Safety and Effectiveness of Stereotactic Laser Ablation for Epileptogenic Cerebral Cavernous Malformations

OBJECTIVE: Magnetic resonance (MR) thermography-guided laser interstitial thermal therapy, or stereotactic laser ablation (SLA), is a minimally invasive alternative to open surgery for focal epilepsy caused by cerebral cavernous malformations (CCMs). We examined the safety and effectiveness of SLA of epileptogenic CCMs.

METHODS: We retrospectively analyzed 19 consecutive patients who presented with focal seizures associated with a CCM. Each patient underwent SLA of the CCM and adjacent cortex followed by standard clinical and imaging follow-up.

RESULTS: All but one patient had chronic medically refractory epilepsy (median duration 8 years, range 0.5-52 years). Lesions were located in the temporal (13), frontal (five), and parietal (one) lobes. CCMs induced magnetic susceptibility artifacts during thermometry, but perilesional cortex was easily visualized. Fourteen of 17 patients (82%) with >12 months of follow-up achieved Engel class I outcomes, of which 10 (59%) were Engel class IA. Two patients who were not seizure-free from SLA alone became so following intracranial electrode-guided open resection. Delayed postsurgical imaging validated CCM involution (median 83% volume reduction) and ablation of surrounding cortex. Histopathologic examination of one previously ablated CCM following open surgery confirmed obliteration. SLA caused no detectable hemorrhages. Two symptomatic neurologic deficits (visual and motor) were predictable, and neither was permanently disabling.

SIGNIFICANCE: In a consecutive retrospective series, magnetic resonance thermography-guided stereotactic laser ablation was an effective alternative to open surgery for epileptogenic cerebral cavernous malformations. The approach was free of hemorrhagic complications, and clinically significant neurologic deficits were predictable. Stereotactic laser ablation presents no barrier to subsequent open surgery when needed.

FDA Approves First Generic Version of Sabril to Help Treat Seizures in Adults and Pediatric Patients with Epilepsy

The FDA approved the first generic version of Sabril (vigabatrin) 500 mg tablets for treating complex partial seizures, also called focal seizures, as an adjunctive therapy in patients 10 years and older who have responded inadequately to several alternative (refractory) treatments.

“Prioritizing the approval of generic drugs to compete with medicines that face little or no competition is a key part of our efforts to support access and reduce drug costs to patients,” said FDA Commissioner Scott Gottlieb, MD. “The availability of high-quality generic alternatives of critically important medicines, once the period of patent protection or exclusivity has ended on the brand drug, helps advance access and saves consumers billions of dollars each year.”

Dr. Gottieb goes on to say, “We know there has been past interest in developing a generic alternative to this product. Earlier this year, we also highlighted this drug, along with many others, on a list of off-patent, off-exclusivity branded drugs without approved generics, to clarify that there were no patents or exclusivities that should impede its approval.

“Today’s action demonstrates that there is an open pathway to approving products like this one. We’re especially focused on new policies aimed at making the generic review process more predictable, efficient and lower cost so we can entice more generic firms to enter this space, and help facilitate more generic drug launches after generic approvals. We know it’s not enough just to approve a record number of generic medicines. We also want to see firms launch these products so that patients can benefit from their availability, and we intend to take steps to advance these goals.”

New Review Study Supports Ability of Epidiolex to Reduce Seizure Frequency in Dravet, Lennox-Gastaut Patients

The objective was to review the efficacy, safety, pharmacology and pharmacokinetics of pure, plant-derived cannabidiol (CBD; Epidiolex) in the treatment of Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

The review, “Epidiolex (Cannabidiol): A New Hope for Patients With Dravet or Lennox-Gastaut Syndromes,” was published in Annals of Pharmacotherapy.

“The frequency and severity of seizures have profound impacts on quality of life, risk for injury (eg, convulsive seizures in [Dravet syndrome], drop seizures in [Lennox-Gastaut syndrome]), health care use, and increased risk for mortality,” the researchers wrote.

It is carbohydrate neutral and compatible with ketogenic diets — a diet high in fats and low in carbs that has been shown to reduce the frequency of seizures and improve cognitive function in children with Dravet syndrome.

Previous clinical trials have found that Epidiolex effectively reduces the frequency of epileptic seizures when used in combination with other anti-epileptic medications.

Researchers in this study reviewed the main findings of these trials regarding the safety, efficacy, and tolerability of Epidiolex for the treatment of children with Dravet and Lennox-Gastaut syndromes.

Researchers ID Factors Predictive of Naming Decline After Epilepsy Surgery

Paper- and online-based externally validated nomograms are effective in predicting naming decline after temporal lobe surgery in patients with epilepsy, according to study results published in Neurology. Factors predictive of postsurgical naming decline in this patient population included side of surgery, age at epilepsy onset, age at surgery, sex, and education, and preoperative naming score.

