Status Epilepticus: Practice Variation and Adherence to Treatment Guideline in a Large Community Hospital

Abstract, published in Journal of Neurological Sciences

Purpose: To evaluate the treatment of status epilepticus (SE) and adherence to treatment guideline in a large Finnish community hospital.

Materials and methods: A consecutive series of 137 patients treated in the emergency department of Kuopio University Hospital. Enrollment took place between March 23 and December 31, 2015. Pediatric patients and postanoxic seizures were excluded. The Finnish Status Epilepticus Current Care Guideline was used as the evaluation benchmark.

Results: Seventeen patients recovered spontaneously. First-line treatment was given to 108 patients with 35.2% efficacy. Second-line treatment was given to 81 patients with 87.7% efficacy. Six patients with refractory SE received successful third-line treatment and four were excluded from intensive care because of futility. The starting dose of a first-line drug was lower than the lowest therapeutic dose in 37.0% of the patients. The escalation from first- to second-line treatment took longer than 60?min in 55.1% of the 70 patients who received both treatments. The first loading dose of a second-line drug was markedly low (<80% of the recommended dose) in 26.2% of the 81 patients treated with second-line drugs.

Conclusions: Prompt and effective pharmacotherapy is the cornerstone of good status epilepticus treatment. Subtherapeutic doses of first-line benzodiazepines should be avoided. Benzodiazepine-resistant status epilepticus must be recognized early to facilitate rapid treatment escalation. The quality of second-line treatment suffers from excessive delays and inadequate weight-based dosing of anti-seizure medications.

Neurodevelopmental Outcomes in Children Exposed to Newer Anti-seizure Medications: A Systematic Review

Abstract, published in Epilepsia

As prenatal exposure to certain older anti-seizure medications (ASMs) has been linked with poorer neurodevelopmental outcomes in children, the use of newer ASMs throughout pregnancy has increased. The current review aimed to delineate the impact of in utero exposure to these newer ASMs on child neurodevelopment. A systematic search of MEDLINE, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature Plus, and PsycINFO was conducted, limiting results to articles available in English and published after the year 2000. Studies investigating neurodevelopmental outcomes following in utero exposure to the following ASMs were eligible for inclusion in the review: eslicarbazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, topiramate, and zonisamide. Thirty-five publications were identified, and a narrative synthesis was undertaken. Methodological quality was variable, with distinct patterns of strengths/weaknesses attributable to design. Most studies examined lamotrigine exposure and reported nonsignificant effects on child neurodevelopment. Comparatively fewer high-quality studies were available for levetiracetam, limiting conclusions regarding findings to date. Data for topiramate, gabapentin, and oxcarbazepine were so limited that firm conclusions could not be drawn. Concerningly, no studies investigated eslicarbazepine, lacosamide, perampanel, or zonisamide. Exposure to certain newer ASMs, such as lamotrigine and levetiracetam, does not thus far appear to impact certain aspects of neurodevelopment, but further delineation across the different neurodevelopmental domains and dosage levels is required. A lack of data cannot be inferred to represent safety of newer ASMs, which are yet to be investigated.

The Use of Computational Models in the Management and Prognosis of Refractory Epilepsy: A Critical Evaluation

Abstract, published in Seizure

Purpose: Drug resistant epilepsy (DRE) affects approximately 30 percent of individuals with epilepsy worldwide. Surgery remains the most effective treatment for individuals with DRE, but referral to surgery is low and only about 60 percent of individuals who undergo surgery experience seizure control postoperatively. The present paper evaluates the evidence for using computational models in the prediction of surgical resection sites and surgical outcomes for patients with DRE.

Methods: We conducted a search in the Medline data base using the terms “refractory epilepsy”, “drug-resistant epilepsy”, “surgery”, “computational model”, and “artificial intelligence”. Inclusion: original articles in English and case reports from 2000 to 2020. Reviews were excluded.

Results: Clinical applications of computational models may lead to increased utilization of surgical services through improving our ability to predict outcomes and by improving surgical outcomes outright. The identification and optimization of nodes that are crucial for the genesis and propagation of epileptiform activity offers the most promising clinical applications of computational models discussed herein.

Conclusion: Advances in computational models may in the future significantly increase the application and efficacy of surgery for patients with drug resistant epilepsy by optimizing the site and amount of cortex to resect, but more research is needed before it achieves therapeutic utility.

