Is It Time to Test the Antiseizure Potential of Palmitoylethanolamide in Human Studies? A Systematic Review of Preclinical Evidence

Antiseizure medications are the cornerstone pharmacotherapy for epilepsy. They are not devoid of side effects. In search for better-tolerated antiseizure agents, cannabinoid compounds and other N-acylethanolamines not directly binding cannabinoid receptors have drawn significant attention. Among these, palmitoylethanolamide (PEA) has shown neuroprotective, anti-inflammatory, and analgesic properties. All studies examining PEA’s role in epilepsy and acute seizures were systematically reviewed. Preclinical studies indicated a systematically reduced PEA tone accompanied by alterations of endocannabinoid levels. PEA supplementation reduced seizure frequency and severity in animal models of epilepsy and acute seizures, in some cases, similarly to available antiseizure medications but with a better safety profile. The peripheral-brain immune system seemed to be more effectively modulated by subchronic pretreatment with PEA, with positive consequences in terms of better responding to subsequent epileptogenic insults. PEA treatment restored the endocannabinoid level changes that occur in a seizure episode, with potential preventive implications in terms of neural damage. Neurobiological mechanisms for PEA antiseizure effect seemed to include the activation of the endocannabinoid system and the modulation of neuroinflammation and excitotoxicity. Although no human study was identified, there is ground for testing the antiseizure potential of PEA and its safety profile in human studies of epilepsy.

BICS01 Mediates Reversible Anti-seizure Effects in Brain Slice Models of Epilepsy

Drug-resistant epilepsy remains a significant clinical and societal burden, with one third of people with epilepsy continuing to experience seizures despite the availability of around 30 anti-seizure drugs (ASDs). Further, ASDs often have substantial adverse effects, including impacts on learning and memory. Therefore, it is important to develop new ASDs, which may be more potent or better tolerated. Here, we report the preliminary preclinical evaluation of BICS01, a synthetic product based on a natural compound, as a potential ASD. To model seizure-like activity in vitro, we prepared hippocampal slices from adult male Sprague Dawley rats, and elicited epileptiform bursting using high extracellular potassium. BICS01 (200 μM) rapidly and reversibly reduced the frequency of epileptiform bursting but did not change broad measures of network excitability or affect short-term synaptic facilitation. BICS01 was well tolerated following systemic injection at up to 1,000 mg/kg. However, we did not observe any protective effect of systemic BICS01 injection against acute seizures evoked by pentylenetetrazol. These results indicate that BICS01 is able to acutely reduce epileptiform activity in hippocampal networks. Further preclinical development studies to enhance pharmacokinetics and accumulation in the brain, as well as studies to understand the mechanism of action, are now required.

Evaluation of the Anticonvulsant Activities of Gastrodia Elata Bl.- Acorus Tatarinowii Decoction on Experimentally Induced Seizures in Mice

Epilepsy is a serious public health problem in the world. At present, the effect of drug treatment of epilepsy is are not satisfactory. Medicinal plants as pharmaceuticals and for healthcare treatments in the management of epilepsy in China for many centuries. Especially, Gastrodia elata Bl.-Acorus tatarinowii, as a classic and important herb pairs in folk medicine, has been used in folk medicine to control seizures. However, the animal experiment data of its anticonvulsant effect is limited in the literature. The objective of this study was to mainly analyze the anticonvulsant activity of Gastrodia elata-Acorus tatarinowii (GEAT) decoction in maximal electroshock (MES), pentylenetetrazole (PTZ) and trimercaptopropionic acid (3-MP) induced seizures in mice, providing scientific basis for the treatment of convulsive disorders in traditional medicine. In addition, the improvement effect were examined on seizure severity, anxiety, cognitive dysfunction, inflammation and oxidative stress in PTZ kindled mice. The results showed that GEAT decoction dose-dependently protected mice against MES, 3-MP and PTZ induced acute seizures. Meanwhile, GEAT decoction ameliorated seizure severity, decreased the accumulation of inflammatory mediators TNF-α, IL-1β, and IL-6, mitigated oxidative stress, as well as alleviated anxious-like behavior and cognitive deficits in PTZ-kindled mice. Our data evidenced that the anticonvulsant properties attributed to GEAT decoction as adjunctive therapy for epileptic patients in folk medicine.

Reductions in Hydrogen Sulfide Precede Onset of Mitochondrial Quality Control in the Corneal Kindled Mouse Model of Epilepsy

Epilepsy is a heterogenous neurological disorder characterized by recurrent unprovoked seizures, mitochondrial stress, and neurodegeneration. Hydrogen sulfide (H2S), a gasotransmitter, promotes mitochondrial function and biogenesis, elicits neuromodulation and neuroprotection, and may acutely suppress seizures. A major gap in knowledge remains in understanding the role of mitochondrial dysfunction and progressive changes in H2S levels following acute seizures and during epileptogenesis. We thus sought to quantify changes in H2S and its methylated metabolite (MeSH) via LC-MS/MS subsequent to acute maximal electroshock and 6 Hz 44 mA seizures in mice, as well as in the corneal kindled mouse model of chronic seizures. Plasma H2S was acutely reduced after a maximal electroshock seizure. H2S or MeSH levels in whole brain homogenate and expression of related genes in corneal kindled mice were not altered. However, plasma H2S and MeSH levels were significantly lower during kindling, but not after established kindling. Morever, we demonstrated a time-dependent increase in expression of mitochondrial membrane integrity-related proteins, Opa1, Mfn2, Drp1, and Mff during kindling, which did not correlate with gene expression. Taken together, short-term reductions in plasma H2S could be a novel biomarker for seizures. Future studies should further define the role of H2S and mitochondrial stress in epilepsy.

