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

Study: Cardiac Arrhythmia and Neuroexcitability Gene Variants in Resected Brain Tissue from Patients with Sudden Unexpected Death in Epilepsy (SUDEP)

[Researcher’s] data shows that genomic analysis of brain tissue resected for seizure control can identify potential genetic biomarkers of SUDEP risk.

Abstract: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in young adults. The exact mechanisms are unknown, but death often follows a generalized tonic-clonic seizure. Proposed mechanisms include seizure-related respiratory, cardiac, autonomic, and arousal dysfunction.

Genetic drivers underlying SUDEP risk are largely unknown. To identify potential SUDEP risk genes, we compared whole-exome sequences (WES) derived from formalin-fixed paraffin embedded surgical brain specimens of eight epilepsy patients who died from SUDEP with seven living controls matched for age at surgery, sex, year of surgery and lobe of resection. We compared identified variants from both groups filtering known polymorphisms from publicly available data as well as scanned for epilepsy and candidate SUDEP genes. In the SUDEP cohort, we identified mutually exclusive variants in genes involved in µ-opiod signaling, gamma-aminobutyric acid (GABA) and glutamate-mediated synaptic signaling, including ARRB2, ITPR1, GABRR2, SSTR5, GRIK1, CTNAP2, GRM8, GNAI2 and GRIK5. In SUDEP patients we also identified variants in genes associated with cardiac arrhythmia, including KCNMB1, KCNIP1, DPP6, JUP, F2, and TUBA3D, which were not present in living epilepsy controls.

Study: Phenotypic Spectrum in Families with Mesial Temporal Lobe Epilepsy Probands

Purpose: The traditional perception of mesial temporal lobe epilepsy (MTLE) as a predominantly acquired disorder is challenged due to emerging evidence of familial aggregation. In this study, we ascertained the extent of familial occurrence of epilepsy in MTLE patients, as well as phenotypic heterogeneity in affected relatives.

Methods: We identified and reevaluated patients with MTLE, treated at Epilepsy Department for a period of two years. All eligible putatively affected relatives were asked to participate in the study. In addition to comprehensive epilepsy interview, they underwent EEG and MRI studies.

Results: 52 patients with MTLE were included; nine of them (17%) had at least one family member with epilepsy. Subsequently, we analyzed nine probands with MTLE and a total of 15 relatives with seizures. Among affected relatives, spectrums of clinical manifestations were observed. Typical MTL seizures were described in five individuals, while other types of focal or generalized tonic-clonic seizures were reported in other ten relatives. A total of seven individuals had febrile seizures. Hippocampal sclerosis was found in three probands and none of the relatives. Two of affected family members had a traumatic brain injury in addition to febrile seizures, prior to the occurrence of their epilepsy.

Conclusion: We demonstrate that familiar occurrence of epilepsy and subsequently putative genetic background, accounts for a substantial proportion MTLE patients. In addition, we foreground the remarkable intra- and interfamilial phenotypic heterogeneity than usually described, displaying the complexity of the genotype-phenotype correlations.

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

 

Study: Cardiac Arrhythmia and Neuroexcitability Gene Variants in Resected Brain Tissue from Patients with Sudden Unexpected Death in Epilepsy (SUDEP)

[Researcher’s] data shows that genomic analysis of brain tissue resected for seizure control can identify potential genetic biomarkers of SUDEP risk.

Abstract: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in young adults. The exact mechanisms are unknown, but death often follows a generalized tonic-clonic seizure. Proposed mechanisms include seizure-related respiratory, cardiac, autonomic, and arousal dysfunction.

