Ultra High Field MRI of Focal Pediatric Epilepsy
Ultra High Field MRI of Focal Pediatric Epilepsy
Epilepsy affects a significant number of children in the United States. The majority of
 patients achieve control of their seizures by conventional treatment strategies including
 medications. However, one third of patients do not achieve satisfactory seizure control with
 medications alone. Ketogenic diet and lifestyle modifications may also be tried. In some of
 these children, the seizure focus can be localized to one area of the brain and the seizures
 are resistant to conservative treatment strategies. These children may have subtle
 structural/developmental abnormalities in their brain, the most frequent of which is focal
 cortical dysplasia. These are localized areas of abnormal lamination of the cerebral cortex
 that can be extremely subtle and difficult to detect, even with state of the art magnetic
 resonance imaging (MRI). More importantly, these lesions may be amenable to surgical
 resection resulting in marked decrease in frequency or even resolution of seizures.

 MRI is a noninvasive imaging modality without ionizing radiation that has played a central
 role in the assessment of anatomy, physiology/pathophysiology of children with epilepsy. It
 is particularly useful in children with refractory focal epilepsy. Prior studies have shown
 that high resolution, high-field (3T) MR imaging of the brain helps to identify subtle focal
 epileptogenic abnormalities, including focal cortical dysplasia, in some patients. However,
 there is scarce data directly comparing the performance of ultra high-field (7T) MRI,
 currently an investigative technique offering optimized contrast and signal-to-noise rations
 and superior spatial resolution, with clinically available 3T MR imaging.

 The purpose of this study is to evaluate whether ultra high-field (7T) MR imaging improves
 detection and characterization of subtle structural epileptogenic abnormalities in children
 with focal epilepsy.

 The importance of this research is that identification of a focal epileptogenic lesion in
 children with refractory epilepsy has fundamental management implications, as surgical
 removal of such lesion may dramatically improve outcomes and the chance of seizure freedom.
1. Abstract Epilepsy affects a significant number of children in the United States. The
 majority of patients achieve control of their seizures by conventional treatment
 strategies including medications. However, one third of patients do not achieve
 satisfactory seizure control with medications alone. Ketogenic diet and lifestyle
 modifications may also be tried. In some of these children, the seizure focus can be
 localized to one area of the brain and the seizures are resistant to conservative
 treatment strategies. These children may have subtle structural/developmental
 abnormalities in their brain, the most frequent of which is focal cortical dysplasia.
 These are localized areas of abnormal lamination of the cerebral cortex that can be
 extremely subtle and difficult to detect, even with state of the art magnetic resonance
 imaging (MRI). More importantly, these lesions may be amenable to surgical resection
 resulting in marked decrease in frequency or even resolution of seizures.

 MRI is a noninvasive imaging modality without ionizing radiation that has played a
 central role in the assessment of anatomy, physiology/pathophysiology of children with
 epilepsy. It is particularly useful in children with refractory focal epilepsy. Prior
 studies have shown that high resolution, high-field (3T) MR imaging of the brain helps
 to identify subtle focal epileptogenic abnormalities, including focal cortical
 dysplasia, in some patients. However, there is scarce data directly comparing the
 performance of ultra high-field (7T) MRI, currently an investigative technique offering
 optimized contrast and signal-to-noise rations and superior spatial resolution, with
 clinically available 3T MR imaging.

 The purpose of this study is to evaluate whether ultra high-field (7T) MR imaging
 improves detection and characterization of subtle structural epileptogenic abnormalities
 in children with focal epilepsy.

 The importance of this research is that identification of a focal epileptogenic lesion
 in children with refractory epilepsy has fundamental management implications, as
 surgical removal of such lesion may dramatically improve outcomes and the chance of
 seizure freedom.

 2. Objectives (include all primary and secondary objectives)

 The objectives of Investigators' project are:

 To evaluate the performance of 7T MRI in detecting structural abnormalities in children
 who have had 3T MRI-negative focal epilepsy.

 To characterize conventional and advanced neuroimaging features of epileptogenic lesions
 such as cortical dysplasias and neuroglial tumors at 7T MRI.

 3. Background High-resolution brain MRI is currently an integral component in the
 diagnostic evaluation of children with focal epilepsy. When focal epileptogenic
 abnormalities are identified, such as cortical dysplasia, the management strategy
 includes evaluation for potential surgical resection, which may dramatically improve
 outcome. The current clinical state of the art of 3T MRI has superior sensitivity over
 conventional 1.5T MRI. However focal cortical dysplasia remains one of the most common
 pathological diagnoses after pediatric epilepsy surgery, even when not detected by
 current MRI exams.

