The Evolving Landscape of Therapeutics for Epilepsy in Tuberous Sclerosis Complex

This review provides a comprehensive overview of the current state of knowledge regarding the pathogenesis, clinical manifestations, and treatment approaches for epilepsy and other neurological features of TSC. While narrative reviews on TSC exist, this review uniquely synthesizes key advancements across the areas of TSC neuropathology, conventional and emerging pharmacological therapies, and targeted treatments. The review is narrative in nature, without any date restrictions, and summarizes the most relevant literature on the neurological aspects and management of TSC. By consolidating the current understanding of TSC neurobiology and evidence-based treatment strategies, this review provides an invaluable reference that highlights progress made while also emphasizing areas requiring further research to optimize care and outcomes for TSC patients.

Neuroinflammation and status epilepticus: a narrative review unraveling a complex interplay

Status epilepticus (SE) is a medical emergency resulting from the failure of the mechanisms involved in seizure termination or from the initiation of pathways involved in abnormally prolonged seizures, potentially leading to long-term consequences, including neuronal death and impaired neuronal networks. It can eventually evolve to refractory status epilepticus (RSE), in which the administration of a benzodiazepine and another anti-seizure medications (ASMs) had been ineffective, and super-refractory status epilepticus (SRSE), which persists for more than 24 h after the administration of general anesthesia. Objective of the present review is to highlight the link between inflammation and SE. Several preclinical and clinical studies have shown that neuroinflammation can contribute to seizure onset and recurrence by increasing neuronal excitability. Notably, microglia and astrocytes can promote neuroinflammation and seizure susceptibility. In fact, inflammatory mediators released by glial cells might enhance neuronal excitation and cause drug resistance and seizure recurrence. Understanding the molecular mechanisms of neuroinflammation could be crucial for improving SE treatment, wich is currently mainly addressed with benzodiazepines and eventually phenytoin, valproic acid, or levetiracetam.

Long-term efficacy and adverse effects of cannabidiol in adjuvant treatment of drug-resistant epilepsy: a systematic review and meta-analysis

Epilepsy is one of the most common chronic brain diseases. Almost one-thirdof patients have drug-resistant epilepsy (DRE). Cannabidiol is being considered as a potential novel drug for treating DRE. To investigate long-term efficacy and safety of cannabidiol in treatment of DRE and the differences in cannabidiol treatment among patients with different characteristics.

Highly purified cannabidiol in the treatment of drug-resistant epilepsies: A real-life impact on seizure frequency, quality of life, behavior, and sleep patterns from a single Italian center

Seizure frequency in treatment-resistant epilepsies seems to be decreased by cannabidiol (CBD), but contrasting data are available on its effect on sleep, behavior, and quality of life (QoL), and no data is reported on its effect on parental stress in patients with epilepsy (PWE). Thus, we conducted a retrospective study on a cohort of children and adults with drug-resistant epilepsy (DRE) who had been treated with highly purified, pharmaceutical-grade CBD to evaluate its effects on seizure frequency, QoL, behavior, parental stress, and sleep. Eighteen patients (12 adults and 6 children) were included in the cohort and followed for a median of 9 months.

Real-Life experience with purified cannabidiol treatment for refractory epilepsy: A multicenter retrospective study

Drug-resistant epilepsy (DRE) significantly affects the development and quality of life of children and young adults. To describe the effectiveness and safety of purified cannabidiol (CBD) in children and young adults with DRE. A retrospective analysis of medical records of 139 children and young adults (54.7% female, median age 12.0 years) with DRE treated with purified CBD from 2018-2022 at 5 medical centers in Israel.

Updated clinical recommendations for the management of tuberous sclerosis complex associated epilepsy

Children with tuberous sclerosis complex (TSC), may experience a variety of seizure types in the first year of life, most often focal seizure sand epileptic spasms. Drug resistance is seen early in many patients, and the management of TSC associated epilepsy remain a major challenge for clinicians. In 2018 clinical recommendations for the management of TSC associated epilepsy were published by a panel of European experts. In the last five years considerable progress has been made in understanding the neurobiology of epileptogenesis and three interventional randomized controlled trials have changed the therapeutic approach for the management of TSC associated epilepsy. Pre-symptomatic treatment with vigabatrin may delay seizure onset, may reduce seizure severity and reduce the risk of epileptic encephalopathy.

