Perampanel Well-Tolerated for Long-Term Epilepsy Treatment

Purpose
To evaluate long-term tolerability, safety and efficacy of adjunctive perampanel in a Phase II, multicenter, open-label, dose-ascending Study 231 (NCT00849212) and its extension (Study 233; NCT00903786) in Japanese patients with refractory partial-onset seizures (POS), with/without secondarily generalized seizures.

Methods
In Study 231, patients received adjunctive perampanel ?12?mg/day during a 10-week treatment period. Patients completing Study 231 could enter Study 233 (?316-week treatment period). Assessments included monitoring of treatment-related treatment-emergent adverse events (TEAEs), median percent change in seizure frequency per 28 days, 50% responder and seizure-freedom rates. During Study 231, a pharmacokinetic analysis assessed the effects of enzyme-inducing antiepileptic drugs.

Results
Overall, 23/30 (76.7%) patients completed Study 231; 21/30 (70.0%) received perampanel ?8?mg/day and 10/30 (33.3%) achieved a maximum tolerated dose of 12?mg/day. Median percent change in seizure frequency per 28 days was –35.0%. 50% responder rate was 37.0%; 4 (13.3%) patients achieved seizure freedom. Twenty-one patients entered Study 233. Mean duration of exposure was 195 weeks; 9 (42.9%) patients received perampanel for ?208 weeks. Seizure control was sustained for 316 weeks in 3/21 (14.3%) patients; 2 achieved seizure freedom. Treatment-related TEAEs were tolerable; the most common was dizziness (Study 231, 53.3%; Study 233, 14.3%). Mean perampanel plasma concentrations were lower with concomitant carbamazepine vs non-inducers (152.7?ng/mL vs 389.4?ng/mL across perampanel groups); small patient numbers for non-inducers (n?=?2) should be considered when interpreting these data.

Conclusion
Adjunctive perampanel demonstrated a favorable safety profile and long-term tolerability in Japanese patients with refractory POS for ?316 weeks.

Parenting Stress and Perceived Stigma in Mothers of Young Children with Epilepsy: A Case–Control Study

The aim of this study was to provide data on parenting stress and perceived stigma in mothers (n?=?47) of young children with epilepsy, and to compare findings with those of mothers (n?=?48) of developmental, age- and gender-matched children with nonepilepsy-related neurodisability (neurological and/or neurodevelopmental concerns).

The study found that thirty-eight percent of mothers of children with epilepsy had significant parenting stress. Efforts at reducing parenting stress and stigma should focus on interventions targeting child development and maternal sleep.

Bhanu Tewari and Harald Sontheimer

Scientists Solve Century-Old Neuroscience Mystery; Answers May Lead to Epilepsy Treatment

Featuring Work by CURE Grantee Dr. Harald Sontheimer

Scientists at the Virginia Tech Carilion Research Institute have solved a 125-year-old mystery of the brain, and, in the process, uncovered a potential treatment for acquired epilepsy.

Since 1893, scientists have known about enigmatic structures called perineuronal nets wrapped around neurons, but the function of the nets remained elusive.

Now, a research team led by Harald Sontheimer has determined the nets modulate electrical impulses in the brain. What’s more, brain seizures can occur if the nets are dissolved.

The discovery, published Friday, November 9 in Nature Communications, has implications in various forms of acquired epilepsy, a type of seizure disorder that results from brain lesions caused by trauma, infection, or tumors in the brain.

UBE3A Gene Reactivation in Inhibitory Neurons May Prevent Seizures, Angelman Mouse Study Shows

Epileptic seizures caused by disturbances in the activity of a specific type of nerve cell called an inhibitory neuron were prevented by the reactivation of the UBE3A gene in young mice with Angelman syndrome features, a study shows.

The study, “Ube3a reinstatement mitigates epileptogenesis in Angelman syndrome model mice,” was published in The Journal of Clinical Investigation.

The disorder is frequently associated with epileptic seizures — estimated to affect between 80% and 95% of patients — that usually fail to respond to anti-epileptic medications. However, the reason why genetic mutations in UBE3A seem to increase patients’ risk of developing epileptic seizures is not yet fully understood.

Although there is no cure for Angelman syndrome, recent studies in mouse models based on UBE3A gene replacement or reactivation in neurons hold great therapeutic potential, including for the treatment of epilepsy.

Development of a Zebrafish Model to Study Childhood Epileptic Encephalopathy Caused by Dynamin 1 (DNM1) Mutations

Next generation sequencing (NGS) technology has led to the identification of causal genes in epileptic encephalopathies. Recently, mutations in the DNM1 gene encoding dynamin 1 (OMIM: 602377) have been recognized to cause early infantile epileptic encephalopathy-31 (OMIM: 616346). While recent studies have provided insights into dynamin-1 structure and function, it is still unclear how the de novo missense mutation in DNM1—a core component of postsynaptic endocytosis machinery—leads to early epileptic encephalopathy (EE).

It is critical to use valid animal models in our effort to understand the pathophysiology of EE caused by DNM1 mutations. The zebrafish is an alternative model system with substantial benefits which is now widely used to study the pathophysiology of human Mendelian disorders, develop cost-efficient breeding, and practice in vivo drug discovery.

Aquestive Therapeutics Announces U.S. Food and Drug Administration (FDA) Approval for SYMPAZAN™ (clobazam) Oral Film

Aquestive Therapeutics announced that the FDA approved SYMPAZAN™ (clobazam) oral film for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. SYMPAZAN is the first and only oral film FDA-approved to treat seizures associated with LGS. Previously, clobazam was marketed as ONFI® and offered in two formulations – either tablet or oral suspension.

