Epilepsy Surgery in Certain Brain Areas Can Constrain Development of Verbal Cognition but Cortical Growth After Surgery Can Support Improvement in IQ

OBJECTIVE: Intelligence quotient (IQ) outcomes after pediatric epilepsy surgery show significant individual variation. Clinical factors such as seizure cessation or antiepileptic medication discontinuation have been implicated, but do not fully account for the heterogeneity seen. Less is known about the impact of neurobiological factors, such as brain development and resection location. This study examines clinical and neuroimaging factors associated with cognitive outcome after epilepsy surgery in childhood.

METHODS: Fifty-two children (28 boys, 24 girls) were evaluated for epilepsy surgery and reassessed on average 7.7 years later. In the intervening time, 13 were treated pharmacologically and 39 underwent focal surgery (17 temporal, 16 extratemporal, six multilobar; mean age at surgery = 14.0 years). Pre- and postsurgical assessments included IQ tests and T1-weighted brain images. Predictors of IQ change were investigated, including voxel-based analyses of resection location, and gray and white matter volume change.

RESULTS: Overall modest IQ improvement was seen in children treated surgically, but not in those treated pharmacologically only. Applying a greater than or equal to 10-point change threshold, 39% of the surgically treated children improved, whereas 10% declined. Clinical factors associated with IQ increases were lower preoperative IQ and longer follow-up duration, whereas seizure and antiepileptic medication cessation were not predictive. Among neuroimaging factors, researchers observed that left anterior temporal resections impacted negatively on verbal reasoning, linked to full-scale IQ decline. In contrast, gray matter volume change in ipsi- and contralesional hemispheres was positively correlated with IQ change. Voxel-based morphometry identified the gray matter volume change in the contralesional dorsolateral frontal cortex as most strongly associated with IQ improvement.

SIGNIFICANCE: This study shows that a variety of factors are likely to contribute to patterns of postsurgical change in IQ. Neuroimaging results indicate that left anterior temporal resections constrain development of verbal cognition, whereas simultaneously cortical growth after surgical treatment can support improvements in IQ.

Intravenous Use of Valproic Acid in Status Epilepticus is Associated with High Risk of Hyperammonemia

PURPOSE: The aim of the study was to examine the frequency of hyperammonemia secondary to valproic acid treatment in status epilepticus and to describe the characteristics of the patients.

METHODS: All patients with established status epilepticus during 2014 to 2016 at Ryhov County Hospital were identified in a retrospective case series. Clinical and laboratory findings were collected from electronic medical files and the Metavision database at the intensive care unit (ICU). Hyperammonemia was defined as a concentration of at least 50 umol/L.

RESULTS: 11 of 40 patients developed hyperammonemia. These patients had a significantly longer stay at the ICU (12.6 vs 2.5 days) and at the hospital (22 vs 11 days). All patients with hyperammonemia were treated at the ICU and all received antibiotics. 12 patients were treated with intravenous valproic acid outside the ICU. Hyperammonemia was not related to Body Mass Index, time to initiation of therapy or laboratory abnormalities except anemia (Hemoglobin 104 vs 122 g/l). There was no difference in mortality between groups.

CONCLUSION: The risk of hyperammonemia is almost 40% in patients receiving intravenous valproic acid in the ICU setting. The underlying mechanisms are probably either individual susceptibility or high metabolic demands. A high vigilance should be recommended. These data require further research via prospective designs in which multiple variables are controlled to explore the effects of individual factors on treatment outcome.

Zogenix Receives Refusal to File Letter from FDA for FINTEPLA® New Drug Application

Zogenix, Inc. (ZGNX) announced April 8 that it received a Refusal to File (RTF) letter from the FDA regarding its New Drug Application (NDA) for FINTEPLA® (ZX008, fenfluramine hydrochloride) for the treatment of seizures associated with Dravet syndrome.

Upon its preliminary review, the FDA determined that the NDA, submitted on February 5, 2019, was not sufficiently complete to permit a substantive review.  In the letter, the FDA cited two reasons for the RTF decision: first, certain non-clinical studies were not submitted to allow assessment of the chronic administration of fenfluramine; and, second, the application contained an incorrect version of a clinical dataset, which prevented the completion of the review process that is necessary to support the filing of the NDA. The FDA has not requested or recommended additional clinical efficacy or safety studies.

