Long-Term Efficacy and Safety of Lacosamide and Levetiracetam Monotherapy in Elderly Patients with Focal Epilepsy: A Retrospective Study

Objectives: Epilepsy management in elderly patients is often complex because of several concomitant comorbidities that may limit the use of some antiepileptic drugs (AEDs). Levetiracetam (LEV) is a second-generation AED widely used in elderly patients with epilepsy while lacosamide (LCM), which has been recently approved in the European Union (EU) as monotherapy for the treatment of focal onset seizures, is affected by a scarcity of data in such frail population. This study is aimed at assessing the efficacy and the tolerability of LCM as monotherapy in elderly patients affected by focal onset epilepsy compared with those receiving LEV.

Methods: A retrospective chart review of patients aged 65 years or older suffering from focal onset seizures, with or without secondary generalization on LCM monotherapy or LEV monotherapy, was performed. Data regarding demographic characteristics, seizure type and etiology, LCM and LEV daily dose, number of lifetime AEDs, seizure frequency at baseline and at 12 months of follow-up, and seizure freedom rates were reported.

Results: In this observational retrospective study, 22 patients on LCM (10 males, 12 females, mean age: 76.23 ± 7.5) and 24 patients on LEV (10 males, 14 females, mean age: 73.58 ± 6.39) were enrolled. Mean LCM daily dose was 204.51 ± 88.51 mg and mean LEV daily dose was 1281.25 ± 378.15 mg. All patients had comorbidities on chronic treatment. At 12 months of follow-up, mean monthly seizure frequency reduced from 4.23 ± 8.53 to 0.33 ± 0.9 (p < .001) in LCM group and from 2.29 ± 6.11 to 0.2 ± 0.81 (p < .001) in LEV group. Furthermore, 16/22 (72.7%) LCM patients were seizure-free at 12 months of follow-up while seizure freedom was achieved by 17/24 (70.8%) patients in LEV group.

Discussion and conclusion: Epilepsy management in elderly patients is often challenging. In this retrospective real-life study, the efficacy and the tolerability of lacosamide as monotherapy was favorable even at low doses in older patients and comparable with levetiracetam with a high rate of long-term seizure freedom. Considering the frequent comorbidities and the risk of drug–drug interactions, levetiracetam monotherapy may be a valuable option in elderly patients with focal onset epilepsy because of its favorable pharmacokinetic profile.

Weaning from Antiseizure Drugs After New Onset Status Epilepticus

Objective: In patients with status epilepticus (SE) without prior epilepsy, there are limited data on the safety of discontinuing antiseizure drugs (ASDs) after seizure control. This study aimed to describe seizure recurrence when weaning from ASDs following new onset SE (NOSE).

Methods: Retrospective review of adult patients with NOSE admitted to Mayo Clinic, Rochester, Minnesota between January 1, 1990 and December 31, 2015 was performed. Weaning was defined as a discontinuation of ASDs following discharge. Patient demographics, SE characteristics, timing of ASD withdrawal, and seizure recurrence were collected.

Results: One hundred seventy-seven patients with mean age 63 ± 18 years were identified; 96 (54.2%) patients had refractory SE (RSE), and 81 (45.8%) had nonrefractory SE. Mean follow-up was 3.8 ± 3.2 years for those successfully weaned off ASDs. One hundred thirty (73.4%) with outpatient follow-up were included in the analysis; 128 (98.5%) patients were discharged on an ASD; 44 of 128 (34.4%) patients underwent weaning from at least 1 ASD following discharge, including 27 of 128 (21.1%) who were completely weaned off of all ASDs. Younger patients (P = 0.009) and those with RSE (P = 0.048, odds ratio = 2.12, 95% confidence interval = 1.00-4.48) tended to undergo weaning. Six of 44 (13.6%) patients had seizure recurrence when weaned off of any ASD, and two of 27 (7.4%) patients completely weaned off all ASDs had seizure recurrence. Two of seven (28.6%) patients who underwent attempted barbiturate weaning experienced seizure recurrence.

Significance: This study found a rate of 13.6% for late seizure recurrence after weaning from at least one antiseizure drug (ASD) in patients with new onset status epilepticus (NOSE); seizure recurrence was more likely in patients with refractory status epilepticus treated with barbiturates. Systematic collection of longitudinal data in patients requiring multiple ASDs for NOSE control will provide more conclusive guidance on weaning from ASDs.

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.