Seizure Threshold Research Articles

White Matter Hyperintensities as a Predictor of Aphasia Recovery

ObjectiveTo examine the relation between baseline white matter hyperintensities (WMH) and change in naming, content production, and efficiency after treatment in subacute aphasia. We hypothesized that more severe baseline WMH would result in less improvement with treatment. DesignRetrospective analysis of a cohort from a double-blind randomized controlled trial (RCT). SettingOutpatient clinical setting or participant home. ParticipantsWe retrospectively reviewed imaging and behavioral data for 52 participants with subacute aphasia due to left-hemisphere ischemic stroke enrolled in the RCT. RCT inclusion criteria: English proficiency, normal/corrected-to-normal hearing/vision, and no history of neurologic conditions other than the stroke resulting aphasia. One participant with a chronic right-hemisphere lesion was retained as she presented with no residual deficits on neurologic examination. Individuals with scalp sensitivities or on medications that lower seizure threshold or any N-methyl-D-aspartate (NMDA) antagonists were excluded. Of the 52 participants, for this analysis, 2 were excluded for not having a magnetic resonance imaging, and 7 were excluded for not participating in treatment or pre/post assessment for at least 1 outcome, resulting in final sample of 43 participants (20 women sex, M [SD] age=64.4 [11.9] and M [SD] education=14.9 [3.1] years). InterventionsParticipants received 15 sessions (2-3 times/week) of computerized lexical-semantic (ie, verification) treatment with [sham/active] transcranial direct current stimulation (tDCS). Sessions were approximately 45 minutes each (tDCS for first 20 minutes). Main Outcome MeasuresNaming accuracy, content units (CUs, a measure of semantically accurate production), and efficiency (ie, syllables/CU) on a picture description task. ResultsPeriventricular WMH severity was independently associated with recovery in picture naming for the active tDCS group. Deep WMH severity was associated with recovery for CU production for the sham tDCS group. ConclusionBaseline periventricular and deep WMH, among other factors, may be an important consideration for prognosis and treatment planning, especially when considered in conjunction with tDCS treatment.

Resting state connectivity biomarkers of seizure freedom after epilepsy surgery

Alterations in brain networks may cause the lowering of the seizure threshold and hypersynchronization that underlie the recurrence of unprovoked seizures in epilepsy. The aim of this work is to estimate functional network characteristics, which may help predicting outcome of epilepsy surgery.Twenty patients were studied (11 females, 9 males, mean age 33 years) with scalp-recorded HD-EEG in resting state (eyes closed, no interictal discharges) before intracranial evaluation, which allowed the precise determination of the epileptogenic zone. Dipole source time courses in the brain were estimated using Weighted Minimum Norm Estimate based on HD-EEG signals. Information inflow and outflow of atlas-based brain regions were computed using partial directed connectivity. A set of graph measures for pairwise connections in standard EEG frequency bands was calculated.After epilepsy surgery 10 patients were seizure-free (Engel 1a) and 10 patients continued suffering from seizures (Engel outcome worse than 1a). Inflow of the regions containing the epileptogenic zone in the beta and delta frequency bands was significantly lower in patients who achieved seizure-freedom after surgery, compared with patients who continued to have seizures (p = 0.012, and p = 0.026, respectively). Average path length in the beta frequency band was significantly higher in patients who achieved seizure freedom (p = 0.012). In the delta frequency band, local efficiency and clustering coefficient were significantly higher in patients who achieved seizure freedom (0.033, 0.046).In patients who achieved seizure freedom after surgery, the preoperative analysis of the epileptic network exhibited stronger separation of the region containing the seizure onset zone, with less inflow of information. In contrast, shorter paths within the epileptic network may facilitate hypersynchronous neuronal activity and thus the recurrence of seizures in non-seizure free patients. This study supports the hypothesis that epileptic network properties might help to define suitable candidates for epilepsy surgery.

Perampanel increases seizure threshold in pentylenetetrazole-kindled mice and improves behavioral dysfunctions by modifying mRNA expression levels of BDNF/TrkB and inflammatory markers

