Potential EEG Biomarkers and Antiepileptogenic Strategies for Epilepsy in TSC

To determine whether EEGs during infancy is a reliable biomarker to identify TSC patients that will develop infantile spasms/epilepsy in the near future and thus are appropriate candidates for an antiepileptogenic drug trial. Since not all patients with TSC develop epilepsy, it would be useful to have a biomarker that could predict those patients destined to have epilepsy and thus identify those TSC patients most appropriate for an antiepileptogenic drug trial. A recent study suggests that treating TSC patients with an abnormal EEG prior to onset of infantile spasms with vigabatrin may improve neurological outcome, but the use of EEG as a reliable biomarker of future epilepsy has not been rigorously validated. In this specific aim, we will test the reliability of EEG in predicting future development of infantile spasms or epilepsy in TSC patients during the first year of life.

Study Overview

• Status: Completed
• Conditions: Tuberous Sclerosis Complex

Detailed Description

Current therapeutic approaches for epilepsy primarily represent symptomatic treatments that suppress seizures, but have not been demonstrated to prevent epilepsy or modify disease progression. In recent years, there have been tremendous interest and effort by basic scientists and clinicians in epilepsy in developing disease-modifying or "antiepileptogenic" therapies. However, these efforts are hindered by a couple significant limitations: 1) difficulty in identifying an appropriate high-risk patient population in which a preventative approach is feasible and justifiable, and 2) lack of appropriate drug targets with antiepileptogenic properties. Tuberous Sclerosis Complex (TSC) is one of the most common genetic causes of epilepsy and a subset of TSC patients may represent a rational, feasible population to target with an antiepileptogenic approach for several reasons. First of all, some patients are diagnosed with TSC at a young age before the onset of epilepsy due to non-neurological findings - thus, it is feasible to identify these patients and initiate a potential antiepileptogenic treatment at an early stage of epileptogenesis. Second, these patients are at high risk for developing epilepsy (~80%) in the future, including infantile spasms (~35%), a particularly devastating type of childhood epilepsy with a poor prognosis - thus, initiating a therapy with potential side effects in a pre-symptomatic stage can likely be justified in TSC patients. Finally, the identification of the mTOR pathway in the pathophysiology of TSC suggests that mTOR inhibitors could have antiepileptogenic properties in TSC, as already supported by pre-clinical animal studies - thus, a rational mechanistically-based treatment potentially already exists and can be readily tested in TSC patients. However, there may be significant risks and side effects of mTOR inhibitors, especially during early childhood, such as chronic immunosuppression and theoretical effects on learning, growth, and development. Thus, before initiating an antiepileptogenic drug trial in TSC patients, it would be beneficial to obtain further evidence to optimize the selection criteria and treatment paradigms to maximize efficacy and minimize side effects of mTOR inhibitors.

The aim of this clinical trial is to determine whether EEGs during infancy is a reliable biomarker to identify TSC patients that will develop infantile spasms/epilepsy in the near future and thus are appropriate candidates for an antiepileptogenic drug trial.

• Study Type: Observational
• Enrollment (Anticipated): 40

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90095
      • UCLA
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas in Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 6 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Infants that are seizure free at the time of the study enrollment and meets genetic or clinical diagnostic criteria for TSC (determined as standard of care); parent/family guardian health status is unknown

Description

Inclusion Criteria:

Cohort 1

• < 6 months of age; Seizure free at the time of study enrollment; and meets genetic or clinical diagnostic criteria for TSC (Tuberous Sclerosis), the latter based on current recommendations for diagnostic evaluation, such as physical exam, neuroimaging, echocardiogram.

Cohort 2

• Parent or family guardian of infant

Exclusion Criteria:

Cohort 1

• ≥ 6months of age; history of seizures and/or infantile spasms; patients receiving vigabatrin or any anti-epileptic medication or mTOR inhibitor prior to study enrollment Cohort 2
• not parent or family guardian

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
seizure free infants with dx of TSC; infants that are seizure free at the time of the study enrollment and meets genetic or clinical diagnostic criteria for TSC
Parents or family guardian of cohort 1; Parent or family guardian of infants that are seizure free at the time of the study enrollment and meets genetic or clinical diagnostic criteria for TSC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of EEG biomarkers as predictors of developing epilepsy in infants with Tuberous Sclerosis Complex	Physical/neurological exam, Video EEG, Developmental assessments, Blood draw from child and parents/guardian, and Seizure diaries.	3 years

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: The University of Texas Health Science Center, Houston; University of California, Los Angeles; Boston Children's Hospital; Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Martina Bebin, MD, University of Alabama at Birmingham

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: January 7, 2013
• First Submitted That Met QC Criteria: January 10, 2013
• First Posted (Estimate): January 14, 2013

Study Record Updates

• Last Update Posted (Actual): April 11, 2019
• Last Update Submitted That Met QC Criteria: April 9, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Epilepsy; Tuberous Sclerosis Complex; Biomarkers; EEG; Infants; Seizures; TSC
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Congenital Abnormalities; Genetic Diseases, Inborn; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neurocutaneous Syndromes; Hamartoma; Neoplasms, Multiple Primary; Epilepsy; Sclerosis; Tuberous Sclerosis
• Other Study ID Numbers: 1P20NS080199-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No