Genetic drivers underlying SUDEP risk are largely unknown. To identify potential SUDEP risk genes, we compared whole-exome sequences (WES) derived from formalin-fixed paraffin embedded surgical brain specimens of eight epilepsy patients who died from SUDEP with seven living controls matched for age at surgery, sex, year of surgery and lobe of resection. We compared identified variants from both groups filtering known polymorphisms from publicly available data as well as scanned for epilepsy and candidate SUDEP genes. In the SUDEP cohort, we identified mutually exclusive variants in genes involved in µ-opiod signaling, gamma-aminobutyric acid (GABA) and glutamate-mediated synaptic signaling, including ARRB2, ITPR1, GABRR2, SSTR5, GRIK1, CTNAP2, GRM8, GNAI2 and GRIK5. In SUDEP patients we also identified variants in genes associated with cardiac arrhythmia, including KCNMB1, KCNIP1, DPP6, JUP, F2, and TUBA3D, which were not present in living epilepsy controls.

Clinical Trial: Investigating Epilepsy – Screening, Evaluation and Treatment

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.

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.

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

 

Study start date: March 28, 2018
Estimated study completion date: August 31, 2027

Study: Detailed Magnetic Resonance Imaging (MRI) Analysis in Infantile Spasms

Purpose: To evaluate initial magnetic resonance imaging (MRI) abnormalities in infantile spasms, correlate them to clinical characteristics, and describe repeat imaging findings.

Methods: A retrospective review of infantile spasm patients was conducted, classifying abnormal MRI into developmental, acquired, and nonspecific subgroups.

Results: MRIs were abnormal in 52 of 71 infantile spasm patients (23 developmental, 23 acquired, and 6 nonspecific) with no correlation to the clinical infantile spasm characteristics. Both developmental and acquired subgroups exhibited cortical gray and/or white matter abnormalities. Additional abnormalities of deep gray structures, brain stem, callosum, and volume loss occurred in the structural acquired subgroup. Repeat MRI showed better definition of the extent of existing malformations.

Conclusion: In structural infantile spasms, developmental/acquired subgroups showed differences in pattern of MRI abnormalities but did not correlate with clinical characteristics.

$2 Million for Medical Research on Epilepsy

The Australian Government will invest $2 million in new medical research to help find a cure for rare genetic epilepsy disorders.

This new funding will support our leading researchers to investigate genetic and other causes of epilepsy including the mutation of the Syngap gene, a rare neurological condition which can lead to epilepsy.

The SYNGAP-1 project will be the first project undertaken by the Australian Epilepsy Research Fund, and will be led by researchers from the respected Florey Institute of Neuroscience and Mental Health.

The Australian Epilepsy Research Fund has been established by the Epilepsy Foundation to provide Australians living with genetic and other types of epilepsy hope for the future through medical research.

Findings From Comprehensive Drug Repurposing Screening To Treat Epileptic Encephalopathy Published In Epilepsia

Pairnomix, LLC announced on March 26, 2018 that results from a comprehensive drug repurposing screen performed for a patient with SCN8A epilepsy were published as an original research article online and in an upcoming print issue of Epilepsia, the official journal of the International League Against Epilepsy (ILAE) and a leading, authoritative source for current research results on all aspects of epilepsy.

The study, A Comprehensive Approach to Identifying Repurposed Drugs to Treat SCN8A Epilepsy details rigorous efforts to identify repurposed drug options for a patient with epileptic encephalopathy caused by the SCN8A R1872Q genetic mutation. Whereas most drug repurposing studies focus on one or a few select compounds, this research highlights a broader approach using high-throughput technologies to screen hundreds of on-market drugs in a single experiment. In this study, 90 drugs were identified to have a significant effect in cellular studies; the majority of these drugs have never been implicated as having effects on ion channels or epilepsy and therefore represent potentially novel mechanistic activity.

Gregory Stewart, PhD, Chief Scientific Officer at Pairnomix, remarked, “We are very pleased to share these results and the research approach we have undertaken to identify drug options for physicians to consider in their medical management of patients with the SCN8A R1872Q variant. Our work demonstrates the utility of comprehensive, high-throughput drug screens to identify new drug options for patients that are available for immediate clinical use.”