Perampanel (PER), a novel 3rd-generation antiseizure drug that modulates altered post-synaptic glutamatergic storming by selectively inhibiting AMPA receptors, is recently approved to treat intractable forms of seizures. However, to date, presumably consequences of long-term PER therapy on the comorbid deleterious psychiatric disturbances and its correlation with neuroinflammatory parameters are not fully investigated in chronic models of epilepsy. Therefore, we investigated the real-time effect of PER on brain electroencephalographic (EEG) activity, behavioral alterations, redox balance, and relative mRNA expression in pentylenetetrazole (PTZ) induced kindling. Male BALB/c mice were pretreated with PER (0.125, 0.25, and 0.5 mg/kg) for 3 weeks and challenged with 11 injections of PTZ at the sub-threshold dose of 40 mg/kg every other day. vEEG from implanted cortical electrodes was monitored to elucidate seizure propagation and behavioral manifestations. Recorded EEG signals exhibited that PER 0.5 mg/kg pretreatment exceptionally impeded the onset of sharp epileptic spike-wave discharges and associated motor symptoms. Additionally, qEEG analysis showed that PER prevented alterations in absolute mean spectral power and reduced RMS amplitude of epileptogenic spikes vs PTZ control. Furthermore, our outcomes illustrated that PER dose-dependently attenuated PTZ-evoked anxiety-like behavior, memory deficits, and depressive-like behavior that was validated by a series of behavioral experiments. Moreover PER, significantly reduced lipid peroxidation, AChE, and increased levels of SOD and total thiol in the mice brain via AMPAR antagonism. Post-PTZ kindling provoked overstimulation of BDNF/TrkB signaling and increased release of pro-inflammatory cytokines that were reversed by PER with suppression of iNOS in brain immune cells. In conclusion, our findings highlight that PER might play an auspicious preventive role in the proepileptic transformation of brain circuits via suppression of BDNF/TrkB signaling and reduced transcriptional levels of neuroinflammatory markers leading to improvised epilepsy-induced neurobehavioral and neurochemical effects.

Female sex steroids and epilepsy: Part 1. A review of reciprocal changes in reproductive systems, cycles, and seizures.

Seizures, antiseizure medications, and the reproductive systems are reciprocally entwined. In Section2 of this review, we outline how seizures may affect the hypothalamic-pituitary-gonadal axis, thereby altering sex steroids, and changes in sex steroids across the menstrual cycle and changes in pharmacokinetics during pregnancy may alter seizure susceptibility. The literature indicates that females with epilepsy experience increased rates of menstrual disturbances and reproductive endocrine disorders. The latter include polycystic ovary syndrome, especially for females on valproate. Studies of fertility have yielded mixed results. We aim to summarize and attempt to detangle the existing knowledge on these reciprocal interactions. The menstrual cycle causes changes in seizure intensity and frequency for many females. When this occurs perimenstrually, during ovulation, or in association with an inadequate luteal phase, it is termed catamenial epilepsy. There is a clear biophysiological rationale for how the key female reproductive neurosteroids interact with the brain to alter the seizure threshold, and Section3 outlines this important relationship. Critically, what remains unknown is the specific pathophysiology of catamenial epilepsy that describes why not all females are affected. There is a need for mechanism-focused investigations in humans to uncover the complexity of the relationship between reproductive hormones, menstrual cycles, and the brain.

Changes in neuronal excitability in the rat hippocampus in a prolonged febrile seizures model

Febrile seizures (FSs) are a prevalent neurological disorder among children aged 3 months to 5 years, with the highest incidence observed in the second year of life [1]. Considering that neuronal and glial cell development and synaptic contact formation are ongoing during this period [2, 3], FSs can potentially influence these processes. However, the present data on the effect of FSs on brain development remain inconsistent. This study aims to examine the impact of extended seizures on the attributes of hippocampal pyramidal neurons in rats of varying ages. Wistar rats were used in this study. FSs were induced on postnatal day (P)10 through placing pups onto the bottom of a glass chamber for 30 minutes and exposing them to a controlled stream of heated air, causing their body temperature to rise to 39 °C and trigger the occurrence of FSs. Only animals that underwent FSs that persisted for at least 15 minutes were included in the study. Littermates were employed as controls and were placed away from the nest for the same duration but kept at room temperature. At postnatal days 12, 21–23, and 51–55, the rats were decapitated, and their brains were extracted. Horizontal brain slices (400 micrometers) were sliced. The study examined the biophysical properties of CA1 pyramidal neurons using the whole-cell patch-clamp method. 1.5-second current pulses were injected, and subthreshold membrane properties such as resting membrane potential, input resistance, membrane time constant, and intrinsic firing properties, were assessed. Extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded from the CA1 stratum radiatum of the hippocampus to assess the efficacy of synaptic neurotransmission at CA3-CA1 pyramidal neuron synapses. The amplitude and fiber volley (FV) amplitude of each fEPSP were measured by applying high amplitude currents to each slice. A sigmoidal Gompertz function was used to evaluate the efficacy of neurotransmission. Paired-pulse stimulation was used to examine potential alterations in short-term synaptic plasticity. Paired pulses were administered at intervals spanning from 10 to 500 ms, and the paired-pulse ratio (PPR) was assessed as the proportion of the amplitude of the second to the first fEPSP for each interval. Maximum electroshock seizure threshold (MEST) was determined two months after FS to assess the animals’ susceptibility to seizures. The lowest current at which tonic hind limb extension was exhibited was determined for every animal. No significant changes in subthreshold firing properties were observed in P12 or P21 rats following FSs. However, we did observe several changes in intrinsic firing properties. For example, the maximum firing frequency decreased by 23% in P12 rats exposed to FSs, relative to age-matched control rats. Additionally, we noticed that firing frequency adaptation was significantly less pronounced in P12 rats that underwent FSs, compared to control rats of the same age. Seizure-induced alterations in firing characteristics were absent in P21 rats. No significant variations in fEPSP or FV amplitudes were found among the different groups of P12 and P55 rats at different current intensities. However, a significant increase in FV amplitudes and decrease in neuronal input-output (I/O) relationships between fEPSP and FV amplitudes were observed in P21 rats following FSs. At P12, short-term synaptic plasticity was disrupted, evidenced by a significant increase in PPR in rats two days post-FS. However, at P21 and P55, experimental and control groups were not significantly different. MEST test displayed a significant rise in the hind limb extension threshold in rats two months following FS as compared to control animals. Overall, these findings suggest alterations in neuronal excitability after prolonged FS. Two days after FS, neuronal excitability transiently decreased while PPR increased, indicating a decrease in the probability of presynaptic glutamate release in hippocampal neurons. The efficiency of synaptic neurotransmission in CA3-CA1 was reduced in three-week-old animals. Additionally, the MEST test demonstrated that rats, two months following FS, exhibited a higher hind limb extension threshold in comparison to control animals.

