MRI for Non-invasive Evaluation of Brain Stress
Phase: NA
Conditions: Craniosynostosis
Sponsor: Washington University School of Medicine

MRI for Non-invasive Evaluation of Brain Stress. Protocol#2 Version 3 
NCT01898650
May 2022 
 
 
 
PI: Kamlesh Patel, MD 
1 
A Introduction 
A1 Study Abstract: 
This study will use non-invasive MR scanning to help answer questions related to 
brain function and development in children suffering from craniosynostosis. 
Craniosynostosis affects roughly 1 in 2000 children.  Primary indication for operative 
treatment for patients with craniosynostosis is to prevent or treat increased Intra-Cranial 
Pressure (ICP) and avoid neurological impairment. Increased ICP is thought to result from 
restricted space for brain growth caused by the abnormal cranial vault. However, the 
literature on the relationship between craniosynostosis and ICP is limited. Due to the 
invasiveness of the test, preoperative ICP monitoring is not routinely performed to decide 
if operative repair is required. Other indirect signs of elevated ICP have been described 
but are not reliable.  
While it is not currently feasible to measure ICP directly, we may be able to 
indirectly determine ICP in children via magnetic resonance imaging (MRI).  We aim to 
compare the assessment of ICP with the conventional, invasive intraventricular shunt to 
an indirect assessment of ICP via MRI.  
Ten children with an intraventricular shunt will be enrolled in this pilot study over a 
one-year period. We will obtain indirect measures of ICP. The results will be compared to 
ICP measures obtained via the shunt.  
Ultimately the assessment of ICP using MRI in patients with craniosynostosis may 
revise surgical indications and timing of surgery, potentially changing the standard of care 
for patients with craniosynostosis. Additionally, this approach might be used for patients 
with other diagnoses which impact ICP. 
A2 Primary Hypothesis 
Indirect (via MRI) and direct measures of ICP will have a significant positive 
correlation.  
A3 Purpose of the Study Protocol 
The purpose of this study is to evaluate the use of magnetic resonance imaging (MRI) to 
determine intra-cranial pressure in young children.   
B Background 

 
MRI for Non-invasive Evaluation of Brain Stress. Protocol#2 Version 3 
NCT01898650
May 2022    PI: Kamlesh Patel, MD 
2 
B1 Prior Literature and Studies 
Literature is limited on the relationship between craniosynostosis and ICP. The 
most widely reported study is by Renier and colleagues.1 In 75 patients preoperative ICP 
monitoring was performed using an epidural sensor. They identified ICP to be normal in 
one-third of the cases, obviously elevated in one-third, and borderline in one-third. When 
counseling patients, practitioners report a 13% rate of increased ICP for single suture 
synostosis and 42% for multiple suture synostosis. However, the authors used adult 
normative values for ICP (normal less than 10mmHg and elevated greater than 15mmHg). 
Normal ICP in children and infants has been identified to be closer to 6 mmHg.2  
B2 Rationale for this Study 
Currently all patients with craniosynostosis are treated surgically due to concern 
that the abnormal cranium restricts the brain, causing increased ICP. However, due to the 
invasiveness and potential harm of the current approach, ICP is rarely measured in 
patients with craniosynostosis. Accurate measures of ICP using MRI in patients with 
craniosynostosis may revise surgical indications and timing of surgery, potentially 
changing the standard of care for patients with craniosynostosis. This would allow family 
members of patients with craniosynostosis to be more informed as to the indication for 
operative repair, i.e., decreased brain metabolic activity and/or cosmetic.  
Our research may ultimately provide a tool for practitioners to not only identify 
which patients need to be treated, but also show adequate surgical therapy with resolution 
of ICP. Some patients, particularly those with syndromic craniosynostosis, require a 
secondary operation at an older age to expand cranial volume. The decision to perform a 
secondary operation is based on clinical signs and symptoms. Development of non-
invasive techniques to identify ICP will also inform this process and allow for early and 
correct identification of patients who need surgical treatment.  
C Study Objectives 
C1 Primary Aim 
To evaluate ICP through the use of magnetic resonance (MR) imaging techniques in 
patients under the age of eight years old. 
C2 Rationale for the Selection of Outcome Measures 
Although multiple tests have been suggested to assess ICP in patients with 
craniosynostosis, including papilledema and copper beaten appearance of the skull on 
plain film, none have been shown to be reliable measures or markers of ICP.  Recent 
advances in MRI suggest that ICP can be indirectly measured with this modality non-
invasively and with minimal patient risk. 

