Alternative Treatment for Epileptic Seizures in Children Identified

A new study published in The Lancet, involving researchers from the University of Liverpool and Alder Hey Children’s Hospital Trust, has identified a ‘user friendly’ treatment for the most common life-threatening neurological emergency in children.

Convulsive status epilepticus (CSE) is the situation when a tonic-clonic seizure doesn’t stop either on its own or with anticonvulsants. It is the most common life-threatening neurological emergency in children.

Currently, CSE is treated using an algorithm which incorporates 10 min intervals between treatments. Second-line treatment is given when CSE persists either after two doses of the first-line treatment, which is an anticonvulsant called a benzodiazepine, or the child’s personalized emergency (rescue) treatment.

The anticonvulsant medication phenytoin has been used as the usual second-line treatment of CSE for several decades and is known to have rare but potentially dangerous side effects. However, some evidence suggests that another medication, levetiracetam could be an effective and safer alternative. To ascertain which treatment was safest and most effective the EcLiPSE Team, made up of doctors from Alder Hey and Bristol Children’s Hospitals together with research teams from the Universities of Liverpool and the West of England, conducted a trial to compare the efficacy and safety of both drugs for second-line management of CSE.

“Our results suggest that levetiracetam could be considered as an alternative treatment to phenytoin for second-line management of pediatric CSE. Possible benefits of levetiracetam over phenytoin include its ease of preparation and administration, minimal interaction with antiepilepsy and other drugs, and easy conversion to oral maintenance therapy. Further randomised clinical trial and meta-analysis data could help to confirm our results and might lead to levetiracetam being the preferred second-line anticonvulsant in children with benzodiazepine-resistant convulsive status epilepticus.

Lower Hospitalization Rates In Epilepsy Patients Treated With Adjunctive FYCOMPA® (perampanel) CIII

Eisai Inc. presented the latest clinical results on FYCOMPA® (perampanel) CIII, at the 2019 American Academy of Neurology Annual Meeting in Philadelphia, including analyses highlighting the health and economic benefits of FYCOMPA. Twenty-one scientific abstracts were presented by both Eisai and independent investigators, underscoring a collective commitment to advancing research in epilepsy care across the age spectrum.

“At Eisai, we are working to develop solutions, including medications and technology, with the ultimate goal of helping epilepsy patients achieve seizure freedom,” said Lynn Kramer, MD, Chief Clinical Officer and Chief Medical Officer, Neurology Business Group, Eisai Inc. “The FYCOMPA data we’ve presented at AAN provides insights that we hope will help improve patient care and shows Eisai’s commitment to continuing research that supports the epilepsy community in this mission.”

Key findings show that:

* Patients treated with perampanel had a significantly greater reduction in all-cause hospitalizations compared to those treated with lacosamide, (25.3% vs 30.3%; p=0.0010; respectively). A similar result was seen for epilepsy-related hospitalizations (a reduction of 19.6% vs. 22.6%; p=0.0376, perampanel and lacosamide, respectively).

* The risk of all-cause inpatient hospitalizations decreased in Medicaid patients with epilepsy who were treated with perampanel for one year (38% pre-perampanel vs 30% post-perampanel; risk ratio of 0.79 [0.69-0.90]). A similar result was seen for epilepsy-related hospitalizations (32% pre-perampanel vs 25% post-perampanel; risk ratio of 0.78 [0.67-0.91]).

* In patients with uncontrolled epilepsy, treatment with a long half-life AED was associated with a significantly lower risk of hospitalization than those treated with a short half-life AED (in both unadjusted [0.81, 95% CI: 0.73, 0.89; p<0.001] and adjusted relative risk of hospitalization [0.84, 95% CI: 0.76, 0.93; p=0.0007]).

Rates of Adherence to Antiepileptic Drug Monotherapy for Focal Seizure

Patients receiving eslicarbazepine acetate (ESL) monotherapy may have similar-to-higher rates of adherence compared with patients receiving generic carbamazepine (CBZ) and oxcarbazepine (OXC), according to research presented at the 2019 American Academy of Neurology’s Annual Meeting, held May 4-10, in Philadelphia.

This retrospective cohort study examined rates of adherence to antiepileptic drug (AED) monotherapy treatment for patients with focal seizures by comparing ESL with generic CBZ and OXC. Investigators analyzed patient-level administrative claims data from the Quintiles IMS PharMetrics Database. These drugs have varied side effect profiles, and prior research has suggested that the differences in adverse effects across AEDs are likely associated with treatment adherence differences. Prior research suggests nonadherence to AEDs is associated with adverse outcomes.

Breakthrough for Children with Serious Epileptic Seizures

Emergency medicine doctors now have a better way to treat severe epileptic seizures in children, thanks to a New Zealand-Australian study.

Prolonged epileptic seizures are the most common neurological emergency in children seen by hospitals. The seizures are potentially fatal: up to five percent of affected children die, and a third suffer long-term complications from brain damage. Crucially, the longer the seizure, the greater the chance of long-term complications.

The study – which will change management of this condition internationally – was published in the prestigious medical journal The Lancet. It was led by Professor Stuart Dalziel from the Faculty of Medical and Health Sciences at the University of Auckland and Starship Children’s Hospital, and the senior author was Professor Franz Babl at Melbourne’s Murdoch Children’s Research Institute.

Diazepam Nasal Spray Safe to Treat Frequent Breakthrough Seizures in Epilepsy

Diazepam nasal spray is safe and well tolerated in patients with epilepsy who experience frequent breakthrough or acute repetitive seizures, according to research presented at the 2019 American Academy of Neurology Annual Meeting, held May 4-10, 2019, in Philadelphia, Pennsylvania.

