Posterior Fossa Decompression With or Without Duraplasty for Chiari Type I Malformation With Syringomyelia
Phase: NA
Conditions: Arnold-Chiari Malformation, Type 1, Chiari Malformation Type I, Type I Arnold-Chiari Malformation, Syringomyelia
Sponsor: Washington University School of Medicine

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Posterior Fossa Decompression with or 
without Duraplasty for Chiari type I 
Malformation with Syringomyelia 

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FULL PROTOCOL TITLE  
 
Posterior Fossa Decompression with or without Duraplasty for 
Chiari type I Malformation with Syringomyelia 
 
  
Study Chairman or Principal Investigator:   
  
David D. Limbrick, Jr., MD, PhD 
T.S. Park Professor of Neurological Surgery and Pediatrics 
St. Louis Children’s Hospital 
Washington University School of Medicine 
 
 
   
Supported by:  
  
Patient-Centered Outcomes Research Institute 
CER-1503-29700 
  
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
Page 
 
Study Team Roster…………………………………………………………………………...1 
 
Participating Study Sites……………………………………………………………………..4 
 
1. Study objectives……………………………………………………………………….7 
 
1.1 Primary Objective………………………………………………………………...7 
 
1.2 Secondary Objectives……………………………………………………………..7 
 
2. Background and Rationale…………………………………………………………...8 
 
2.1 Background on Condition, Disease, or Other Primary Study Focus…………..8 
 
2.2 Study Rationale……………………………………………………………………9 
 
3. Study Design…………………………………………………………………………..11 
 
4. Selection and Enrollment of Participants……………………………………………12 
 
4.1 Inclusion Criteria………………………………………………………………….12 
 
4.2 Exclusion Criteria…………………………………………………………………12 
 
4.3 Study Enrollment Procedures…………………………………………………….13 
 
4.4 Subject Recruitment……………………………………………………………….13 
 
4.5 Parental Permission and Child Assent……………………………………………13 
 
4.6 Randomization and Treatment Allocation……………………………………….13 
 
5. Study Interventions…………………………………………………………………….14 
 
5.1 Interventions, Administration, and Duration…………………………………….14 
 
5.2 Handling of Study Interventions…………………………………………………..14 
 
5.3 Concomitant Interventions………………………………………………………...15 
 
 
 
5.3.1 Allowed Interventions……………………………………………………15 
 
 
 
5.3.2 Required Interventions…………………………………………………..15 

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5.3.3 Prohibited Interventions…………………………………………………15 
 
5.4 Adherence Assessment……………………………………………………………..15 
 
6. Study Procedures……………………………………………………………………….15 
 
6.1 Schedule of Evaluation……………………………………………………………..15 
 
6.2 Description of Evaluation………………………………………………………….16 
 
6.2.1 Screening of Evaluation……………………………………………………16 
 
6.2.2 Enrollment, Baseline, and/or Randomization…………………………….17 
 
6.2.3 Follow-up Visits…………………………………………………………….18 
 
6.2.4 Completion/Final Evaluation………………………………………………19 
 
7. Safety Assessments……………………………………………………………………...20 
 
7.1 Specification of Safety Parameters……………………………………………….. 21 
 
 
7.2 Methods and Timing for Assessing, Recording, and Analyzing Safety  
 
      Parameters…………………………………………………………………………..23 
 
 
 
 
 
7.2.1 Preliminary Data………………………………………………………….23 
 
7.2 Adverse Events and Serious Adverse Events……………………………………..26 
 
7.3 Reporting Procedures………………………………………………………………31 
 
7.4 Follow-up for Adverse Events……………………………………………………...32 
 
7.5 Safety Monitoring…………………………………………………………………..32 
 
8. Intervention Discontinuation…………………………………………………………..32 
 
9. Statistical Consideration……………………………………………………………….33 
 
9.1 General Design Issues………………………………………………………………33 
 
9.2 Sample Size and Randomization…………………………………………………..34 
 
9.3 Interim Analyses and Stopping Rules……………………………………………..34 
 

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9.4 Outcomes……………………………………………………………………………35 
 
9.5 Data Analysis………………………………………………………………………..35 
 
10. Data Collection and Quality Assurance…………………………………………………...39 
 
 
10.1 Data Collection Forms…………………………………………………………….39 
 
 
10.2 Data Management…………………………………………………………………39 
 
 
10.3 Quality Assurance…………………………………………………………………40 
 
 
 
10.3.1 Training………………………………………………………………….41 
 
 
 
10.3.2 Quality Control Committee…………………………………………….41 
 
 
 
10.3.3 Metrics…………………………………………………………………...41 
 
 
 
10.3.4 Protocol Deviations……………………………………………………...43 
 
10.3.5 Monitoring………………………………………………………………43 
 
11. 
Participant Rights and Confidentiality………………………………………………..43 
 
 
11.1 Institutional Review Board (IRB) Review……………………………………….46 
 
11.2 Informed Consent Forms…………………………………………………………46 
 
11.3 Participant Confidentiality……………………………………………………….47 
 
11.4 Study Discontinuation…………………………………………………………….47 
 
12. 
Committees……………………………………………………………………………...47 
 
13. 
Publication of Research Findings……………………………………………………...47 
 
14. 
References……………………………………………………………………………….49 
 
15. 
Supplement/Appendices………………………………………………………………..53 
 
 
 
 
 

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STUDY TEAM ROSTER 
Research Team 
Member 
Role in 
Study 
Stakeholder 
Grouping 
Responsibilities 
David D. Limbrick, 
Jr., M.D., Ph.D. 
P.I. 
Clinician/ 
Physician 
Oversees design, implementation, and 
conduct of entire study.  Supervises the 
conduct of human subjects research, 
protects rights, safety and welfare of 
subjects.  Reviews and submits interim and 
final reports on study. Leads meetings of 
the Investigators Committee.  Responsible 
for research partners, stakeholders, and 
patient 
partners 
input 
during 
study 
meeting. Reviews and presents data to the  
DSMB. Oversees dissemination of study 
results 
with 
all 
members 
of 
the 
Investigators Committee. 
Chevis Shannon, 
Ph.D. 
Co-P.I. 
Research 
Stakeholder 
Serves as a liaison to patient advocacy 
groups. Oversees training and oversight of 
the quality of life instrument and study 
aim. Participates as a Site PI. Serves as a 
member of the Dissemination Committee. 
Participates in the development and 
writing 
of 
presentations 
and 
study 
manuscripts. 
James Torner, Ph.D. 
Co-P.I. 
Research 
Stakeholder 
Oversees 
Data 
Coordinating 
Center.  
Responsible 
for 
data 
analysis 
and 
interpretation.  Participates in the writing 
of the development of presentations and 
study manuscripts. Assists with the 
preparations and presentation of reports for 
the DSMB. 
Gerald Tuite, M.D. 
Co-I 
Clinician/ 
Physician 
Serves as a liaison to patient advocacy 
groups. Oversees training and oversight of 
the quality of life instrument and study 
aim. Participates as a Site PI. Serves as a 
member of the Dissemination Committee. 
Participates 
in 
the 
writing 
of 
the 
development of presentations and study 
manuscripts. 
Emine Bayman, Ph. 
D.   
Co-I 
Research 
Stakeholder 
Performs data analysis and assists with 
interpretation.  Participates in the writing 
of the development of presentations and 
study manuscripts. Assists with the 
preparations and presentation of reports 
for the DSMB. 

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T.S. Park, M.D. 
Co-I 
Clinician/ 
Physician 
Oversees the network and its resources.  
Serves as administrative leader and study 
advisor. Facilitates the annual PRSRC 
meeting. 
Michael Kelly, M.D. 
Co-I 
Clinician/ 
Physician 
As a spinal deformity expert, is responsible 
for interpretation of all spinal deformity x-
rays 
and 
the 
determination 
of 
progression/stability/improvement 
of 
deformity after surgery. 
Hailey Vance, P.N.P. 
Co-I 
Clinician/ 
Nurse 
Practitioner 
As a first point of contact for patients, 
provides important insight into concerns of 
patient/family members at all stages, from 
diagnosis 
through 
the 
post-operative 
period. 
Attends 
annual 
investigator 
meeting and participates on Investigator 
Committee calls.  Assists in dissemination 
of study results. 
Elaine Kennedy 
Co-I 
Clinician/ 
Nurse 
Practitioner 
As a first point of contact for patients, 
provides important insight into concerns of 
patient/family members at all stages, from 
diagnosis 
through 
the 
post-operative 
period. 
Attends 
annual 
investigator 
meeting and participates on Investigator 
Committee calls.  Assists in dissemination 
of study results. 
Thanda 
Meehan 
R.N., B.S.N.  
Co-I 
Clinician/ 
Research 
Nurse 
Ensures all study site surgeons and 
research coordinators are trained on the 
study protocol and procedures. Fields 
questions and assists with day-to-day 
issues for PRSRC (e.g. data entry, registry 
function). Organizes all study documents 
and coordinates efforts of multiple sites. 
Samuel Reeves 
Co-I 
Patient 
Partner/ 
Family 
Inspirational 
leader 
of 
PRSRC.  
Participates 
in 
study 
design, 
implementation, 
conduct, 
and 
dissemination of results. Provides input 
from a patient’s or family’s perspective 
about all study decisions. Ensures patient-
centeredness of outcomes.  Participates in 
all Investigator Committee meetings. 
Lisa Reynolds 
Co-I 
Patient 
Partner / 
Family 
Participates 
in 
study 
design, 
implementation, 
conduct, 
and 
dissemination of results. Provides input 
from a patient’s or parent’s perspective 
about all study decisions. Ensures patient-
centeredness of outcomes.  Participates in 

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all Investigator Committee meetings.  
Facilitates approachable language for 
social media posts, press releases and 
website blogs. 
Gina Tramelli 
Co-I 
Patient 
Partner / 
Family 
Participates 
in 
study 
design, 
implementation, 
conduct, 
and 
dissemination of results. Provides input 
from a patient’s or parent’s perspective 
about all study decisions. Ensures patient-
centeredness of outcomes.  Participates in 
all Investigator Committee meetings.  
Facilitates approachable language for 
social media posts, press releases and 
website blogs. 
Dorothy Poppe 
Co-I 
Patient 
Partner/ 
Patient 
Advocate 
C.E.O. of Chiari and Syringomyelia 
Foundation.  Participates in study design, 
implementation, 
conduct, 
and 
dissemination of results. Ensures patient-
centeredness of outcomes.  Participates in 
all Investigator Committee meetings.  
Assists with coordination of patient focus 
groups and dissemination of results. 
Rick Labuda 
Co-I 
Patient 
Partner/ 
Patient 
Advocate 
Executive Director, Conquer Chiari patient 
advocacy group.  Participates in study 
design, implementation, conduct, and 
dissemination of results. Ensures patient-
centeredness of outcomes.  Participates in 
all Investigator Committee meetings.  
Responsible for social media posts, press 
releases and website blogs. 
Jacob 
Greenberg, 
M.D., M.S.C.I. 
Consultant Clinician/ 
Researcher 
Participates 
in 
study 
design, 
implementation, 
conduct, 
and 
dissemination of results. Participates in the 
interpretation and refinement of clinical 
outcomes metrics. Participates in the 
writing 
of 
the 
development 
of 
presentations and study manuscripts. 
Angela 
Eschmann, 
R.N. 
Consultant Clinician/ 
O.R. Nurse 
As the resource nurse and leader of the St. 
Louis Children’s neurosurgical operating 
room staff, provides input regarding 
operative 
conditions 
potentially 
contributing to surgical complications. 
Toni Goelz 
Consultant Clinician/ 
Physical 
Therapist 
Provides unique perspective and insight 
into assessment and treatment of physical 
limitations related to CM+SM. Participates 

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in study design, implementation, conduct, 
and dissemination of results. 
 
