A Drug From Resin to Combat Epileptic Seizures

Originally published in EurekAlert

New molecules, developed by researchers at Linköping University, have promising properties as possible drugs against epilepsy. A study published in the journal Epilepsia shows that several of the molecules have antiseizure effects.

In people with epilepsy, the nerve cells in the brain become overactive, causing epileptic seizures.

“More than 60 million people in the world have epilepsy. A third of them still experience seizures despite taking medication, so there is a pressing need for new types of drugs”, says Nina Ottosson, principal research engineer in the Department of Biomedical and Clinical Sciences, Linköping University.

In the newly published study, the researchers have examined an ion channel that affects how readily a nerve impulse is stimulated. This channel, the potassium ion channel denoted by hKV7.2/7.3, plays an important role in epilepsy. If it is closed, an epileptic seizure can occur, while the seizure can be stopped if the channel opens. One drug, retigabine, can open hKV7.2/7.3, and this was useful in treating severe epilepsy. Retigabine, however, affects other ion channels, in particular channels in the smooth muscle found in, for example, the bladder and blood vessels. This gave undesired effects, such as abnormally low blood pressure and difficulties in urinating. Retigabine was withdrawn a couple of years ago.

The researchers have shown in the study that several of the new resin acid molecules can open hKV7.2/7.3. They also investigated whether the molecules affect a closely related ion channel, hKV7.4, which is opened by retigabine and contributes to its undesired effects. Experiments in tissue from rats demonstrated that the new molecules have less effect on smooth muscle, and it is thus less probable that they give undesired effects on blood vessels and the bladder. The new resin acids influence ion channels using a different mechanism than that used by retigabine. The researchers believe that the difference in the mechanism of action is significant for the effects in different tissues.

Exercise-Linked Consequences of Epilepsy

Abstract, originally published in Epilepsy & Behavior

Objective: Epilepsy is a brain disorder that leads to seizures and neurobiological, cognitive, psychological, and social consequences. Physical inactivity can contribute to worse epilepsy pathophysiology. Here, we review how physical exercise affects epilepsy physiopathology.

Methods: An extensive literature search was performed and the mechanisms of physical exercise on epilepsy were discussed. The search was conducted in Scopus and PubMed. Articles with relevant information were included. Only studies written in English were considered.

Results: The regular practice of physical exercise can be beneficial for individuals with neurodegenerative diseases, such as epilepsy by decreasing the production of pro-inflammatory and stress biomarkers, increasing socialization, and reducing the incidence of epileptic seizures. Physical exercise is also capable of reducing the symptoms of depression and anxiety in epilepsy. Physical exercise can also improve cognitive function in epilepsy. The regular practice of physical exercise enhances the levels of brain-derived neuro factor (BDNF) in the hippocampi, induces neurogenesis, inhibits oxidative stress and reactive gliosis, avoids cognitive impairment, and stimulates the production of dopamine in the epileptic brain.

Conclusion: Physical exercise is an excellent non-pharmacological tool that can be used in the treatment of epilepsy.

Development of an Antiepileptogenesis Drug Screening Platform: Effects of Everolimus and Phenobarbital

Featuring the work of CURE Epilepsy Scientific Advisory Council member Dr. Steve White

Abstract, originally published in Epilepsia

Objective: The kainic acid (KA)-induced status epilepticus (SE) model in rats is a well-defined model of epileptogenesis. This model closely recapitulates many of the clinical and pathological characteristics of human temporal lobe epilepsy (TLE) that arise following SE or another neurological insult. Spontaneous recurrent seizures (SRS) in TLE can present after a latent period following a neurological insult (traumatic brain injury, SE event, viral infection, etc.). Moreover, this model is suitable for preclinical studies to evaluate the long-term process of epileptogenesis and screen putative disease-modifying/antiepileptogenic agents. The burden of human TLE is highly variable, similar to the post-KA SE rat model. In this regard, this model may have broad translational relevance. This report thus details the pharmacological characterization and methodological refinement of a moderate-throughput drug screening program using the post-KA-induced SE model of epileptogenesis in male Sprague Dawley rats to identify potential agents that may prevent or modify the burden of SRS. Specifically, we sought to demonstrate whether our protocol could prevent the development of SRS or lead to a reduced frequency/severity of SRS.

Methods: Rats were administered either everolimus (2–3 mg/kg po) beginning 1, 2, or 24 h after SE onset, or phenobarbital (60 mg/kg ip) beginning 1 h after SE onset. All treatments were administered once/day for 5–7 days. Rats in all studies (n = 12/treatment dose/study) were then monitored intermittently by video-electroencephalography (2 weeks on, 2 weeks off, 2 weeks on epochs) to determine latency to onset of SRS and disease burden.

Results: Although no adverse side effects were observed in our studies, no treatment significantly modified disease or prevented the presentation of SRS by 6 weeks after SE onset.

Significance: Neither phenobarbital nor everolimus administered at several time points after SE onset prevented the development of SRS. Nonetheless, we demonstrate a practical and moderate-throughput screen for potential antiepileptogenic agents in a rat model of TLE.