Emerging Therapeutic Potential of Cannabidiol (CBD) in Neurological Disorders: A Comprehensive Review

Δ9-Tetrahydrocannabinol (Δ9-THC) is a principal psychoactive extract of Cannabis sativa and has been traditionally used as palliative medicine for neuropathic pain. Cannabidiol (CBD), an extract of hemp species, has recently attracted increased attention as a cancer treatment, but Δ9-THC is also requiring explored pharmacological application. This study evaluated the pharmacological effects of Δ9-THC in two human colorectal cancer cell lines. We inves-tigated whether Δ9-THC treatment induces cell death in human colorectal cancer cells.

Real-World evidence on the use of cannabidiol for the treatment of drug resistant epilepsy not related to Lennox-Gastaut syndrome, Dravet syndrome or Tuberous Sclerosis Complex

Highly purified cannabidiol (CBD) has a broad spectrum of action and could be useful for the treatment of drug resistant epilepsy regardless of etiology or syndrome. Multicenter retrospective study that evaluated the efficacy and safety of CBD for the treatment of drug resistant epilepsy of different etiologies in patients >2 years of age.

A comparison of advertised versus actual cannabidiol (CBD) content of oils, aqueous tinctures, e-liquids and drinks purchased in the UK

To evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting.
In this retrospective observational study, we included PwE with epilepsy who received a prescription for CBD between 01.03.2019 and 30.11.2022 and had a follow-up period ≥ 3 months. Participants were evaluated at baseline and after 3, 6, and 12 months. “Responders” were defined as individuals experiencing a reduction in seizure frequency > 30% but < 80% compared to baseline, while "super responders" were those with a reduction ≥ 80%. Adverse events were recorded to assess safety.

Real-world experience with cannabidiol as add-on treatment in drug-resistant epilepsy

To evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting.
In this retrospective observational study, we included PwE with epilepsy who received a prescription for CBD between 01.03.2019 and 30.11.2022 and had a follow-up period ≥ 3 months. Participants were evaluated at baseline and after 3, 6, and 12 months. “Responders” were defined as individuals experiencing a reduction in seizure frequency > 30% but < 80% compared to baseline, while "super responders" were those with a reduction ≥ 80%. Adverse events were recorded to assess safety.

Cannabidiol in the acute phase of Febrile Infection-Related Epilepsy Syndrome (FIRES)

Febrile infection-related epilepsy syndrome (FIRES) is a prolonged refractory status epilepticus (SE) that develops among healthy individuals after a febrile infection.

FIRES treatment is challenging due to its poor response to anti-seizure medications (ASMs) and anesthetic drugs. The use of cannabidiol (CBD) as an adjunctive treatment has been suggested, albeit data about its role in the acute phase is lacking. This report describes the use of purified CBD in the acute phase of two pediatric cases of FIRES and their long-term outcome.

Both children were treated with several ASMs, immunomodulators, anesthetics, and non-pharmacological treatment (ketogenic diet). CBD was administered, as an adjunctive treatment, through nasogastric tube about 30 days after onset. SE resolved within three days of reaching the target dose and both were seizure-free for one year after.

Although it is difficult to define the extent to which each previous therapy contributed to recovery, in both cases CBD therapy was a turning point, reinforcing its potential role as add-on treatment in the acute phase of FIRES.

Cannabidiol Negatively Regulates Androgenic Signal in Prostate Cancer Cells and Fine-Tunes the Tumorigenesis by Modulating Endoplasmic Reticulum-Associated Degradation, Unfolded Protein Response, and Autophagy

Cannabis sativa L., Cannabaceae, has been used as a herbal medicine for several thousand years in many cultures and it has more than 540 metabolites that provide therapeutic effects. Cannabinoids are the major compounds derived from the Cannabis species. There are over 120 isolated and identified cannabinoids from C. sativa and (−)-cannabidiol is one of the most well-researched among them. Recent studies have focused on the expanding usage of cannabidiol in many therapeutic areas as well as cancer. Studies demonstrated a negative correlation between cannabidiol administration and the growth of various cancer types, including prostate cancer. However, the detailed mode of action of cannabidiol on prostate cancer remains unclear. In the present study, we investigated the molecular mechanism of cannabidiol prostate cancer cells. For this aim, we examined the effect of cannabidiol on autophagy, endoplasmic reticulum-associated degradation, endoplasmic reticulum stress, unfolded protein response, epithelial-mesenchymal transition, angiogenesis, and androgenic signaling in vitro. We found that cannabidiol remarkably inhibited autophagy. Also, it strongly induced unfolded protein response and endoplasmic reticulum-associated degradation mechanisms. Moreover, it exerted anti-cancer activity by reducing epithelial-mesenchymal transition and causing cell cycle arrest. Additionally, cannabidiol importantly disrupted androgenic signaling by affecting basal androgen receptor levels and inhibiting nuclear translocation of this receptor.