Comparative Analysis of Zero Echo-time MRI and CT for Pediatric Craniosynostosis
Phase: NA
Conditions: Craniosynostosis
Sponsor: Mayo Clinic

 
 
Comparative Analysis of Zero Echo-time MRI 
and CT for Pediatric Craniosynostosis 
 
NCT#04704284 
 
23May2022 

Title of the Study: Comparative analysis of zero echo-time MRI and CT for pediatric craniosynostosis.  
Ver 3 May 23, 2022. 
 
Principle Investigator: Julie Guerin, MD 
Neuroradiology 
 
 
Abstract 
 
Zero echo-time (ZTE) MRI (K132376) is an emerging technique that has been shown to 
adequately image bone and will likely allow eventual widespread imaging of osseous structures. 
The opportunity to exchange standard CT evaluation for a radiation-free modality is desirable, 
particularly in the pediatric population. A promising clinical application is the use of ZTE for 
diagnosing craniosynostosis, potentially precluding the use of the standard volumetric head CT 
scan. We propose a comparative analysis between zero echo-time MRI and CT to assess their 
effectiveness in diagnosing this entity. Our hypothesis is that ZTE is concordant with CT for suture 
visualization and imaging diagnosis, permitting its use in the clinical setting for this purpose. 
 
Research Plan 
 
 
1. Specific Aims 
To establish whether ZTE imaging of the infant calvarium can provide equivalent 
information to CT and allow for a reliable diagnosis of craniosynostosis in a child. 
This aim is based on the hypothesis that there will be 90% or greater concordance 
between ZTE and CT findings.  
 
2. Background & Significance 
Magnetic resonance imaging (MRI) has become the primary workhorse for pediatric 
neuroradiology, providing superior imaging of soft tissues in the brain, head, neck and spine, 
while offering the added benefit of having no ionizing radiation. Evaluating cortical bone, 
however, continues to be a limitation with conventional MRI sequences. The contents within 
cortical bone (inorganic minerals, collagen matrix and various water concentrations) and 
their tightly organized structure result in very short T2 values (T2 ∼ 300-400 μs) and rapid 
magnetization decay which yield signal voids and insufficient image contrast.   
 
Computed tomography (CT), therefore, continues to be the primary modality for evaluating 
osseous structures.  This modality is not ideal in children who have increased sensitivity to 
the adverse effects of radiation. Developing a comparable MR sequence which can evaluate 
bone without radiation is critical and aligns with the ALARA (“as low as reasonably 
achievable”) radiation safety principle to minimize radiation doses in children.  
 
Three dimensional proton density-weighted zero echo-time (ZTE) is a developing technique 
that uses proton density differences rather than T2 relaxation time differences to achieve 
contrast.  It has been used to better image bone structure within the calvarium, spine and 

extremities1-5and has been explored for use in attenuation correction for PET/MR studies6-8. 
The sequence is performed without preparation pulses or multiple echoes, rendering it time-
efficient and (if performed alone), usually precluding the need for sedation1. Alternatively, it 
can easily be added to a more complete MR exam, providing an efficient “one stop” 
evaluation. 
 
The diagnostic utility of ZTE is not yet established and a comparative validation study of ZTE 
with CT is needed before reliably using this in the clinical setting for preoperative purposes. If 
ZTE is shown to be non-inferior to CT for evaluation of craniosynostosis, clinical practice will 
be substantially improved; neurosurgeons as well as parents and children may be offered a 
radiation free imaging tool. This is particularly advantageous for this population of children 
which may require multiple follow-up exams after surgical correction. Moreover, this could 
serve as an initial study preceding evaluation of other osseous structures including facial bones 
and skull base. The findings in this study could also drive further technological advancements 
to include the creation of surface renderings based on ZTE data for anatomic modeling.  
 
 
3. Study Design 
3.1 Study population/Patient Enrollment 
           Eligibility criteria - Inclusion:   
Pediatric patients 0-18 of age will be recruited by our surgical colleagues based on the 
clinical concern for craniosynostosis and possible need for calvarial reconstruction.   
Study Team will also review the surgical calendars and Mayo Clinic data base (MDE, 
i2b2) searching for potential pediatric patients.  When a patient is found they will email 
the surgeons for a review and verification of qualification for the study.  Patients must 
have gotten a clinically indicated CT within a 6 week time period from the ZTE MRI. 
Eligibility criteria - Exclusion:   
Exclusion criteria include lack of consent, clinical CT scan of the head, 
contraindication/inability to undergo both examinations within the designated 
time period and/or undiagnostic image quality. Pregnancy (women of 
childbearing age will be given a urine pregnancy test). 
Patients will undergo ZTE within a 6 week time period from the CT scan (though 
attempting with each patient to schedule on the same day). ZTE MRI examinations will 
be added, when possible, to a patient’s already scheduled MRI or will take place as a 
standalone appointment without sedation.  
 
 

Patient preparation 
A Review Preparatory to Research will be conducted by the study coordinators to 
determine if the patient meets inclusion criteria including a pre-screen for MRI 
safety. 
 