Epilepsy Research Findings: April 2019

This month’s news features technological advances that may make seizure detection more reliable and surgery for intractable epilepsy more accurate, while also deepening our understanding of how epilepsy arises in a healthy brain.

In other news, important research on Sudden Unexpected Death in Epilepsy (SUDEP) highlighted the association between SUDEP and change in tissue volume in areas of the brain important in cardiorespiratory function, as well as the lack of understanding about SUDEP among people with epilepsy and their relations.

In addition, we spotlight a recent statement by the FDA reporting that some people, mainly youth and young adults, who use e-cigarettes are experiencing seizures, as well as a recent TEDx Talk about how artificial intelligence may be used to help prevent SUDEP.

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 Clinical Trial of Reformulated Antiepileptic Drug to Treat Medically Refractory Epilepsy
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An approved antiepileptic drug used to treat seizures has been modified and is currently being used in an Australian clinical trial for medically refractory epilepsy. The trial tests a proprietary, reformulated, specialty pharmaceutical, which bypasses the blood-brain barrier using a chronic implantable infusion system.

Multicenter Clinical Study of Long-Term Brivaracetam Use Finds It Effective and Well-Tolerated in Patients with Drug-Resistant Epilepsy
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Researchers assessed long-term effectiveness and tolerability of brivaracetam in patients with focal epilepsy. According to this multicenter, retrospective study, brivaracetam was effective and well-tolerated in a large population of patients with predominantly drug-resistant epilepsy. There were no unexpected adverse side effects over 1 year. The most frequently reported adverse side effects were somnolence, irritability, and dizziness.

Diagnostic Advances

Motion Recognition Technology Assists Epilepsy Diagnosis
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Motion recognition technology is being used to help neurologists study patients’ behavior during seizures. They hope to get clues on the sub-type of epilepsy the patient has and identify unusual seizure movements requiring further investigation.

Model Developed to Help Identify Patients Who Will Not Experience Remission Again After Breakthrough Seizures
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A model has been created to help identify people with epilepsy who are unlikely to regain seizure remission within 2 years after experiencing a breakthrough seizure following an initial 12-month remission. Researchers note that their model is a useful first step in developing a tool for identifying patients who develop drug resistance after an initial remission.

Research Discoveries

Potential Biomarkers of Cardiac Stress After Generalized Convulsive Seizures Identified
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The measurement of certain substances in the blood, such as the protein high-sensitive troponin T and the peptide copeptin, may be helpful as biomarkers to identify cardiac stress after generalized convulsive seizures in patients with refractory epilepsy, according to study results published in Epilepsia.

SUDEP Associated with Tissue Volume Change in Brain Areas Important in Cardiorespiratory Recovery
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In a retrospective imaging study of SUDEP cases, researchers found that people who passed away due to SUDEP show significant tissue loss in areas of the brain essential for cardiorespiratory recovery. They also found enhanced volumes in areas that trigger hypotension or impede respiratory patterning. According to the study, these changes in brain tissue may shed light on the mechanisms of SUDEP and help detect patterns to identify those at risk for SUDEP.

Literature Review Shows That There is a Lack of Understanding of SUDEP for People with Epilepsy and Their Relations
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A comprehensive electronic search of peer-reviewed qualitative studies showed an overall lack of understanding about unexpected epilepsy-related death among people with epilepsy and their relations. The authors conclude that it would be appropriate and necessary to discuss SUDEP with patients and their family members upon diagnosis.

Also Notable

Some E-cigarette Users Are Having Seizures; Most Reports Involving Youth and Young Adults
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The FDA has become aware that some people who use e-cigarettes have experienced seizures, with most reports involving youth or young adult users. A recent uptick in voluntary reports of adverse events with tobacco products that mentioned seizures occurring with e-cigarette use (e.g., vaping) signal a potential emerging safety issue, according to the FDA.