PARTICIPATING STUDY SITES   
Sites 
Principal Investigators 
All Children's Hospital 
Tuite, Gerald, Jallo, George 
Arkansas Children’s Hospital/University of 
Arkansas School of Medicine 
Albert, Greg 
Arnold Palmer Hospital-Orlando Health 
Olavarria, Greg 
Boston Children's Hospital 
Stone, Scellig 
Children's Healthcare of Atlanta 
Chern, Joshua 
Children’s Hospital at Dartmouth-Hitchcock/ 
Dartmouth Geisel School of Medicine 
Bauer, David 
Children’s Hospital Colorado 
O’Neill, Brent 
Children’s Hospital of Birmingham 
Johnston, James 
Children’s Hospital of New York-
Presbyterian/ Weill Cornell/Cornell 
University Medical College 
Greenfield, Jeffrey 
Children’s Hospital of Phoenix 
Adelson, David 
Children’s National Medical Center 
Keating, Robert 
Children’s Hospital of Philadelphia 
Heuer, Greg 
Cincinnati Children’s Hospital 
Mangano, Francesco 
Columbia University 
Anderson, Richard 
Dell (Seton) Children’s Medical Center 
George, Timothy, Tyler-Kabara, Elizabeth 
Gillette Children’s Hospital Minnesota 
Graupman, Patrick 
John Hopkins Children’s Center/ Johns 
Hopkins School of Medicine 
Jackson, Eric 
Levine Children’s Hospital/Carolinas Medical 
Center 
Wait, Scott 
Los Angeles Children’s Hospital 
McComb, J. Gordon 
Lurie Children’s Hospital of Chicago 
Alden, Tord 
Mayo Clinic Children’s Hospital 
Daniels, David 
Miami Children’s Hospital 
Bhatia, Savjiv, Ragheb, John 
MUSC Children’s Hospital/Medical 
University of South Carolina School of 
Medicine 
Eskandari, Ramin 
Oregon Health & Science University 
Selden, Nathan 
Pennsylvania State University 
Iantosca, Mark 
Pittsburgh Children’s Hospital 
Tamber, Mandeep, Greene, Stephanie 
Primary Children’s Hospital 
Brockmeyer,Doug 
St. Louis Children’s Hospital 
Limbrick, David 
Seattle Children’s Hospital 
Ellenbogen, Richard 
Stanford University 
Grant, Gerald 
Texas Children’s Hospital 
Whitehead, Bill 
The Children’s Hospital at OU Medical 
Mapstone, Timothy, Gross, Naina 

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Center/ Oklahoma University College of 
Medicine 
Nationwide Children’s Hospital 
Leonard, Jeffrey 
University of Florida HSC-Jacksonville 
Aldana, Philipp 
University of Iowa 
Menezes, Arnold 
University of Michigan 
Maher, Cormac 
University of Texas – Houston 
Shah, Manish 
University of Minnesota 
Guillaume, Dan 
University of Vermont Children’s Hospital/ 
University of Vermont College of Medicine 
Durham, Susan 
University of Wisconsin 
Iskandar, Bermans 
Vanderbilt University 
Shannon, Chevis and Wellons, Jay 
Wake Forest University 
Couture, Daniel 
 
Study Title  
Posterior Fossa Decompression with or without Duraplasty for Chiari type I Malformation with 
Syringomyelia: A prospective, cluster randomization trial of up to 238 subjects recruited from 36 
centers of the Park-Reeves Syringomyelia Research Consortium as well as an additional 8 research 
centers. 
  
Objectives 
Children with Chiari type I malformation (CM) and syringomyelia (SM), a ‘rare disease’, may 
suffer debilitating pain, spinal deformity, neurological deficits (myelopathy, weakness, sensory 
loss, and impaired gait), and a diminished quality of life (QOL) [1-3].  CM+SM is treated with 
neurosurgical decompression of the craniovertebral junction with either of two technical 
variations: 1) posterior fossa decompression with duraplasty (PFDD), the gold standard operation, 
which involves intradural microsurgical dissection and duraplasty; or 2) extradural posterior fossa 
decompression (PFD), in which the dura is not opened.  The Central Hypothesis of this proposal 
is that, compared with PFDD, PFD will be associated with fewer surgical complications and 
less harm to patients, yet will provide non-inferior clinical improvement and syrinx 
regression.  With a more favorable risk profile and non-inferior clinical outcomes, patients 
undergoing PFD will experience superior QOL.  We will conduct a prospective, cluster 
randomized controlled trial of PFD versus PFDD in order to test this hypothesis and achieve the 
following Specific Aims: 
 
Specific Aim 1: Determine if PFD is associated with fewer surgical complications and less harm 
to patients than PFDD. 
Hypothesis: PFD will be associated with fewer surgical complications and less potential harm to 
patients than PFDD.     
Anticipated Outcome:  Cerebrospinal fluid (CSF)-related complications ≤6 months (e.g. CSF 
leak, pseudomeningocele, aseptic meningitis, infection, and hydrocephalus) and requirement for 
additional surgery for wound revision or CSF diversion will be lower after PFD compared with 
PFDD. 
 

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Specific Aim 2:  Determine if PFD provides non-inferior clinical improvement and syrinx 
regression compared to PFDD.   
Hypothesis: Clinical improvement and syrinx regression provided by PFD will be non-inferior 
compared to those provided by PFDD. 
Anticipated Outcome:  Clinical symptoms, neurological function, and syrinx regression ≤12 
months will be non-inferior following PFD when compared with PFDD.  Rates of revision 
decompression surgery (PFD or PFDD) and progression of spinal deformity ≤12 months after PFD 
also will be non-inferior to PFDD. 
 
Specific Aim 3:  Determine if PFD is associated with superior QOL compared with PFDD. 
Hypothesis:  With fewer surgical complications, PFD will be associated with superior QOL 
compared with PFDD. 
Anticipated Outcome: PFD will have superior QOL and will show improvements in overall QOL 
over time (≤12 months post-operatively) compared to PFDD.  In particular, both physical metrics 
(evaluated by pain frequency, pain severity and non-pain symptoms) and psychosocial metrics will 
improve at a higher rate and in a shorter period of time after PFD compared to PFDD. 
 
Design and Outcomes   
This will be a cluster randomized control trial of up to 238 patients (see section 9.5 data analysis, 
re-estimation in power calculations section below) recruited from the 36 centers of the Park-
Reeves Syringomyelia Research Consortium (PRSRC) as well as an additional 8 research centers.  
Randomization will occur at the center level with standardized surgical technique, and data will 
be recorded in the PRSRC prospective registry.  In order to examine the main comparative 
effectiveness research (CER) question of surgical complications and potential harm to patients 
(Aim 1), intra-operative complications and short (≤6 months) and long-term (6-12 months) 
postoperative complications will be recorded for both PFD and PFDD.  For Aim 2, clinical 
symptoms, neurological function, and modified Chicago Chiari Outcome Scale (mCCOS) [22] 
scores will be measured pre-operatively and longitudinally at ≤6 weeks, 3-6 months, and 12±2 
months after surgery.  MRIs will be obtained (at a minimum) ≤ 6 months pre-operatively and 122 
months post-operatively to compare the effect of surgery on syrinx size and spinal deformity.  In 
order to test Aim 3 hypothesis, QOL will be assessed at the same time points using the Chiari 
Health Index Pediatrics (CHIP), and the Health Utilities-3 (HUI-3), holistically evaluating patients 
across psychosocial and physical dimensions. 
Interventions and Duration  
This study will compare the outcomes of PFDD vs PFD.  The study will occur over a five year 
period.  The enrollment period will last for two years and 8 months.  Data collection for each 
participant is for the primary analysis is  to be one year and will be structured in the following 
manner: 
- 
Pre-operative (the initial outpatient neurosurgery visit prior to decompression) including 
CHIP & HUI-3 QOL questionnaire 
- 
Intra-operative 
- 
Post-Operative 
- 
≤6 weeks post-operation including CHIP & HUI-3 QOL questionnaire 
- 
3-6 months post-operation including CHIP & HUI-3 QOL questionnaire 
- 
12±2months post-operation including CHIP & HUI-3 QOL questionnaire 

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- 
Data related to additional outpatient neurosurgery visits that occur during the one year 
collection period will also be collected. 
MRI of the brain and cervical and thoracic spine are required prior to PFD or PFDD.  Pre-operative 
lumbar spine MRI will be left to the discretion of the surgeon.  MRI of the cervical and thoracic 
spine are required 12±2 months post-operatively.   
- 
Imaging not required for study but included for review if available during the 1-year +/- 2 
month study collection period: 
o Additional MRIs of the brain or cervical, thoracic, or lumbar spine obtained for the 
clinical care of the patient, including those performed due to: 
 Revision/redo decompression  
 Syrinx fenestration or syrinx shunt  
 Spinal Fusion  
o CT of the brain or cervical, thoracic, and lumbar spine 
o “Long cassette” or “scoliosis” X-rays  and X-rays of the cervical, thoracic, and 
lumbar spine 
 
Sample Size and Population  
Overall sample size during the two years and 8 months enrollment period is 148 participants. Of 
this total, approximately 74 will have a PFD and approximately 74 will have PFDD.  Participants 
will be between the ages of 0-21 years old and diagnosed with CM+SM without bias to gender, 
race, or ethnicity. 
 
1. STUDY OBJECTIVES 
1.1 Primary Objective  
 
Specific Aim 1:  Determine if PFD is associated with fewer surgical complications and less harm 
to patients than PFDD.   
Hypothesis:  PFD will be associated with fewer surgical complications and less potential harm to 
patients than PFDD.   
Anticipated Outcome:  Cerebrospinal fluid (CSF)-related complications ≤6 months (e.g. CSF 
leak, pseudomeningocele, aseptic meningitis, infection, hydrocephalus), and the requirement for 
additional surgery for wound revision or CSF diversion will be lower after PFD compared with 
PFDD. 
 
1.2 Secondary Objectives 
 
Specific Aim 2:  Determine if PFD provides non-inferior clinical improvement and syrinx 
regression compared to PFDD.   
Hypothesis: Clinical improvement and syrinx regression provided by PFD will be non-inferior 
compared to those provided by PFDD. 
Anticipated Outcome:  Clinical symptoms, neurological function, and syrinx regression ≤12 
months will be non-inferior following PFD when compared with PFDD.  Rates of revision 
decompression surgery (PFD or PFDD) and progression of spinal deformity ≤12 months after PFD 
also will be non-inferior to PFDD. 

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Specific Aim 3:  Determine if PFD is associated with superior QOL compared with PFDD. 
Hypothesis:  With fewer surgical complications, PFD will be associated with superior QOL 
compared with PFDD. 
Anticipated Outcome: PFD will have superior QOL and will show improvements in overall QOL 
over time (≤12 months post-operatively) compared to PFDD.  In particular, both physical metrics 
(evaluated by pain frequency, pain severity and non-pain symptoms) and psychosocial metrics will 
improve at a higher rate and in a shorter period of time after PFD compared to PFDD.  
2. BACKGROUND AND RATIONALE  
2.1 Background on Condition, Disease, or Other Primary Study Focus 
Chiari type I malformation (CM) and syringomyelia (SM) are closely associated but incompletely 
understood disorders of the craniovertebral junction and spinal cord, respectively (Fig. 1). 
Syringomyelia (SM) is a potentially debilitating neurological condition characterized by the 
abnormal accumulation of fluid within the spinal cord and is observed most commonly in the 
setting of CM [1].  SM is classified as a ‘rare disease’ by the Office of Rare Diseases of the National 
Institutes of Health (NIH), with an estimated 7-9 new cases/year/100,000, and about 40,000 people 
currently affected in the United States [2-6].  Children with CM+SM frequently suffer chronic 
pain, including headaches and spinal cord dysesthesias, spinal deformity, and neurological deficits 
such as sensory loss or weakness [7-10].  Left untreated, these symptoms may progress to result 
in debilitating paralysis, progressive scoliosis requiring surgical correction, sexual dysfunction, or 
bladder and bowel incontinence.  High cervical or brainstem SM may result cranial nerve 
dysfunction, respiratory failure, or apnea.  Fortunately, progression of disease is gradual and may 
be halted—and in some cases reversed—with effective neurosurgical treatment [9-13].   
 