Electroconvulsive Therapy Across Nations: A 2022 Survey of Practice.

We aimed to characterize worldwide electroconvulsive therapy (ECT) practice and compare practice across nations and global regions. Our anonymous survey was open on SurveyMonkey.com from January to June 2022. We sent invitations to providers identified using a Medicare provider database, an advanced PubMed search function, and professional group listservs. Participants were instructed to submit one survey per ECT site. Response frequencies were pooled by global region and compared using nonparametric methods. Responses came from 126 sites, mostly in the United States (59%, n = 74), Europe (18%, n = 23), Canada (10%, n = 12), and South/East Asia (6%, n = 8). With some exceptions, sites were broadly consistent in practice as indicated by: a likely shift internationally from bitemporal to right unilateral electrode placement; predominant use of pulse widths <1 ms; preference for seizure threshold titration over age-based dosing methods; widespread availability of continuation/maintenance ECT (97%); and frequent use of quantitative outcome measures for depressive symptoms (88%) and cognitive adverse effects (80%). This is the first, published survey that aimed to characterize worldwide ECT practice. With some exceptions, responses suggest a concordance in practice. However, responses were primarily from the Global North. To obtain a truly worldwide characterization of practice, future surveys should include more responses from the Global South.

Chronic intermittent convection-enhanced delivery of vigabatrin to the bilateral subthalamic nucleus in an acute rat seizure model

Targeted intracerebral drug delivery is an attractive experimental approach for the treatment of drug-resistant epilepsies. In this regard, the subthalamic nucleus (STN) represents a focus-independent target involved in the remote modulation and propagation of seizure activity. Indeed, acute and chronic pharmacological inhibition of the STN with vigabatrin (VGB), an irreversible inhibitor of GABA transaminase, has been shown to produce antiseizure effects. This effect, however, is lost over time as tolerance develops with chronic, continuous intracerebral pharmacotherapy. Here we investigated the antiseizure effects of chronic intermittent intra-STN convection-enhanced delivery of VGB in an acute rat seizure model focusing on circumventing tolerance development and preventing adverse effects. Timed intravenous pentylenetetrazol (PTZ) seizure threshold testing was conducted before and after implantation of subcutaneous drug pumps and bilateral intra-STN cannulas. Drug pumps infused vehicle or VGB twice daily (0.4 µg) or once weekly (2.5 µg, 5 µg) over three weeks. Putative adverse effects were evaluated and found to be prevented by intermittent compared to previous continuous VGB delivery. Clonic seizure thresholds were more clearly raised by intra-STN VGB compared to myoclonic twitch. Both twice daily and once weekly intra-STN VGB significantly elevated clonic seizure thresholds depending on dose and time point, with responder rates of up to 100% observed at tolerable doses. However, tolerance could not be completely avoided, as tolerance rates of 40–75% were observed with chronic VGB treatment. Results indicate that the extent of tolerance development after intermittent intra-STN VGB delivery varies depending on infusion dose and regimen.