 4. Study Procedures

 1. Study design, including the sequence and timing of study procedures. The
 investigators plan to perform 7T brain MRI in children with the diagnosis of
 epilepsy and findings on EEG suggestive of a focal structural abnormality. The 7T
 MRI exams will be performed at Kennedy Krieger Institute (KKI) as part of their
 outpatient evaluation. The investigators plan to accrue approximately 50
 participants.

 Before recruiting children with epilepsy, approximately 2-10 healthy adult
 volunteers will be recruited for the purpose of optimizing the imaging acquisition
 protocol. These adults will be consented using a separate consent form, also
 attached to this application.

 Children will be eligible if they have already had a 3T MRI examination and do not
 have any contraindications to MR examinations. A consent form signed by the
 patients' parent/legal care giver will be required to indicate agreement to
 participate in the study. In addition, a consent form signed by the patient (if
 over 15 year of age) or an assent form signed by the patient (if between 8-15 years
 of age) will be required to indicate agreement to participate. Patient charts will
 be reviewed for history and diagnosis.

 2. Study duration and number of study visits required of research participants. The
 anticipated duration of this study will be 2-5 years beginning in April 2017. The
 7T MRI exam will be performed in a single visit. This project may involve one
 additional trip to the hospital for patient subjects.

 3. Blinding, including justification for blinding or not blinding the trial, if
 applicable.

 N/A

 4. Justification of why participants will not receive routine care or will have
 current therapy stopped.

 N/A

 5. Justification for inclusion of a placebo or non-treatment group. N/A

 6. Definition of treatment failure or participant removal criteria. Removal criteria
 will be defined as participants who are unable to tolerate the MR procedure due to
 previously unknown claustrophobia, inability to tolerate lying still for the exam
 period, or due to presence of ferromagnetic implants preventing imaging.

 7. Description of what happens to participants receiving therapy when study ends or if
 a participant's participation in the study ends prematurely.

 Not applicable. This is not a treatment study.

 Data collection and management will be implemented with the following guidelines to ensure
 their confidentiality and safety:

 1. Confidentiality of Data: A master list separate from data forms that have only a study
 number will be used to maintain confidentiality of data.

 2. Security: The master list and backup copy will both be kept only on secure Johns Hopkins
 computers. Only de-identified data will be stored on a non-Johns Hopkins personal
 computer.

 3. Anonymization: The identifiers will be destroyed after publication. The other data will
 be retained for three years.

 4. Confidentiality: All data and records generated during this study will be kept
 confidential in accordance with Institutional policies and HIPAA on subject privacy and
 that the Investigator and other site personnel will not use such data and records for
 any purpose other than conducting the study. Safeguards are described under Data
 Collection and Management.

 5. Inclusion/Exclusion Criteria

 a. Inclusion Criteria i. Male or female children between 6-21 years of age undergoing an
 MRI for focal epilepsy at the Johns Hopkins Hospital OR ii. Adult healthy volunteer.
 iii. Willing to undergo an additional MRI exam in the 7T scanner at Kennedy Krieger
 Institute.

 b. Exclusion Criteria i. Presence of any contraindication to MR examinations as defined
 by MRI Safety Screening Sheet ii. History of Metal in the Skull/Eyes iii. Pregnancy at
 the time of the scan iv. Patient subjects in unstable clinical condition

 6. Drugs/ Substances/ Devices

 1. The rationale for choosing the drug and dose or for choosing the device to be used.

 Only patients with a clinical indication for brain MRI examination will undergo 7T
 MRI. All examinations will be performed without intravenous contrast and in an
 outpatient setting, without the need for deep sedation or general anesthesia.
 Although classified by FDA as an investigational device, the 7T MR system has been
 ruled as a non-significant risk device by the same agency. This finding is
 stipulated in Guidance for Industry and FDA Staff --Criteria for Significant Risk
 Investigations of Magnetic Resonance Diagnostic Devices issued July 14, 2003. A
 copy of the ruling has been uploaded in Section 3.0 for your review. In well over
 1000 studies done at 7T in the last decade at multiple institutions (University of
 Minnesota, Massachusetts General Hospital, NIH), no significant risks have been
 found. Some subjects have experienced dizziness. A potential concern with MR
 studies at high fields is radiofrequency heating due to radiofrequency power
 deposition in the subject. The FDA has set strict guidelines to guard against this
 risk. Such power deposition increases with the square of the magnetic field
 strength. However, even at 7T it is possible to stay well within these guidelines,
 especially with the pulse sequences the investigators will employ. To be 100% sure
 of compliance with FDA guidelines, the software of the manufacturer monitors power
 deposition continuously and scans are not possible to implement if the power
 deposition would exceed guidelines.

