focal epileptic discharges in the centrotemporal regions. Abnormal neuroimaging occurred in 100% of the patients with ESESg and in 38.9% of the patients with ESESf (p=0.037). Other clinical data did not show significant differences between the groups. All patients with ESESg had structural etiology, while only 39% of patients with ESESf had structural etiology and the remaining 61% potentially genetic epilepsies of the rolandic spectrum. Conclusion: ESESg occurred predominantly in patients with structural lesions, while most patients with ESESf had normal neuroimaging scans and electrical dysfunction mainly in the rolandic region. Significance: ESESg seems to occur mostly in structural epilepsies. Distinctly, ESESf occurs in epileptic syndromes within the functional spectrum of rolandic epilepsy.

scholarly journals Breakthrough spikes in rapid eye movement sleep from the epilepsy monitoring unit are associated with peak seizure frequency

SLEEP ◽  
2019 ◽  
Vol 43 (5) ◽  
Author(s):  
Marna B McKenzie ◽  
Michelle-Lee Jones ◽  
Aoife O’Carroll ◽  
Demitre Serletis ◽  
Leigh Anne Shafer ◽  
...  
Keyword(s):  
Eye Movement ◽  
Seizure Frequency ◽  
Epileptiform Activity ◽  
Rapid Eye Movement ◽  
Rapid Eye Movement Sleep ◽  
Epileptiform Discharges ◽  
Interictal Epileptiform Discharges ◽  
Patient Reported ◽  
Eeg Recordings ◽  
Epilepsy Monitoring

Abstract Study Objectives Rapid eye movement sleep (REM) usually suppresses interictal epileptiform discharges (IED) and seizures. However, breakthrough IEDs in REM sometimes continue. We aimed to determine if the amount of IED and seizures in REM, or REM duration, is associated with clinical trajectories. Methods Continuous electroencephalogram (EEG) recordings from the epilepsy monitoring unit (EMU) were clipped to at least 3 h of concatenated salient findings per day including all identified REM. Concatenated EEG files were analyzed for nightly REM duration and the “REM spike burden” (RSB), defined as the proportion of REM occupied by IED or seizures. Patient charts were reviewed for clinical data, including patient-reported peak seizure frequency. Logistic and linear regressions were performed, as appropriate, to explore associations between two explanatory measures (duration of REM and RSB) and six indicators of seizure activity (clinical trajectory outcomes). Results The median duration of REM sleep was 43.3 (IQR 20.9–73.2) min per patient per night. 59/63 (93.7%) patients achieved REM during EMU admission. 39/59 (66.1%) patients had breakthrough IEDs or seizures in REM with the median RSB at 0.7% (IQR 0%–8.4%). Every 1% increase in RSB was associated with 1.69 (95% CI = 0.47–2.92) more seizures per month during the peak seizure period of one’s epilepsy (p = 0.007). Conclusions Increased epileptiform activity during REM is associated with increased peak seizure frequency, suggesting an overall poorer epilepsy trajectory. Our findings suggest that RSB in the EMU is a useful biomarker to help guide about what to expect over the course of one’s epilepsy.

Block of Glutamate-Glutamine Cycle Between Astrocytes and Neurons Inhibits Epileptiform Activity in Hippocampus

2002 ◽  
Vol 88 (5) ◽  
pp. 2302-2310 ◽  
Author(s):  
Alberto Bacci ◽  
Giulio Sancini ◽  
Claudia Verderio ◽  
Simona Armano ◽  
Elena Pravettoni ◽  
...  
Keyword(s):  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Brain Slices ◽  
Rhythmic Activity ◽  
Pharmacological Treatments ◽  
Metabolic Interaction ◽  
Epileptiform Discharges ◽  
Gaba Inhibition ◽  
Hippocampal Cultures ◽  
Glutamine Uptake

Recurrent epileptiform activity occurs spontaneously in cultured CNS neurons and in brain slices in which GABA inhibition has been blocked. We demonstrate here that pharmacological treatments resulting in either the block of glutamine production by astrocytes or the inhibition of glutamine uptake by neurons suppress or markedly decrease the frequency of spontaneous epileptiform discharges both in primary hippocampal cultures and in disinhibited hippocampal slices. These data point to an important role for the neuron-astrocyte metabolic interaction in sustaining episodes of intense rhythmic activity in the CNS, and thereby reveal a new potential target for antiepileptic treatments.

