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.

Clinical Trail: Study to Investigate Safety and Tolerability of Intravenous Lacosamide in Children

The ASPIRE study is investigating whether Lacosamide (Vimpat®) given intravenously (into the vein) is safe for children and what it does in the body. This study enrolls children who are between 1 month and 16 years of age who have epilepsy, and for whom intravenous infusion is an option. All children will receive Lacosamide for a period that can last up to 45 days, but may be as short as one day, depending on the child’s condition. The study is running in a total of seven countries, including the US.

Eligibility Criteria:

Ages Eligible for Study: 4 Years to 16 years (child)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria:

  • Male or female from >=4 to <17 years of age
  • Subject has a diagnosis of epilepsy with partial-onset seizures or primary generalized tonic-clonic seizures
  • Subject meets 1 of the following criteria:
    • Open-label lacosmide (OLL) subject: Subject is currently receiving oral lacosmide (LCM) as adjunctive or monotherapy as participants in an open label long-term study (SP848, EP0034, or other pediatric study); OR,
    • Prescription lacosamide (RxL) subject: Subject is currently receiving prescribed oral LCM from commercial supply (eg, VIMPAT) as adjunctive or monotherapy; OR,
    • Initiating intravenous lacosamide (IIL) subject: Subject is not currently receiving LCM and will receive intravenous (iv) LCM as adjunctive treatment in EP0060. Initiation of LCM monotherapy is not permitted in IIL subjects.
  • Subject is an OLL or RxL subject and meets both of the following criteria:
    • Subject has been administered LCM for the treatment of epilepsy for at least 2 weeks prior to Screening; AND,
    • Subject has been administered (OLL) or prescribed (RxL) oral LCM at a dose of 2mg/kg/day to 12mg/kg/day (for subjects <50kg) or 100mg/day to 600mg/day (for subjects >=50kg). Open-label study drug LCM (OLL) or prescribed oral LCM dose (RxL) must be stable for at least 3 days prior to first LCM infusion; OR,
  • Subject is an ILL subject and is on a stable dosage regimen of at least 1 antiepileptic drug (AED). The daily dosage regimen of concomitant AED therapy must be kept constant for a period of at least 2 weeks prior to Screening.
  • Subject is an acceptable candidate for venipuncture and iv infusion
  • Subject is, in the opinion of the investigator, able to comply with all study requirements. Subject (or parent[s] or legal representative) is willing to comply with all study requirements

 

Exclusion Criteria:

  • Subject has previously received intravenous (iv) lacosamide (LCM) in this study
  • Subject has any medical, neurological, or psychiatric condition that, in the opinion of the investigator, could jeopardize the subject’s health or compromise the subject’s ability to participate in EP0060
  • Subject has clinically significant hypotension or bradycardia in the opinion of the investigator
  • Subject >=6 years of age has a lifetime history of suicide attempt (including an actual attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by positive responses (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening

Vagus Nerve Stimulation (VNS) Therapy Update

Vagus nerve stimulation (VNS) therapy has been an option to treat pharmacoresistant seizures for 30?years. In this update, researchers review the clinical data that support the device’s efficacy in children, adolescents, and adults. They also review its side-effect profile, quality of life and cost benefits, and the impact the device has on sudden unexpected death in epilepsy (SUDEP). Researchers then discuss candidate selection and provide guidance on dosing and future models.

Vagus nerve stimulation therapy is an effective treatment for many seizure types and epilepsy syndromes with a predictable and benign side-effect profile that supports its role as the most commonly prescribed device to treat pharmacoresistant epilepsy.

Zogenix Announces Positive Top-line Results from Second Pivotal Phase 3 Clinical Trial of ZX008 in Dravet Syndrome

Zogenix, Inc. reported positive top-line results from its second confirmatory Phase 3 study (Study 1504) for its investigational drug, ZX008 (low-dose fenfluramine hydrochloride), for the treatment of children and young adults with Dravet syndrome. The study results, which are consistent with those reported in Study 1, Zogenix’s first pivotal Phase 3 study, successfully met the primary endpoint and all key secondary endpoints, demonstrating that ZX008, at a dose of 0.5 mg/kg/day (maximum 20 mg/day), is superior to placebo when added to a stiripentol regimen.

