Cannabidiol Improves Frequency and Severity of Seizures and Reduces Adverse Events in an Open-Label Add-On Prospective Study

The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study.

Researchers initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5?mg/kg/day and titrated it up to a maximum dosage of 50?mg/kg/day. At each visit, they monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars.

Data for the enrollment and visits at 12, 24, and 48?weeks was analyzed. Researchers recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year.

There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p?<?0.0001) with stable AEP scores thereafter (all p???0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12?weeks (p?<?0.0001) and stable CSSS thereafter (all p???0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12?weeks (p?=?0.01) and remained stable thereafter (all p???0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30?mg/kg/day.

For the first time, this prospective, open-label safety study of CBD in treatment-resistant epilepsy provides evidence for significant improvements in the adverse event profile, Chalfont seizure severity scale, and seizure frequency at 12?weeks that are sustained over the 48-week duration of treatment.

Compound from Spider Venom Reduces Seizure Susceptibility, Mortality in Dravet Syndrome Mice

A compound isolated from spider venom called Hm1a helps reduce seizure susceptibility and mortality in mice with Dravet syndrome, according to researchers.

Their study, “Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death,” was published in PNAS.

Dravet syndrome is resistant to several pharmaceutical therapies that are geared toward treatment of other types of epilepsy. This creates an urgent need to develop new therapeutic strategies to treat this genetic disease.

Most patients with Dravet syndrome have a mutation in the SCN1A gene which results in a deficiency in the sodium channel NaV1.1. In the brain, NaV1.1 is expressed on the surface of nerve cells and plays a critical role in nerve-nerve cell signaling.

Spider venom is a rich source of compounds that target ion channels, much like Nav1.1.

Hm1a is a peptide — short chains of amino acids, which are the building blocks of proteins — present in spider venom that selectively improves the functioning of Nav1.1.

Drug Interactions With Carbamazepine: An Ever Expanding List?

Abstract
In a study that applied a nonlinear mixed effect model to evaluate factors affecting steady-state serum carbamazepine concentrations in elderly nursing home residents, co-administration of iron supplements was reported to reduce serum carbamazepine concentrations by approximately one third. Although these findings suggest that iron ions reduce the oral bioavailability of carbamazepine, the influence of confounders cannot be excluded. Further studies are required to confirm this interaction.

Rewiring the Brain to Fight Epilepsy

Biologist Suzanne Paradis’ lab suppressed seizures in mice by changing the connections between neurons.

Researchers in the lab of Associate Professor of Biology Suzanne Paradis have discovered a novel treatment for reducing seizure activity in the brains of rodents, a discovery they hope might one day help people living with epilepsy. The research was published this spring in the journal Epilepsia.

Paradis’s lab researches synapses, the connections between brain cells. Most synapses are excitatory — they facilitate the passage of signals from one brain cell to another. Others though are inhibitory, thwarting transmission.

In the latest research, the Paradis group worked with mice with symptoms resembling those found in epileptic humans. They applied an infusion of Sema4D into the animals’ brains. The mice experienced a reduction in the severity of their seizures.

 

Pregnant with Epilepsy? Folic Acid May Prevent Language Delays for Baby

Women who take epilepsy drugs while they are pregnant may have a lower risk of having a child with delays in language skills if they take folic acid supplements before and early in pregnancy, according to a study published in the August 1, 2018, online issue of Neurology®, the medical journal of the American Academy of Neurology.

The study found that among children whose mothers took epilepsy drugs while they were pregnant, those whose mothers did not take folic acid supplements were four times more likely to have delays in their language skills when they were 18 months old compared to children of mothers without epilepsy whose mothers did not take folic acid supplements. By three years old, those whose mothers took no supplements were nearly five times as likely to have language delays compared to children of mothers without epilepsy.

The study was conducted in Norway, where the government does not require foods to be fortified with folic acid, which is required in the United States. Even with folic acid added to foods, taking additional supplements is recommended for pregnant women in the United States.

Perampanel Improves Seizure Outcomes in Idiopathic Generalized Epilepsy: The 12-Month GENERAL Study

OBJECTIVE: To analyze the effectiveness and tolerability of perampanel across different seizure types in routine clinical care of patients with idiopathic generalized epilepsy (IGE).

METHODS: This multicenter, retrospective, 1-year observational study collected data from patient records at 21 specialist epilepsy units in Spain. All patients who were aged ?12 years, prescribed perampanel before December 2016, and had a confirmed diagnosis of IGE were included.