Synaptic and Nonsynaptic Ictogenesis Occurs at Different Temperatures in Submerged and Interface Rat Brain Slices

2002 ◽  
Vol 87 (6) ◽  
pp. 2929-2935 ◽  
Author(s):  
S. Schuchmann ◽  
H. Meierkord ◽  
K. Stenkamp ◽  
J. Breustedt ◽  
O. Windmüller ◽  
...  
Keyword(s):  
Intracellular Ph ◽  
Extracellular Space ◽  
Room Temperature ◽  
Epileptiform Activity ◽  
Brain Slices ◽  
Extracellular Potassium ◽  
Interface Conditions ◽  
Epileptiform Discharges ◽  
Submerged Conditions ◽  
Space Volume

To investigate the temperature sensitivity of low-Ca2+-induced nonsynaptic and low-Mg2+-induced synaptic ictogenesis under submerged and interface conditions, we compared changes of extracellular field potential and extracellular potassium concentration at room temperature (23 ± 1°C; mean ± SD) and at 35 ± 1°C in hippocampal-entorhinal cortex slices. The induction of spontaneous epileptiform activity under interface conditions occurred at 35 ± 1°C in both models. In contrast, under submerged conditions, spontaneous epileptiform activity in low-Mg2+ artificial cerebrospinal fluid (ACSF) was observed at 35 ± 1°C, whereas epileptiform discharges induced by low-Ca2+ ACSF occurred only at room temperature. To investigate the different temperature effects under submerged and interface conditions, measurements of extra- and intracellular pH and extracellular space volume were performed. Lowering the temperature from 35 ± 1°C to room temperature effected a reduction in extracellular pH under submerged and interface conditions. Under submerged conditions, temperature changes had no significant influence on the intracellular pH in presence of either normal or low-Mg2+ ACSF. In contrast, application of low-Ca2+ ACSF effected a significant increase in intracellular pH at room temperature but not at 35 ± 1°C under submerged conditions. Therefore increasing intracellular pH by lowering the temperature in low-Ca2+ ACSF may push slices to spontaneous epileptiform activity by opening gap junctions. Finally, extracellular space volume significantly decreased by switching from submerged to interface conditions. The reduced extracellular space volume under interface conditions may lead to an enlarged ephaptic transmission and therefore promotes low-Mg2+- and low-Ca2+-induced spontaneous epileptiform activity. The results of the study indicate that gas-liquid interface and total-liquid submerged slice states impart distinct physiological parameters on brain tissue.

scholarly journals Efficacy of levetiracetam monotherapy in epilepsy associated with benign epileptiform discharges of childhood

2019 ◽  
Vol 11 (1) ◽  
pp. 63-68 ◽  
Author(s):  
N. A. Borovkova ◽  
A. G. Malov
Keyword(s):  
Valproic Acid ◽  
Pediatric Patients ◽  
Slow Wave Sleep ◽  
Epileptiform Activity ◽  
Functional Tests ◽  
Antiepileptic Treatment ◽  
Epileptiform Discharges ◽  
First Choice ◽  
Eeg Recordings ◽  
Patients With Epilepsy

Aim. To analyze efficacy of levetiracetam monotherapy in patients with epilepsy associated with benign epileptiform discharges of childhood (BEDC). Materials and methods. We examined 29 pediatric patients with idiopathic and symptomatic BEDC-associated epilepsy, including continuous spike-and-wave epileptiform activity during slow-wave sleep (CSWS) in the stage of clinical remission. Of those, 12 children received antiepileptic treatment with valproic acid, and 17 children received levetiracetam. The examination included passive awake EEG recordings (with functional tests) as well as daytime sleep EEG recordings (within 60 minutes). Results. Levetiracetam was no less efficient in monotherapy of BEDC-associated epilepsy (including the CSWS patterns) than the traditionally used valproic acid, especially in idiopathic forms of epilepsy. Conclusion. Levetiracetam can be recommended for the first-choice basic anti-epileptic monotherapy treatment.

Adult EEG

2016 ◽  
pp. 97-109
Author(s):  
Katherine H. Noe ◽  
Joseph F. Drazkowski
Keyword(s):  
Epileptiform Activity ◽  
Sharp Waves ◽  
Epileptiform Discharges ◽  
Inappropriate Treatment ◽  
Delta Activity ◽  
Epilepsy Diagnosis ◽  
Interictal Eeg ◽  
Eeg Recordings ◽  
Rhythmic Delta Activity ◽  
Normal Background

Epileptiform discharges present on routine EEG recordings highly correlate with a tendency for clinical seizures. When present, they can help confirm a diagnosis of epilepsy and classify epilepsy type, localization, and syndrome. EEG’s sensitivity for detecting epileptiform activity depends on many factors, including the site of seizure origin and seizure frequency. Even in persons with known epilepsy, a routine EEG can often be normal; thus a normal interictal EEG should not be used to exclude an epilepsy diagnosis. Misinterpretation or “over-reading” of artifacts and normal background activity on the EEG as epileptiform is common by inexperienced readers. Unfortunately, this can lead to misdiagnosis and inappropriate treatment. The EEG reader should be familiar with the commonly encountered epileptiform patterns of generalized spike and wave, generalized slow spike and wave, generalized paroxysmal fast activity, focal spike and sharp waves, and temporal intermittent rhythmic delta activity.

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