Ultra High Field MRI of Focal Pediatric Epilepsy

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.

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

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.

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

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