Clinical Outcomes of Magnetic Seizure Therapy vs Electroconvulsive Therapy for Major Depressive Episode

Electroconvulsive therapy (ECT) is highly effective and rapid in treating depression, but it carries a risk of significant cognitive adverse effects. Magnetic seizure therapy (MST), an investigational antidepressant treatment, may maintain the robust antidepressant efficacy of ECT while substantially reducing adverse effects due to its enhanced focality and weaker stimulation strength; however, previous clinical trials of MST were limited by small sample sizes. To compare the antidepressant efficacy of MST vs ultrabrief pulse right unilateral (RUL) ECT. A between-participants, double-blinded, randomized clinical trial was conducted at 3 academic hospitals from June 2007 to August 2012. Adults aged 18 to 90 years who were referred for treatment with ECT, had a major depressive episode in the context of major depressive disorder or bipolar disorder, and had a baseline 24-item Hamilton Depression Rating Scale (HDRS-24) total score of 18 or higher were included. Participants were randomly assigned 1:1 to treatment with MST or ultrabrief pulse RUL ECT. After the treatment course, patients were naturalistically followed up for up to 6 months to examine the durability of clinical effects. Treatment with MST, applied at 100 Hz at 100% of the maximum device power for 10 seconds, or ultrabrief pulse RUL ECT, applied at 6 times seizure threshold. The primary outcome was change from baseline in HDRS-24 total score, with patients followed up for up to 6 months. A reduction of at least 50% in the HDRS-24 score indicated response, and at least a 60% decrease in the HDRS-24 score and a total score of 8 or less indicated remission. Of the 73 participants (41 [56.2%] female; mean [SD] age, 48 [14.1] years), 35 were randomized to MST and 38 to ECT. Among them, 53 (72.6%) were classified as completers (29 in the MST group and 24 in the ECT group). Both MST and ECT demonstrated clinically meaningful antidepressant effects. In the intent-to-treat sample, 18 participants (51.4%) in the MST group and 16 (42.1%) in the ECT group met response criteria; 13 (37.1%) in the MST group and 10 (26.3%) in the ECT group met remission criteria. Among completers, 17 of 29 (58.6%) in the MST group and 15 of 24 (62.5%) in the ECT group met response criteria; 13 of 29 (44.8%) in the MST group and 10 of 24 (41.7%) in the ECT group met remission criteria. There was no significant difference between MST and ECT for either response or remission rates. However, the mean (SD) number of treatments needed to achieve remission was 9.0 (3.1) with MST and 6.7 (3.3) with ECT, a difference of 2.3 treatments (t71.0 = 3.1; P = .003). Both MST and ECT showed a sustained benefit over a 6-month follow-up period, again with no significant difference between them. Compared with MST, ECT had significantly longer time to orientation after treatment (threshold level: F1,56 = 10.0; P = .003) and greater severity of subjective adverse effects, particularly in the physical and cognitive domains. This randomized clinical trial found that the efficacy of MST was indistinguishable from that of ultrabrief pulse RUL ECT, the safest form of ECT currently available. These results support the continued development of MST and provide evidence for advantages relative to state-of-the-art ECT. ClinicalTrials.gov Identifier: NCT00488748.

Biallelic variants in SLC4A10 encoding a sodium-dependent bicarbonate transporter lead to a neurodevelopmental disorder

PurposeSLC4A10 encodes a plasma membrane-bound transporter, which mediates Na+-dependent HCO3− import, thus mediating net acid extrusion. Slc4a10 knockout mice show collapsed brain ventricles, an increased seizure threshold, mild behavioral abnormalities, impaired vision, and deafness. MethodsUtilizing exome/genome sequencing in families with undiagnosed neurodevelopmental disorders and international data sharing, 11 patients from 6 independent families with biallelic variants in SLC4A10 were identified. Clinico-radiological and dysmorphology assessments were conducted. A minigene assay, localization studies, intracellular pH recordings, and protein modeling were performed to study the possible functional consequences of the variant alleles. ResultsThe families harbor 8 segregating ultra-rare biallelic SLC4A10 variants (7 missense and 1 splicing). Phenotypically, patients present with global developmental delay/intellectual disability and central hypotonia, accompanied by variable speech delay, microcephaly, cerebellar ataxia, facial dysmorphism, and infrequently, epilepsy. Neuroimaging features range from some non-specific to distinct neuroradiological findings, including slit ventricles and a peculiar form of bilateral curvilinear nodular heterotopia. In silico analyses showed 6 of 7 missense variants affect evolutionarily conserved residues. Functional analyses supported the pathogenicity of 4 of 7 missense variants. ConclusionWe provide evidence that pathogenic biallelic SLC4A10 variants can lead to neurodevelopmental disorders characterized by variable abnormalities of the central nervous system, including altered brain ventricles, thus resembling several features observed in knockout mice.