A total of 719 patients with epilepsy who underwent temporal lobe epilepsy surgery at the Cleveland Clinic were included in the study. In addition, the investigators enrolled an external validation cohort of 138 patients who also underwent temporal lobe surgery at Columbia University Medical Center, Emory University School of Medicine, or University of Washington School of Medicine.

Summary of Antiepileptic Drugs Available in the US

This resource provides an overview of the use, dosage, side effects, and contraindications of antiepileptic drugs (AEDs).

This publication is intended to assist professionals who treat patients with epilepsy and serve as a teaching tool for those in healthcare training programs. It is in two parts—the first is a condensed summary of each AED and the second is expanded to include data on pharmacokinetics, side effects, and drug interactions.

Use of Common Epilepsy Drug in Pregnancy Tied to ADHD in Kids

When a woman with epilepsy uses the anti-seizure drug valproate during a pregnancy, the odds that her baby will go on to develop ADHD rise, a new study suggests.

The Danish report can’t prove that valproate causes attention-deficit/hyperactivity disorder (ADHD) in these cases, only that there’s an association.

But in the new study, fetal exposure to valproate was tied to 48 percent higher odds of a child developing ADHD, according to a team led by Dr. Jakob Christensen at Aarhus University.

The study included more than 900,000 babies born in Denmark between 1997 and 2011. The children’s mental health was tracked from birth until they averaged about 10 years of age.

Christensen’s group concluded that “maternal use of valproate during pregnancy was associated with a small but significantly increased risk of ADHD in the offspring, even after adjusting for maternal psychiatric disease, maternal epilepsy,” and other factors.

Other epilepsy drugs appeared to have no effect on ADHD rates, the researchers noted. The findings were published online Jan. 4 in JAMA Network Open.

Pharmacokinetic evaluation of vigabatrin dose for the treatment of Refractory Focal Seizures in Children Using Adult and Pediatric Data

Vigabatrin is indicated as adjunctive therapy for refractory focal seizures. For children, European recommendations indicate maintenance doses varying from 30 to 100?mg/kg/day for this indication. Since cumulated dose was associated with retinal toxicity, it is essential to administrate the lowest effective dose to patients.

This work was conducted with the purpose to determine the pediatric doses of vigabatrin that allow a similar exposure than effective doses in adults (2-3?g/day) through a pharmacokinetic (PK) study, using both pediatric and adult data.

For this study, we focused on the active S(+) enantiomer of vigabatrin. First, the adult effective exposition range of vigabatrin-S was determined from an adult PK model. Then, this same model was scaled to the pediatric population using allometry and maturation principles to account for growth and development. The ability of the model to predict pediatric data was assessed by comparing population predictions with observed pediatric data. Finally, the extrapolated pediatric model was used to simulate pediatric expositions which were compared to the adult exposition range (36.5-77.9?mg.h/L).

From those simulations, we determined that, for children aged between 3 months and 18 years, doses between 40 and 50?mg/kg/day allow vigabatrin-S expositions similar to those found in adults at the recommended posology. We proposed those doses as optimal maintenance doses that may be increased, if necessary, by slow titration.

Ovid Therapeutics Announces Phase 1b/2a Results of OV935/TAK-935 in Adults with Rare Epilepsies

Ovid Therapeutics announced results from a 12-week, Phase 1b/2a clinical trial of OV935/TAK-935 that enrolled 18 adults with rare developmental and epileptic encephalopathies (DEE) who were not successfully treated with available treatment regimens. The trial achieved its primary endpoint of safety and tolerability and showed OV935 was generally well tolerated.

Exploratory analysis of OV935 showed reduction in seizure frequency that was correlated with decreases in plasma 24-hydroxycholesterol (24HC) levels in adults across multiple DEE. OV935 is a potent, highly-selective first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H) being investigated as a novel approach to treating epilepsy. Preclinical data suggest that inhibition of brain CH24H indirectly reduces glutamatergic signaling via NMDA receptors and modulates glial function and inflammation, which may impact disease pathology and epileptogenesis.

Epilepsy Research Findings: December 2018

Exciting epilepsy research discoveries include two groundbreaking studies. Dr. Steven Petrou created “minibrains” using stem cells to better understand how neurons behave in children with epilepsy. Dr. Harald Sontheimer discovered the previously unknown function of perineuronal nets, which may lead to new treatments for acquired epilepsy. Both Dr. Petrou and Dr. Sontheimer are CURE grantees, and we’re thrilled to see these innovations from them beyond the work they do with us!

In diagnostic news regarding children with epilepsy, scientists are calling for parents to have their children’s genes reviewed at least every two years. This is to ensure their diagnoses and treatments are based on the latest discoveries.