While it is widely recognized that surgical 
decompression of the craniovertebral junction 
provides symptomatic improvement and syrinx 
regression in up to 80-90% of patients with 
CM+SM [7, 9, 10, 12, 13], the optimal surgical 
technique remains highly controversial. The 
fundamental difference between the two major 
operative approaches for treating CM+SM is the 
surgical opening of the dura mater, the thickest and 
strongest of the three linings of the central nervous 
system.  Opening the dura in this region provides 
access to the cerebrospinal fluid (CSF) cisterns, the 
surface of the cerebellar tonsils, the foramen of 
Magendie (the opening of the 4th ventricle), the brainstem, and the spinal cord.  In cases when the 
dura is opened, a duraplasty is performed, which involves an expansile closure of the dura, 
typically with graft material. Many surgeons fervently believe that opening the dura, with or 
without intradural microsurgical dissection, followed by duraplasty is critical to restoring normal 
cerebrospinal fluid hydrodynamics at the craniovertebral junction (CVJ) and permitting reduction 
in the SM size.  
Figure 1. Schematic drawing (left) and T2-weighted 
sagittal MRI (right) demonstrating Chiari type 1 
malformation (CM-1) and syringomyelia. 

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2.2 Study Rationale 
Syringomyelia is a rare disease associated with substantial, lifelong disability, ranging from 
chronic pain to debilitating paralysis, spinal deformity, and death from respiratory failure [14].  
While some types of SM are not treatable, CM-associated SM is readily treated by neurosurgical 
decompression of the craniovertebral junction, which provides symptomatic improvement and 
syrinx regression in up to 90% of patients [15].  However, the optimal surgical technique—one 
that effectively eliminates symptoms and prevents disability while minimizing complications and 
harm to patients—remains unclear.  The debate over which surgical technique, PFDD or PFD, to 
recommend to patients is among the most controversial topics in pediatric neurosurgery[16], and 
currently these decisions are being made in the absence of evidence about the comparative 
effectiveness of PFDD or PFD.    
 
Termed posterior fossa decompression with 
duraplasty (PFDD), this combination of 
procedures 
is 
considered 
the 
‘gold 
standard’ operation for CM+SM (Fig. 2).  
However, opening the dura carries a 
significant risk to patients (Table 1); a 
recent 
meta-analysis 
of 
numerous 
retrospective clinical series demonstrated surgical complications noted in 18.5% of patients who 
underwent PFDD (range 8.3-66.7%, Table 2).  Due to this alarmingly high rate of complications, 
there has been increasing interest in recent years in extradural posterior fossa decompression 
without dural opening or duraplasty (PFD).  PFD markedly reduces the surgical risks of PFDD, 
but its efficacy remains unclear, and patients who undergo PFD may experience inferior resolution 
of symptoms and may be more likely to require revision decompression surgery (Table 2).  
However, available data are derived primarily from single-center retrospective analyses [17-25], 
and at present, the choice of PFD or PFDD is largely based on surgeon preference or surgeon 
experience rather than medical evidence [26]; no evidence-based guidelines exist.  The current 
study proposes to address this critical gap in the management of CM+SM to compare the 
risk of harm to patients, the effectiveness, and the change in QOL associated with PFDD 
versus PFD.  
 
Table 1. Common surgical complications after PFDD or PFD. 
Surgical Complication 
Surgical Procedures for 
Complication Management 
Pseudomeningocele 
Oversewing of Wound 
CSF Leak 
Wound Revision 
Chemical Meningitis 
External CSF Drainage 
Hydrocephalus 
Req. for CSF Shunt 

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Figure 2.  Surgical techniques for decompression for CM+SM. A, Planned areas of bone removal from the suboccipital region of the skull and C1 
lamina. B, After bony decompression, the constricting epidural band at the level of the foramen magnum is resected.  This is the end of the operation 
for the extradural posterior fossa decompression (PFD). If posterior fossa decompression with duraplasty (PFDD) is performed, the dura is opened 
sharply, exposing the cerebellar tonsils, brainstem, and upper spinal cord (C).  After microsurgical dissection, the dura is sewn closed with a dural graft 
(D). 
Table 2.  Summary of existing literature comparing PFD and PFDD for CM+/-SM. 
 
N value 
% Clinical 
Improvement 
% Syrinx 
Improvement 
% CSF-related 
Complications 
% Req. Repeat 
Decompression 
Article 
PFDD 
PFD 
PFDD 
PFD 
PFDD 
PFD 
PFDD 
PFD 
PFDD 
PFD 
Munshi (2000) 
21 
11 
85.7 
72.7 
100 
50.0 
66.7 
0 
0 
18.2 
Ventureyra (2003) 
8 
8 
100 
62.5 
100 
0 
NR 
NR 
--- 
--- 
Navarro (2004) 
53 
56 
62.3 
72.2 
NR 
NR 
34.0 
3.6 
9.4 
14.3 
Limonadi (2004) 
12 
12 
OR 1.5* 
OR 1.7* 
100 
--- 
8.3 
0 
NR 
NR 
Yeh (2006) 
85 
40 
97.6 
90.0 
85.0 
66.7 
10.0 
0 
5.9 
0 
Galarza (2007) 
40 
20 
79.2 
33.3 
77.7 
40.0 
NR 
NR 
NR 
NR 
Mutchnick (2010) 
64 
56 
NR 
NR 
NR 
NR 
NR 
NR 
3.1 
12.5 
Litvack (2013) 
47 
63 
91.4 
90.0 
NR 
NR 
19.2 
0 
0 
1.6 
Lee (2014) 
36 
29 
CCOS 
14.6** 
CCOS 
14.7** 
76.9 
100 
19.4 
0 
2.8 
6.9 
 
 
 
 
 
 
 
 
 
 
 
Meta-Analysis 
Durham (2008) 
316 
266 
78.6 
64.6 
87.0 
56.3 
18.5 
1.8 
2.1 
12.6 
    p-value 
NA 
p=0.12 
p=0.56 
p=0.0003 
p=0.01 
*Odds Ratio (OR) reported; **Chicago Chiari Outcome Scale (CCOS) reported; NR=Not reported; NA=Not Applicable 
 
 
The current study—which has been guided by patients and families, patient advocacy 
organizations, physician and non-physician stakeholders, and supported by the American 
Association of Neurologic Surgeons (AANS), the Congress of Neurological Surgeons (CNS), 
and the Joint AANS/CNS Pediatric Section —is designed to address this critical gap in the 
management of CM+SM by comparing the risk of harm, effectiveness, and impact on QOL 
between PFDD and PFD. 
 
The information that will be obtained from this study is of paramount importance to patients and 
families who are faced with making critically important and consequential healthcare decisions at 
a time of extreme duress.  Patients and families are often overwhelmed to learn that they have a 
complex and progressive neurological disorder with long-term implications for their health. This 
shock is often compounded by disappointment upon learning that there are significant unknowns 
in the treatment of their condition— “Which surgery should we choose?”  “Which has higher 
risks?”  “Which is more likely to harm my child?”  “Is one more likely to help my child?”  “I 
don’t want them to suffer through this more than once.”  Right now, these questions are 
unanswerable; the current study will help patients and families to answer these questions and make 
informed healthcare decisions about how best to help their children while minimizing the risk of 
harm.  In designing this study with patient partners and advocacy groups, this was a resounding 
priority for research in CM+SM. 
 
This study will have tremendous impact by identifying the surgical approach (PFDD or PFD) that: 
1) minimizes surgical complications and potential harm to patients; 2) maximizes symptomatic 
relief and syrinx resolution; and 3) provides the highest Quality of Life (QOL) for patients.  The 
results of this study will transform management of this disorder in real and substantial ways that 
are critically important to patients and families, stakeholders, and clinicians by: 

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1. Addressing the knowledge gap in treating CM+SM: No high quality evidence-based 
data exist for the treatment of CM+SM.  The results of this study will enable us to 
establish best neurosurgical practices to improve healthcare delivery and 
outcomes for CM+SM by minimizing patient harm while maximizing 
symptomatic relief and QOL. 
2. Assist patients and families with difficult healthcare decisions: The information 
provided through this study will create a paradigm shift away from the current 
reliance on individual surgeon preferences and experiences. In its place, these 
results will enable patients and families to appreciate the rationale, risks, and 
benefits of the various surgical strategies for CM+SM so that they can make 
informed, consequential decisions regarding their own healthcare. 
3. Understand the impact of CM+SM, both acutely and chronically, on QOL in children.  
To date, nearly all CM+SM studies have focused on physician assessment of clinical 
outcomes in CM+SM.  By employing disease-specific, patient-centered QOL 
instruments, this study will provide entirely novel, rigorously determined insights 
into the impact of CM+SM on QOL in children and how QOL changes in the 
short- and long-term after surgery. 
3. STUDY DESIGN  
SPECIFIC AIMS 
Children with Chiari type I malformation (CM) and syringomyelia (SM), a ‘rare disease’, may 
suffer debilitating pain, spinal deformity, neurological deficits (myelopathy, weakness, sensory 
loss, and impaired gait), and diminished quality of life (QOL) (2, 7, 8, 27).  CM+SM is treated 
with neurosurgical decompression of the craniovertebral junction with either of two technical 
variations: 1) posterior fossa decompression with duraplasty (PFDD), the gold standard operation, 
which involves intradural microsurgical dissection and duraplasty; or 2) extradural posterior fossa 
decompression (PFD), in which the dura is not opened.  The Central Hypothesis of this proposal 
is that, compared with PFDD, PFD will be associated with fewer surgical complications and 
less harm to patients, yet will provide non-inferior clinical improvement and syrinx 
regression.  With a more favorable risk profile and non-inferior clinical outcomes, patients 
undergoing PFD will experience superior QOL.  We will conduct a prospective, cluster 
randomized controlled trial of PFD versus PFDD in order to test this hypothesis and achieve the 
following Specific Aims: 
Specific Aim 1: Determine if PFD is associated with fewer surgical complications and less harm 
to patients than PFDD. 
Hypothesis: PFD will be associated with fewer surgical complications and less potential harm to 
patients than PFDD.     
Anticipated Outcome:  Cerebrospinal fluid (CSF)-related complications ≤6 months (e.g. CSF 
leak, pseudomeningocele, aseptic meningitis, infection, and hydrocephalus) and requirement for 
additional surgery for wound revision or CSF diversion will be lower after PFD compared with 
PFDD. 
 
Specific Aim 2:  Determine if PFD provides non-inferior clinical improvement and syrinx 
regression compared to PFDD.   

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Hypothesis: Clinical improvement and syrinx regression provided by PFD will be non-inferior 
compared to those provided by PFDD. 
Anticipated Outcome:  Clinical symptoms, neurological function, and syrinx regression ≤12 
months will be non-inferior following PFD when compared with PFDD.  Rates of revision 
decompression surgery (PFD or PFDD) and progression of spinal deformity ≤12 months after PFD 
also will be non-inferior to PFDD. 
 
Specific Aim 3:  Determine if PFD is associated with superior QOL compared with PFDD. 
Hypothesis:  With fewer surgical complications, PFD will be associated with superior QOL 
compared with PFDD. 
Anticipated Outcome: PFD will have superior QOL and will show improvements in overall QOL 
over time (≤12 months post-operatively) compared to PFDD.  In particular, both physical metrics 
(evaluated by pain frequency, pain severity and non-pain symptoms) and psychosocial metrics will 
improve at a higher rate and in a shorter period of time after PFD compared to PFDD. 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS. 
This study will leverage the unique resources of the Park-Reeves Syringomyelia Research 
Consortium (PRSRC), a U.S.-based network of major children’s hospitals, each with a high-
volume pediatric neurosurgery and orthopedic surgery center.  For the current study,  additional 
PRSRC sites have been recruited and agreed to participate, (please refer to Appendix I for a full 
listing of the structure of the PRSRC).  Due to the highly specialized pediatric neurosurgical care 
required for the management of CM+SM, each site serves as a regional referral center for this rare 
condition, and the demographics of patients cared for at each site are thus representative of the 
demographic distribution of each region. 
 
