Study: Off-Label Use and Manipulations of Antiepileptic Drugs in Children – Analysis of the Outpatient Prescriptions in a Tertiary Center

Conclusion: Off-label use and manipulations of AEDs remains an important problem in home care of children with epilepsy. This is mainly a concern for the most vulnerable groups, i.e., young patients, patients undergoing polytherapy, and patients with developmental and epileptic encephalopathy (DEE). International initiatives have been launched to improve the availability of labeled and adapted drugs in this population.

Objectives: Little is known about off-label use and manipulations to achieve the prescribed dose of antiepileptic drugs (AEDs) in outpatient prescriptions. This study aimed to evaluate this practice in a tertiary center for child epilepsy.

Methods: We reviewed off-label use and manipulations of AEDs delivered to the outpatient’s epilepsy clinic. Multivariate logistic regressions were used to determine the factors associated with off-label and manipulated uses.

Results: Five hundred eleven consultations generated 897 AED deliveries (1.75/consultation). Off-label use involved 182 (20.3%) of prescribed AEDs. Factors associated with off-label use were polytherapy and new AEDs while increase of age and nondevelopmental and structural-metabolic etiologies have a protective effect. Among the 1725 doses of AEDs prescribed per day, 33.5% generated manipulations (n=582): 40% inadequate (n=237) and 60% adequate (203 syrups, 112 scored tablets, 30 drops medicine). Polytherapy (p<10-4) and the absence of market authorization significantly favored manipulations whereas the increase in age restricted them.

Clinical Trial: Application of Novel Diagnostic and Therapeutical Methods in Epilepsy and Neurodevelopmental Abnormalities in Children (EPIMARKER)

Brief Summary: Epilepsy affects 1% of the world’s population and 6 million people in Europe. The estimated total cost of €20 billion in Europe in 2014 makes epilepsy a significant socioeconomic burden. Despite great progress in the management of epilepsy and increasing numbers of antiepileptic drugs, 30-40% of epilepsy patients are refractory to all available medications. Moreover, in childhood epilepsy is a causative factor of psychiatric and behavioral comorbidities, including developmental delay and autism spectrum disorder. In spite of multiple trials no reliable biomarker of epilepsy development has been identified. There are no studies on biomarkers of drug-resistance or epilepsy recurrence after the drug withdrawal.

EPIMARKER is a first project, carried out in humans, which is going to examine in prospective way clinical, electroencephalographic and molecular biomarkers to produce an integrative tool useful in everyday diagnosis and treatment of epilepsy in children to prevent the development of drug-resistant epilepsy and its behavioral comorbidities as mental retardation and autism. The set of molecular biomarkers will be determined by quantitative transcriptomic and proteomic studies and validated in reprogrammed cellular models.

Actual Study Start Date: April 1, 2017
Estimated Primary Completion Date: March 30, 2020

Eligibility Criteria

Ages Eligible for Study: up to 16 Years (Child)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: Yes

Inclusion Criteria WP1:

  • Male or female children with a definite diagnosis of TSC (Roach 1998)
  • Aged up to 4 years
  • Diagnosis of epilepsy established on the basis of clinical seizures or
  • Epileptiform changes on EEG within 1-7 days prior to baseline
  • Written informed consent of caregivers

 

Inclusion Criteria WP2:

  • Male or female children with a definite diagnosis of TSC (Roach criteria: Roach 1998) with epilepsy
  • Aged up to 16 years
  • Seizure free, in whom a decision to withdraw antiepileptic drugs was made
  • Written informed consent of caregivers

Study: Association of Time to Treatment With Short-term Outcomes for Pediatric Patients With Refractory Convulsive Status Epilepticus

Importance: Treatment delay for seizures can lead to longer seizure duration. Whether treatment delay is associated with major adverse outcomes, such as death, remains unknown.

Objective: To evaluate whether untimely first-line benzodiazepine treatment is associated with unfavorable short-term outcomes.

Main Outcomes and Measures: The primary outcome was death during the related hospital admission. The secondary outcome was the need for continuous infusion for seizure termination. Multivariate analysis of mortality controlled for structural cause, febrile RCSE, age, and previous neurological history (including previous RCSE events). Use of continuous infusions was additionally adjusted for generalized RCSE, continuous RCSE, and 5 or more administrations of antiseizure medication.