New TEDx Talk Issues Call to Action for SUDEP
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Every year worldwide, more than 50,000 otherwise healthy people with epilepsy suddenly die — a condition known as SUDEP. These deaths may be largely preventable, says artificial intelligence researcher Rosalind Picard. Learn how Picard helped develop a cutting-edge smartwatch that can detect epileptic seizures before they occur and alert nearby loved ones in time to help.

Laser Light Examines How Epilepsy Arises in the Healthy Brain
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Scientists have developed a new method to study how seizures arise in healthy brains. Using laser light guided through ultra-thin optic fibers in rodent brains, the researchers “turned on” light-sensitive proteins in selective brain cells and were able to eventually cause seizures through repeated laser stimulation.

Developing a Universal Automated Tool for Reliable Seizure Detection in Rodent Models of Acquired and Genetic Epilepsy
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The development of an automated tool for reliable seizure detection has the potential to improve the efficiency and rigor of preclinical research and therapy development for rodent models of acquired and genetic epilepsy, according to research published in Epilepsia.

Robotics Makes Intractable Epilepsy Surgery More Accurate
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Patients with intractable epilepsy who had a minimally invasive surgery evaluation procedure called robotic stereoelectroencephalography (SEEG) experienced fewer complications, according to a study published in JAMA Neurology. Those who went on to have brain surgery were more likely to be seizure-free than patients who had the more invasive evaluation procedure.

Multicenter Clinical Study of Long-Term Brivaracetam Use Finds Brivaracetam Effective and Well-Tolerated in Patients with Drug-Resistant Epilepsy

Researchers assessed long-term effectiveness and tolerability of brivaracetam in patients with focal epilepsy. According to this multicenter retrospective study, brivaracetam was effective and well-tolerated in a large population of patients with predominantly drug-resistant epilepsy. There were no unexpected adverse events (AEs) over 1 year. The most frequently reported AEs were somnolence, irritability and dizziness.

First Clinical Trial of Reformulated Antiepileptic Drug to Treat Medically Refractory Epilepsy

A currently approved antiepileptic drug to treat seizures has been modified by a University of Colorado Anschutz Medical Campus professor and is currently being used in a clinical trial in Australia for medically refractory epilepsy.

Tom Anchordoquy, Professor at the CU Skaggs School of Pharmacy and Pharmaceutical Sciences and Dan Abrams, M.D., CEO of Cerebral Therapeutics have developed a proprietary reformulated specialty pharmaceutical, which bypasses the blood-brain barrier using a chronic implantable infusion system, to improve the lives of patients with severe medically refractory epilepsy.

The two have worked together for over a decade developing drug formulations to be injected directly into the brain where it is needed.

Cerebral Therapeutics is currently conducting a proof of concept study in adult patients at Australia’s University of Melbourne using its proprietary anti-epileptic specialty formulation via direct intracerebroventricular (ICV) administration. This proof of concept study has demonstrated potentially enhanced efficacy and reduced toxicity in patients with medically refractory epilepsy.

Antiseizure Medication Eslicarbazepine Acetate Demonstrates Less Adverse Neuropsychological Effects Than Carbamazepine Immediate-Release in Healthy Volunteers

People with epilepsy are at increased risk for neuropsychological dysfunction due to multiple factors, of which the most amendable are antiseizure medications (ASMs). Antiseizure medication effectiveness is frequently determined by tolerability.

In this study, researchers compared the neuropsychological effects of eslicarbazepine acetate (ESL) and carbamazepine immediate-release (CBZ) using a randomized, double-blind, crossover design in healthy volunteers with a 2-week titration and 4-week maintenance phase in each treatment arm (CBZ = 400?mg BID and ESL = 800 mg qAM).

Neuropsychological testing was performed at the initial visit, repeated at 1st baseline nondrug condition, end treatment #1, 2nd nondrug condition one month after treatment #1, end treatment #2, and 3rd nondrug condition one month after treatment #2. Neuropsychological testing was conducted 2 h after morning dose and included computer (i.e., dual task test, selective attention test, symbol digit, verbal memory, visuospatial memory, and 1- & 2-back continuous performance) and noncomputer tasks (i.e., Medical College of Georgia (MCG) paragraph memory, Stroop, Symbol Digit Modalities Test, Profile of Mood States). z-Scores calculated from nondrug conditions were used to compare ESL and CBZ for the 23 completers. Follow-up analyses included individual test scores and distribution of individual raw means. Mean blood levels on test day were CBZ = 8.9 ug/ml and ESL = 15.3 ug/ml. Omnibus z-score was significantly better for ESL (p = .0001).