 
MRI for Non-invasive Evaluation of Brain Stress. Protocol#2 Version 3 
NCT01898650
May 2022    PI: Kamlesh Patel, MD 
3 
D Investigational Agent 
D1 Clinical Data to Date 
The MR sequences for this study have been used in studies of traumatic brain 
injury.  To our knowledge these sequences have not yet been used for patients 
with craniosynostosis. 
D2 Dose Rationale and Risk/Benefits 
The main risk of the MR scan in this population is the feeling of being closed in or 
discomfort from lying still.  This is an acceptable risk given the benefit of obtaining 
hard evidence of brain stress in subjects with synostosis.  The time patients are in 
the scanner (approximately 45 minutes) has been adequate to obtain useful data in 
populations of minors post traumatic brain injury and normal controls.  These tests 
were performed by Drs. Jose Pineda and Dustin Ragan.7   
E Study Design 
E1 Overview or Design Summary 
Up to 12 patients with craniosynostosis will be enrolled in this pilot study. Various 
measures of cerebral metabolism and perfusion will be taken during a single visit via MR 
scanning.   
The results may also be compared to age and gender matched normative data.  These 
controls will be recruited in the plastic surgery clinic and/or deidentified data from normal 
subjects from another study will be used. Participation in this research study consists of 
one to two parts. First, all patients will be asked to extend a clinical visit for MRI. During 
this time the intra-cranial pressure MRI testing will be done, lasting approximately 10 
minutes. The scan will be performed in the radiology center on the 1st floor of Children's 
Hospital. The clinical scan will be done under sedation. Secondly, during the same visit, 
a transducer will be attached to the participant's intraventricular catheter if it is not 
already in place. The patients ICP will be measured directly with this transducer. 
Subjects have no further commitment once the scan (and ICP measurement) is 
complete. 
E2 Subject Selection and Withdrawal 
2.a 
Inclusion Criteria
•
Subjects presenting to the Plastic Surgery clinic with unrepaired single-suture
craniosynostosis.
•
Age-matched controls
Exclusion Criteria
•
Implants (e.g. pacemakers) that might rule out use of MR scanning.

 
MRI for Non-invasive Evaluation of Brain Stress. Protocol#2 Version 3 
NCT01898650
May 2022    PI: Kamlesh Patel, MD 
4 
•
History of other abnormalities known to affect brain topology or function.
•
Control subjects must have no history of craniofacial abnormality or head trauma.
2.b 
Subject Recruitment Plans and Consent Process
Subjects will be recruited through the Plastic Surgery clinic. 
2.c 
Risks and Benefits
Risks: the risk of discomfort of claustrophobia during the MR scan 
Benefits:  Future patients with craniosynostosis might benefit from this study because it 
may lead to a revision of surgical indications and timing of surgery, potentially changing 
the standard of care for patients with craniosynostosis. 
2.d 
Early Withdrawal of Subjects
Subjects may withdraw at any time before or during the study. 
2.e 
When and How to Withdraw Subjects
Subjects or their parents/guardians may withdraw verbally. 
2.f 
Data Collection and Follow-up for Withdrawn Subjects
There will be no follow-up data collection 
F Study Procedures 
F1 Screening for Eligibility 
Craniosynostosis will be diagnosed via computed tomography performed as part of 
standard care 
F2 Schedule of Measurements 
There will be a single visit consisting of the MR scan, performed in the Center for 
Clinical Imaging Research. 
F3 Safety and Adverse Events 
3.a 
Medical Monitoring
Prior to MR scanning, subject’s parent or guardian will complete an MRI safety 
questionnaire.  The subject's heart rate and blood pressure will be continuously 
monitored and recorded every 15 minutes during the MR scan. 