RESULTS: The population comprised 149 patients with IGE (60 with juvenile myoclonic epilepsy, 51 generalized tonic-clonic seizures [GTCS] only, 21 juvenile absence epilepsy, 10 childhood absence epilepsy, 6 adulthood absence epilepsy, and one Jeavons syndrome). Mean age was 36 years. The retention rate at 12 months was 83% (124/149), and 4 mg was the most common dose. At 12 months, the seizure-free rate was 59% for all seizures (88/149); 63% for GTCS (72/115), 65% for myoclonic seizures (31/48), and 51% for absence seizures (24/47). Seizure frequency was reduced significantly at 12 months relative to baseline for GTCS (78%), myoclonic (65%), and absence seizures (48%). Increase from baseline seizure frequency was seen in 5.2% of patients with GTCS seizures, 6.3% with myoclonic, and 4.3% with absence seizures. Perampanel was effective regardless of epilepsy syndrome, concomitant antiepileptic drugs (AEDs), and prior AEDs, but retention and seizure freedom were significantly higher when used as early add-on (after ?2 prior AEDs) than late (?3 prior AEDs). Adverse events were reported in 50% of patients over 12 months, mostly mild or moderate, and irritability (23%), somnolence (15%), and dizziness (14%) were most frequent.

SIGNIFICANCE: In routine clinical care of patients with idiopathic generalized epilepsy, perampanel improved seizure outcomes for generalized tonic-clonic seizures, myoclonic seizures, and absence seizures, with few discontinuations due to adverse events. This is the first real-world evidence with perampanel across different seizure types in idiopathic generalized epilepsy.

CURE Discovery: Transplanting Inhibitory Neurons Can Reduce Seizures

CURE Grantee Dr. Janice Naegele of Wesleyan University has been working on harnessing the brain’s own inhibitory power as a treatment to reduce excitability and “quiet” the overly excitable epileptic brain. As a promising first step, she and her team have successfully shown that transplantation of mouse inhibitory neurons into the mouse hippocampus – a brain structure that is often involved in epilepsy – can reduce the number of seizures in mice with temporal lobe epilepsy. (1)

Temporal lobe epilepsy is the most common form of epilepsy, with neuronal loss being one of its hallmark traits. (2,3) The loss of inhibitory neurons can be an important factor in the development or worsening of the disorder, (4) because the balance between excitatory and inhibitory neuronal activity is essential for proper brain function. Fewer inhibitory neurons can decrease inhibitory neurotransmission, in turn leading to excessive neuronal excitation, seizures, and epilepsy. One focus of Dr. Naegele’s epilepsy research has been to find a way to increase inhibition in the hyperexcitable epileptic brain. (5)

Dr. Naegele used her CURE grant to focus on transplanting both mouse and human inhibitory neurons into the hippocampus of mice with temporal lobe epilepsy. She hypothesized that these inhibitory neurons would wire up with existing neurons, increasing inhibitory transmission and decreasing the hyperexcitability that characterizes temporal lobe epilepsy. This type of treatment is called “regenerative medicine” because it uses healthy tissue to restore normal brain functioning. An advantage of regenerative medicine is that the transplanted cells can potentially replace lost or damaged inhibitory neurons and also integrate into the existing brain circuitry. This treatment would provide a cure for seizures by addressing the root cause, unlike standard antiepileptic drugs that simply treat the symptoms of seizures.

Indeed, as shown by advanced imaging techniques, the inhibitory neurons Dr. Naegele’s team transplanted into the brains of mice with temporal lobe epilepsy formed new, functional connections with excitatory neurons already present in the hippocampus, providing the increased inhibition that likely led to fewer seizures in these mice. (1)

Following the success of quieting seizures using the implantation of mouse inhibitory neurons, Dr. Naegele and her team are now focused on a means to quiet seizures by implanting human inhibitory neurons, pushing this research one step closer to being a viable treatment for people with epilepsy. As part of their strategy, they are keeping in mind important potential differences in neuronal generation and transmission between humans and mice. (6)

Dr. Naegele’s research brings an exciting possibility to the future of epilepsy treatment: the transplantation of a type of neuron that already exists in the human brain with the goal of stopping seizures. While work still remains, CURE applauds the progress Dr. Naegele has made thus far. We share Dr. Naegele’s hopes that her approach becomes a non-drug method of treating those affected by not only temporal lobe epilepsy, but other forms of epilepsy as well.

