Seizure Severity Score Research Articles

Analysis of factors influencing the efficacy of vagus nerve stimulation for the treatment of drug-resistant epilepsy in children and prediction model for efficacy evaluation.

Vagus nerve stimulation (VNS) has been widely used in the treatment of drug-resistant epilepsy (DRE) in children. We aimed to explore the efficacy and safety of VNS, focusing on factors that can influence the efficacy of VNS, and construct a prediction model for the efficacy of VNS in the treatment of DRE children. Retrospectively analyzed 45 DRE children who underwent VNS at Qilu Hospital of Shandong University from June 2016 to November 2022. A ≥50% reduction in seizure frequency was defined as responder, logistic regression analyses were performed to analyze factors affecting the efficacy of VNS, and a predictive model was constructed. The predictive model was evaluated by receiver operating characteristic curve (ROC), calibration curves, and decision curve analyses (DCA). A total of 45 DRE children were included in this study, and the frequency of seizures was significantly reduced after VNS treatment, with 25 responders (55.6%), of whom 6 (13.3%) achieved seizure freedom. There was a significant improvement in the Quality of Life in Childhood Epilepsy Questionnaire (15.5%) and Seizure Severity Score (46.2%). 16 potential factors affecting the efficacy of VNS were included, and three statistically significant positive predictors were ultimately screened: shorter seizure duration, focal seizure, and absence of intellectual disability. We developed a nomogram for predicting the efficacy of VNS in the treatment of DRE children. The ROC curve confirmed that the predictive model has good diagnostic performance (AUC = 0.864, P < 0.05), and the nomogram can be further validated by bootstrapping for 1,000 repetitions, with a C-index of 0.837. Besides, this model showed good fitting and calibration and positive net benefits in decision curve analysis. VNS is a safe and effective treatment for DRE children. We developed a predictive nomogram for the efficacy of VNS, which provides a basis for more accurate selection of VNS patients.

The longitudinal effects of cannabidiol on brain temperature in patients with treatment-resistant epilepsy

Neuroinflammation (NI) is a key pathophysiological contributor to treatment-resistant epilepsy (TRE) that remains challenging to observe in vivo. Magnetic resonance spectroscopic imaging and thermometry (MRSI-t) is an emerging technique that can be used to non-invasively map brain temperature, whereby brain temperature elevations serve as a surrogate for the cellular and biochemical processes associated with NI. In a previous multimodal imaging study of focal epilepsy patients, we observed MRSI-t-based brain temperature elevations ipsilateral to the seizure onset zone (SOZ) that were concordant with evidence of edema (Sharma et al., 2023). Despite its potential as tool, it is unclear if MRSI-t can monitor changes in brain temperature in response to treatment. We imaged 25 participants approximately 12-weeks apart. Eight patients with TRE were imaged before receiving highly-purified pharmaceutical grade cannabidiol (CBD; pre-CBD) and after 12-weeks of CBD (on-CBD) therapy. Seventeen healthy controls (HCs) were also imaged twice. Repeated measures t-tests computed changes in TRE patients’ seizure symptoms, mood, and brain temperature within their respective SOZs. Repeated measures ANOVAs tested Group*Time changes in imaging data. Participants with TRE had abnormally high peak brain temperatures within their SOZs that decreased after CBD initiation (p < 0.0001). Seizure severity scores also improved after CBD initiation (p < 0.001). These findings provide insights into the possible neural effects of CBD, and further demonstrate MRSI-t’s potential as a tool for delineating SOZ. Further investigations into MRSI-t as a longitudinal measure of therapy-induced changes in NI are warranted.

The beneficial effect of probiotics as an adjuvant treatment in childhood drug resistant epilepsy: A prospective pilot study.

One of the most common long-term neurological disorders affecting children is epilepsy. Even with effective antiseizure medications, one-third of epileptic patients develop drug-resistant epilepsy (DRE). Numerous treatments have been offered to these DRE patients, though with varying degrees of effectiveness. This study aimed to evaluate the effectiveness of probiotics in improving the quality of life (QoL) and lowering the severity and frequency of epileptic episodes in DRE patients. As well as to assess the anti-inflammatory effects of probiotics. DRE patients were daily supplemented with one probiotic for 4months. During these 4months, patients continued their routine anti-epileptics with no change in the doses. Before and following the 4-month trial, patients had their QoL evaluated using the validated Arabic version of QoL in epilepsy-31 inventory (QoLIE-31) questionnaire, an electroencephalogram (EEG) examination, and serum soluble CD14 (sCD14) evaluation by ELISA. Of the 21 DRE patients who completed the study, 42.9% achieved the therapeutic goal, which was a ≥50% reduction in seizures. After probiotic, there was a significant increase in time elapsed since the last seizure (p = 0.001) and a decrease in seizure duration (p = 0.038), frequency (p = 0.002), and severity by Chalfont Seizure Severity Score (p < 0.001), as compared to pre-probiotic data. Moreover, there was a significant decrease in serum levels of sCD14 (p < 0.001) and a significant improvement in QoL (p < 0.05). Probiotics may be used as a DRE adjuvant treatment. They can lessen the number and severity of seizures, alleviate the associated inflammation, and enhance the QoL for DRE patients.