4.1 Inclusion Criteria  
1) Age ≤21 years old 
2) Chiari malformation type I with ≥5 mm tonsillar ectopia 
3) Syrinx diameter (recorded as the greatest antero-posterior or transverse diameter) 3-9 mm 
4) MRI of the brain and cervical and thoracic spine are required prior to surgery and available 
to be shared with the DCC 
4.2 Exclusion Criteria  
1) Syrinx <3 mm and/or ≥10 mm 
2) Neuro-imaging demonstrating basilar invagination (position of the superior tip of 
 
dens 5 mm above Chamberlain’s line) 
3) Neuro-imaging demonstrating clival canal angle <120°  
4) Prior PFD, PFDD, or other surgery at the craniovertebral junction 
5) CM+SM secondary to other pathology (e.g. a tumor) 
6) Unable to share pre-decompression MRI of the brain and cervical and thoracic spine  
7) Patients who do not wish to participate 
 
4.3 Study Enrollment Procedures  
Potential participants will be identified, screened, and recruited through the clinical practices of 
48 participating sites.  In this trial, the randomization unit will be the PRSRC center; therefore, the 
same intervention will be used for all qualifying patients enrolled at each center.  If a surgeon in a 
PRSRC center strongly believes that a patient should undergo a certain procedure (PFDD or PFD) 

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and should not be randomized, that patient will be excluded from the study.   Effective 
randomization will occur through the random distribution of patients to centers employing each 
procedure (PFDD and PFD).   
 
Barriers to enrollment will be addressed by monthly review of each site’s screening log and 
REDCap screening/enrollment tool, which includes individuals who were eligible for enrollment, 
but were not enrolled in the study. These logs (see Appendix III) REDCap results will be supplied 
by St. Louis Children’s Hospital/Washington University-St. Louis and will be reviewed to assure 
that each participating hospital is enrolling subjects actively and without significant bias. If study 
enrollment is slower than anticipated, more ancillary PRSRC sites will be added.  PRSRC has been 
approached by numerous other pediatric neurosurgical centers, and adding more ancillary sites is 
readily feasible.  
 
4.4 Subject Recruitment 
When the clinical site coordinator and/or investigator becomes aware of a patient who is 
potentially eligible for enrollment into the study, patient eligibility will be confirmed, and the study 
investigator or coordinator will approach the child’s parent/guardian and/or the patient (as 
applicable) to offer participation.  Each center will maintain a screening log and complete a 
REDCap screening/enrollment tool for any participants who are eligible for enrollment, but are 
not enrolled into the study.  These data will be reviewed to assure that each participating center is 
enrolling subjects without significant bias. 
 
4.5 Parental Permission and Child Assent 
After determining that a subject is eligible, the site investigator or designee will approach the 
parent/guardian to offer participation for their child in the study.  The parent/guardian will be 
informed about the objectives of the study and the potential risks and benefits of trial participation.  
If the parent/guardian refuses permission for their child to participate, then all clinical care will be 
provided to the child in accordance usual institutional practice.  Assent will be obtained for patients 
meeting age requirements for assent.  Informed consent/assent will be obtained in the relatively 
focused atmosphere of a clinic or similar room rather than the more chaotic pre-operative holding 
area just before surgery. 
 
 
4.6 Randomization and Treatment Allocation 
A cluster randomized controlled trial (C-RCT) will be conducted to compare the two major 
neurosurgical treatments for CM+SM, PFDD and PFD.  The cluster size is expected to be on 
average 6 participants per center.  In order to participate, PRSRC centers with multiple pediatric 
neurosurgeons were given the option of complying with the treatment allocation and following a 
standardized procedure or selecting a single study neurosurgeon for the group.  If the latter scenario 
was chosen, the group had to agree that all CM+SM patients referred to that center must be treated 
by the study neurosurgeon.  For cluster randomization, a computer-generated randomization 
sequence will be generated independently by the study statistician.  All eligible participants within 
each cluster will then be approached for informed consent for the purposes of data collection for 
the trial.   

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5. STUDY INTERVENTIONS  
5.1 Interventions, Administration, and Duration  
The intervention performed will either be a PFD or PFDD.  It will be predetermined, based on 
cluster randomization, which procedure each center performs on their respective participants.  A 
computer-generated randomization sequence will be generated independently by the study 
statistician. The surgery will occur in each respective center’s operating room.  With the exception 
of uniformly receiving the designated center intervention, all research participants will receive 
usual clinical care in accordance with institutional practice and judgment.  Clinical care will 
include at a minimum an initial clinical evaluation by a participating pediatric neurosurgeon, 
surgical treatment (PFDD or PFD) and associated perioperative care, and routine post-operative 
care with prescribed follow-up clinical assessments at ≤6 weeks, 3-6 months, and 12 months (+/- 
2 months = 10-14 months) after surgery. Patients will be given the opportunity to re-consent into 
a study extension where any visits occurring within 5 years postoperatively will be documented, 
and the QOL questionnaires may be given annually.  Research data will be collected at all stages 
by trained study research assistants/coordinators with strict oversight by site investigators using 
standard data collection forms.  Neuro-imaging is a critical element of the trial, required both for 
enrollment and to monitor treatment efficacy.  As such, MRI of the brain and cervical and thoracic 
spine are required prior to surgery.  Pre-operative lumbar spine MRI will be left to the discretion 
of the surgeon.  MRI of the cervical and thoracic spine are required 12 months (+/-2 months = 10-
14 months) post-operatively.   These are required for clinical care of CM+SM patients, regardless 
of participation in the study, and funding is not requested for these examinations. MRI of the 
lumbar spine, CT of the brain or cervical/thoracic/lumbar spine, “long cassette” or “scoliosis” X-
rays, and/or X-rays of the cervical/thoracic/lumbar spine are not required but, will be reviewed if 
obtained. In the case where the patient returned outside the window for primary analyses, a 
secondary analysis will include those visits up to 24 months. 
 
Each center will be informed which arm they have been randomized to before enrollment occurs.  
Therefore, every potential participant/family will be aware of which procedure would be 
performed if s/he agreed to participate.   If the procedure is not an appropriate fit for a particular 
patient or, the patient/family is not comfortable with the predetermined procedure, the patient will 
not be enrolled and they will be offered standard of care treatment by the clinical team at that 
center 
 
 
5.2 Handling of Study Interventions  
All pediatric neurosurgeons involved in the study have completed both an accredited neurosurgery 
residency and a 1-year subspecialty fellowship in pediatric neurosurgery at a program accredited 
by the Accreditation Council for Pediatric Neurosurgery Fellowships (ACPNF) or by The 
American Osteopathic Association (AOA) and are either certified or eligible for certification by 
both the American Board of Neurological Surgeons (ABNS) and the American Board of Pediatric 
Neurological Surgery (ABPNS) or the American Osteopathic Board of Surgery (AOBS).  Prior to 
participating in the study, each pediatric neurosurgeon must submit documentation verifying that 
s/he has performed ≥20 PFDD/PFD cases at the level of attending pediatric neurosurgeon or that 
that s/he performed ≥5 PFDD/PFD cases in the year preceding the participation in the study; and 

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3) review two videos showing the study-approved operative technique for PFDD and PFD in step-
wise fashion.  As detailed in the videos, PFDD and PFD both begin with a midline posterior 
suboccipital incision extending from the level of the inion inferiorly. Suboccipital craniectomy ± 
cervical laminectomies are performed based upon the level of tonsillar position on the pre-
operative MRI.  The posterior atlanto-occipital membrane and any additional constricting epidural 
bands are then dissected off the dura and bisected.  For PFD, the operation is complete (dural 
scoring or splitting is permitted), and wound closure is initiated.  For PFDD, the dura is then incised 
and retracted for microsurgical dissection. Intradural maneuvers are performed at the surgeon’s 
discretion based on the intra-operative findings, but may include exploration/fenestration of an 
arachnoid veil, lysis of adhesions, or tonsillar reduction.  Following the intradural dissection, the 
duraplasty is performed with autologous graft or dural substitute, and the wound is closed in 
standard fashion.  Dural opening without subsequent dural closure is not permitted for PFDD or 
PFD.  
5.3 Concomitant Interventions   
5.3.1 Allowed Interventions 
Medications or other treatments may be administered per usual institutional clinical 
practice.  PFD or PFDD must follow the procedural guidelines outlined in this protocol.  
5.3.2 Required Interventions  
There are no required interventions outside of the PFD or PFDD procedure itself. 
5.3.3  Prohibited Interventions 
PFD or PFDD must be in accordance with the procedural guidelines outlined in this 
protocol.  For the purposes of this study, PFD performed with dural opening but no dural 
closure is not permitted.  Similarly, cases requiring concomitant cervical or occipito-
cervical fusion or upfront direct syrinx surgery (syrinx fenestration or shunt) are not 
permitted. 
5.4 Adherence Assessment  
Periodic quality assurance checks will be performed primarily via remote monitoring by 
reviewing a random subset of operative notes at each participating site. 
 
 
 
6. STUDY PROCEDURES  
6.1 Schedule of Evaluation 
 
Assessment 
Initial Visit 
<6 Weeks 
Follow-Up 
Visit 
3-6 Month 
Follow-up 
Visit 
12 Month 
Follow-up 
Visit 
14 months to 
5 years 
postoperative  
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
Cluster Randomization 
X 
 
 
 
 

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Informed Consent Form 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Presenting Symptoms 
X 
 
 
 
 
Childhood History 
X 
 
 
 
 
Developmental History 
X 
 
 
 
 
Allergies 
X 
 
 
 
 
Concomitant Medications 
X 
 
 
 
 
Family History 
X 
 
 
 
 
Social History 
X 
 
 
 
 
General Exam 
X 
 
 
 
 
Musculoskeletal Exam 
X 
 
 
 
 
Initial Radiology 
X 
 
 
 
 
Diagnosis 
X 
 
 
 
 
Clinical Course of 
Treatment 
X 
X 
X 
X 
Optional 
Complications 
X 
X 
X 
X 
Optional 
Pt Status 
X 
X 
X 
X 
Optional 
CHIP 
X 
X 
X 
X 
Required 
HUI-3 QOL 
X 
X 
X 
X 
Required 
Follow-up Symptoms 
 
X 
X 
X 
Optional 
Follow-up Medications 
 
X 
X 
X 
Optional 
Follow-up General Exam 
 
X 
X 
X 
Optional 
Follow-up Neurological 
Exam 
 
X 
X 
X 
Optional 
Follow-up Musculoskeletal 
Exam 
 
X 
X 
X 
Optional 
Follow-up Radiology 
 
^ 
^ 
X 
Optional 
Additional 
Neurological/Orthopedic 
Exam 
 
X 
X 
X 
Optional 
^ Any subsequent pre-operative images (Brain/spine MRI/CT/X-rays) will be shared, including in the   
   following scenarios: 
 
- Revision/redo decompression  
  
- Syrinx shunt or fenestration  
- Spinal Fusion  
6.2 Description of Evaluations  
6.2.1 Screening Evaluation 
Screening evaluations and associated studies for determining eligibility must be 
completed within 6 months of study entry. 
 
 
Inclusion Criteria  
1) Age ≤21 years old 
2) Chiari malformation type I with ≥5 mm tonsillar ectopia 
3) Syrinx diameter (recorded as the greatest antero-posterior or transverse diameter) 3-9 
mm. 
4) MRI of the brain and cervical and thoracic spine are required prior to surgery and 
available to be shared with the DCC 
 

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Exclusion Criteria  
1) Syrinx <3 mm and/or ≥10 mm 
2) Neuro-imaging demonstrating basilar invagination (position of the superior tip of 
      dens 5 mm above Chamberlain’s line) 
3) Neuro-imaging demonstrating clival canal angle <120°  
4) Prior PFD, PFDD, or other surgery at the craniovertebral junction 
5) CM+SM secondary to other pathology (e.g. a tumor) 
6) Unable to share pre-decompression MRI of the brain and cervical and thoracic spine  
7) Patients who do not wish to participate 
 
Consenting Procedure 
Informed consent will be obtained in the relatively focused atmosphere of a clinic or 
similar room rather than the more chaotic pre-operative holding area just before surgery. 
 