Electroconvulsive therapy parameters for behavioral and psychological symptoms of dementia

AbstractIntroductionBehavioral and Psychological Symptoms of Dementia (BPSD) are a heterogenous group of non‐cognitive symptoms impacting up to 90% of patients with dementia, and include emotional disturbance, psychosis, agitation, aberrant motor behavior, and circadian rhythm disturbance. Multiple reviews have found ECT to be efficacious in treating BPSD that have not responded to other interventions. However, no published guidelines exist to inform clinicians about how protocols for ECT should be implemented in the treatment of BPSD. This study aims to identify ECT parameters commonly utilized for BPSD in the literature.MethodsMEDLINE and APA PsychInfo were searched from database inception until September 2022. Two reviewers independently screened and full text reviewed the retrieved articles. Articles included in the full text review stage discussed how ECT is implemented for patients experiencing BPSD.ResultsAfter duplicate removal, 800 unique citations were identified for screening. Of these, 160 were included in full text review. 32 studies were ultimately included (Figure 1). Characteristics of included studies are highlighted in Figures 2 and 3.Most studies utilized thrice weekly ECT, however, twice weekly was suggested to carry a lower risk of ECT‐related cognitive side effects. The number of sessions needed for response ranged between 2‐15, with improvement typically observed within 3‐6 treatments. The choice between unilateral and bilateral placement rests on weighing the risk of confusion with improved clinical response. Multiple authors recommend starting with unilateral treatment to reduce cognitive side effects and switching to bilateral if response is inadequate after 3‐5 sessions. Typical pulse width was 0.30‐0.37ms for ultrabrief and 1‐2s for brief treatment. Minimum recommendations for adequate seizure duration varied from 25 to 30 seconds on EEG and 15 to 20 seconds by observed motor movements. Stimulus dosage ranged between 1.5‐2.5x seizure threshold for bilateral placement, and 4‐6x seizure threshold for unilateral placement. Maintenance ECT was commonly used to reduce the risk of relapse.DiscussionECT is both safe and efficacious for patients with BPSD, and the present review focuses on commonly implemented ECT parameters in the literature. Notably, studies are limited by inconsistent reporting of ECT parameters and short follow‐up durations.

Unmasking hidden risks: The surprising link between PDE5 inhibitors and seizure susceptibility.

Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous system effects, that can cause seizures in susceptible patients. This study aims to describe the changes caused by the use of Sildenafil and Tadalafil through the analysis of abnormalities expressed in the electrocorticogram (ECoG) of rats and evaluate the seizure threshold response and treatment of seizures with anticonvulsants. The study used 108 rats (Wistar). Before surgery for electrode placement in dura mater, the animals were randomly separated into 3 experiments for electrocorticogram analysis. Experiment 1: ECoG response to using PD5i (Sildenafil 20mg/kg and Tadalafil 2.6mg/kg p.o.). Experiment 2: ECoG response to the use of PD5i in association with Pentylenetetrazole (PTZ-30 mg/kg i.p.), a convulsive model. Experiment 3: ECoG response to anticonvulsant treatment (Phenytoin, Phenobarbital and Diazepam) of seizures induced by association IPDE5 + PTZ. All recordings were made thirty minutes after administration of the medication and analyzed for ten minutes, only once. We considered statistical significance level of *p<0.05, **p<0.01 and ***p < 0.001. After administration of Sildenafil and Tadalafil, there were increases in the power of recordings in the frequency bands in oscillations in alpha (p = 0.0920) and beta (p = 0.602) when compared to the control group (p<0.001). After the use of Sildenafil and Tadalafil associated with PTZ, greater potency was observed in the recordings during seizures (p<0.001), however, the Sildenafil group showed greater potency when compared to Tadalafil (p<0.05). Phenobarbital and Diazepam showed a better response in controlling discharges triggered by the association between proconvulsant drugs. PDE5i altered the ECoG recordings in the rats' motor cortexes, demonstrating cerebral asynchrony and potentiating the action of PTZ. These findings demonstrate that PDE5i can lower the seizure threshold.