Results: A total of 218 patients were included, among whom 116 (53.2%) were male and the median (interquartile range) age was 4.0 (1.2-9.6) years. The RCSE started in the prehospital setting for 139 patients (63.8%). Seventy-four patients (33.9%) received their first-line benzodiazepine treatment in less than 10 minutes, and 144 (66.1%) received untimely first-line benzodiazepine treatment. Multivariate analysis showed that patients who received untimely first-line benzodiazepine treatment had higher odds of death, had greater odds of receiving continuous infusion, had longer convulsive seizure duration, and had more frequent hypotension. In addition, the timing of the first-line benzodiazepine treatment was correlated with the timing of the second-line and third-line antiseizure medications.

Conclusions and Relevance: Among pediatric patients with RCSE, an untimely first-line benzodiazepine treatment is independently associated with a higher frequency of death, use of continuous infusions, longer convulsion duration, and more frequent hypotension. Results of this study raise the question as to whether poor outcomes could, in part, be prevented by earlier administration of treatment.

Incorporating Multidimensional Psychosocial Interventions Improves the Well-being of Individuals With Epilepsy Clinical Trial

Detailed Description: Though tremendous advances have been made in the diagnosis and treatment of individuals with epilepsy, much remains to be done when it comes to improving their psychosocial well-being. Many individuals with epilepsy have difficulty adhering to treatment, documenting their seizure types, coping with memory difficulties, dealing with stress, and suffer from depression. These factors limit the quality of life of epilepsy patients and prevent them from realizing their full potential.

Patients will enroll in one of four interventions that help improve medication adherence, increase seizure awareness and documentation, improve memory and deal with stress and depression. Patient assessments will be conducted before and after intervention to gauge the efficacy of the programs.

The specific aims of this study are to assess the feasibility and patient acceptability of incorporating multidimensional self-management and psychosocial interventions into routine epileptic care, as well as, determine whether these incorporations improve self-management, quality-of-life, and other measures of well-being.

Anticipated Study Start Date: April 9, 2018
Estimated Study Completion Date: April 30, 2020

Eligibiliy Criteria

Ages Eligible for Study: 18 Years to 88 Years (Adult, Senior)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria

  • Clinical diagnosis of epilepsy using established criteria
  • Patient self-identified as own primary caregiver
  • English fluency
  • Ability to provide informed consent
  • Ability to complete the study assessments

 

Exclusion Criteria

  • History of non-epileptic seizures
  • History of cognitive impairments that prevents them from providing informed consent and completing study assessments

Epilepsy Drug Exposure in Womb is Linked to Poorer School Test Results, Study Reveals

The research published recently online in the Journal of Neurology Neurosurgery & Psychiatry recommends that mums-to-be need to be fully informed of the risks of treatment, but these should be weighed against the need for effective seizure control during pregnancy, say the researchers.

Women with epilepsy who need drugs to control their seizures are currently advised to continue taking them during pregnancy because convulsions can harm both mother and the unborn child.

Several studies indicate that epilepsy drugs, particularly sodium valproate, taken during pregnancy, are associated with neurodevelopmental disorders, but few of these studies have been based on real-life population circumstances (population data).

To address this, the researchers from the Neurology Research Group in Swansea University Medical School used routinely-collected healthcare data from the Secure Anonymous Information Linkage (SAIL) databank and national school test (key stage 1) data to compare the academic performance of 7 year olds in Wales born to mothers with epilepsy. SAIL contains the anonymized primary care health records of 80 percent of Welsh family doctors, corresponding to around 77 percent of the Welsh population (2.3 million people).

Stem Cell Discovery Could Aid in Developing Treatments to Control Epileptic Convulsions

A new line of human stem cells shows promise for one day advancing treatment for epileptic seizures. As reported in STEM CELLS Translational Medicine (SCTM), the cells are designed to deliver adenosine – which calms down overexcited neurons and protects them from damage — to the central nervous system (CNS). The research was conducted by scientists at the University of Bonn and the Central Institute of Mental Health (CIMH) in Mannheim.

Adenosine is a powerful regulator that helps the body maintain its inner balance. When an injury occurs to the CNS, it releases high levels of adenosine, which calms down the overexcited neurons and alleviates neurological damage caused by stroke, trauma, reduced oxygen, pain and, in particular, epileptic seizures. “But attempts to systemically deliver adenosine to needed areas in the CNS during a crisis have been hampered by adenosine’s fast metabolic breakdown, the inability to sufficiently permeate the blood-brain-barrier and serious side effects of such cardiac suppression,” said Philipp Koch, M.D., of the Hector Institute for Translational Brain Research at the CIMH. Dr. Koch headed up the study described in SCTM, which was conducted at the Institute of Reconstructive Neurobiology of the University of Bonn Medical Faculty together with Dr. Oliver Brüstle.