When a clinical site investigator and/or research coordinator identifies a candidate for the 
study, patient eligibility will be confirmed, and the study investigator or coordinator will 
approach the individual to offer participation. After a thorough discussion to inform the 
patient and family of the rationale and objectives of the study and the risks, benefits, and 
alternatives to participation, written informed consent will be obtained from a parent or 
legal guardian (patient <18 years of age) or the patient themselves (patient ≥18 years of 
age).  Additionally, assent will be obtained for patients of appropriate age, according to 
individual institutional practices.  If study participation is declined, then all clinical care 
will be provided to the child in accordance with institutional practice and judgment.  Each 
center will maintain a log of any individuals who are eligible for enrollment, but are not 
enrolled in the study. These logs will be reviewed to assure that each participating hospital 
is enrolling subjects without significant bias. In uncertain cases, adjudication of patient 
eligibility will be performed by a committee blinded to intervention and outcome and 
considering only the information available at the time of enrollment. Patients will be 
offered the opportunity to re-consent to participate in continued data collection for five 
years post-operatively.  
 
6.2.2 Enrollment, Baseline, and/or Randomization 
Enrollment 
In order to allow participants and their families the opportunity to make an informed 
decision about participating in the study, the consent and assent shall be reviewed and 
signed prior to surgery.  Enrollment may occur in one of the follow manners: 1) the 
participant signs the consent (participant 18 years); 2) at least one parent/legal guardian 
signs the consent (participant less than 18 years old); or 3) participant less than 18 years 
old co-signs the consent with at least one parent/legal guardian (requires that the 
participant is able to read the consent and understands and agrees with it; this may vary 
by the institution’s local IRB’s guidelines).  For those participants who are unable to read 
and understand the consent, but are able to read, understand, and agree with the assent, 
that document will be signed based on the IRB guidelines.   
 
Baseline Assessments 
Baseline assessment data to be collected at the initial visit includes the following: 

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o Demographics 
o Symptoms 
o Childhood History 
o Developmental History 
o Allergies 
o Concomitant Medications 
o Family History 
o Social History 
o General Exam 
o Neurological Exam 
o Musculoskeletal Exam 
o Radiology 
 Brain and cervical and thoracic spine MRI 
 MRI of the lumbar spine, CT of the brain or cervical/thoracic/lumbar 
spine, “long cassette” or “scoliosis” X-rays, and/or  X-rays of the 
cervical/thoracic/lumbar spine are not required but will be reviewed if 
obtained. 
o Diagnosis 
o Clinical Course of Treatment 
 PFD or PFDD 
o Complications 
o CHIP 
o HUI-3 QOL 
o Patient Status 
o Additional Neurological/Orthopedic surgery (if applicable) 
 
Randomization 
Individual trial centers will be randomized to perform either PFDD or PFD.  In order to 
participate, trial centers with multiple pediatric neurosurgeons were given the option of 
complying with the treatment allocation and following a standardized procedure or 
selecting a single study neurosurgeon for the group.  If the latter scenario was chosen, the 
group had to agree that all CM+SM patients referred to that center must be treated by the 
study neurosurgeon.  For cluster randomization, a computer-generated randomization 
sequence will be generated independently by the study statistician before the respective 
participating site enrolls a participant.  All eligible participants within each cluster will then 
be approached for informed consent for the purposes of data collection for the trial. Each 
participant/guardian will know the randomized treatment selection at the time of the 
informed consent process. 
6.2.3 Follow-up Visits    
Data to be collected at follow-up visits includes the following: 
 ≤ 6 weeks postoperative visit: 
o Clinical Course of Treatment 
 Any orthotics  
 Decompression 
 Any fusion or syrinx surgery 
o Complications 

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o CHIP (if > 1 visit during this period only collect for 1st visit) 
o HUI-3 QOL(if > 1 visit during this period only collect for 1st visit) 
o Patient Status 
o Follow-up Symptoms 
o Follow-up Medications 
o Follow-up General Exam 
o Follow-up Neurological Exam 
o Follow-up Musculoskeletal Exam 
o Follow-up Radiology Exam (if applicable) 
o Additional Neurological/Orthopedic Surgery 
  
 3-6 months postoperative visit: 
o Clinical Course of Treatment 
 Any orthotics  
 Decompression 
 Any fusion or syrinx surgery 
o Complications 
o CHIP (if > 1 visit during this period only collect for 1st visit) 
o HUI-3 QOL (if > 1 visit during this period only collect for 1st visit) 
o Patient Status 
o Follow-up Symptoms 
o Follow-up Medications 
o Follow-up General Exam 
o Follow-up Neurological Exam 
o Follow-up Musculoskeletal Exam 
o Follow-up Radiology Exam (if applicable) 
o Additional Neurological/Orthopedic Surgery 
 
6.2.4 Completion/Final Evaluation   
 
 
 
 
 
Data to be collected at the final visit (12 +/- 2 months postoperative) includes the  
following: 
 12 ±2 months postoperative visit: 
o Clinical Course of Treatment 
 Any orthotics  
 Decompression 
 Any fusion or syrinx surgery 
o Complications 
o CHIP (if > 1 visit during this period only collect for 1st visit) 
o HUI-3 QOL (if > 1 visit during this period only collect for 1st visit) 
o Patient Status 
o Follow-up Symptoms 
o Follow-up Medications 
o Follow-up General Exam 
o Follow-up Neurological Exam 
o Follow-up Musculoskeletal Exam 
o Follow-up Radiology Exam  

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 MRI of the cervical (including craniovertebral junction) and 
thoracic spine MRI 
 MRI of the brain or lumbar spine, CT of the brain or 
cervical/thoracic/lumbar spine, “long cassette” or “scoliosis” X-
rays, and X-rays of the cervical/thoracic/lumbar spine are not 
required but will be reviewed if obtained. 
o Additional Neurological/Orthopedic Surgery 
7. SAFETY ASSESSMENTS  
Complications will be recorded at the following time points: 
o Intra-operatively 
o ≤ 6 months after initial PFD or PFDD 
o 6-12 (+/- 2 months)  months after initial PFD or PFDD 
 
**For definitions of complications for this trial, see Section 7.1. 
 
Known potential complications include the following: 
o Intra-operatively 
 Vascular injury 
 Hemorrhage requiring evacuation 
 Neurologic Injury 
 Cranial nerve injury or palsy 
 Weakness 
 Sensory Changes 
 Bowel Dysfunction 
 Bladder Dysfunction 
 Death 
 
o Complications ≤ 6 months after PFD or PFDD 
 Pseudomeningocele 
 CSF Leak 
 Hydrocephalus 
 Infection 
 Chemical meningitis 
 True meningitis 
 Cervical instability 
 Cerebellar ptosis with intractable headaches 
 
Other unexpected complications that are related to the surgery and other adverse events 
that occur that are not related to the surgery will be recorded for the first 6 months. 
 
o Complications > 6 months after PFD or PFDD 
 Cervical instability 
 Infection 
 Hydrocephalus 

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 Cerebellar ptosis with intractable headaches 
 
Other unexpected complications that are related to the surgery will be recorded at the 
time interval of >6 months postoperatively. 
 
Possible interventions for known complications are as follows: 
o Intra-operative complications 
 Evacuation of hemorrhage 
 Open or endovascular repair vascular injury 
o ≤ 6 months postoperative complications 
 External drainage for the following: 
 Hydrocephalus 
 CSF leak 
 Pseudomeningocele 
 Infection 
 Shunt malfunction/infection 
 Simple over-sewing of wound for CSF leak 
 Surgical revision in operating room for the following: 
 CSF leak 
 Infection 
 Pseudomeningocele 
 Lumbar puncture and steroids for the following: 
 Chemical meningitis 
 True meningitis 
 Shunt placement for hydrocephalus 
 Cervical collar and/or fusion for cervical instability 
 Cerebellopexy for cerebellar ptosis 
 
o > 6 months postoperative complications 
 Surgical revision in operating room for the following: 
 Infection 
 Pseudomeningocele 
 Lumbar puncture for true meningitis 
 Shunt placements for hydrocephalus 
 Cervical collar and/or fusion for cervical instability 
 Cerebellopexy for cerebellar ptosis 
7.1 Specification of Safety Parameters 
The presence of any of the following items will be considered as a poor outcome (harm to 
patients). 
 Intra-operative Complication 
o Vascular injury resulting in dissection or stroke 
o Intracranial hemorrhage requiring return to surgery for evacuation 
o Neurological injury  
 Cranial nerve deficit 

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 New weakness 
 Sensory loss 
 Bowel or bladder dysfunction 
o Death 
 Complications ≤ 6 months after PFD or PFDD 
 Pseudomeningocele: an extradural and/or subcutaneous fluid collection 
resulting in discomfort or pain, limitation of movement, or CSF leak.  
Radiological evidence of fluid collection alone is not sufficient for 
diagnosis of pseudomeningocele. 
 CSF Leak 
 Hydrocephalus: requires external drainage, shunting, or endoscopic 3rd 
ventriculostomy. 
 Infection: clinical diagnosis that may include fever, wound drainage, 
dehiscence, or elevated laboratory parameters in association with 
antibiotic treatment ± surgical debridement. 
 Chemical (or aseptic) meningitis: clinical diagnosis prompting medical 
treatment (e.g. steroids); lumbar puncture and analysis of CSF cell profile 
not required but will be tracked if available. 
 True meningitis: lumbar puncture and positive cultures required. 
 Cervical instability 
 Cerebellar ptosis with intractable headaches 
 Need for interventions for complication management <6 months after initial PFDD 
or PFD 
 External drainage for the following: 
 Hydrocephalus 
 CSF leak 
 Pseudomeningocele 
 Infection 
 Shunt malfunction/infection 
 Simple over-sewing of wound for CSF leak 
 Surgical revision in operating room for the following: 
 CSF leak 
 Infection 
 Pseudomeningocele 
 Lumbar puncture and steroids for the following: 
 Chemical meningitis 
 True meningitis 
 Implantation of ventriculo-peritoneal or other permanent shunt or 
endoscopic 3rd ventriculostomy for hydrocephalus. 
 Cervical collar and/or fusion for cervical instability 
 Cerebellopexy for cerebellar ptosis 
 Complication ≤12 (+/- 2 months) months after initial PFDD or PFD 
o Pseudomeningocele: an extradural and/or subcutaneous fluid collection resulting 
in discomfort or pain, limitation of movement, or CSF leak.  Radiological 
evidence of fluid collection alone is not sufficient for diagnosis of 
pseudomeningocele. 

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o CSF leak 
o Hydrocephalus: requires external drainage, shunting, or endoscopic 3rd 
ventriculostomy. 
o Infection: clinical diagnosis that may include fever, wound drainage, dehiscence, 
or elevated laboratory parameters in association with antibiotic treatment ± 
surgical debridement. 
o Chemical (or aseptic) meningitis: clinical diagnosis prompting medical treatment 
(e.g. steroids); lumbar puncture and analysis of CSF cell profile not required but 
will be tracked if available. 
o True meningitis: lumbar puncture and positive cultures required. 
o Cerebellar ptosis with intractable headaches 
 
 Need for interventions for complication management ≤12 (+/- 2 months) after initial 
PFDD or PFD 
 External drainage for the following: 
 Hydrocephalus 
 CSF leak 
 Pseudomeningocele 
 Infection 
 Shunt malfunction/infection 
 Simple over-sewing of wound for CSF leak 
 Surgical revision in operating room for the following: 
 CSF leak 
 Infection 
 Pseudomeningocele 
 Lumbar puncture and steroids for the following: 
 Chemical meningitis 
 True meningitis 
 Implantation of ventriculo-peritoneal or other permanent shunt or 
endoscopic 3rd ventriculostomy for hydrocephalus. 
 Cervical collar and/or fusion for cervical instability 
 Cerebellopexy for cerebellar ptosis 
 
7.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
Complications and adverse events will be captured starting with intra-operative period and will 
continue for one year postoperatively.  Additional surgeries, such as a decompression 
redo/revision, fusion surgery, anterior/ventral decompression, syrinx shunt, and syrinx 
fenestration will also have surgical complications and adverse events monitored and recorded 
for the one year collection period. 
 