Alterations in Rat Hippocampal Glutamatergic System Properties after Prolonged Febrile Seizures

Febrile seizures during early childhood may result in central nervous system developmental disorders. However, the specific mechanisms behind the impact of febrile seizures on the developing brain are not well understood. To address this gap in knowledge, we employed a hyperthermic model of febrile seizures in 10-day-old rats and tracked their development over two months. Our objective was to determine the degree to which the properties of the hippocampal glutamatergic system are modified. We analyzed whether pyramidal glutamatergic neurons in the hippocampus die after febrile seizures. Our findings indicate that there is a reduction in the number of neurons in various regions of the hippocampus in the first two days after seizures. The CA1 field showed the greatest susceptibility, and the reduction in the number of neurons in post-FS rats in this area appeared to be long-lasting. Electrophysiological studies indicate that febrile seizures cause a reduction in glutamatergic transmission, leading to decreased local field potential amplitude. This impairment could be attributable to diminished glutamate release probability as evidenced by decreases in the frequency of miniature excitatory postsynaptic currents and increases in the paired-pulse ratio of synaptic responses. We also found higher threshold current causing hind limb extension in the maximal electroshock seizure threshold test of rats 2 months after febrile seizures compared to the control animals. Our research suggests that febrile seizures can impair glutamatergic transmission, which may protect against future seizures.

Anti-epileptic and Neuroprotective Effects of Ultra-low Dose NADPH Oxidase Inhibitor Dextromethorphan on Kainic Acid-induced Chronic Temporal Lobe Epilepsy in Rats.

Neuroinflammation mediated by microglia and oxidative stress play pivotal roles in the development of chronic temporal lobe epilepsy (TLE). We postulated that kainic acid (KA)-Induced status epilepticus triggers microglia-dependent inflammation, leading to neuronal damage, a lowered seizure threshold, and the emergence of spontaneous recurrent seizures (SRS). Extensive evidence from our laboratory suggests that dextromethorphan (DM), even in ultra-low doses, has anti-inflammatory and neuroprotective effects in many animal models of neurodegenerative disease. Our results showed that administration of DM (10 ng/kg per day; subcutaneously via osmotic minipump for 4 weeks) significantly mitigated the residual effects of KA, including the frequency of SRS and seizure susceptibility. In addition, DM-treated rats showed improved cognitive function and reduced hippocampal neuronal loss. We found suppressed microglial activation-mediated neuroinflammation and decreased expression of hippocampal gp91phox and p47phox proteins in KA-induced chronic TLE rats. Notably, even after discontinuation of DM treatment, ultra-low doses of DM continued to confer long-term anti-seizure and neuroprotective effects, which were attributed to the inhibition of microglial NADPH oxidase 2 as revealed by mechanistic studies.

Effect of dietary supplementation with Lactobacillus helveticus R0052 on seizure thresholds and antiseizure potency of sodium valproate in mice

ObjectiveBoth animal and human studies, though limited, showed that multi-strain probiotic supplementation may reduce the number of seizures and/or seizure severity. Here, we evaluated the effect of a single strain probiotic supplementation on seizure susceptibility, antiseizure efficacy of sodium valproate, and several behavioral parameters in mice.MethodsLactobacillus helveticus R0052 was given orally for 28 days. Its influence on seizure thresholds was evaluated in the ivPTZ- and electrically-induced seizure tests. The effect on the antiseizure potency of valproate was assessed in the scPTZ test. We also investigated the effects of probiotic supplementation on anxiety-related behavior (in the elevated plus maze and light/dark box tests), motor coordination (in the accelerating rotarod test), neuromuscular strength (in the grip-strength test), and spontaneous locomotor activity. Serum and brain concentrations of valproate as well as cecal contents of SCFAs and lactate were determined using HPLC method.ResultsL. helveticus R0052 significantly increased the threshold for the 6 Hz-induced psychomotor seizure. There was also a slight increase in the threshold for myoclonic and clonic seizure in the ivPTZ test. L. helveticus R0052 did not affect the threshold for tonic seizures both in the maximal electroshock- and ivPTZ-induced seizure tests. No changes in the antiseizure potency of valproate against the PTZ-induced seizures were reported. Interestingly, L. helveticus R0052 increased valproate concentration in serum, but not in the brain. Moreover, L. helveticus R0052 did not produce any significant effects on anxiety-related behavior, motor coordination, neuromuscular strength, and locomotor activity. L. helveticus R0052 supplementation resulted in increased concentrations of total SCFAs, acetate, and butyrate.ConclusionsAltogether, this study shows that a single-strain probiotic – L. helveticus R0052 may decrease seizure susceptibility and this effect can be mediated, at least in part, by increased production of SCFAs. In addition, L. helveticus R0052 may affect bioavailability of valproate, which warrants further investigations.