The seizure severity score: a quantitative tool for comparing seizures and their response to therapy

Objective. Epilepsy is a neurological disorder characterized by recurrent seizures which vary widely in severity, from clinically silent to prolonged convulsions. Measuring severity is crucial for guiding therapy, particularly when complete control is not possible. Seizure diaries, the current standard for guiding therapy, are insensitive to the duration of events or the propagation of seizure activity across the brain. We present a quantitative seizure severity score that incorporates electroencephalography (EEG) and clinical data and demonstrate how it can guide epilepsy therapies. Approach. We collected intracranial EEG and clinical semiology data from 54 epilepsy patients who had 256 seizures during invasive, in-hospital presurgical evaluation. We applied an absolute slope algorithm to EEG recordings to identify seizing channels. From this data, we developed a seizure severity score that combines seizure duration, spread, and semiology using non-negative matrix factorization. For validation, we assessed its correlation with independent measures of epilepsy burden: seizure types, epilepsy duration, a pharmacokinetic model of medication load, and response to epilepsy surgery. We investigated the association between the seizure severity score and preictal network features. Main results. The seizure severity score augmented clinical classification by objectively delineating seizure duration and spread from recordings in available electrodes. Lower preictal medication loads were associated with higher seizure severity scores (p = 0.018, 97.5% confidence interval = [−1.242, −0.116]) and lower pre-surgical severity was associated with better surgical outcome (p = 0.042). In 85% of patients with multiple seizure types, greater preictal change from baseline was associated with higher severity. Significance. We present a quantitative measure of seizure severity that includes EEG and clinical features, validated on gold standard in-patient recordings. We provide a framework for extending our tool’s utility to ambulatory EEG devices, for linking it to seizure semiology measured by wearable sensors, and as a tool to advance data-driven epilepsy care.

Anticonvulsant potential of Grewia tiliaefolia in pentylenetetrazole induced epilepsy: insights from in vivo and in silico studies.

Epilepsy, a chronic neurological condition, impacts millions of individuals globally and remains a significant contributor to both illness and mortality. Available antiepileptic drugs have serious side effects which warrants to explore different medicinal plants used for the management of epilepsy reported in Traditional Indian Medicinal System (TIMS). Therefore, we explored the antiepileptic potential of the Grewia tiliaefolia (Tiliaeceae) which is known for its neuroprotective properties. Aerial parts of G. tiliaefolia were subjected to extraction with increasing order of polarity viz. hexane, chloroform and methanol. Antioxidant potential of hexane, chloroform and methanol extracts ofG. tiliaefoliawas evaluated by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) assay, total antioxidant capacity (TAC) assay, reducing power assay (RPA) and DNA nicking assay. Additionally, quantitative antioxidant assays were also conducted to quantify total phenolic (TPC) and total flavonoid content (TFC). As revealed by in vitro assays, methanol extract was found to contain more phenolic content. Hence, the methanol extract was further explored for its anticonvulsant potential in pentylenetetrazole (PTZ) induced acute seizures in mice. The methanol extract (400mg/kg) significantly increased the latency to occurrence of myoclonic jerks and generalized tonic clonic seizures (GTCS). Additionally, it also reduced duration and seizure severity score associated with GTCS. The Grewia tiliaefolia methanol extract was further screened by Ultra High-Performance Liquid Chromatography (UHPLC) for presence of polyphenolic compounds, among which gallic acid and kaempferol were present in higher amount and were further analysed by in silico study to predict their possible binding sites and type of interactions these compounds show with gamma amino butyric acid (GABA) receptor and glutamate α amino-3- hydroxyl-5-methyl-4-isoxazolepropionic acid (Glu-AMPA) receptor. It was revealed that gallic acid and kaempferol had shown agonistic interaction for GABA receptor and antagonistic interaction for Glu-AMPA receptor. We concluded thatG. tiliaefoliashowed anticonvulsant potential possibly because of gallic acid and kaempferol possibly mediated through GABA and Glu-AMPA receptor.