7.2.1 Preliminary Data  

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The 
Park-Reeves 
Syringomyelia 
Research 
Consortium (PRSRC) is a 
U.S.-based network of 36 
major 
pediatric 
neurosurgery 
centers 
focused on improving the 
care 
of 
children 
with 
CM+SM. 
 
The 
largest 
research effort for CM+SM 
to date, PRSRC began 
enrolling 
patients 
both 
retrospectively 
and 
prospectively 
in 
2011.  
Through 
the 
PRSRC, 
comprehensive clinical and 
radiographic data have been 
obtained on >600 CM+SM 
patients. 
Table 
3 
summarizes 
the 
post-
operative 
complications 
observed in 589 subjects 
with complete data who 
underwent PFDD or PFD 
since 2011, as support for 
PFD has grown. Within the 
PRSRC, 
rates 
of 
complications are remarkably consistent with those reported in the meta-analysis by Durham and 
Fjeld-Olenec in 2008 (Table 2)[27], with complications noted in 17.8% following PFDD versus 
2.7% after PFD.  In addition, a corrective neurosurgical procedure for complication management 
was needed more often after PFDD compared to PFD (10.1% versus 2.7%).  However, repeat 
decompression surgery for persistent disease was required in only 5.0% of PFDD cases versus 
12.3% after PFD.  
In planning a clinical trial for CM+SM, it is important to select appropriate inclusion 
criteria for study patients in order to: 1) enhance homogeneity in disease severity among study 
participants; 2) permit appropriate comparisons across participants and groups; and 3) ensure 
clinical equipoise among treating physicians.  With this goal in mind, our group recently created 
the Chiari Severity Index, or CSI, a pre-operative instrument that stratifies children with CM+/-
SM based on their probability of postoperative improvement[12].  The CSI was developed in 
conjunction with patient and families and uses their input as a critical arbiter of outcome.  Two 
advanced methodologies, sequential sequestration and conjunctive consolidation, were used to 
identify key clinical and radiographic predictors of clinical outcome and then to integrate them 
into one useful CSI (Fig. 3). 
Table 3.  Complications and Need for Repeat Surgical Decompression for 
CM+CM in the Park-Reeves Syringomyelia Research Consortium. 
 
 
 
 
 
PFDD 
PFD 
 
n 
% 
n 
% 
Surgical Complications 
 
 
 
 
 
Vascular Injury 
1 
0.20% 
0 
0% 
Pseudomingocele 
28 
5.4% 
1 
1.4% 
CSF Leak 
20 
3.9% 
1 
1.4% 
Infection 
2 
0.4% 
0 
0% 
Chemical Meningitis 
24 
4.7% 
0 
0% 
Hydrocephalus 
15 
2.9% 
0 
0% 
Cervical Instability 
2 
0.40% 
0 
0% 
Total 
92 
17.8% 
2 
2.7% 
 
 
 
 
 
Surgical Procedures for 
Complication Management 
 
 
 
 
Oversewing of Wound 
6 
1.2% 
1 
1.4% 
Wound Revision 
13 
2.5% 
1 
1.4% 
External CSF Drainage 
22 
4.3% 
0 
0 
Shunt Required 
10 
1.9% 
0 
0% 
Req. for Cervical Fusion 
1 
0.20% 
0 
0% 
Total 
52 
10.1% 
2 
2.7% 
 
 
 
 
 
 
PFDD 
PFD 
 
n 
% 
n 
% 
Repeat Decompression 
Surgery (PFDD or PFD) 
26** 
5.0% 
9 
12.3% 
*n=589 total.  Imbalance in PFDD (n=516) vs PFD (n=73) results from the epoch of 
enrollment (2002-2014); PFD only offered routinely since 2010).  
**One patient had 3 repeat decompressions. 

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We also recently completed a 
systematic review of outcome methods 
used in studies of CM+SM and noted that 
studies of CM+SM were significantly 
impeded by inconsistent and limited 
methods 
of 
evaluating 
clinical 
outcomes[28]. The majority of papers used 
a clinician’s “gestalt” impression of 
symptomatic improvement (Fig. 4).  Only 3 
papers used scales validated in patients 
with CM+/-SM, and only 7 articles 
incorporated patient-response instruments.  
Our review emphasized the need for 
CM+SM-specific 
patient-based 
instruments to improve research in this field [28]. 
The Chiari Health Index in Pediatrics (CHIP) was developed in response to the deficiencies 
noted in our systematic review and addresses the following criteria: 1) it focuses on the complaints 
most important to CM + SM patients; 2) it relies on patient involvement in answering the 
questions; 3) it is age-appropriate; and 4) and it helps inform clinical decision making regarding 
the treatment and management of these patients [29].  As with other Health-Related QOL 
(HRQOL) inventories, the CHIP was designed to be discriminative, evaluative, and predictive [30, 
31].  A single 45-item form, the CHIP can be completed by a parent only, a child only, or a parent 
and child together. 
Psychometric research methodologies, 
including item generation and development, 
evaluation of construct validity, test-retest 
reliability, and confirmatory factor analysis were 
used in the development and validation of the 
CHIP (Table 4).   The number of items for each 
component is as follows: pain frequency 5, pain 
severity 
5, 
non-pain 
symptoms 
11, 
and 
psychosocial characteristics 24.  In our initial 
studies, we have demonstrated that the CHIP is a 
feasible, reliable, and valid assessment of 
HRQOL in pediatric CM + SM patients. In 
particular, each domain and the overall HRQOL tool showed strong feasibility (i.e. the practical 
ability of participants to complete the survey) and internal consistency within their respective 
domain (α ≥ 75%), a measure of reliability of the test [32]. In addition, the physical (r = 0.73) and 
psychosocial components (r = 0.94), as well as overall HQROL score (r = 0.83), had high test-
retest reliability, even over a median test-retest interval of 70 days. Finally, we demonstrated the 
construct validity of the CHIP by showing the correlation between CHIP scores and concurrent 
HUI-3 scores within similar domains [32].  
 
Table 4.   Chiari Health Index for Pediatrics (CHIP) Instrument Characteristics [29]. 
 
Mean±SD 
Range 
Floor 
effect 
Ceiling 
effect 
Feasibility 
(% complete) 
Consistency 
(Cronbach’s α) 
Test Re-test 
Reliability 
(Pearson’s r) 
Figure 3. The Chiari Severity Index, or CSI, was developed using sequential 
sequestration of pre-operative clinical and radiographic parameters, 
followed by  conjunctive consolidation of independent clinical and 
radiographic indices via [12]. Syrinx size was the only radiographic measure 
associated with clinical outcome, with a critical threshold of 6 mm diameter. 
Figure 4.  Systematic review of outcome methods used in 74 CM+/-
SM studies revealed inconsistent and limited methods of evaluating 
clinical outcomes; a majority of papers relied on clinician ‘gestalt’ 
assessments 
rather 
than 
CM+SM-specific, 
patient-based 
instruments.[28] 

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Physical 
0.66±0.20 
0.27-1.00 
0% 
2% 
84% 
0.89 
0.73 
Pain Frequency 
0.59±0.26 
0.00-1.00 
2% 
7% 
100% 
0.84 
0.62 
Pain Severity 
0.69±0.20 
0.19-1.00 
0% 
7% 
95% 
0.75 
0.83 
Non-Pain 
0.82±0.17 
0.32-1.00 
0% 
22% 
87% 
0.85 
0.83 
Psychosocial 
0.68±0.17 
0.29-0.97 
0% 
0% 
85% 
0.92 
0.94 
Overall HRQOL 
0.66±0.18 
0.33-0.97 
0% 
0% 
75% 
0.92 
0.83 
 
and Serious Adverse Events  
SAFETY ASSESSMENTS  
Complications will be recorded at the following time points: 
o Intra-operatively 
o ≤ 6 months after initial PFD or PFDD 
o 6-12±2 months after initial PFD or PFDD 
 
The following definitions are provided for clarification: 
o Pseudomeningocele: an extradural and/or subcutaneous fluid collection resulting 
in discomfort or pain, limitation of movement, or CSF leak.  Radiological 
evidence of fluid collection alone is not sufficient for diagnosis of 
pseudomeningocele. 
o Hydrocephalus: requires external drainage, shunting, or endoscopic 3rd 
ventriculostomy. 
o Infection: clinical diagnosis that may include fever, wound drainage, dehiscence, 
or elevated laboratory parameters in association with antibiotic treatment ± 
surgical debridement. 
o Chemical (or aseptic) meningitis: clinical diagnosis prompting medical treatment 
(e.g. steroids); lumbar puncture and analysis of CSF cell profile not required but 
will be tracked if available. 
o True meningitis: lumbar puncture and positive cultures required. 
 
Known potential complications include the following: 
o Intra-operatively 
 Vascular injury 
 Hemorrhage requiring evacuation 
 Neurologic Injury 
 Cranial nerve injury or palsy 
 Weakness 
 Sensory Changes 
 Bowel Dysfunction 
 Bladder Dysfunction 
 Death 
 
o Complications ≤ 6 months or 6-12±2 months after PFD or PFDD 

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 Pseudomeningocele 
 CSF Leak 
 Hydrocephalus 
 Infection 
 Chemical meningitis 
 True meningitis 
 Cervical instability 
 Cerebellar ptosis with intractable headaches 
 
Possible interventions for known complications are as follows: 
o Intra-operative complications 
 Evacuation of hemorrhage 
 Open or endovascular repair vascular injury 
o ≤ 6 month or 6-12±2 month postoperative complications 
 Hydrocephalus  
 External ventricular or lumbar drain placement 
 Implantation of ventriculo-peritoneal or other permanent shunt 
 Endoscopic 3rd ventriculostomy for hydrocephalus 
 CSF leak: 
 Over-sewing of wound 
 External ventricular or lumbar drain placement 
 Surgical revision in the operating room 
 Pseudomeningocele 
 Percutaneous drainage 
 External ventricular or lumbar drain placement 
 Surgical revision in the operating room 
 Infection 
 Bedside debridement 
 Surgical revision in the operating room. 
 Shunt malfunction/infection 
 External ventricular or lumbar drain placement 
 Shunt externalization or removal with or without external 
ventricular or lumbar drain placement 
 Shunt revision in the operating room 
 Chemical meningitis 
 Lumbar puncture 
 Steroids 
 Bacterial meningitis 
 Lumbar puncture 
 IV antibiotics 
 Cervical instability 
 External orthosis (e.g. cervical collar, halo vest) 
 Surgical fusion 
 Cerebellar ptosis 
 Cerebellopexy 

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Separate from these complications, other unexpected complications that are related to the surgery 
and other adverse events that occur that are not related to the surgery will be recorded for the < 6 
month and 6-12 (+/- 2 months) month time intervals. Such events will be reported by site 
investigators. For inclusion of all followed patients in the case where the patient returned outside 
the planned study follow-up window, a secondary analysis will include those visits up to 24 
months. 
Specification of Safety Parameters 
The presence of any of the following items will be considered as a harm to patients. 
 