A Drug from Resin to Combat Epileptic Seizures

Article, 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 anti-seizure 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.

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

Abstract, 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.

Experiences of Emotional and Psychosocial Functioning after Frontal Lobe Resection for Epilepsy

Abstract, published in Epilepsy & Behavior

Purpose: Frontal lobe resection (FLR) is the second most common epilepsy surgery procedure in adults. Few studies address neuropsychological consequences after FLR. The aim of this study was to explore patients’ and relatives’ experiences of cognitive, emotional and social cognitive functioning after frontal lobe epilepsy surgery.

Methods: Semi-structured interviews were held with 14 patients having gone through FLR as adults during the years 2000-2016 and 12 of their relatives. Interviews were audio-recorded, transcribed and analyzed with inductive qualitative content analysis.

Results: Positive as well as negative consequences were described both by patients and relatives. Feelings of relief and an increased capacity to experience emotions of well-being were mainly experienced as related to seizure freedom. A newfound autonomy and a more grown-up identity as opposed to a self-image based on epilepsy was also highlighted. However, results also showed that even for seizure free patients, FLR could give rise to negative experiences, the most prominent of which were mental fatigue, lowered mood and social withdrawal. Coping strategies included planning ahead to avoid mental exhaustion. Over all, respondents considered that the epilepsy surgery had been a risk well worth taking and that positive consequences outweighed the negative ones.

Conclusions: This study shows a range of positive as well as negative outcomes after frontal lobe resection for epilepsy. The findings indicate that lowered mood and mental fatigue could affect the life situation in a negative way, regardless of seizure outcome. This is important to consider in the preoperative counselling of patients and their families, as well as in the postsurgical follow-up. It is also crucial that the epilepsy surgery team has the possibility to offer rehabilitation and support to families regarding these aspects after surgery.

Exercise-linked Consequences on Epilepsy

Abstract, 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.

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

Abstract, 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.

New Research Could Lead to Better Treatment for Epilepsy

Summary, published in Science Daily

Scientists have discovered that the way in which neurons are connected within regions of the brain, can be a better indicator of disease progression and treatment outcomes for people with brain disorders such as epilepsy.

Many brain diseases lead to cell death and the removal of connections within the brain. In a new study, published in Human Brain Mapping, a group of scientists, led by Dr Marcus Kaiser from the School of Medicine at the University of Nottingham, looked at epilepsy patients undergoing surgery.

They found that changes in the local network within brain regions can be a better predictor of disease progression, and also whether surgery will be successful or not.

The team found that looking at connectivity within regions of the brain showed superior results to the current approach of only observing fiber tract connectivity between brain regions. Dividing the surface of the brain into 50,000 network nodes of comparable size, each brain region could be studied as a local network with 100-500 nodes. These local networks showed distinct changes compared to a control group not suffering from epileptic seizures.

Researchers Identify Potential Approach to Controlling Epileptic Seizures

Article, published in Medical Xpress

Researchers from Case Western Reserve University have identified a potential new approach to better controlling epileptic seizures. Lin Mei, professor and chair of the Department of Neurosciences at the Case Western Reserve School of Medicine, who led the new study in mouse models, said the team found a new chemical reaction that could help control epileptic seizures.

Their findings were recently published in The Journal of Clinical Investigation.

In Dravet syndrome, a genetic type of epilepsy that is among the more severe forms of the condition, the sodium channel—a membrane pore critical for inhibiting neuron activation—is mutated and allows excitatory neurons to misfire, causing seizures.

“It would be great if you could find a mechanism to make the sodium channels more stable,” Mei said.

He and his colleagues found that a chemical reaction in the brain, called neddylation, stabilizes the sodium channel in mouse models. When the researchers produced a mouse that lacked the protein required for neddylation in inhibitory neurons, it developed epilepsy. The surprising emergence of the condition inspired the team to explore the neddylation process in more depth; eventually they discovered that neddylation plays a critical role of for the sodium channel.

The next step in their research, he said, is to identify drugs or approaches that can manipulate this chemical reaction to stabilize the sodium channel. The researchers are also conducting further experiments to determine whether this applies to patients with other types of epilepsy, not just Dravet patients.