Protective Effects of Intranasally Administrated Oxytocin-Loaded Nanoparticles on Pentylenetetrazole-Kindling Epilepsy in Terms of Seizure Severity, Memory, Neurogenesis, and Neuronal Damage.

Pentylenetetrazole (PTZ)-induced kindling is an animal model for studying human temporal lobe epilepsy (TLE), which is characterized by alterations of hippocampal neurons and memory. Although the intranasal (IN) administration of oxytocin (OT) has limited efficiency, nanoparticles (NPs) are a promising candidate to deliver OT to the brain. However, there are very limited data on epilepsy research about oxytocin-loaded nanoparticles (NP-OTs). The aim of this study is to investigate the effects of IN administration of chronic NP-OTs on the hippocampus of PTZ-induced male epileptic rats in terms of seizure severity, memory, neurogenesis, and neuronal damage. Saline/OT/NP-OTs were administrated to both control (Ctrl) and PTZ groups intranasally. Consequently, saline and PTZ were injected, respectively, 25 times every 48 h. Then, seizure severity (score and latency) was calculated for the PTZ groups. A spatial working memory evaluation test (SWMET) was performed after the last injection. Hippocampus histopathology, neurogenesis, and apoptosis were demonstrated. Serum total antioxidant status (TAS) and total oxidant status (TOS) levels and the oxidative stress index (OSI) were measured. We showed that OTs and NP-OTs prevented the kindling development and had positive effects on seizure severity. SWMET-related behaviors were also recovered in the PTZ + NP-OT group. A significant increase of neurogenesis and decrease of apoptosis in the hippocampus of the PTZ + NP-OT group were observed, while OTs and NP-OTs had protective effects against PTZ-induced damage to hippocampal neurons. Our results indicate that the chronic administration of NP-OTs may have positive effects on hippocampal damage via increasing neurogenesis and decreasing apoptosis and seizure severity.

Factors associated with seizure severity among children with epilepsy in Northern Nigeria.

To describe how seizure severity in children with epilepsy may be affected by certain socio-demographic and clinical variables. A cross-sectional study. At the Abubakar Tafawa Balewa University Teaching Hospital, Bauchi, Nigeria. Sixty children and adolescents who were being followed up for seizure disorder at the child neurology clinic. Information on socio-demographic characteristics was obtained with a questionnaire, details of neurological co-morbidities were extracted from the participants' records, and seizure severity was assessed with the National Hospital Seizure Severity Score 3 tool. Chi-square test was used to establish the relationship between categorical variables, while the Independent t-test was used in describing the differences between means. Simple linear regression was calculated to assess the predictability of seizure severity. The median age was ten years (IQR = 6-13 years), with a male dominance (1.5:1). The Seizure Severity Score (SSS) ranged between 3 and 24 units, with a mean of 12.22 ± 4.29 units. The only characteristic that had a significant association with SSS on bivariate analysis was the "presence of co-morbidities" (p=0.019). A simple linear regression revealed that the presence of a neurological co-morbidity predicted an increase in the SSS by 2.67 units. [R2 = 0.091, F (1, 58)= 5.837, p = 0.019. β = 2.67, t= 2.42, p= 0.019.]. This study shows that neurological co-morbidities predict worsening seizure severity. This knowledge may influence prognostication and the charting of a treatment trajectory. No external funding.

The effects of regular swimming exercise during sodium valproate treatment on seizure behaviors and EEG recordings in pentylenetetrazole-kindled rats

We investigated the effects of alone/combined regular swimming exercise and sodium valproate on epileptic seizure behaviors and EEG recordings, anti-oxidative mechanism, learning, and memory in pentylenetetrazole (PTZ)–kindled rats. Forty-eight healthy rats were randomly divided into eight equal groups as control (CONT), swimming exercise (EX), sodium valproate (SV), SV+EX, PTZ, EX+PTZ, SV+PTZ and SV+EX+PTZ. The rats were forced to regular swimming exercise for 60 min every other day, 13 doses of PTZ (40 mg/kg) were given to induce epileptic seizures and 200 mg/kg SV was given for 28 days. Epileptic seizures were evaluated by visual observation and EEG recordings (total spike numbers and number of epileptiform discharges). Memory and learning skills were assessed with passive avoidance test. According to our visual seizure observations, seizure latency was prolonged only in SV+EX+PTZ (p < 0.001) group, seizure severity score decreased in SV+PTZ (p < 0.05) and SV+EX+PTZ (p < 0.001) groups and seizure frequency was reduced in SV+PTZ (p < 0,001), EX+PTZ (p < 0,001), and SV+EX+PTZ (p < 0,001) groups. Total spike numbers and number of epileptiform discharges highly increased in PTZ group, whereas they decreased in swimming exercise and/or SV treatment groups. The most effective result was seen in the combined therapy group. Memory deficit was observed in PTZ –kindling group, but it didn’t change with exercise or SV. Based on our results, regular swimming exercise had positive effects on PTZ-induced seizure frequency, and combined therapy of regular swimming exercise and SV is the most effective way to ameliorate visual seizure behaviors and decrease spike numbers and number of epileptiform discharges according to EEG recordings. Regular swimming exercise could be an alternative option to reduce the dose of SV and the side effects of SV can be avoided in clinical aspects.