In this interim analysis, investigators assessed the long-term safety of diazepam after repeat doses administered to patients with epilepsy who experienced frequent breakthrough seizures or acute repetitive seizures over 12 months. Doses (5 mg, 10 mg, 15 mg, or 20 mg) were based on age and body weight and were modified as needed; participants documented time and duration of seizures in patient diaries, along with any outcome events.

The safety population included 109 patients who received at least 1 dose of diazepam. A total of 1585 seizure episodes were treated with diazepam over the study period. In 1457 (92%) episodes, a single dose of diazepam was adequate to stop the seizure.

Study Reveals How Glial Cells May Play Key Epilepsy Role

A study provides potential new targets for treating epilepsy and novel fundamental insights into the relationship between neurons and their glial “helper” cells. In eLife, scientists at MIT’s Picower Institute for Learning and Memory report finding a key sequence of molecular events in which the genetic mutation in a fruit fly model of epilepsy leaves neurons vulnerable to becoming hyper activated by stress, leading to seizures.

About 60 million people worldwide have epilepsy, a neurological condition characterized by seizures resulting from excessive neural activity. The “zydeco” model flies in the study experience seizures in a similar fashion. Since discovering zydeco, the lab of MIT neurobiologist Troy Littleton, Menicon Professor in Neuroscience, has been investigating why the flies’ zydeco mutation makes it a powerful model of epilepsy.

Heading into the study, the team led by postdoc Shirley Weiss knew that the zydeco mutation was specifically expressed by cortex glial cells and that the protein it makes helps to pump calcium ions out of the cells. But that didn’t explain much about why a glial cell’s difficulty maintaining a natural ebb and flow of calcium ions would lead adjacent neurons to become too active under seizure-inducing stresses such as fever-grade temperatures or the fly being jostled around.

The activity of neurons rises and falls based on the flow of ions – for a neuron to “fire,” for instance, it takes in sodium ions, and then to calm back down it releases potassium ions. But the ability of neurons to do that depends on there being a conducive balance of ions outside the cell. For instance, too much potassium outside makes it harder to get rid of potassium and calm down.

The need for an ion balance – and the way it is upset by the zydeco mutation – turned out to be the key to the new study. In a four-year series of experiments, Weiss, Littleton and their co-authors found that excess calcium in cortex glia cells causes them to hyper-activate a molecular pathway that leads them to withdraw many of the potassium channels that they typically deploy to remove potassium from around neurons. With too much potassium left around, neurons can’t calm down when they are excited, and seizures ensue.

“No one has really shown how calcium signaling in glia could directly communicate with this more classical role of glial cells in potassium buffering,” Littleton said. “So this is a really important discovery linking an observation that’s been found in glia for a long time – these calcium oscillations that no one really understood – to a real biological function in glial cells where it’s contributing to their ability to regulate ionic balance around neurons.”

Paving the Way for Innovative Treatment of Epilepsy

A drug commonly used to treat multiple sclerosis may, after necessary modifications, one day be used to treat patients with epilepsy, researchers in Prof. Inna Slutsky’s lab at the Sackler Faculty of Medicine and Sagol School of Neuroscience at Tel Aviv University have discovered.

This is good news for patients with Dravet syndrome, one of the most dangerous forms of childhood epilepsy, for which there is currently no effective treatment.

According to a new study published on April 29 in Neuron, Tel Aviv University researchers uncovered a piece of a puzzle that has eluded scientists for 100 years of studying homeostasis: What is the mechanism that maintains activity set points in neural circuits?

While it is well-understood that the brain functions in a narrow range of activity between status epilepticus and coma, how neural circuits maintain stable activity in a constantly changing environment has remained unknown.

“The concept of homeostasis has a long history in physiology, starting from the work of Claude Bernard in the middle of 19th century on the stability of the milieu interior. In the middle of 20th century, James Hardy proposed a model in which homeostatic mechanisms maintain physiological variables with an acceptable range around a ‘set point’ value. However, the research of neuronal homeostasis began only 25 years ago, and we still don’t understand how it works,” explains Prof. Slutsky. “What we have found is a homeostatic mechanism that acts as a sort of a thermostat of the neural circuits, which ensures the return to a set point after each event that increases or decreases brain activity.

“Our findings may serve as a basis for the development of drugs for a range of neurological and neurodegenerative diseases such as Alzheimer’s and Parkinson’s, which, like epilepsy, are characterized by instability of brain activity.”

Study Shows Vagus Nerve Stimulation Has a Beneficial Effect on Symptoms of Depression in Patients with Difficult-To-Treat Epilepsy

PURPOSE: Vagus nerve stimulation (VNS) is well established in the treatment of epilepsy and disorders of depression. The prevalence of depression is high in patients with epilepsy, but still it remains unclear how patients with a comorbidity of epilepsy and symptoms of depression respond to VNS.

METHODS: Researchers investigated 59 patients with different subtypes of disorders of depression as a comorbidity of epilepsy, who underwent VNS-surgery. Before and one year after VNS surgery, the severity of symptoms of depression was evaluated by a psychiatrist using Montgomery-Åsberg Depression Rating Scale (MADRS) and Beck-Depressions-Inventory (BDI). Response towards epilepsy was measured by a seizure reduction of at least 50%.

RESULTS: Symptoms of depression ameliorated in response to VNS in the overall of all patients MADRS 29 to 18 (p < 0,001) and BDI 24 to 14 (p < 0,001) and all subtypes of disorders of depression. Seizure reduction of at least 50% was achieved in two out of three of all patients two years after VNS.

CONCLUSION: This study was able to show the beneficial effect of vagus nerve stimulation in the treatment of patients with pharmacoresistant epilepsy and a comorbidity of symptoms of depression.

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.