 Intra-operative Complication 
o Vascular injury resulting in dissection or stroke. Dissection will be diagnosed via 
angiographic imaging (CT angiogram, MR angiogram, catheter angiogram) and 
stroke via CT or MRI imaging. 
o Intracranial hemorrhage requiring return to surgery for evacuation 
o Neurological injury resulting in: 
 Cranial nerve deficit 
 New weakness 
 Sensory loss 
 Bowel or bladder dysfunction 
o Death 
 Complications ≤ 6 months after PFD or PFDD 
See definitions above. 
 Pseudomeningocele 
 CSF Leak 
 Hydrocephalus 
 Infection 
 Chemical (or aseptic) meningitis 
 Bacterial meningitis 
 Cervical instability 
 Cerebellar ptosis with intractable headaches 
 Interventions for complication management <6 months after initial PFDD or PFD 
 Hydrocephalus  
 External ventricular or lumbar drain placement 
 Implantation of ventriculo-peritoneal or other permanent shunt 
 Endoscopic 3rd ventriculostomy for hydrocephalus 
 CSF leak: 
 Over-sewing of wound 
 External ventricular or lumbar drain placement 
 Surgical revision in the operating room 
 Pseudomeningocele 
 Percutaneous drainage 
 External ventricular or lumbar drain placement 
 Surgical revision in the operating room 
 Infection 

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 Bedside debridement 
 Surgical revision in the operating room. 
 Shunt malfunction/infection 
 External ventricular or lumbar drain placement 
 Shunt externalization or removal with or without external 
ventricular or lumbar drain placement 
 Shunt revision in the operating room 
 Chemical meningitis 
 Lumbar puncture 
 Steroids 
 Bacterial meningitis 
 Lumbar puncture 
 IV antibiotics 
 Cervical instability 
 External orthosis (e.g. cervical collar, halo vest) 
 Surgical fusion 
 Cerebellar ptosis 
 Cerebellopexy 
 
 Complication 6-12 (+/- 2 months) months after initial PFDD or PFD 
o Pseudomeningocele 
o CSF leak 
o Hydrocephalus 
o Infection 
o Chemical (or aseptic) meningitis 
o Bacterial meningitis 
o Cervical instability 
o Cerebellar ptosis with intractable headaches 
o  
 
 Interventions for complication management 6-12 (+/-2 months) months after initial 
PFDD or PFD 
 Hydrocephalus  
 External ventricular or lumbar drain placement 
 Implantation of ventriculo-peritoneal or other permanent shunt 
 Endoscopic 3rd ventriculostomy for hydrocephalus 
 CSF leak: 
 Over-sewing of wound 
 External ventricular or lumbar drain placement 
 Surgical revision in the operating room 
 Pseudomeningocele 
 Percutaneous drainage 
 External ventricular or lumbar drain placement 
 Surgical revision in the operating room 
 Infection 
 Bedside debridement 

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 Surgical revision in the operating room 
 Shunt malfunction/infection 
 External ventricular or lumbar drain placement 
 Shunt externalization or removal with or without external 
ventricular or lumbar drain placement 
 Shunt revision in the operating room 
 Chemical meningitis 
 Lumbar puncture 
 Steroids 
 Bacterial meningitis 
 Lumbar puncture 
 IV antibiotics 
 Cervical instability 
 External orthosis (e.g. cervical collar, halo vest) 
 Surgical fusion 
 Cerebellar ptosis 
 Cerebellopexy 
 
Adverse Events and Serious Adverse Events  
 
Adverse Event Reporting 
All adverse events will be evaluated as to whether their occurrence was expected or unexpected. 
For this study, expected AEs include the following common surgical complications (see above for 
definitions): 
- 
Pseudomeningocele 
- 
CSF leak 
- 
Infection 
- 
Chemical meningitis 
- 
Bacterial meningitis 
- 
Hydrocephalus 
- 
Need for surgical procedure for complication management 
 
Oversewing of wound 
 
Bedside debridement 
 Surgical revision in the operating room 
 External ventricular or lumbar drain placement 
 
Implantation of ventriculo-peritoneal or other permanent shunt 
 
Endoscopic third ventriculostomy for hydrocephalus 
 Shunt revision in the operating room 
 
Unexpected AEs will include uncommon surgical complications and AEs which may be unrelated 
to the study intervention: 
- 
Clinically significant intracranial hemorrhage 
- 
Skull fracture 
- 
Positioning/pressure sores 
- 
Cerebellar ptosis with intractable headaches 
- 
Cervical instability 
- 
Urinary tract infection 
- 
Need for surgical procedure for complication management 
 
Evacuation of hematoma 

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 
Cerebellopexy for cerebellar ptosis 
 
Cervical or occipital-cervical fusion 
- 
Deep venous thrombosis 
- 
Unsolicited complications related to decompression surgery 
- 
Unsolicited complications not related to decompression surgery 
 
Data Collection Procedures for Adverse Events 
After enrollment, AEs, whether expected or unexpected, will be recorded according to the date of 
first occurrence, severity, duration, and any treatment prescribed.  Any medical condition present 
at the time of enrollment, which remains unchanged or improved, will not be recorded as an 
adverse event on the Adverse Events Log.  All study subjects will be monitored for adverse events  
from the time of enrollment until the time of discharge from the hospital and at each follow-up  
evaluation. Adverse events for subjects who withdraw from the study will be monitored and 
reported until the point of study withdrawal.  
 
 
Serious Adverse Events 
Serious adverse events (SAEs) will be defined as untoward medical occurrences that 
result in a life-threatening change of condition, require further inpatient hospitalization, 
or result in persistent or significant disability/incapacity or death.  In the current study, 
SAEs will include the following: 
- 
Intra-operative vascular injury or stroke 
- 
Neurological injury (cranial nerve deficit, new weakness, sensory loss, bowel or 
bladder dysfunction) 
- 
Visceral injury 
- 
Pulmonary embolism 
- 
Pneumothorax 
- 
Need for unexpected re-intubation 
- 
Cardiopulmonary arrest 
- 
Death 
- 
Unsolicited SAEs related to decompression surgery 
Unsolicited SAEs not related to decompression surgery 
7.3  Reporting Procedures 
Reporting Procedures 
The PI of the Study, Dr. Limbrick, will act as the medical monitor for the study. If Dr. 
Limbrick is unavailable, a qualified physician will be designated to fulfill this function.  SAEs 
will be reported by the clinical site investigator to the Clinical and Data Coordinating Centers 
(CCC and DCC) within 24 hours.  The DCC will report all events that are classified as serious, 
unexpected, and study-related to the study Steering Committee, and the DSMB, by fax or 
telephone, within 3 calendar days of receiving the report from the clinical site.  A written 
report will be sent to the DSMB within 15 calendar days and these reports will be sent to 
clinical investigators for their submission to their respective IRBs.  The DSMB will also 
review all AEs (not necessarily serious, unexpected, and study-related) during scheduled 
DSMB meetings.  The DCC will provide written summary of the DSMB’s periodic review of 
AEs to clinical site investigators for submission to their respective IRBs. 
 
Institutional Review Board (IRB) Reporting 

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SAEs that are judged to be related to participation in the study will be reported to site 
investigators at all participating clinical centers.  Each site investigator will need to report 
these to the site’s local IRB.  Each IRB will assess the impact of these reports on its judgement 
to allow the study to continue at the respective site.  After each DSMB meeting, the DSMB 
report indicating approval to continue the study will be provided to each participating clinical 
center, and should be included in the annual IRB renewal materials.  This DSMB 
recommendation will be based on DSMB examination of all SAEs that have been reported, 
review of interim reports, and ongoing validity and scientific merit of the study. 
7.4 Follow-up for Adverse Events 
Data Collection Procedures for Adverse Events 
All study subjects will be monitored for adverse events.  Adverse events, whether expected or 
unexpected, will be recorded according to the time frame of first occurrence.  Time frames are 
distinguished as intra-operative, ≤6 months, and >6 months.  Each time the participant returns for 
an outpatient neurosurgery visit, s/he will be queried by the study staff for adverse events.  Details 
of an event should be investigated and study documentation supported with the related medical 
records.  Interventions related to the adverse event will be noted in the study database per the Data 
Elements.  Any medical condition present at the time of enrollment, which remains unchanged or 
improved, will not be recorded as an adverse event.   
7.5 Safety Monitoring  
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) comprised of two pediatric neurosurgeons 
with relevant expertise in CM+SM, a biostatistician, a clinical ethicist, and a patient partner will 
assess and monitor the safety of the trial.  The purpose of the DSMB is to advise the funding 
agency (PCORI), the study Principal Investigator (Dr. Limbrick), and the Investigators Committee 
regarding the continuing safety of study participants and the continuing validity and scientific 
merit of the study.  The DSMB is responsible for monitoring accrual of study subjects, adherence 
to the study protocol, assessment of data quality, performance of individual clinical sites, review 
of serious adverse events and other subject safety issues, and review of formal interim statistical 
analyses of treatment efficacy.  The DCC will send reports relating to these topics to DSMB 
members 10 days prior to each DSMB meeting.  Based on prospectively defined guidelines to be 
outlined in the DSMB charter, the DSMB should recommend whether or not to terminate 
enrollment in the study because of potential safety concerns or high evidence of efficacy.  The 
DSMB will also have the option to recommend stopping the study due to low likelihood of finding 
an effect if the trial continues (futility), or if the risks/benefit ratio is not favorable. Each DSMB 
meeting will result in a summary report that will be provided to the Investigator Committee, 
PCORI, and each local IRB.  
8. INTERVENTION DISCONTINUATION  
For the purposes of this trial, the intervention is either of two technical variants of surgical 
decompression for CM+SM, PFD or PFDD.  While it is possible that intra-operative factors that 
could influence a surgeon’s plan to carry out the intended procedure (PFD or PFDD), this would 
be highly unlikely.  Nevertheless, if the surgical technique is aborted or changed during the 

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procedure, participants will be followed per study protocol with all associated clinical care and 
data collection. 
9. STATISTICAL CONSIDERATIONS  
9.1 General Design Issues  
The Central Hypothesis of this proposal is that, compared with PFDD, PFD will result in fewer 
surgical complications and thus less harm to patients within 12 (+/- 2 months) months of 
surgery. With a more favorable risk profile and non-inferior effect on clinical outcome and 
syrinx size compared with PFDD, PFD will be associated with superior QOL. In the case 
where the patient returned outside planned study follow-up window, a secondary analysis will 
include those visits up to 24 months. 
 
This study is designed as a cluster randomized controlled trial (C-RCT) of the two major 
neurosurgical treatments for CM+SM: posterior fossa decompression with duraplasty (PFDD) and 
extradural posterior fossa decompression (PFD).  This design was chosen with input from site 
investigators (neurosurgeons) in order to obtain participation from a large number of pediatric 
neurosurgeons and reduce crossovers and non-participation resulting from physician bias. While 
there is inherent individual surgeon bias, clinical equipoise exists across the field; this is 
underscored by the participation of >50% of the pediatric neurosurgeons in the United States in 
this RCT and support of this study by the AANS, the CNS, and the Joint AANS/CNS Pediatric 
Section. 
 
Specific Aim 1: Determine if PFD is associated with fewer surgical complications and less harm 
to patients than PFDD. 
Hypothesis: PFD will be associated with fewer surgical complications and less potential harm to 
patients than PFDD.     
Anticipated Outcome:  Cerebrospinal fluid (CSF)-related complications ≤6 months (e.g. CSF 
leak, pseudomeningocele, aseptic meningitis, infection, and hydrocephalus) and requirement for 
additional surgery for wound revision or CSF diversion will be lower after PFD compared with 
PFDD. 
 
Specific Aim 2: Determine if PFD provides non-inferior clinical improvement and syrinx 
regression compared to PFDD. 
Hypothesis: Clinical improvement and syrinx regression provided by PFD will be non-inferior 
compared to those provided by PFDD. 
Anticipated Outcome: Clinical symptoms, neurological function, and syrinx regression ≤12 
months will be non-inferior following PFD when compared with PFDD. Rates of revision 
decompression surgery (PFD or PFDD) and progression of spinal deformity ≤12 months after 
PFD also will be non-inferior to PFDD. 
 