Clustering of Spontaneous Recurrent Seizures in a Mouse Model of Extended Hippocampal Kindling.

Acute repetitive seizures or seizure clusters are common in epileptic patients. Seizure clusters are associated with a high risk of developing status epilepticus and increased morbidity and mortality. Seizure clusters are also recognizable in spontaneous recurrent seizures (SRS) that occur in animal models of epilepsy. The electrical kindling of a limbic structure is a commonly used model of temporal lobe epilepsy. Although classic kindling over the course of a few weeks does not generally induce SRS, extended kindling over the course of a few months can induce SRS in several animal species. SRS in kindled cats often occur in clusters, but the existence of seizure clusters in rodent models of extended kindling remains to be demonstrated. We explored the existence of seizure clusters in mice following extended hippocampal kindling. Adult male mice (C57BL/6) experienced twice daily hippocampal stimulations and underwent continuous 24-hour electroencephalogram (EEG)-video monitoring after ≥80 stimulations. SRS events were recognized by EEG discharges and associated motor seizures. Seizure clusters, defined as ≥4 seizures per cluster and intra-cluster inter-seizure intervals ≤ 120 min, were observed in 19 of the 20 kindled mice. Individual mice showed variable seizure clusters in terms of cluster incidence and circadian-like expression patterns. For clusters consisting of 4–7 seizures and intra-seizure intervals ≤ 20 min, no consistent changes in inter-seizure intervals, EEG discharge duration, or motor seizure severity scores were observed approaching cluster termination. These results suggested that seizure clustering represents a prominent feature of SRS in hippocampal kindled mice. We speculate that, despite experimental limitations and confounding factors, systemic homeostatic mechanisms that have yet to be explored may play an important role in governing the occurrence and termination of seizure clusters.

Transcutaneous vagus nerve stimulation in the treatment of drug-resistant epilepsy.

Epilepsy is a common chronic neurological disease with a high burden of illness. Invasive vagus nerve stimulation (iVNS) is a well-established treatment option in patients with epilepsy (PWE). More recently, transcutaneous vagus nerve stimulation (tVNS) was introduced, an alternative option which is particularly interesting because it does not require surgery and is instantaneously removable. Here, we thoroughly reviewed clinical data on efficacy and safety of tVNS in epilepsies. Five prospective trials in 118 patients with drug-resistant epilepsies and 3 randomized controlled trials in 280 patients with drug-resistant epilepsies were carried out. Study protocols were heterogeneous in terms of patients' characteristics, used device, stimulation parameters, study duration and endpoints. Seizure reduction amounted up to 64%, with responder rates (seizure reduction ≥50%) up to 65%. Seizure freedom was reached in up to 24%, and even to 31% in a small pediatric study group. Seizure severity scores were provided in 4 studies, showing significant improvement in two of them. Adverse side effects were mostly headache, ear pain and skin alteration and rated as mild to moderate. Drowsiness might be depend on stimulation intensity. Quality of life scores reflecting burden of illness showed significant improvement in two studies. Efficacy and safety of tVNS in PWE has to be interpreted as promising. Multicenter randomized double-blind clinical trials with standardized stimulation protocols and long-term follow-up studies are necessary to finally assess tVNS treatment outcome in drug-resistant epilepsies.