 
MRI for Non-invasive Evaluation of Brain Stress. Protocol#2 Version 3 
NCT01898650
May 2022    PI: Kamlesh Patel, MD 
5 
3.b 
Definitions of Adverse Events
Typical adverse events during MR scans are claustrophobia and issues relating to 
metallic implants.   
3.c 
Data Collection Procedures for Adverse Events
Any adverse events will be duly recorded and noted by the investigators 
3.d 
Reporting Procedures
A summary of any adverse events will be included in continuing review forms sent to the 
IRB. 
3.e 
Adverse Event Reporting Period
Annually (in the continuing review forms) 
F4 Study Outcome Measurements and Ascertainment 
MR spectroscopy (MRS) will be used to obtain concentrations of N-acetyl aspartate 
(NAA) and lactate.  NAA is a highly sensitive marker of brain injury and the 
presence of lactate can indicate compromised metabolism. We will measure whole-
brain oxygen extraction (OEF) using a magnetic field mapping approach.  Elevated 
OEF is a key indicator of compromised perfusion.  Cerebral blood flow (CBF) will be 
measured using an arterial spin labeling (ASL) sequence, which will allow direct 
measurement of perfusion deficiencies.  We will also obtain functional connectivity 
data using an rfcMRI sequence, which is sensitive to developmental delay. The 
analysis for OEF and ASL data will be performed by Dr. Dustin Ragan. The MRI 
images will be read by Dr. Robert McKinstry, Chief of Radiology at Saint Louis 
Children's Hospital. Measures will include location and severity of metabolic effects, 
size of the optic nerve sheath, and cerebral perfusion.    
G Statistical Plan 
G1  Sample Size Determination and Power 
As this is a pilot study there is no relevant data to determine the power of this 
study.  The data collected here will be used as a guide for sample size 
determination of future studies.   
G2  Interim Monitoring and Early Stopping 
N/A 
G3  Analysis Plan 
The data obtained from the pilot study will be evaluated for patterns in the data between 
the subjects with craniosynostosis and the matched controls. 

MRI for Non-invasive Evaluation of Brain Stress. Protocol#2 Version 3 
NCT01898650
May 2022    PI: Kamlesh Patel, MD 
6 
G4  Statistical Methods 
Various graphical and image analysis approaches will be applied to tease out 
potential patterns between cases and controls and between the affected and 
unaffected sides of patients with unilateral craniosynostosis.  
H Data Handling and Record Keeping 
H1 Confidentiality and Security 
Privacy during the recruitment and consent process will be protected by 
performing these procedures in private patient rooms in the hospital or clinic 
setting.  
The MRI will be performed in the Center for Clinical Imaging Research (CCIR). 
No unnecessary PHI will be collected. Data will be a coded.   
H2 Training 
All members of the research team will be familiar with this protocol and the 
standard prosecution of clinical trials. 
H3 Records Retention 
Patient records will be stored behind a double lock system in the craniofacial 
laboratory in the division of Plastic Surgery. 
I Study Administration 
I1 
Organization and Participating Centers 
Division of Plastic Surgery in cooperation with the Department of Radiology 
I2 
Funding Source and Conflicts of Interest 
None at this time. 
I3 
Subject Stipends or Payments 
None. 
I4 
 Study Timetable 
We anticipate obtaining all pilot data within a year of IRB approval. 
J Publication Plan 

 
MRI for Non-invasive Evaluation of Brain Stress. Protocol#2 Version 3 
NCT01898650
May 2022    PI: Kamlesh Patel, MD 
7 
Within one year of final data collection the results of this pilot study are to be submitted 
for presentation at a national craniofacial or neurosurgical conference.  Similarly, the 
results will be submitted for publication in a peer-reviewed journal within the same time 
frame. 
K  Attachments 
K1 Informed consent documents 
Included in the IRB submission. 
L References 
The following publications are related either to ICP in patients with craniosynostosis or to 
the non-invasive, MR-based methods of determining cranial metabolism. 
1.
Renier D, Sainte-Rose C, Marchac D, Hirsch JF. Intracranial pressure in
craniostenosis. Journal of neurosurgery 1982;57:370-7.
2.
Minns RA. Intracranial pressure monitoring. Archives of Disease in
Childhood 1984;59:486-8.
3.
Braun KP, Vandertop WP, Gooskens RH, Tulleken KA, Nicolay K. NMR
spectroscopic evaluation of cerebral metabolism in hydrocephalus: a review.
Neurological research 2000;22:51-64.
4.
Jain V, Langham MC, Wehrli FW. MRI estimation of global brain oxygen
consumption rate. Journal of cerebral blood flow and metabolism : official journal
of the International Society of Cerebral Blood Flow and Metabolism
2010;30:1598-607.
5.
Wu WC, Fernandez-Seara M, Detre JA, Wehrli FW, Wang J. A theoretical
and experimental investigation of the tagging efficiency of pseudocontinuous
arterial spin labeling. Magnetic resonance in medicine : official journal of the
Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in
Medicine 2007;58:1020-7.
6.
Ragan DK, McKinstry R, Benzinger T, Leonard JR, Pineda JA. Alterations
in cerebral oxygen metabolism after traumatic brain injury in children. Journal of
cerebral blood flow and metabolism : official journal of the International Society of
Cerebral Blood Flow and Metabolism 2012.
7.
Ragan DK, McKinstry R, Benzinger T, Leonard J, Pineda JA. Depression
of whole-brain oxygen extraction fraction is associated with poor outcome in
pediatric traumatic brain injury. Pediatric research 2012;71:199-204.