Epilepsy Research Findings: July 2018

This month’s promising epilepsy news includes the FDA approval of the cannabidiol-based drug EPIDIOLEX® for the treatment of seizures associated with Dravet Syndrome and Lennox-Gastaut Syndrome, two forms of epilepsy that are challenging to treat. This decision brings hope to families facing these difficult diagnoses. In addition, a report discusses epilepsy genetics and the utility of next-generation sequencing in the diagnosis of early-life epilepsies.

In more sobering news, a study shows that the incidence of Sudden Unexpected Death in Epilepsy (SUDEP), once thought to be greater in adults than in children, may be the same in both populations. However, we have included a report discussing the recent discovery of a potential biomarker for SUDEP, which could lead to preventative measures for this devastating occurrence.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

Treatment Advances

First Prescription Formulation of Cannabidiol (CBD) Approved for Lennox-Gastaut Syndrome 

The US Food and Drug Administration (FDA) approved EPIDIOLEX® (cannabidiol/CBD) for the treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients two years of age or older. EPIDIOLEX® is the first prescription pharmaceutical formulation of highly purified CBD and the first in its class of antiepileptic drugs.

Learn More

New Technique Fine-Tunes Treatment for Severe Epilepsy Cases 

An advance by researchers will enable surgeons to more precisely target areas of the brain which cause debilitating symptoms in a subset of epilepsy patients. The technology, called magnetoencephalography or MEG, measures small amounts of magnetic-electrical activity on the surface of epileptic brain areas, and researchers have developed a novel way to employ it.

Learn More

Treating Refractory Epilepsy with Transcutaneous Vagal Nerve Stimulation 

This study found that transcutaneous vagal nerve stimulation (t-VNS) had no or minimal side effects and significantly reduced seizures in about one third of the enrolled patients.

Learn More

Sunovion Announces Health Canada Approval of Aptiom (eslicarbazepine acetate) as Monotherapy to Treat Partial-Onset Seizures in Adults with Epilepsy

Health Canada approved the use of Aptiom (eslicarbazepine acetate) as monotherapy for partial-onset seizures in adults with epilepsy.

Learn More

Diagnostic Advances

Next-Generation Sequencing May Improve Pediatric Epilepsy Treatment

Next-generation sequencing can improve treatment efficacy and reduce hospitalization in children with drug-resistant epilepsy, according to a study published in CNS Neuroscience & Therapeutics.

Learn More

Prediction Method for Epileptic Seizures Developed 

Scientists have proposed a generalized, patient-specific seizure-prediction method that can alert epilepsy sufferers of the likelihood of a seizure within 30 minutes, according to a paper published in Neural Networks.

Learn More

Research Discoveries

Incidence of Sudden Unexpected Death in Epilepsy in Children is Similar to Adults

SUDEP may be more common in children than widely reported, with the incidence rate of definite/probable SUDEP in children being similar to rates reported in adults.

Learn More

Heart Rate Variability in Epilepsy: A Potential Biomarker of Sudden Unexpected Death in Epilepsy Risk

These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of heart rate variability to SUDEP merits further study; heart rate variability may eventually have potential as a biomarker of SUDEP risk. This would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

Learn More

Also Notable

Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy

This study reports that levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

Learn More

Variability in Gene-Sequencing Panels Could Mean Missed Early-Life Epilepsy Diagnoses

Variability among next-generation sequencing (NGS) panels for early-life epilepsies could cause some confirmed epilepsy genes to be missed, researchers report. NGS panels have demonstrated utility for diagnosing genetic variants linked to early-life epilepsies, but little is known about the variability in genes tested among clinically available NGS panels.

Learn More

Generic Antiepileptic Drugs — Safe or Harmful in Patients with Epilepsy?

Sufficient evidence indicates that most generic antiepileptic drugs (AEDs) are bioequivalent to innovator AEDs; they do not pose a relevant risk for patients with epilepsy. However, some patients are reluctant towards variations in color and shape of their AEDs which may result in nonadherence. This report recommends administering generics when a new AED is initiated. Switches from brand to generic AEDs for cost reduction and between generics, which is rarely required, generally seem to be safe, but should be accompanied by thorough counseling of patients on low risks.

Learn More

Health Care Expenditures Among Elderly Patients with Epilepsy in the United States

Epilepsy is common among elderly individuals, and health care expenditures among this growing group are two times higher than in those without epilepsy.

Learn More