Clinico-radiological Profile in Children with Drug Resistant Focal Epilepsy

Abstract Objective To assess the clinical and neuroimaging findings of pediatric patients with drug-resistant focal epilepsy, comparing conventional MR technique to the "essential 6” protocol. Methods An observational study of 18 children with drug resistant focal seizures identified both clinically and/or by EEG findings. Available clinical data as well as EEG and MRI data in patients’ files at the pediatric neurology clinic at Ain Shams University was retrospectively evaluated and documented. All patients then underwent a new MRI study using a novel MR technique - the essential six sequence protocol to determine whether the latter technique was superior to standard at picking subtle anatomical abnormalities in children with drug resistant focal epilepsy. Results 18 children (10 males and 8 females) with a mean age of 8.49 ±3.20 years were enrolled. The mean age at onset of epilepsy was 3.24 ±2.79 years. 15 out of 18 patients (83%) had an abnormal EEG. The mean Chalfont Seizure Severity Scale Score was 63.71 ±34.35. There was no statistically significant difference in Chalfont seizure severity scores between patients with normal vs abnormal EEG, and with normal vs abnormal MRI. The novel MRI technique could pick on an abnormality in 12 out of the 18 cases (66%), which is six times more than what could be identified using the baseline/conventional MRI technique. Conclusions The essential 6 MRI protocol is superior to conventional MRI protocols at picking structural abnormalities in patients with drug resistant focal epilepsy.

Assessing seizure burden in pediatric epilepsy using an electronic medical record-based tool through a common data element approach.

Improvement in epilepsy care requires standardized methods to assess disease severity. We report the results of implementing common data elements (CDEs) to document epilepsy history data in the electronic medical record (EMR) after 12months of clinical use in outpatient encounters. Data regarding seizure frequency were collected during routine clinical encounters using a CDE-based form within our EMR. We extracted CDE data from the EMR and developed measurements for seizure severity and seizure improvement scores. Seizure burden and improvement was evaluated by patient demographic and encounter variables for in-person and telemedicine encounters. We assessed a total of 1696 encounters in 1038 individuals with childhood epilepsies between September 6, 2019 and September 11, 2020 contributed by 32 distinct providers. Childhood absence epilepsy (n=121), Lennox-Gastaut syndrome (n=86), and Dravet syndrome (n=42) were the most common epilepsy syndromes. Overall, 43% (737/1696) of individuals had at least monthly seizures, 17% (296/1696) had a least daily seizures, and 18% (311/1696) were seizure-free for >12months. Quantification of absolute seizure burden and changes in seizure burden over time differed between epilepsy syndromes, including high and persistent seizure burden in patients with Lennox-Gastaut syndrome. Individuals seen via telemedicine or in-person encounters had comparable seizure frequencies. Individuals identifying as Hispanic/Latino, particularly from postal codes with lower median household incomes, were more likely to have ongoing seizures that worsened over time. Standardized documentation of clinical data in childhood epilepsies through CDE can be implemented in routine clinical care at scale and enables assessment of disease burden, including characterization of seizure burden over time. Our data provide insights into heterogeneous patterns of seizure control in common pediatric epilepsy syndromes and will inform future initiatives focusing on patient-centered outcomes in childhood epilepsies, including the impact of telemedicine and health care disparities.

Evaluating the impact of pharmaceutical care services on the clinical outcomes of epilepsy: a randomised controlled trial

The involvement of pharmacists in the provision of specialised care to patients with epilepsy is poor. To evaluate the impact of pharmaceutical care services on the clinical outcomes of epilepsy. Two selected major referral epilepsy treatment centres in southern Nigeria were used for the study. Patients were recruited from the Neurology and Medical out-patient clinics of the hospitals. An open randomised controlled study was carried out on epilepsy patients receiving clinical care at the selected hospitals. Patients in the intervention group were offered pharmaceutical care services. The impact of the pharmaceutical care services on the clinical outcomes of epilepsy (seizure frequency and severity) was evaluated. The effect of pharmaceutical care services on seizure frequency and severity in patients with epilepsy. There was a statistically significant difference between the usual care (UC) and the pharmaceutical care (PC) group on the clinical outcomes of epilepsy post-PC intervention. Comparison between the groups (UC versus PC) revealed that patients in the PC group had a significantly lower seizure frequency score than those in the UC group at 3months and 6months-(pre-intervention: 3.09 versus 3.34; t = -1.685; p = 0.094) (3months 2.45 versus 1.68; t = 4.494; p = 0.001), (6months: 1.97 versus 0.92; t = -3.137; p = 0.001). Also, comparisons between the groups (UC versus PC) showed that patients in the PC group had a significantly lower seizure severity score than those in the UC group at 3months and 6months-(pre-intervention 18.46 versus 20.38; t = -3.102; p = 0.01) (3months: 17.51 versus 14.79; t = 4.202; p = 0.001) (6months 16.41 versus 11.66; t = 8.930; p = 0.001). Pharmaceutical care interventions may significantly reduce seizure frequency and severity in patients with epilepsy. These findings provide justification for the integration of pharmaceutical care services with other elements of health care for epilepsy patients.