 Documents have been uploaded in Section 3.0 regarding federal guidelines supporting
 the position that a 7 Tesla MR scanner represents no significant risk to human
 subjects.

 Theoretical concepts and prior clinical studies justify the interest in applying
 high-resolution, ultra high-field MRI as a tool to evaluate detailed brain anatomy
 and physiology in children with focal epilepsy. Most studies comparing the
 diagnostic yield of 3T versus 1.5T imaging in detecting structural lesions in
 patients with focal epilepsy reached positive conclusions concerning the rates of
 newly detected lesions at 3T Very few comparative studies have investigated the
 diagnostic yield of 7T with respect to conventional MRI, however these included
 both examinations performed at 1.5T and at 3T.

 The employment of 7T MRI provides superior capability in characterizing anatomical
 and physiological brain parameters. In collaboration with MR physicists affiliated
 with Johns Hopkins and with Kennedy Krieger Institute, our imaging acquisition
 protocol should include:

 -  High-resolution anatomical sequences, such as volumetric T1-weighted MP2RAGE
 and 2D gray-white tissue border enhancement (TBE) Fast Spin Echo
 (FSE)-Inversion Recovery (IR). These images are optimal for evaluating the
 interface between the cortex and the juxtacortical white matter when
 attempting to detect subtle focal cortical dysplasias, an important cause of
 focal refractory epilepsy in children.

 -  Susceptibility-weighted imaging. 7T has been shown to offer superior
 sensitivity in detecting abnormal blood products and iron deposition in the
 cerebral parenchyma, in addition to the exquisite depiction of the normal and
 abnormal cerebral venous anomaly. These images may also be used for subjective
 evaluation of oxygen extraction fraction in the brain, and for quantitative
 mapping of iron deposition.

 -  Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI). Both
 techniques explore the diffusivity of water molecules in the intra- and
 extracellular spaces of the brain, along with the directionality of movement.
 The acquisition generates parameters of white matter integrity and anisotropy,
 including mean diffusivity, longitudinal and radial diffusivity, and
 fractional anisotropy. With this information, detailed in vivo maps of white
 matter fibers (tractography) can be produced, as well as maps of anatomic
 connectivity (connectome). DKI is a novel diffusion imaging technique that
 explores the non-Gaussian distribution of white matter molecules and is able
 to further characterize the complexity of white matter microstructure. DKI has
 thus far been scarcely explored in the study of pediatric neurological
 disorders.

 -  Resting-state functional MRI. Several studies have shown disturbance of
 functional pathways in children with focal refractory epilepsy. This technique
 relies on the blood-oxygen level dependent (BOLD) effect, does not require
 tasks as in other Functional MRI (fMRI) acquisitions, and can be postprocessed
 to generate maps of functional connectivity.

 -  MR Spectroscopy (MRS): 1H MRS is a noninvasive imaging technique that can
 easily be added to the conventional MRI sequences and is able to measure
 metabolism in the brain. Metabolic changes arising from pathology that can be
 visualized by MRS may not be apparent from anatomy. During a seizure, the
 metabolic demands exceed the supply of oxygen and nutrients to the portion of
 the brain that is undergoing the enhanced electric activity. Under these
 circumstances, metabolic changes can be detected by MRS, including the
 production of lactate and, if prolonged, the reduction of N-Acetyl Aspartate
 (NAA), and an increase in Cho. These abnormalities can still be observed after
 seizure activity ceases. Another common clinical scenario for the use of MRS
 is temporal-lobe epilepsy (TLE) to help localize the source of the seizures.

 Images acquired from 7T MRI examinations will not be used in isolation to guide
 patient care. In the event that 7T discloses a focal structural abnormality of the
 brain that was not detected at 3T MRI, this finding will be evaluated by a
 multidisciplinary team responsible for care of the particular patient. Management
 decisions will then be suggested to the patient and family considering all the
 clinical, electrographic, and neuroimaging data available.