1 Henderson et al. Long-term seizure suppression and optogenetic analysis of synaptic connectivity in epileptic mice with hippocampal grafts of GABAergic interneurons. J Neurosci 2014; 34(40):13492-13504.
2 Pitkänen A, Sutula TP. Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal-lobe epilepsy. Neurol 2002; 1(3):173-181.
3 Engel J Jr, Williamson PD, Weiser HG. Mesial temporal lobe epilepsy. In: Epilepsy: a comprehensive textbook (Engel J Jr, Pedley TA, eds) 1997: 2417-2426.
4 Kumar SS, Buckmaster PS. Hyperexcitability, interneurons, and loss of GABAergic synapses in entorhinal cortex in a model of temporal lobe epilepsy. J Neurosci 2006; 26(17):4613-4623.
5 Van Zandt MA, Naegele JR. GABAergic synapse dysfunction and repair in temporal lobe epilepsy. (2017) Synaptic Plasticity Thomas Heinbockel, IntechOpen; DOI: 10.5772/67218. Available from: https://www.intechopen.com/books/synaptic-plasticity/gabaergic-synapse-d….
6 Naegele JR. Controversial brain study has scientists rethinking neuron research. (2018) Available from: https://theconversation.com/controversial-brain-study-has-scientists-ret…

Vagus Nerve Stimulation Generally Safe for the Treatment of Refractory Epilepsy in the CDKL5 Deficiency Disorder

BACKGROUND: Variants within the CDKL5 gene result in a severe epileptic encephalopathy now known as the CDKL5 Deficiency Disorder. Phenotypic characteristics include global developmental delay and early seizure onset with poor response to anti-epileptic medications. Vagus nerve stimulation (VNS) has been used in other populations as an adjunct treatment for refractory epilepsy with seizure reduction reported in over half of patients. This study aimed to investigate the role of VNS in the CDKL5 Deficiency Disorder.

METHODS: The International CDKL5 Disorder Database collects information on individuals with the CDKL5 Deficiency Disorder. Families provide information regarding seizure characteristics and their pharmaceutical and non-pharmaceutical management including VNS use. Descriptive statistics and time to event analyses were performed. Clinical vignettes were also provided from patients attending the CDKL5 Center of Excellence at Children’s Hospital Colorado.

RESULTS: Individuals who had a pathogenic CDKL5 variant and on whom information regarding VNS treatment was available were identified (n?=?222). Previous or current use of VNS was reported for 38 (17.1%), with a median age at implantation of 4.9 years. Improvements in seizure control were reported in over two-thirds (25/36, 69%); including reduction in frequency (17/25, 68%), duration (18/25, 72%) and intensity (15/25, 60%) of seizures. Median duration of VNS use before any seizure improvement was 73 days. Behavioural changes such as improved mood and alertness were reported in nine individuals. Early termination of VNS secondary to side effects was reported in three cases. There was no reduction in number of AEDs for those with VNS treatment.

CONCLUSION: This study suggests that VNS is a generally safe and effective adjunct treatment for CDKL5-associated epilepsy. Additional benefits such as mood and behavioural improvements provide further support of its use in the CDKL5 Deficiency Disorder. Future studies are required to determine the optimal settings and therapeutic potential for this treatment.

Takeda and Ovid Therapeutics Expand Clinical Program for TAK-935/OV935 with Three New Studies in Rare Developmental and Epileptic Encephalopathies (DEE)

Takeda Pharmaceutical Company Limited and Ovid Therapeutics Inc. provided an overview of their TAK-935/OV935 broad clinical development program. The companies plan to initiate three clinical trials: in pediatric patients with Dravet syndrome and Lennox-Gastaut syndrome, in pediatric patients with CDKL5 deficiency disorder (CDD) and Duplication 15q (Dup15q) syndrome, and an extension trial for patients with developmental and epileptic encephalopathies (DEEs) who participated in a previous TAK-935/OV935 clinical study.

These trials join the clinical development program that includes a fully enrolled Phase 1b/2a trial of adults with DEE. Together, these trials will further investigate the potential of TAK-935/OV935 to modulate the N-Methyl-D-Aspartate (NMDA) signaling receptor, which has been implicated in several neurologic disorders.

Evidence for Clobazam Monotherapy Use in Focal, Generalized Seizures Reviewed

The safety and efficacy of clobazam monotherapy in patients with new-onset focal or generalized seizures was investigated in a new Cochrane systematic review.

Researchers searched various databases to identify trials that compared clobazam monotherapy to placebo or another antiepileptic drug in patients with ?2 unprovoked seizures or a single acute symptomatic seizure requiring short-term continuous treatment. Retention time, defined as time on allocated treatment, was set as the primary outcome, while short- and long-term efficacy, tolerability, quality of life, and tolerance measures were considered secondary outcomes.

The researchers identified 3 studies that met the inclusion criteria (N=206), however none of the trials reported on the selected primary outcome. “Lack of detail regarding allocation concealment and a high risk of performance and detection bias in 2 studies prompted us to downgrade the quality of evidence (by using the GRADE approach) for some of our results due to risk of bias,” the authors noted.