Long-term safety and efficacy of highly purified cannabidiol for treatment refractory epilepsy

ObjectiveTo evaluate the safety, efficacy, and tolerability of highly purified cannabidiol (CBD) for the treatment of seizures in children and adults with treatment-resistant epilepsy (TRE) in an open-label, expanded access program (EAP). MethodsOne hundred sixty-nine participants (89 children and 80 adults) with TRE received plant-derived highly purified CBD (Epidiolex® in the U.S.; 100 mg/mL oral solution) with a starting dose of 5 mg/kg/day divided twice per day and titrated to a maximum dose of 50 mg/kg/day over the study period to seizure control and tolerability and followed for up to 2 years. Seizure frequency (calendars) and severity (Chalfont Seizure Severity Score; CSSS) were collected at every study visit. Adverse Events were reported at/between study visits as required, and participants also completed Adverse Events Profile (AEP) which generates a numerical representation of AEs. Response to CBD was defined as ≥50% reduction in seizure frequency. Given non-normal distribution of seizure frequency, a log transformation was applied after which the generalized least squares regression model for longitudinal data was used. ResultsEvidence from the adjusted model revealed a significant mean reduction in seizure frequency compared to baseline in children and adults at all time points (1 month and 1 and 2 years). Percentage of children achieving ≥50% seizure frequency reduction was 44% at month 1, and 41% at year 1, and 61% reduction at year 2, while adult responder rates were 34% at month 1, 53% at year 1, and 71% at year 2 (all P < 0.0001). CSSS showed a sustained reduction from baseline to all 3 time points. Children displayed 52% seizure reduction at month 1, a 51% reduction at year 1, and 75% reduction at year 2. Seizure reductions in adults were 60%, 81%, and 85%, respectively (all P < 0.0001). While there were no significant differences between seizure frequency reduction between children and adults at all time points, there was a significant difference in seizure severity reduction at year 1, with adults reporting greater improvement in seizure severity (P < 0.001). The most commonly reported adverse events in the study period were diarrhea, sedation, and decreased appetite. AEP revealed significant improvement from baseline at multiple time points in adults and children, and the mean AEP scores were always lower compared to baseline over the duration of the study. SignificanceOur study provides further evidence of sustained seizure frequency and severity reduction over two years of treatment with highly purified CBD in TRE. In addition, CBD was generally well tolerated with minority of participants experiencing adverse events resulting in stopping CBD.

Correlation between severity of seizures and anxiety among epileptics: Evidence from a case-control study

Introduction: Very often patients who have epilepsy also develop psychiatric illnesses, most commonly either depression or anxiety or both. The current study was conducted with the objective to determine the correlation between severity of seizures and anxiety symptoms in patients having epilepsy. Materials and Methods: This was a case-control study. The cases were subjects diagnosed with epilepsy and controls were attendants of other patients who came to the out-patient departments of Hamidia Hospital, Bhopal. A total of 45 cases and 45 sex and age-matched controls were included in the study. The severity of seizures was assessed by the National Hospital Seizure Severity Scale questionnaire. The level of anxiety was assessed both among cases and controls using the Indian version of Taylor's Manifest Anxiety Scale, Developed by D. Sinha in 1961. Results: 91% of the control group showed normal anxiety score and 44.4 % of epileptics were categorised as having normal anxiety score. Only 13.3% of cases reported having very high anxiety score. We observed that the mean anxiety scores of epileptic patients and controls differed very significantly (p < 0.001). The anxiety scores among epileptics showed a positive correlation (R2 = 0.49) with seizure severity scores. Conclusions: There was a correlation between seizure severity level with the arising anxiety symptoms. Keywords: Anxiety, Epilepsy, Seizure, Severity.

Development and validation of chemical kindling in adult zebrafish: A simple and improved chronic model for screening of antiepileptic agents