Epilepsy, Antiepileptic Drugs, and the Risk of Major Cardiovascular Events

Abstract, originally published in Epilepsia

Objective: This study was undertaken to determine whether epilepsy and antiepileptic drugs (including enzyme-inducing and non-enzyme-inducing drugs) are associated with major cardiovascular events using population-level, routinely collected data.

Methods: Using anonymized, routinely collected, health care data in Wales, UK, we performed a retrospective matched cohort study (2003-2017) of adults with epilepsy prescribed an antiepileptic drug. Controls were matched with replacement on age, gender, deprivation quintile, and year of entry into the study. Participants were followed to the end of the study for the occurrence of a major cardiovascular event, and survival models were constructed to compare the time to a major cardiovascular event (cardiac arrest, myocardial infarction, stroke, ischemic heart disease, clinically significant arrhythmia, thromboembolism, onset of heart failure, or a cardiovascular death) for individuals in the case group versus the control group.

Results: There were 10 241 cases (mean age = 49.6 years, 52.2% male, mean follow-up = 6.1 years) matched to 35 145 controls. A total of 3180 (31.1%) cases received enzyme-inducing antiepileptic drugs, and 7061 (68.9%) received non-enzyme-inducing antiepileptic drugs. Cases had an increased risk of experiencing a major cardiovascular event compared to controls (adjusted hazard ratio = 1.58, 95% confidence interval [CI] = 1.51-1.63, p < .001). There was no notable difference in major cardiovascular events between those treated with enzyme-inducing antiepileptic drugs and those treated with non-enzyme-inducing antiepileptic drugs (adjusted hazard ratio = .95, 95% CI = .86-1.05, p = .300).

Significance: Individuals with epilepsy prescribed antiepileptic drugs are at an increased risk of major cardiovascular events compared with population controls. Being prescribed an enzyme-inducing antiepileptic drug is not associated with a greater risk of a major cardiovascular event compared to treatment with other antiepileptic drugs. Our data emphasize the importance of cardiovascular risk management in the clinical care of people with epilepsy.

Quality of Life at 6 Years in Children Treated for West Syndrome with Hormonal Therapy

Abstract, originally published in Epilepsy & Behavior

Introduction: West syndrome is a severe epileptic encephalopathy occurring in infancy. Majority of affected children suffer from poor epilepsy control in later life and are dependent on care-givers for daily living. There is no previous study evaluating the Quality of Life (QOL) in children suffered from WS.

Method: A prospective cohort study was performed at six years in a group of children with West syndrome, followed up in the Sri Lanka Infantile Spasm Study (SLISS). The quality of life was evaluated using Sri Lankan Health-Related Quality-of-Life Index for school children (SLHRQ-S), an age-specific, primary caregiver proxy-rated, validated questionnaire for Sri Lankan children with epilepsy. Information on epilepsy, medication, and daily activities was obtained from the parents.

Results: Fifty parents of initial 97 children treated for WS participated. The majority had no ongoing epilepsy (56%) at time of evaluation. The mean QOL was 67.22 (SD 15.68). Mean QOL scores for individual domains showed that physical domain was the worst affected (58.51 (SD = 22.11)). Psychological and social function domains were 68.73 (SD = 17.74) and 75.2 (SD = 14.87), respectively. Male sex (0.02), using multiple anti-seizure medications (0.00) and lower ILAE epilepsy control scale (0.02) were significantly associated with a poor quality of life. Age at onset, delay in treatment, and early spasm control were among the factors that did not influence quality of life.

Conclusion: Despite having control of their epilepsy in the majority, these children suffered from poor quality of life. The greater impact on the physical domain possibly is related to the effect of underlying pathologies.

Surgery for Drug-Resistant Epilepsy in Children

Summary, originally published on docwirenews.com

A systematic review published in Child’s Nervous System evaluated factors associated with and outcomes following hemispherotomy in children with drug-resistant epilepsy.

“Several variations of functional disconnection surgery have been described for the treatment of lateralized, hemispheric, drug-resistant epilepsy in children,” the study authors explained. “The purpose of this study is to investigate the existing literature regarding patient selection, approach, and outcomes after hemispherotomy.”

They performed a systematic review of literature published in English through February 2019. Articles were stratified based on level of evidence. Data on seizure and functional outcomes, surgical techniques, complications, and patient selection were analyzed.

“Both vertical and lateral hemispherotomy approaches result in durable, reproducible benefits to epilepsy severity and functional status in appropriately selected pediatric patients,” the researchers concluded.

Imaging Approach to Stop Epilepsy Seizures

Summary, originally published on medicalxpress.com

An advanced imaging approach developed at the University of Virginia School of Medicine could let surgeons determine the best target in the brain to stop epilepsy seizures, new research suggests.

UVA’s approach could improve patient outcomes and open underused surgical options to patients who are now ineligible, the research team reports.

“This imaging approach is significant, as it creates 4D brain maps that offer additional sensitivity over standard-of-care imaging by revealing rates of glucose uptake rather than final absolute glucose uptake,” said imaging expert Bijoy Kundu of UVA’s Department of Radiology and Medical Imaging and UVA’s Department of Biomedical Engineering. “This imaging approach might be beneficial, as it may offer non-invasive localization of potential epileptic foci.”