“Aquestive Therapeutics is pleased to bring SYMPAZAN to the LGS community,” said Keith J. Kendall, Chief Executive Officer of Aquestive Therapeutics. “Treating LGS can be difficult; patients may have a hard time swallowing oral medications. We’re optimistic SYMPAZAN can help address unmet medical needs and be an important treatment option for this patient population.”

Subcentimeter Epilepsy Surgery Targets by Resting State Functional Magnetic Resonance Imaging Can Improve Outcomes in Hypothalamic Hamartoma

OBJECTIVE:
The purpose of this study is to investigate the outcomes of epilepsy surgery targeting the subcentimeter-sized resting state functional magnetic resonance imaging (rs-fMRI) epileptogenic onset zone (EZ) in hypothalamic hamartoma (HH).

METHODS:
Fifty-one children with HH-related intractable epilepsy received anatomical MRI-guided stereotactic laser ablation (SLA) procedures. Fifteen of these children were control subjects (CS) not guided by rs-fMRI. Thirty-six had been preoperatively guided by rs-fMRI (RS) to determine EZs, which were subsequently targeted by SLA. The primary outcome measure for the study was a predetermined goal of 30% reduction in seizure frequency and improvement in class I Engel outcomes 1 year postoperatively. Quantitative and qualitative volumetric analyses of total HH and ablated tissue were also assessed.

RESULTS:
In the RS group, the EZ target within the HH was ablated with high accuracy (>87.5% of target ablated in 83% of subjects). There was no difference between the groups in percentage of ablated hamartoma volume (P = 0.137). Overall seizure reduction was higher in the rs-fMRI group: 85% RS versus 49% CS (P = 0.0006, adjusted). The Engel Epilepsy Surgery Outcome Scale demonstrated significant differences in those with freedom from disabling seizures (class I), 92% RS versus 47% CS, a 45% improvement (P = 0.001). Compared to prior studies, there was improvement in class I outcomes (92% vs 76%-81%). No postoperative morbidity or mortality occurred.

SIGNIFICANCE:
For the first time, surgical SLA targeting of subcentimeter-sized EZs, located by rs-fMRI, guided surgery for intractable epilepsy. These outcomes demonstrated the highest seizure freedom rate without surgical complications and are a significant improvement over prior reports. The approach improved freedom from seizures by 45% compared to conventional ablation, regardless of hamartoma size or anatomical classification. This technique showed the same or reduced morbidity (0%) compared to recent non-rs-fMRI-guided SLA studies with as high as 20% permanent significant morbidity.

Neuroene Therapeutics Awarded $1.5 Million to Develop Anti-Seizure Compound for Epilepsy

Neuroene Therapeutics has received a $1.5 million NIH Phase II Small Business Innovation Research grant to optimize vitamin K analogues that could improve seizure control in patients with drug-resistant epilepsy. Richard Himes, Ph.D., a chemist at the College of Charleston, serves as the company’s Chief Scientific Officer.

The SBIR grant will enable Neuroene Therapeutics to test the efficacy and safety of its lead compounds, which are analogues of a naturally occurring form of vitamin K that is essential for mitochondrial and neuronal health.

The form of vitamin K needed by the brain is not the same as the vitamin K we get from foods in our diet. The vitamin K we eat must first be processed by intestinal bacteria before transport to the brain, and then within neurons must be converted into the specific form of Vitamin K that is needed for mitochondrial and neuronal health.

Because the compound developed by Neuroene Therapeutics mimics this specific form of Vitamin K that the neuron needs (not the ingested form) and because it travels directly to the brain, it bypasses the need for transport systems.

The Community-Targeted Self-Management of Epilepsy and Mental Illness (C-TIME) Initiative: A Research, Community, and Healthcare Administration Partnership to Reduce Epilepsy Burden

AIMS: Comorbid mental health conditions (MHCs) such as depression and anxiety are common in people with epilepsy. Targeted Self-Management for Epilepsy and Mental Illness (TIME) is a behavioral program that targets mood symptoms in adults with epilepsy and comorbid MHCs. Building upon positive findings of a randomized controlled study to establish the efficacy of TIME, the Community-TIME (C-TIME) initiative assessed the implementation feasibility and pre-/post-outcomes of this new evidence-based epilepsy self-management intervention in a community setting and in collaboration with key stakeholders.

CONCLUSIONS: The C-TIME program can be successfully implemented in the community and is associated with improved outcomes in adults with epilepsy and comorbid MHCs. Continued and broader scale-up of C-TIME and similar approaches could reach larger groups of adults with epilepsy and improve the health of our communities.

Epilepsy, Identity, and the Experience of the Body

Living with a chronic condition can challenge a person’s identity, yet there is a paucity of research exploring this experience for people with epilepsy and particularly for those diagnosed in adulthood. Consequently, through an interpretative phenomenological approach, the current study aimed to explore what the experience of adult-onset epilepsy meant for a person’s identity.

Thirty-nine people with adult-onset epilepsy from across the UK took part in up to two semi-structured interviews. A modified form of interpretative phenomenological analysis was conducted and identified three themes: 1) disarming the impact of seizures considered strategies used to control seizure occurrence and regain a sense of control over the body; 2) distinguishing the self from the body highlighted participants’ attempts to separate their sense of self from the unpredictability of their bodies; 3) separating epilepsy from themselves demonstrated how participants externalized epilepsy from themselves in order to reject it as part of their identity.

The findings highlighted that living with adult-onset epilepsy can challenge a person’s sense of self and trust in their body, resulting in the adoption of various strategies to manage the threat to their identity. As such, practitioners must pay attention to the impact that adult-onset epilepsy can have on a person’s identity and faith in their body.