3.2 Patient Scanning Protocol  
CT examinations will include age-appropriate protocols for radiation dose minimization, with 
three-dimensional reconstruction, per the cranisynostosis protocol. MR imaging will be 
performed on a 3T scanner capable of ZTE imaging. The pediatric whole-head ZTE protocol is 
set up to acquire volumetric proton density-weighted images with the following acquisition 
parameters: TE  0.016ms, field-of-view 18×18 cm, readout matrix 180×180, number of slices 
180, slice thickness 1 mm, bandwidth 31.25kHz, flip angle 2°. The image resolution is 1-mm 
isotropic and therefore can be reformatted in any plane.  The acquisition time for each 
acquisition is approximately 2 minutes.  The acquisition is repeated to achieve better SNR by 
averaging the two acquisitions during post-processing offline after rigid body registration. In 
case significant motion is observed in one of the acquisitions, only the acquisition with less 
motion will be used during post-processing to generate the bright-bone images.  An adjunct 3D 
GRE sequence will be made available to aid with differentiating between cortical bone and soft 
tissue. The acquisition parameters for the axial 3D GRE sequence are: TR 6.8ms, TE 2.3ms (“in 
phase”), flip angle 5-degree, field-of-view: 18X18 cm, acquisition matrix 256 X 256, slice 
thickness 1mm. The scan time for the 3D GRE sequence is ~6 minutes.  
 
3.3 MRI and CT evaluation 
Four CAQ certified neuroradiologists will independently evaluate CT and ZTE images in 
separate sessions. There will be at least a two-week time window between readings of CT 
and ZTE to diminish recall bias. ZTE data will be presented in three display formats: (1) 
raw magnitude image with multiplanar reformats, (2) bright-bone reconstructions, (3) 3D 
volume renderings. CT data will be presented in two display formats: (1) source images 
with multiplanar reformats and (2) 3D volume renderings. The images will be reviewed 
in a blinded fashion during separate interpretation sessions to prevent recall bias. 
3.4 Data Collection: 
Each observer will provide ordinal ratings with regard to (a) visibility of each major cranial 
suture and fontanelles [1 = poorly seen, 2 = partially seen, 3 = fully seen] and (b) 
confirmation of diagnosis based on the clinical question [+1 = pathologic abnormality 
present, 0 = unable to tell, -1 = pathologic abnormality absent].  
3.5 Data Analysis 
Sample size estimation for this interobserver agreement study was based on a confidence 
interval approach9. Using 4 raters and 3 levels of rating for their assessment, with type I 
error (alpha) fixed at 0.05 and an expected 80/20 probability of the absence or presence 
of craniosynostosis, respectively, we will have 80% power to claim the interobserver 
kappa statistics is greater than 0.7 when the true kappa is 0.95 with a sample size of 37 

patients. Interobserver agreement will be summarized by the kappa coefficient statistic 
and corresponding 95% confidence intervals.   
3.6 Associated staff 
A research coordinator (Suson Walsh) will work with the ordering staff from the 
plastic surgery or neurosurgery group and the radiology schedulers to arrange for 
scheduling the CT and MRI exams for the patient. The research coordinator will 
also be contacting or meeting patient before the scans to obtain consent. 
Biomedical Imaging Resource (BIR) will create a viewing platform that will be 
used to evaluate the de-identified images presented in a randomized and blinded 
fashion. Statistics support will be used for data analysis. 
3.7 Budget and Research Category B Time 
Funding will go to research coordinators, statistics, and BIR for their contributions as 
detailed above. Statistics has used approximately 4 hours for study planning and 
anticipates an additional 40 hours for performing statistical analysis, preparation of 
publication tables and figures, as well as abstract and manuscript support.  Research category B 
days are requested for the neuroradiologists who will be involved with project 
management/organization for MRI and the time intensive process of evaluating both ZTE 
and CT images for the multiple criteria detailed above.  Time will also be used for data 
interpretation, manuscript drafting, editing and submission. 
3.8 Project Timeline 
It is expected that patient recruitment will be readily achievable drawing from the 
plastic surgery and neuroradiology practices with the first half of patients 
recruited and tested by 6 months.  Data will be available for analysis as soon as 
ZTE and CT evaluation has been performed.  It is expected that the data accrual 
will be completed 1 year from the start of the project.  As a continuation of this 
project, comparing anatomic modeling and operative planning based on the 3D 
datasets from these ZTE and CT studies could be a subsequent endeavor.  
 
 
4. Innovation 
The zero-echo time MR sequence is an exciting tool that certainly challenges our current clinical 
paradigms, offering a radiation free method for assessing osseous structures. These comparative 
analyses will likely lead to additional analyses of other osseous pathologies and open the door 
for further application of this MRI technique. 
 
5. References  
 
1. 
Delso G, Wiesinger F, Sacolick LI, et al. Clinical evaluation of zero-echo-time MR 
imaging for the segmentation of the skull. J Nucl Med 2015; 56(3): 417-22. 

2. 
Chang EY, Du J, Chung CB. UTE imaging in the musculoskeletal system. J Magn Reson 
Imaging 2015; 41(4): 870-83. 
3. 
Leynes AP, Yang J, Wiesinger F, et al. Zero-Echo-Time and Dixon Deep Pseudo-CT 
(ZeDD CT): Direct Generation of Pseudo-CT Images for Pelvic PET/MRI Attenuation 
Correction Using Deep Convolutional Neural Networks with Multiparametric MRI. J 
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4. 
Breighner RE, Endo Y, Konin GP, Gulotta LV, Koff MF, Potter HG. Technical 
Developments: Zero Echo Time Imaging of the Shoulder: Enhanced Osseous Detail by 
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Larson PE, Han M, Krug R, et al. Ultrashort echo time and zero echo time MRI at 7T. 
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Sekine T, Ter Voert EE, Warnock G, et al. Clinical Evaluation of Zero-Echo-Time 
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8. 
Sousa JM, Appel L, Engstrom M, et al. Evaluation of zero-echo-time attenuation 
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9.  
Rotondi MA, Donner A. (2012). A Confidence Interval Approach to Sample Size 
Estimation for Interobserver Agreement Studies with Multiple Raters and Outcomes. 
Journal of Clinical Epidemiology, 65:778-784.