LivaNova Launches Microburst VNS Drug-Resistant Epilepsy Trial

LivaNova announced on March 28 it launched a new feasibility trial of its Microburst Vagus Nerve Stimulation therapy system exploring its safety and effectiveness in treating patients with drug-resistant epilepsy.

The London-based company said that Dr. Rebecca O’Dwyer of Chicago’s Rush University Medical Center has enrolled the first patient in the trial, which aims to enroll a total of 40 patients at 15 US sites.

“At the Rush Epilepsy Center, we are very dedicated to research and advancing the field of epilepsy therapeutics for patients. It is an honor to have enrolled the first patient in the Microburst VNS Therapy Feasibility Study, and we look forward to the resulting impact it will have on this patient population,” Dr. O’Dwyer said in a press release.

The trial will consist of a cohort of 20 patients with primary generalized tonic-clonic seizures and a 20-patient cohort of patients with partial onset seizures, including complex partial seizures with or without secondary generalization.

Patients in the trial will be monitored for 15 months with a primary endpoint measuring the percent change in seizure frequency and stimulation-related adverse events as compared to a baseline. Brain activation in response to stimulation will be assessed using functional magnetic resonance imaging.

Study: Astrocytic Kir4.1 Channels and Gap Junctions Account for Spontaneous Epileptic Seizures

Abstract: Experimental recordings in hippocampal slices indicate that astrocytic dysfunction may cause neuronal hyper-excitation or seizures. Considering that astrocytes play important roles in mediating local uptake and spatial buffering of K+ in the extracellular space of the cortical circuit, we constructed a novel model of an astrocyte-neuron network module consisting of a single compartment neuron and 4 surrounding connected astrocytes and including extracellular potassium dynamics. Next, we developed a new model function for the astrocyte gap junctions, connecting two astrocyte-neuron network modules. The function form and parameters of the gap junction were based on nonlinear regression fitting of a set of experimental data published in previous studies. Moreover, we have created numerical simulations using the above single astrocyte-neuron network module and the coupled astrocyte-neuron network modules.

Our model validates previous experimental observations that both Kir4.1 channels and gap junctions play important roles in regulating the concentration of extracellular potassium. In addition, we also observe that changes in Kir4.1 channel conductance and gap junction strength induce spontaneous epileptic activity in the absence of external stimuli.

Staccato Alprazolam in Epilepsy With Predictable Seizure Pattern (StATES) Clinical Trial: Inpatient, Dose-Ranging Study

Brief Summary: This is a multi-center, double-blind, randomized, parallel group, dose-ranging study to investigate the efficacy and clinical usability of staccato alprazolam in adult (18 years of age and older) subjects with epilepsy with a predictable seizure pattern. These subjects have an established diagnosis of focal or generalized epilepsy with a documented history of predictable seizure episodes. This is an in-patient study. The subjects will be admitted to a Clinical Research Unit (CRU) or Epilepsy Monitoring Unit (EMU) for study participation. The duration of the stay in the in-patient unit will be 2-8 days. One seizure event per subject will be treated with study medication. The duration and timing of the seizure event and occurrence of subsequent seizures will be assessed by the Staff Caregiver(s)1 through clinical observation and confirmed with video electroencephalogram (EEG).

Primary Outcome Measure: Cessation of seizure activity [time frame: 2 hours post-dosing].

Anticipated Study Start Date: March 2018
Anticipated Study Completion Date: May 2019

Eligibility Criteria

Inclusion Criteria

  1. Subject is able to provide, personally signed, and dated informed consent to participate in the study before completing any study related procedures.
  2. Male or female ? 18 years of age.
  3. Has an established diagnosis of focal or generalized epilepsy with a documented history of predictable seizure episodes that includes at least one of the following:
    • Generalized seizure episodes starting with a flurry of absence seizures or myoclonic seizures with a minimum duration of 5 minutes
    • Episodes of a prolonged focal seizure with a minimum duration of 3 minutes
    • Episodes of multiple (?2) focal seizures within a 2-hour time period
  4. Prior to randomization, has experienced ?4 seizure episodes with predictable pattern during the last 4 weeks (qualification period) and no more than one week without a predictable seizure episode before the Screening Visit.
  5. Female participants (if of child-bearing potential and sexually active) and male participants (if sexually active with a partner of child-bearing potential) who agree to use a medically acceptable and effective birth control method throughout the study and for 1 week following the end of the study. Medically acceptable methods of contraception that may be used by the participant and/or his/her partner include abstinence, birth control pills or patches, diaphragm with spermicide,intrauterine device (IUD), surgical sterilization, and progestin implant or injection. Prohibited methods include: the rhythm method, withdrawal, condoms alone, or diaphragm alone.
  6. Subject is able to comply by the requirements of the protocol, particularly the requirements and specific Institution policies during the in-clinic stay.