 2. Justification and safety information if FDA approved drugs will be administered for
 non-FDA approved indications or if doses or routes of administration or participant
 populations are changed.

 Not applicable.

 3. Justification and safety information if non-FDA approved drugs without an
 Investigational New Drug (IND) will be administered.

 Not applicable.

 7. Study Statistics

 1. Primary outcome variable. The primary outcome variable is the sensitivity of 7T
 brain MRI in the detection of subtle cortical abnormalities in children with focal
 epilepsy.

 2. Secondary outcome variables. The secondary outcome variables include subjective
 characterization of subtle epileptogenic lesions, and quantitative metrics from
 advanced MR sequences such as apparent diffusion coefficient (ADC) and fractional
 anisotropy (FA) may be obtained from DTI sequences. Quantitative parameters may
 also be obtained from other imaging techniques such as MR spectroscopy.

 3. Statistical plan including sample size justification and interim data analysis. N/A

 4. Early stopping rules. N/A

 8. Risks

 1. Medical risks, listing all procedures, their major and minor risks and expected
 frequency.

 All participants will undergo the informed consent process. Children over the age
 of 15 will be asked to document their consent by signing the consent form. Children
 between the ages of 8 and 15 years of age will be asked to indicate their assent by
 signing the assent document. Assent will be obtained for children <8 years of age
 by monitoring visual and vocal indications as well as body language. Parents of all
 children will be asked to document their consent of the procedure on the consent
 form.

 The effects of magnetic fields in an MRI scanner have been extensively studied, and
 there are no known risks with an MRI exam. Participants may, however, be bothered
 by feelings of confinement (claustrophobia), and by the noise made by the image
 acquisition during the procedure.

 2. Steps taken to minimize the risks. Participants will be asked about
 contraindications to MR examinations (as outlined by the MRI screening sheet).
 Participants will wear earplugs and earphones while in the magnet. Participants may
 not participate in this study if they have a pacemaker, an implanted defibrillator
 or other implanted electronic or metallic devices.

 3. Plan for reporting unanticipated problems or study deviations. Adverse events,
 unanticipated problems, and study deviations will be reported to the IRB in writing
 by study personnel within 5 days of learning of the event. Serious adverse events
 will be reported immediately.

 4. Legal risks such as the risks that would be associated with breach of
 confidentiality.

 There are no known or anticipated legal risks associated with participating in this
 study.

 5. Financial risks to the participants. There are no known or anticipated financial
 risks associated with participating in this study.

 9. Benefits

 a. Description of the probable benefits for the participant and for society. i.
 Individual participant

 Individual participants may benefit by receiving higher end, non-invasive, non-contrast
 MR imaging studies that may (or may not) increase sensitivity and specificity of
 diagnosis and prognosis.

 ii. Society Society may benefit if investigators are able to establish the value of 7T
 MR imaging in focal pediatric epilepsy. By developing a high-resolution 7T brain MRI
 protocol for pediatric epilepsy, the data obtained from these exams may serve as the
 basis to alter diagnostic workup. This may ultimately improve early detection and
 characterization of lesions, and guide surgical planning, and may facilitate better
 outcomes.

 10. Payment and Remuneration

 a. Detail compensation for participants including possible total compensation, proposed
 bonus, and any proposed reductions or penalties for not completing the protocol.

 All studies will be performed in addition to a clinically indicated MRI appointment. No
 additional costs or billing will be generated to the patients. Subjects may receive a
 copy of their images on compact disc upon request.

 11. Costs a. Detail costs of study procedure(s) or drug (s) or substance(s) to participants
 and identify who will pay for them.

 Patient subjects will not incur any additional costs directly related to their participation
 in this project. The 7T MRI exams will be funded by a research grant.
Inclusion Criteria:

 -  Male or female children between 6-21 years of age undergoing an MRI for focal epilepsy
 at the Johns Hopkins Hospital OR ii. Adult healthy volunteer. iii. Willing to undergo
 an additional MRI exam in the 7T scanner at Kennedy Krieger Institute.

 Exclusion Criteria:

 -  Presence of any contraindication to MR examinations as defined by MRI Safety Screening
 Sheet ii. History of Metal in the Skull/Eyes iii. Pregnancy at the time of the scan
 iv. Patient subjects in unstable clinical condition