BackgroundZebrafish has emerged as a potential animal model of acute convulsion for early screening of antiepileptic agents. There is a need for alternative chronic zebrafish models of epilepsy with more correlation to the clinical condition. New MethodAdult zebrafish were repeatedly exposed to subeffective concentrations of pentylenetetrazole (PTZ), until appearance to tonic-clonic seizures, considered as kindled. Valproic acid (VPA) exposure was given during kindling and in kindled fish in 2 different groups. The neurotransmitters level and expression of the genes associated with kindling were studied in the fish brain. ResultsThere was an increase in seizure severity score at 1.25 mM concentration of PTZ, and 66.66 % of fish achieved kindling after 22 days’ exposure. A marked increase in c-fos, crebbpa and crebbpbexpression, and glutamate/GABA level was observed in the brain of kindled fish. VPA inhibited the induction of PTZ-mediated kindling and reduced seizure severity in kindled fish. Comparison with existing methodIn contrast to an existing adult zebrafish kindling method, the present protocol is of longer duration, with more similarity to clinical epilepsy. Moreover, the induction of kindling involves a simple non-invasive technique without the use of anesthesia. The protocol can be used for evaluation of both antiepileptic and antiepileptogenic agents. ConclusionRepeated exposure of 1.25 mM PTZ induced kindling in zebrafish, altering the brain neurotransmitter levels and gene expression. Inhibition of kindling induction and decrease in seizures in normal and kindled fish, respectively by VPA validated application of the model for preclinical testing of agents against epilepsy.

Disrupted white matter connectivity and organization of brain structural connectomes in tuberous sclerosis complex patients with neuropsychiatric disorders using diffusion tensor imaging.

Tuberous sclerosis complex (TSC) is a genetic neurocutaneous syndrome with variable and unpredictable neurological comorbidity that includes epilepsy, intellectual disability (ID), autism spectrum disorder, and neurobehavioral abnormalities. The degree of white matter involvement is believed to be associated with the severity of neurological impairment. The goal of the present study was to evaluate diffusion characteristics of tubers, white matter lesions, and brain structural network alterations in TSC patients using diffusion tensor imaging (DTI), graph theoretical analysis (GTA), and network-based statistical (NBS) analysis. Forty-two patients with a definitive diagnosis of TSC were recruited for this study. All patients underwent brain DTI examination using a 3T magnetic resonance imaging system. Mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) values, and fractional anisotropy (FA) mapping in 52 tubers and white matter lesions were measured and compared with those of contralateral normal regions. GTA was performed on the inter-regional connectivity matrix, and NBS analysis was used to identify the significance of any connected subnetworks evident in the set of altered connections. For neurological severity subgrouping, a neurological severity score was assigned to TSC patients including those with ID, seizure, autism, and other neuropsychiatric disorders (NPDs). Significantly higher MD, AD, and RD, and lower FA values, were found in TSC lesions compared with those measured in contralateral normal regions for tubers (P < 0.05). GTA and NBS analysis provided better local segregation but worse global integration of the structural network (regular-like network) in TSC patients with ID, seizure, and higher Neurological Severity Score. Disrupted subnetworks in TSC patients with severe status included connections from the frontal lobe to the parietal lobe, temporal lobe to the caudate, and temporal lobe to the insula. DTI has the potential to provide valuable information about cytoarchitectural changes in TSC lesions beyond morphological MRI findings alone. Using GTA and NBS, current results provide the information of disrupted white matter connectivity and organization in TSC patients with different neuropsychological impairments.

Ceftriaxone pretreatment confers neuroprotection in rats with acute glaucoma and reduces the score of seizures induced by pentylenotetrazole in mice.

β-Lactam antibiotics such as ceftriaxone, are potent stimulators of the expression of l-glutamate transporter GLT-1 and may exert neuroprotective effects when chronically used in rats and mice. In this study, we used two animal models to test the neurological effect of subchronic treatment with ceftriaxone: experimental acute glaucoma in Wistar rats and induction of acute seizures with pentylenetetrazole in mice. We also assessed the performance of mice in the rotarod to calculate therapeutic indexes and exploratory activity in the open field. Our results showed that subchronic use of ceftriaxone was neuroprotective in both models, reducing injury in acute ischemia and ischemia/reperfusion in specific layers of retina and leading to a decrease in the seizure severity score. In behavioral experiments, we observed that ceftriaxone increased hyperactivity followed by a decrease in exploratory behavior in the open field, and there was no motor impairment in the rotarod test. We conclude that ceftriaxone may be useful as a tool in the development of new neuroprotective drugs targeting diseases which present a possible dysfunction in the balance of glutamatergic neurotransmission.