 

Exclusion Criteria

  1. History or diagnosis of non-epileptic seizures (e.g. metabolic or pseudo-seizures).
  2. History of status epilepticus in the 6 months prior to Screening
  3. Has a progressive neurological disorder such as brain tumor, demyelinating disease, or degenerative central nervous system (CNS) disease that is likely to progress in the next 3 months
  4. Receiving chronic benzodiazepine treatment (defined as an average of ? 4 administrations per week) prior to admission to the in-patient unit
  5. Use of strong CYP 3A4 inhibitors; including azole antifungal agents (e.g., etoconazole, itraconazole), nefazodone, fluvoxamine, cimetidine, HIV protease inhibitors (e.g., ritonavir)
  6. Has severe chronic cardio-respiratory disease
  7. History of HIV-positivity.
  8. Pregnant or breast-feeding.
  9. Clinically significant renal or hepatic insufficiency (hepatic transaminases >2 times the upper limit of normal (ULN) or creatinine ? 1.5 x ULN).
  10. History of acute narrow angle glaucoma, Parkinson’s disease, hydrocephalus, or history of significant head trauma.
  11. Subjects who use medications to treat airways disease, such as asthma or COPD or have any acute respiratory signs/symptoms (e.g., wheezing).
  12. Use of any investigational drug within 30 days or 5 half-lives of the investigational drug prior to administration of study medication, whichever is longer
  13. A history within the past 1 year of drug or alcohol dependence or abuse.
  14. Positive urine screen for drugs of abuse at Screening.
  15. Known allergy or hypersensitivity to alprazolam.
  16. History of glaucoma.
  17. Subjects who currently have an active major psychiatric disorder where changes in pharmacotherapy are needed or anticipated during the study.
  18. Hypotension (systolic blood pressure ?90 mm Hg, diastolic blood pressure ?50 mm Hg), or hypertension (systolic blood pressure ?140 mm Hg, diastolic blood pressure ?100 mm Hg) measured while seated at screening or baseline.
  19. Significant hepatic, renal, gastroenterologic, cardiovascular (including ischemic heart disease and congestive heart failure), endocrine, neurologic or hematologic disease.
  20. Subjects who, in the opinion of the Investigator, should not participate in the study for any reason, including if there is a question about the stability or capability of the subject to comply with the trial requirements.

Investigating Epilepsy Clinical Trial: Screening, Evaluation and Treatment

Objectives: The primary objective is to screen patients who are referred to the NIH with a known or suspected diagnosis of epilepsy for eligibility to participate in ongoing epilepsy-related protocols. The secondary objectives are to provide standard of care evaluation and treatment of patients with drug-resistant epilepsy, to provide training for clinical fellows in the evaluation and treatment of epilepsy and related disorders, and to allow for descriptive and/or correlational studies based on the data collected through clinical care of these patients. This study aims learn more about seizures and find ways to best treat people with drug-resistant epilepsy.

Background: Epilepsy affects about 1 percent of the U.S. population. Most people with epilepsy respond well to medicine, but some do not. Researchers want people who have diagnosed or suspected epilepsy to participate in ongoing studies. They want to learn more about clinical care for epilepsy. They want fellows and residents to learn more about the care of people with epilepsy.

Anticipated Study Start Date: March 30, 2018
Anticipated Study Completion Date: August 31, 2027

Eligibility Criteria 

Ages Eligible for Study: 8 Years and older (Child, Adult, Senior)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Sampling Method: Non-Probability Sample

Inclusion Criteria

  • Age 8 years or older
  • Known or suspected diagnosis of epilepsy
  • Ability to give informed consent or have a legally authorized representative able to give consent (for adults without consent capacity) or parent/guardian able to provide informed consent (for a child)
  • If unable to give informed consent, ability to give assent (for minors 8 and older or adults without consent capacity)

 

Exclusion Criteria

  • Patients with unstable medical conditions that, in the opinion of the investigators, makes participation unsafe, or who, in the opinion of the investigators may be unable to comply with the protocol
  • Patients who are unable to travel to the NIH