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

Diacomit Add-On Therapy More Effective in Children with Dravet Syndrome Who Carry Pathogenic SCN1A Mutations, Study Shows

Diacomit (stiripentol) add-on therapy is more effective in children with Dravet syndrome who have pathogenic (disease-causing) SCN1A mutations than in those with variants of unknown significance and benign SCN1A mutations, a study has found.

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GW Pharmaceuticals Announces Second Positive Phase 3 Pivotal Trial for EPIDIOLEX® (Cannabidiol) Oral Solution CV in Patients with Dravet Syndrome

GW Pharmaceuticals announces positive top-line results of the second randomized, double-blind, placebo-controlled Phase 3 clinical trial of EPIDIOLEX® (cannabidiol or CBD) CV in the treatment of seizures associated with Dravet syndrome, a rare and severe form of childhood-onset epilepsy.

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Aquestive Therapeutics Announces FDA Approval for SYMPAZAN™ (clobazam) Oral Film

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.

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Diagnostic Advances

Reanalyzing Gene Tests Prompts New Diagnoses in Kids

A new study from UT Southwestern quantifies for the first time how quickly rapid advancements in genomics may benefit patients. Research published in JAMA Pediatrics includes a five-year review of more than 300 epilepsy cases showing nearly a third of children had a change in diagnosis based on new data.

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Research Discoveries

Could Lab-Grown Human Minibrains Help Treat Alzheimer’s and Epilepsy?

Featuring the work of CURE Grantee Dr. Steven Petrou

Florey Institute Director Dr. Steven Petrou leads research creating organoids to mimic the behavior of children’s brains with rare, debilitating forms of epilepsy. Replicating the way neurons behave in children with epilepsy using stem cells in a dish allowed the researchers to tailor a treatment; Petrou is on the verge of announcing a clinical trial of a gene therapy to treat one variant of the disorder.

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

Featuring the work of CURE Grantee Dr. Harald Sontheimer

A research team led by Dr. Harald Sontheimer determined that perineuronal nets, whose function was previously unknown, modulate electrical impulses in the brain. Seizures can occur if the nets are dissolved. This discovery may lead to a potential treatment for acquired epilepsy.

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Epidemiology of Status Epilepticus in Adults: A Population-Based Study on Incidence, Causes, and Outcomes

The first population-based study using the International League Against Epilepsy 2015 definition and classification of status epilepticus found an increase of incidence of 10% compared to previous definitions. The study also provides epidemiologic evidence that different patterns of status evolution and level of consciousness have strong prognostic implications.

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Can Genetic Therapy Help Kids with Angelman Syndrome Overcome Seizures?

Scientists at the UNC School of Medicine found evidence that genetic therapy may prevent the enhanced seizure susceptibility common in children with Angelman Syndrome. The research marks the first time scientists reduced seizure susceptibility in mice by activating a dormant copy of the UBE3A gene, so it could replace the faulty mutant version.

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Also Notable

Parents and Researchers Work to Find Cause of Neonatal Epilepsy

Three US families aim to help researchers develop better treatments for neonatal-onset epilepsy with a US-wide study called Early Recognition of Genetic Epilepsy in Neonates (ERGENT). This study provides free-of-charge genetic testing to babies who have features suggestive of a genetically-caused epilepsy.

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Alzheimer’s and Epilepsy: Intimate Connections

Like people with Alzheimer’s disease, people with epilepsy can experience memory loss or confusion. As part of an aura, they may hear or see things that aren’t there. When older adults display these symptoms, they may be misdiagnosed with Alzheimer’s disease, when in fact they are having (or just had) a seizure.

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RogCon Biosciences Launches with Late-Breaking Presentation on SCN2A Epilepsy at the 2018 AES Meeting

RogCon and its collaborators from The Florey Institute of Neuroscience presented preclinical data on the company’s lead program, RC-222, an antisense oligonucleotide designed to down-regulate SCN2A, which is being developed with Ionis Pharmaceuticals, Inc. (Ionis), the leader in RNA-targeted drug discovery and development.

In preclinical studies evaluating the antisense oligonucleotide in an SCN2A mouse model, efficacy was evaluated by survival, seizure number, electroencephalography (EEG), behavioral test batteries and whole cell recording in brain slices. Results demonstrated that:

  • The therapeutic effect of a single peri-natal dose of the antisense oligonucleotide was significant and long lasting, with nearly 70% of treated mice surviving to 80 days compared to 0% survival at 30 days in untreated mice or those receiving current standard of care.
  • Treatment with the antisense oligonucleotide mitigated spontaneous seizures and largely restored neuronal excitability, EEG activity and behavioral characteristics of treated mice to wildtype levels.
  • These results demonstrate the remarkable efficacy of SCN2A down-regulation and has laid an important foundation for the accelerated clinical development of the RC-222 program.