For individual measures, executive function and selective attention tests were statistically significantly better for eslicarbazepine acetate. Individual test raw means favored eslicarbazepine acetate over carbamazepine immediate-release on 22 of 30 measures (p = .016, 2-tailed sign test). Eslicarbazepine acetate demonstrated less adverse neuropsychological effects than carbamazepine immediate-release.

Perampanel May Increase Scores Indicative of Aggression, Depression in Epilepsy

For patients with epilepsy, treatment with perampanel increases both aggression and depression significantly, according to results published in the journal Seizure.

The study included participants with epilepsy who were given perampanel (n=77). Examinations were performed at baseline (before perampanel administration) and after 12-weeks of follow-up. At each examination, the researchers used the Buss Perry Aggression Questionnaire (BAQ) and the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) to assess aggression and depression, respectively.

A total of 59 participants completed the study, with 3.9% discontinuing perampanel because of adverse psychiatric effects.

No Liver Toxicity Found with Valproic Acid but Evidence of Oxidative Damage in Children with Epilepsy Taking Therapeutic Doses of Levetiracetam

BACKGROUND AND AIMS: The relationship between anti-epileptic usage and oxidative damage has not yet been clearly understood. In this study, researchers investigated oxidative stress parameters, carnitine levels, liver function tests (LFT) and their relationship in epileptic children treated with valproic acid or levetiracetam.

METHOD: LFTs, serum free carnitine and oxidative damage markers and their relations with each other were determined in patients who are on valproic acid or levetiracetam treatment at least for 6 months. 25 patients on therapeutic doses of valproic acid, 26 patients on therapeutic doses of levetiracetam and 26 healthy volunteers as controls were included. LFTs, ammonia, carnitine, lipid peroxidation biomarker malondialdehyde (MDA) and a sensitive marker of DNA damage, 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were measured. Results of patients are compared to healthy controls. The data is evaluated with IBM SPSS Statistics 22.0.

RESULTS: Ammonia and MDA levels were elevated in patients using levetiracetam; 8-OHdG levels were elevated in both patient groups. Carnitine levels were significantly low in patients under valproic acid therapy, however they were not found to be correlated with MDA, 8-OHdG or LFTs. MDA showed positive correlation with ammonia and 8-OHdG in the levetiracetam group.

CONCLUSION: The researchers did not observe hepatotoxicity in patients under therapeutic doses of valproic acid. However, epileptic children under therapeutic doses of levetiracetam showed significantly elevated levels of MDA and 8-OHdG, which is supportive for oxidative damage under levetiracetam therapy. This result was observed for the first time in childhood epilepsies and further studies are needed to understand its mechanism.

Improved Quality of Life and Seizure Control with Clobazam in Children with Lennox-Gastaut Syndrome: A Pilot Study

In this prospective study of children with Lennox-Gastaut syndrome receiving clobazam as adjunctive therapy, researchers tested medication efficacy as it relates to seizure reduction as well as improvement in the behavior and quality of life (QOL) reported by parents.

In this 6-week, 4 phase study, they involved 10 patients with Lennox-Gastaut syndrome (aged 3-11 years). Patients exhibited improvement on indices of QOL, including physical activities, well-being, cognition, social activities, behavior, general health, and overall QOL.

The Quality of Life in Childhood Epilepsy (QOLCE) questionnaire showed significant improvement in cognition, social activities, behavior, and overall QOL. An improvement was observed in all patients with documented baseline seizures (8/10), with 5 showing significant improvement (95%-100% reduction) and 3 showing minor improvement (7%-23% reduction). In patients with clobazam, an overall trend towards positive well-being was seen as an adjunct therapy in children for Lennox-Gastaut syndrome.