Leitner (Monatsschrift f. Kinderheilkunde Bd. 48, H. 3/4, 1930)

(Monatsschrift f. Kinderheilkunde Bd. 48, H. 3/4, 1930) used luminar sodium with great success in the treatment of acute seizures in infants and infants, which proved to be the chosen remedy in the treatment of persistent convulsions in infants.

Incidence and predictors of epilepsy in children with congenital heart disease

Objective: Children with CHD may be at increased risk for epilepsy. While the incidence of perioperative seizures after surgical repair of CHD has been well-described, the incidence of epilepsy is less well-defined. We aim to determine the incidence and predictors of epilepsy in patients with CHD. Methods: Retrospective cohort study of patients with CHD who underwent cardiopulmonary bypass at <2 years of age between January, 2012 and December, 2013 and had at least 2 years of follow-up. Clinical variables were extracted from a cardiac surgery database and hospital records. Seizures were defined as acute if they occurred within 7 days after an inciting event. Epilepsy was defined based on the International League Against Epilepsy criteria. Results: Two-hundred and twenty-one patients were identified, 157 of whom were included in our analysis. Five patients (3.2%) developed epilepsy. Acute seizures occurred in 12 (7.7%) patients, only one of whom developed epilepsy. Predictors of epilepsy included an earlier gestational age, a lower birth weight, a greater number of cardiac surgeries, a need for extracorporeal membrane oxygenation or a left ventricular assist device, arterial ischaemic stroke, and a longer hospital length of stay. Conclusions: Epilepsy in children with CHD is rare. The mechanism of epileptogenesis in these patients may be the result of a complex interaction of patient-specific factors, some of which may be present even before surgery. Larger long-term follow-up studies are needed to identify risk factors associated with epilepsy in these patients.

Clinical characteristics of post-traumatic epilepsy and the factors affecting the latency of PTE

Objectives To summarize the clinical characteristics of post-traumatic epilepsy (PTE), and to identify the factors affecting the latency of PTE after traumatic brain injury (TBI). Methods We conducted a retrospective clinical analysis in patients with PTE who visited the outpatient Department of Epilepsy, Beijing Tiantan Hospital from January 2013 to December 2018. The clinical characteristics, including gender, age distribution, seizure type, and latency were summarized. Factors affecting the latency of PTE were evaluated using Kaplan-Meier curves and Cox proportional hazard regression analysis. Results Complete clinical information was available for 2862 subjects, of which 78.48% were males. The mean age at TBI was 21.4 ± 15.1 years and peaked in the 0 to 12-year-old and 15 to 27-year-old groups. Generalized onset seizure was the most frequent seizure type (72.82% of patients). Approximately 19.95% PTE patients developed drug-resistant epilepsy. The latency of PTE ranged from 8 days to 20 years, with a median of 24.0 (IQR, 5.0–84.0) months. The Kaplan-Meier curves demonstrated that gender, age at TBI, severity of TBI, multiple craniocerebral injuries, post-TBI treatments, acute seizures, and residual disability were associated with PTE latency. The Cox regression model indicated that age ≥ 18 years old, severe TBI with multiple surgical operations, acute seizures, and residual disability were risk factors for shorter PTE latency. Conclusions PTE is more common in males than females, and peaked in the 0 to 12-year-old and 15 to 27-year-old groups. Generalized onset seizure was the most common seizure type and 19.95% of participants developed drug-resistant epilepsy. Patients aged ≥18 years old, who suffered severe TBI followed by multiple surgical operations, experienced acute seizures, or with residual disabilities had shorter PTE latency.

Managing Acute Seizures: New Rescue Delivery Option and Resources to Assist School Nurses

Approximately 470,000 children and adolescents in the United States have epilepsy, 30% of whom experience seizures despite antiseizure drug regimens. School nurses, teachers, caregivers, and parents play integral roles in implementing a care plan that avoids triggers, recognizes signs, and provides supportive care—ideally, guided by a patient-specific seizure action plan, which may include the use of rescue medication. Benzodiazepines are the mainstay of seizure rescue medication; for decades, rectally administered diazepam was the only approved rescue medication for seizure clusters outside the hospital setting. However, rectal administration has limitations that could delay treatment (e.g., social acceptability, removal of clothing, positioning). More recently, intranasal midazolam (for patients ≥12 years) and intranasal diazepam (for patients ≥6 years) were approved for this indication. Training and education regarding newer forms of rescue medication should improve confidence in the ability to treat seizures in school with the goal of increasing the safety of students with epilepsy.