Impact of Reduced ASIC2 and Pregnancy on Seizure Susceptibility in Mice

RationalePreeclampsia, a hypertensive disorder of pregnancy, can advance to eclampsia with the occurrence of new‐onset seizures in the mother. What induces this progression is unknown. Previous research found that utero‐placental ischemia, modeled by reducing uterine perfusion pressure (RUPP) in the rat, reduced latency to drug‐induced seizures. While acid sensing ion channels (ASICs) have been implicated in reducing seizure longevity and severity, the role ASICs have in seizure susceptibility in the context of pregnancy or placental ischemia has not been investigated.HypothesisIn this study, we tested the hypothesis that placental ischemia reduces hippocampal ASIC2 expression and that reduced ASIC2 increases seizure severity and longevity in pregnancy.MethodsUtero‐placental ischemia was induced in female C57BL/6 mice by ligating the uterine arteries between the ovaries and the first pup at day 13.5 post coitus. Hippocampi (SHAM=6, RUPP=5) were harvested on day 18.5 and processed for Western blot analysis to assess ASIC2a expression. Using Image Lab software, ASIC2a expression was normalized to total protein on the Western blot. The role of ASIC2 in seizure activity was assessed by inducing seizures using pentylenetetrazol (PTZ, 40mg/kg, i.p.) in pregnant and non‐pregnant ASIC2 wild type (WT) and heterozygous (HET) transgenic mice (n=4–11). After injection, mice were video monitored for 30 minutes. Using Observer XT software, seizure behavior was scored using a modified Racine Scale with scores ranging from 0 to 7, where 0 indicates normal behavior and 7 indicates respiratory arrest. Seizure activity was determined based on the following: latency to first seizure behavior, duration of all seizures, highest seizure severity score, and duration of seizure behavior associated with grand mal seizures (scores 4–7). Unpaired t‐test was used to analyze ASIC2a expression, and 2‐way ANOVA using a Sidak’s multiple comparison test was used to assess seizure behavior (factors: genotype and pregnancy status).ResultsHippocampal ASIC2a expression was reduced in RUPP (0.47±0.088) compared to SHAM (1±0.19; p= 0.021) mice. In WT mice, pregnancy increased latency to first seizure (116±43.3 vs 50±10.5s; p=0.057), decreased seizure duration (1026±142 vs.1643±44s; p=0.053), and decreased duration of grand‐mal associated seizure scores (23.5±23.5 vs1092±205s; p=0.018) compared to non‐pregnant mice. There was no effect of pregnancy on any of the seizure activity measures within the HET mice (p&gt;0.05). However, there was a significant increase in duration of grand‐mal associated seizures in HET (1065±238s) vs WT pregnant mice (23.5±23.5; p=0.038). No significant difference in highest seizure severity score or survival was observed with pregnancy or reduced ASIC2.ConclusionOur finding of reduced hippocampal ASIC2 in placental ischemic mice and the absence of improved seizure latency and severity with pregnancy in HET mice, support the hypothesis that reduced ASIC2 contributes to increased seizure severity and longevity in placental ischemia.SignificanceASIC2a is a potential novel therapeutic target for the treatment of seizures in pregnancy as occurs in eclampsia.Support or Funding InformationNIH R00HL129192 and R00HL129192‐S1

Modulatory Effect of Serotonergic System in Pentylenetetrazole-Induced Seizures and Associated Memory Deficit: Role of 5-HT&lt;sub&gt;1A&lt;/sub&gt; and 5-HT&lt;sub&gt;2A/2C&lt;/sub&gt;

Background and PurposeRecent studies have recognised the memory deficit as one of the most common psychiatric issues in the patients with epilepsy, which severely affects the quality of life. Our previous studies have demonstrated the possible involvement of serotonergic system in the pathogenesis of epilepsy and associated memory deficit. The possible involvement of 5-HT1A and 5-HT2A/2C receptor has not been explored yet. Therefore, this study has been envisaged to explore the effect of 5-HT1A and 5-HT2A/2C receptor modulation on epilepsy and memory deficit in pentylenetetrazole-kindled mice.MethodsIn the present experimental approach, we examined the efficacy of modulation of 5-HT1A and 5-HT2A/2C receptor in pentylenetetrazole-induced kindling in male Swiss mice (n=75). Mice were kindled by sub-convulsive dose of pentylenetetrazole (35 mg/kg, intraperitoneal injection), at the interval of 48±2 hours). Successfully kindled animals were treated with 5-HT1A and 5-HT2A/2C receptor modulators. The effect of different treatments on seizure severity score and memory impairment was analysed.Results5-HT1A receptor agonist improved the memory functions while seizure severity was not improved, and the opposite effect was observed with 5-HT1A receptor antagonist. On the other hand, 5-HT2A/2C receptor agonist significantly improved memory deficit as well as seizure severity in the kindled animals.ConclusionsThe outcome of the study indicates the possible involvement of 5-HT2A/2C receptor in the pathogenesis of epilepsy and associated memory deficit, which can be further explored for its management.