NCMP-23. EVALUATION OF IMMUNOTHERAPY EFFECTS IN CANCER PATIENTS ON EPILEPTIFORM ACTIVITY

Abstract BACKGROUND/OBJECTIVE Immune checkpoint inhibitors are associated with increased risk of autoimmune neurologic conditions, both in the peripheral and central nervous system. Increased activation of the immune system can lower seizure threshold, potentially increasing a patient’s risk of seizures. We hypothesize that patients treated with immune checkpoint inhibitors have a higher rate of seizures. METHODS We retrospectively reviewed 465 cancer patients undergoing electroencephalography (EEG) monitoring performed at Memorial Sloan Kettering Cancer Center from January 2022 to March 2023. Data was gathered from an EEG RedCap database containing patient demographic and seizure data. Patients were separated based on whether they had received immune checkpoint inhibitors (+ICI) prior to seizure occurrence or were never exposed to immune checkpoint inhibitors (-ICI) and had a seizure. Patient cancer type and presence of brain lesions (primary or metastases) were also reviewed. RESULTS Out of 465 patients, 109 received immune checkpoint inhibitors (+ICI) during their treatment. Seven of those patients were reported to have had at least one seizure (7/109, 6.42%) following treatment with ICI. The remaining 356 patients did not undergo immune checkpoint inhibitor treatment (-ICI), of which 30 were reported to have had at least one seizure (30/356, 8.43%). Of the +ICI patients who were experiencing seizures, 5 of them had brain lesions; 4 had primary brain tumors and 1 had brain metastases. Of –ICI patients, 21 patients had brain lesions; 15 had primary brain tumors and 6 had brain metastases. DISCUSSION Although immune checkpoint therapy may lead to increased activation of the immune system, our data did not reveal a higher incidence of seizures. Limitations to our study include its retrospective design, low number of patients, and low overall number of seizures captured on EEG.

Specificity of seizure genesis during electroconvulsive therapy and modified pentylenetetrazole kindling

Comparison of the development of chemically induced seizures in the experiment with the change in convulsive thresholds during electroconvulsive therapy (ECT) has demonstrated that repeated ‘chemical’ seizures can initiate the development of the kindling phenomenon, but regular ECT from the first to the 14th session most likely cause an increase in convulsive thresholds. However, the repeated ECT over 15 sessions is associated with a rapid decrease in the threshold current dose and probable dysregulation of endogenous anticonvulsant mechanisms, with the risk of the development of uncontrolled paroxysmal conditions and the risk of organic CNS lesions. The mechanisms of the convulsive action of ECT and pentylenetetrazolinduced kindling are fundamentally different. Differences in the pathogenesis of systemic convulsive reactions determine the divergent change in seizure thresholds during ECT and pentylenetetrazol stimulations.

Anticonvulsant effect of equilibrative nucleoside transporters 1 inhibitor in a mouse model of Dravet syndrome.

There are limited therapeutic options for patients with Dravet syndrome (DS). The equilibrative nucleoside transporters 1 (ENT1) mediate both the influx and efflux of adenosine across the cell membrane exerted beneficial effects in the treatment of epilepsy. This study aimed to evaluate the anticonvulsant effect of the ENT1 inhibitor in an animal model of DS (Scn1aE1099X/+ mice). J7 (5 mg/kg) treatment was efficacious in elevating seizure threshold in Scn1aE1099X/+ mice after hyperthermia exposure. Moreover, the J7 treatment significantly reduced the frequency of spontaneous excitatory post-synaptic currents (sEPSCs, ~35% reduction) without affecting the amplitude in dentate gyrus (DG) granule cells. Pretreatment with the adenosine A1 receptor (A1R) antagonist, DPCPX, abolished the J7 effects on sEPSCs. These observations suggest that the J7 shows an anticonvulsant effect in hyperthermia-induced seizures in Scn1aE1099X/+ mice. This effect possibly acts on presynaptic A1R-mediated signaling modulation in granule cells.

Neocortical and cerebellar malformations affect flurothyl-induced seizures in female C57BL/6J mice.

Brain malformations cause cognitive disability and seizures in both human and animal models. Highly laminated structures such as the neocortex and cerebellum are vulnerable to malformation, affecting lamination and neuronal connectivity as well as causing heterotopia. The objective of the present study was to determine if sporadic neocortical and/or cerebellar malformations in C57BL/6J mice are correlated with reduced seizure threshold. The inhaled chemi-convulsant flurothyl was used to induce generalized, tonic-clonic seizures in male and female C57BL/6J mice, and the time to seizure onset was recorded as a functional correlate of brain excitability changes. Following seizures, mice were euthanized, and brains were extracted for histology. Cryosections of the neocortex and cerebellar vermis were stained and examined for the presence of molecular layer heterotopia as previously described in C57BL/6J mice. Over 60% of mice had neocortical and/or cerebellar heterotopia. No sex differences were observed in the prevalence of malformations. Significantly reduced seizure onset time was observed dependent on sex and the type of malformation present. These results raise important questions regarding the presence of malformations in C57BL/6J mice used in the study of brain development, epilepsy, and many other diseases of the nervous system.