UVA’s new approach uses an enhanced form of positron-emission tomography, or PET, to measure glucose use in the brain. This allows doctors to pinpoint the trouble spot in the brain that is triggering seizures. Once that spot is identified, it can be removed surgically, stopping the seizures.

Sodium Channel Blockers for the Treatment of Epilepsy in CDKL5 Deficiency Disorder: Findings From a Multicenter Cohort

Abstract, originally published in Epilepsy & Behavior

Objective: This study was aimed to analyze the effectiveness of sodium channel blockers (SCBs) in CDKL5 deficiency disorder (CDD)-related epilepsy.

Methods: A retrospective, observational study was performed, including patients with CDD diagnosis evaluated between 2016 and 2019 at three tertiary Epilepsy Centers. Demographic, electroclinical and genetic features, as well as ASM treatments and their outcomes were analyzed, with special focus on SCBs.

Results: Twenty-one patients evaluated at three tertiary Epilepsy Centers were included, of which 19 presented with epilepsy (90.5%); all had pathogenic mutations of CDKL5. Six patients (31.6%) were classified as SCB responders (more than 50% reduction), four being currently seizure free (mean seizure-free period of 8 years). Most frequent SCB drugs were oxcarbazepine (OXC), carbamazepine (CBZ), and lacosamide (LCM). None of them presented relevant adverse events. In contrast, three patients showed seizure aggravation in the non-responder group. When comparing both groups, responders had statistically significant younger age at SCB treatment and epilepsy onset, higher proportion of focal epileptiform activity and less frequent history of West syndrome.

Conclusions: The results of this study indicate that treatment with sodium channel blockers might be effective and safe in a subset of patients with CDKL5 deficiency disorder-related epilepsy.

Epilepsy Drugs For Newly Diagnosed Patients: What’s Best?

Summary, originally published in MedPageToday

Valproate (Depakene) emerged as the best first-line choice for generalized epilepsy in a pragmatic study and lamotrigine (Lamictal) as the best first-line treatment for focal epilepsy, British researchers said.

The conclusions came from the phase IV open-label Standard and New Antiepileptic Drugs (SANAD II) study with two parts: a randomized trial of levetiracetam (Keppra) and valproate in newly diagnosed generalized epilepsy patients, and a randomized trial of levetiracetam, lamotrigine, and zonisamide (Zonegran) in newly diagnosed focal epilepsy patients. Results were published in separate papers in The Lancet.

In new patients with generalized or unclassified epilepsy, levetiracetam did not meet non-inferiority criteria compared with valproate in intention-to-treat analysis of time to 12-month remission (HR 1.19, 95% CI 0.96-1.47; non-inferiority margin 1.329), reported Anthony Marson, MD, of University of Liverpool in England, and co-authors. Treatment failure due to inadequate seizure control was more likely with levetiracetam, and a per-protocol analysis that took treatment failure into account found valproate to be superior (HR 1.68, 95% CI 1.30–2.15). Cost-effectiveness based on differences in costs and quality-adjusted life years found valproate to be superior.

“The available evidence now identifies valproate as more clinically and cost effective than both lamotrigine and levetiracetam,” Marson said in a statement. “Levetiracetam has been widely adopted in the U.K. and worldwide as a first-line treatment for focal epilepsy, but this should no longer be the case as it is neither clinically nor cost effective compared to lamotrigine,” he added.

Stiripentol in the Treatment of Adults With Focal Epilepsy: A Retrospective Analysis

Abstract, originally published in Seizure

Objectives: The aim of the present study was to evaluate the safety and efficacy of the add-on treatment of stiripentol (STP) in adult patients with severely pharmacoresistant focal or multifocal epilepsy.

Methods: Data on adult patients treated with STP from March 2007 to July 2020 and with at least one clinical follow-up (FU) were retrospectively reviewed. Data on tolerability, efficacy and concomitant medication were evaluated at baseline, 6 months (5.5 ± 1.6 months (mean ± SD)) and 12 months (13.1 ± 3.9 months (mean ± SD)).

Results: Data of 22 patients (54.5% male, mean age 34.4 ± 17.79 years (mean ± SD), including mean duration of epilepsy 17.6 ± 25.5 years (mean ± SD), median seizure frequency 30 ± 20 (median ± MAD) per month, and 63.6% being severely intellectually disabled, with 3 to 18 previous anti-seizure-drugs (ASD), were collected. After 6 months, 72.7% of the patients were still taking STP, and 31% of the patients were responders, including 13% who were seizure-free. The 12-month retention rate was 54.4 %, the response rate was 36.4% and 13.6% of patients were seizure-free at the 12-month FU. Reasons for discontinuation were increased seizure frequency, hyperammonaemia and encephalopathy.

Conclusion: Stiripentol seems to be a useful option in the treatment of patients with severely pharmacoresistant epilepsy. Prospective trials are necessary to examine the efficacy of stiripentol in adult patients with pharmacoresistant focal epilepsy.