Noradrenaline and Seizures: A Perspective on the Role of Adrenergic Receptors in Limbic Seizures.

Noradrenergic fibers originating from the locus coeruleus densely innervate limbic structures, including the piriform cortex, which is the limbic structure with the lowest seizure threshold. Noradrenaline (NA) modulates limbic seizures while stimulating autophagy through β2- adrenergic receptors (AR). Since autophagy is related to seizure threshold, this perspective questions whether modulating β2-AR focally within the anterior piriform cortex affects limbic seizures. In this perspective, we analyzed a potential role for β2-AR as an anticonvulsant target within the anterior piriform cortex, area tempestas (AT). We developed this perspective based on current literature on the role of NA in limbic seizures and autophagy. The perspective is also grounded on preliminary data obtained by microinfusing within AT either a β2-AR agonist (salbutamol) or a β2-AR antagonist (butoxamine) 5 minutes before bicuculline. β2-AR stimulation fully prevents limbic seizures induced by bicuculline micro-infusion in AT. Conversely, antagonism at β2-AR worsens bicuculline-induced seizure severity and prolongs seizure duration, leading to self-sustaining status epilepticus. These data indicate a specific role for β2-AR as an anticonvulsant in AT. NA counteracts limbic seizures. This relies on various receptors in different brain areas. The anterior piriform cortex plays a key role in patients affected by limbic epilepsy. The anticonvulsant effects of NA through β2-AR may be related to the stimulation of the autophagy pathway. Recent literature and present data draw a perspective where β2-AR stimulation while stimulating autophagy mitigates limbic seizures, focally within AT. The mechanism linking β2-AR to autophagy and seizure modulation should be extensively investigated.

SAT316 Severe Cushing’s Syndrome Due To Ectopic ACTH In Newly Diagnosed Small Cell Lung Cancer: The Pivotal Role Of Etomidate In Acute Treatment

Abstract Disclosure: H. Belal: None. G.Y. Gandhi: None. Introduction: Ectopic ACTH syndrome can present as an endocrine emergency. Etomidate, the only parenteral steroidogenesis inhibitor, can rapidly treat critically ill patients with Cushing’s syndrome (CS) and concurrent significant metabolic derangements, severe hypertension, or psychosis. Case Description: A 66-year-old female presented with abdominal pain, vomiting, proximal muscle weakness, and confusion for 6 months. Physical exam revealed hypertension, bilateral supraclavicular fat pads, and abdominal distention, while laboratory evaluation uncovered severe hypokalemia &amp;lt;1.5 mmol/L, metabolic alkalosis, and elevated proBNP. A hilar soft tissue mass with mediastinal lymphadenopathy and bilaterally enlarged adrenal glands were seen on CT imaging. Serum cortisol was high at 114 mcg/dL. ACTH was inappropriately elevated at 111 pg/mL. MRI revealed a normal pituitary gland. She developed hypertensive emergency and status epilepticus, requiring intubation. Due to her life-threatening presentation, a guideline-based hypercortisolism workup was forgone for emergent treatment with continuous etomidate infusion. Serum cortisol normalized after 4 days of etomidate therapy. Due to concerns of reduced seizure threshold with etomidate therapy, it was weaned off after 14 days and replaced by ketoconazole. She subsequently developed recurrent hypercortisolism (serum cortisol 92 mcg/dL). After 14 days of etomidate, 9 days of ketoconazole, and 3 days of chemotherapy for biopsy-proven small-cell lung carcinoma, serum cortisol reached a trough of 22 mcg/dL. At this point, hydrocortisone therapy was initiated (block-and-replace). Recurrent clinical hypercortisolism then developed, and hydrocortisone was discontinued. Hypercortisolism comorbidities were treated appropriately: trimethoprim-sulfamethoxazole for pneumocystis pneumonia prophylaxis, anticoagulation for DVT prophylaxis, antibiotics for acute diverticulitis, and insulin for hyperglycemia. Despite treatment, her condition worsened; she was transitioned to comfort care one month after admission and died 4 days later. Discussion: Etomidate inhibits steroidogenesis through 11 beta-hydroxylate blockade and works rapidly (within 12-24 hours) to decrease cortisol levels versus ketoconazole (several days) and has a reduced risk of hepatic injury. Side effects of etomidate include respiratory depression, myoclonus, and reduced seizure threshold. Several experts have suggested a block-and-replace strategy in severe CS treatment. While effective, this strategy poses risks of etomidate toxicity and makes serum cortisol interpretation unreliable. Etomidate analogs are on the horizon that retain the potent adrenostatic action of etomidate without its sedative-hypnotic activity, offering an alternative treatment option for treating patients with severe CS in non-ICU hospital settings. Presentation: Saturday, June 17, 2023