Specific Aim 3:  Determine if PFD is associated with superior QOL compared to PFDD. 
Hypothesis: With fewer surgical complications, PFD will be associated with superior QOL 
compared with PFDD.   
Anticipated Outcome: PFD will have superior QOL and will show improvements in overall 
QOL over time (≤12 months post-operatively) compared to PFDD.  In particular, both physical 

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metrics (evaluated by pain frequency, pain severity and non-pain symptoms) and psychosocial 
metrics will improve at a higher rate and in a shorter period of time after PFD compared to 
PFDD.   
9.2 Sample Size and Randomization 
9.2.1 Treatment Assignment Procedures 
This study is designed as a cluster randomized controlled trial (C-RCT) of the two major 
neurosurgical treatments for CM+SM: posterior fossa decompression with duraplasty (PFDD) 
and extradural posterior fossa decompression (PFD).  This design was chosen with input from 
site investigators (neurosurgeons) in order to obtain participation from a large number of 
pediatric neurosurgeons and reduce crossovers and non-participation resulting from physician 
bias.  During extensive discussions with PRSRC investigators and patient partners, there was 
significant concern for selection bias due to crossovers and selective enrollment if individual 
patients were randomized, a known problem in surgical trials [33].  Site investigators felt that 
having their entire practice randomized to one technique would increase surgeon comfort and 
experience with that approach, thereby decreasing tendencies for biased enrollment. 
Consequently, individual PRSRC centers will be randomized to perform either PFDD or PFD.  
In this design, PRSRC centers will be serve as the unit of inference for comparing PFDD and 
PFD, and the cluster size is expected to be 6 per center.  For cluster randomization, a 
computer-generated randomization sequence will be generated independently by the study 
statistician.  Overall sample size of up to 238 participants will be enrolled. Approximately 
50%  participants per procedure over the enrollment period. 
 
Potential participants will be identified, screened, and recruited through the clinical practices 
of 36 participating PRSRC sties in addition to 8 other sites.  In this trial, the randomization 
unit will be the PRSRC center; therefore, the same intervention will be used for all qualifying 
patients enrolled at each center.  If a surgeon in a PRSRC center strongly believes that a patient 
should undergo a certain procedure (PFDD or PFD), the patient will not be randomized. 
Effective randomization will occur through the random distribution of patients to centers 
employing each procedure (PFDD and PFD).  
9.3 Interim analyses and Stopping Rules  
The Posterior Fossa Decompression with or without Duraplasty for Chiari type I 
Malformation with Syringomyelia study will appoint an independent Data Safety Monitoring 
Board (DSMB) of members.  The DSMB will meet once prior to the start of the study, and will 
approve the final protocol prior to its implementation.  Additionally, the DSMB will establish 
a charter to guide its function. The charter would include rules of procedure, definitions of a 
meeting quorum, and information about meeting logistics.   
 
The purpose of the DSMB is to advise PCORI, the Principal Investigator (Dr. Limbrick), and 
the Investigators Committee regarding the continuing safety of study participants and the 
continuing validity and scientific merit of the study. The DSMB is responsible for monitoring 
accrual of study subjects, adherence to the study protocol, assessment of data quality, 
performance of individual clinical sites, review of serious adverse events and other subject 
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will send reports relating to these topics to DSMB members 10 days prior to each DSMB 
meeting.  Based on prospectively defined guidelines to be outlined in the DSMB charter, the 
DSMB should recommend whether or not to terminate enrollment in the Posterior Fossa 
Decompression with or without Duraplasty for Chiari type I Malformation with Syringomyelia 
study because of potential safety concerns or high evidence of efficacy.  The DSMB will also 
have the option to recommend stopping the study due to low likelihood of finding an effect if 
the trial continues (futility), or if the risks/benefit ratio is not favorable. Each DSMB meeting 
will result in a summary report that will be provided to the Investigator Committee, PCORI, 
and each local IRB.  
9.4 Outcomes  
The goal of this study is to supply patients and families with the information about the risks 
and benefits of PFDD and PFD that they feel are most important in making informed clinical 
decisions.  As such, the primary outcome of interest is reduction in harm to patients, measured 
as surgical complications and/or requirement for reoperation for complication management 
≤12 (+/- 2 months) months after initial PFDD or PFD.  Complications and reoperation are 
associated with additional pain as well as emotional and psychological stress, longer hospital 
stays, and lost time from school/work.  Secondary outcomes focus on efficacy outcomes and 
will include: 1) comparison of pre-operative symptoms and neurological deficits at ≤6 weeks, 
3-6 months, and 12 (+/- 2 months) months after surgery and syrinx size and spinal alignment 
(coronal and sagittal Cobb angles) at 12 (+/- 2 months) months after surgery; and 2) assessment 
of QOL (including psychosocial and physical dimensions) at baseline, ≤6 weeks, 3- 6 months, 
and 12 (+/- 2 months) months after surgery. This outcome will be evaluated using the CHIP 
and the HUI-3 QOL instruments. 
 
Because this is a surgical trial, an Adjudication Committee, consisting of two pediatric 
neurosurgeons and one pediatric neuroradiologist and independent of the design and conduct 
of the trial, will adjudicate the primary outcome measure.  The committee will review the 
primary endpoint based on a blinded review of clinical notes, data forms and imaging studies.  
Decisions by the adjudication committee will determine final outcomes. Consensus definitions 
of CSF-related complications following neurosurgery have been developed [34]. These 
definitions have been reviewed and approved by the neurosurgeons participating in the study, 
and will be used in this trial. Likewise, the extent of syrinx resolution following surgery will 
be determined by centralized review of blinded imaging studies.  By contrast, treatment failure 
(i.e. need for revision PFDD or PFD) will be determined individually by the treating surgeon 
in consultation with the patient/family, since such decisions are inherently subjective and based 
both on the surgeon’s level of concern and the patient’s discomfort and relative acceptance to 
the inherent risks of surgery (either PFD or PFDD). 
9.5 Data Analyses   
A Priori Plans for Data Analysis 
Descriptive Statistics 
Using CONSORT guidelines for cluster-randomized trials,53 We will present descriptive statistics, 
for continuous variables the mean (+/-standard deviation) or median (minimum, maximum) values 

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and for categorical variables the frequencies and proportion for each cluster; These presentations 
will be carried out at baseline and at 12-month follow-up. We will provide reasons for dropouts. 
 
 
Final Comparative Analysis  
 
Planned sensitivity analyses to determine the impact of key assumptions: Due to the fact that each 
patient in a given center will be assigned to the same procedure, it is possible to observe unequal 
overall sample sizes for each procedure. The initial analysis plan is to give equal weights to all 
clusters. If there is imbalance in the prognostic factors, we will use weighted analyses where the 
cluster-level summary score is weighted inversely proportional to the reciprocal of its estimated 
variance. 
 
Comparison methods 
 
The primary outcome is a binomial outcome measured as a surgical complication and/or 
requirement for reoperation for complication management ≤6 months after initial PFDD or PFD. 
To account for within cluster correlation, possibly variable cluster size and the relatively small 
number of clusters in this cluster randomized trial, generalized estimating equations (GEE) with 
small-sample correction or random effect logistic regression will be used for the primary analysis 
of this cluster randomized trial [35, 36].  
 
Secondary outcomes include Treatment Efficacy variables and Quality of Life variables. 
Continuous variables measured at 3 time points over the 12 (+/- 2 months) month follow-up will 
be analyzed using longitudinal analysis with linear mixed models including the random cluster 
effect. Binomial and ordinal data will be analyzed using GEE methods accounting for cluster. In 
the case where the patient returned outside the planned study follow-up window, a secondary 
analysis will include those visits up to 24 months. 
 
Missing data: Based on PRSRC data and early data from this trial, loss to follow-up rate is expected 
to be low (<2%). To prevent missing data, we will meet with patients at 1 month, 3-6 months and 
at 12+/-2 months after the procedure. Every effort, including phone call reminders to patients, will 
be made to decrease loss to follow-up. Loss to follow-up, missing data, and the reasons leading to 
loss of follow-up or data will be recorded.  In case of missing data, we will impute missing data 
using different methods. Because of the repeated measures nature of the data, the ‘last observation 
carried forward’ method will be utilized [37].  In addition, Buck’s method, which is the extended 
version of regression imputation, will be used [38]. The Buck’s imputation will be based on the 
observed values of patient’s age, CM (≥ 5mm tonsillar ectopia), syrinx diameter, and pre-operative 
comorbidities.  In addition to the overall rates of missing data for each procedure, because of the 
cluster randomized trial, we will also monitor the missing data within each cluster and center and 
report the discrepancy between the loss to follow-up rates for each procedure. Special attention 
will be given and separately reported if the entire cluster is loss to follow-up.  As a sensitivity 
analysis for the missing data, study results will be compared for the following three conditions: 1) 
patients with missing primary outcome variable are excluded from analyses; 2) results with last 
observation carried forward, and 3) results with Buck’s method. Robustness of the results under 
each scenario will be assessed.  

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Heterogeneity of Treatment Effect (HTE): As an exploratory analyses, to assess if the procedure is 
most beneficial for a specific subgroup, the heterogeneity of the effect of performing PFDD vs 
PFD will be assessed within the following pre-determined subgroups based on: 1) patient age at 
the time of surgery (<5 years, 5-12 years, 13-18 years); 2) CM status (5-12 mm tonsillar ectopia, 
>12 mm tonsillar ectopia) [39]; 3) syrinx diameter (3-6 mm, 7-9 mm); and 4) preoperative 
hydrocephalus or neuromuscular disease, two comorbidities associated with increased morbidity 
following pediatric CM +/- SM surgery [40]. Demographic and comorbidity data will be collected 
by trained study research assistants/coordinators with strict oversight by site investigators using 
standard data collection forms.  As the 5th subgroup, the effect of surgeon’s experience on the 
occurrence of surgical complications and requirements for re-operations for complications for each 
procedure during the 1st vs 2nd year of the award period will be assessed.  For HTE analysis, the 
test of procedure (PFD vs PFDD) by subgroup effect (such as age) interaction will be performed 
to assess the homogeneity of the procedure effect within each subgroup. If the test of interaction 
indicates a significant interaction for any subgroup, then, Gail and Simon’s test of qualitative 
interaction will be performed [41].   All pre-specified subgroup analyses (patient’s age, CM status, 
syrinx diameter, comorbidity, and surgeons’ experience) will be reported regardless of observing 
a statistically significant or not-significant effect.  
 
Sub-analysis by Syrinx size (3-6 mm, 7-9 mm):  A planned subgroup analysis for the syrinx 
diameter will be performed. Each of the three specific aims will be separately analyzed within the 
syrinx diameters of 3 to 6 mm and 7 to 9 mm for exploratory purposes. The test of interaction will 
be used to assess if the treatment effect is homogeneous within each of the syrinx size subgroups 
(3- 6 mm vs 7-9 mm). If the test of interaction indicates heterogeneity, using the whole 3 to 9 mm 
syrinx diameter range, analyses will be performed, to identify, if any, a cut-off point to propose 
using one surgical method over the other. For example, whether the PFD is associated with greatly 
fewer surgical complications when the syrinx diameter is less than 5mm, but surgical complication 
rates are similar for PFD and PFDD when the syrinx diameter is ≥6 mm will be examined.    
  
Aim 1: Sample Size Recalculation (November 29, 2017) 
The original sample size calculation was performed based on surgical complication rates (≤12 
months) from Park-Reeves Syringomyelia Research Consortium (PRSRC) estimates (17.8% in 
PFDD and 2.7% in PFD cases). We originally did not have an estimate for the ICC. Based on the 
literature, we assumed ICC of 0.05 in our calculations [43]. The overall sample size of enrolled 
patients would be 238 patients, approximately 119 patients per procedure over the two years of 
enrollment. 
In preparation for our PFD trial annual meeting on November 29, 2017, we performed a sample 
size re-calculation, using the ICC observed from the 47 patients enrolled in the study and for which 
complete data was available as of November 28, 2017. It should be noted that the data was only 
used to calculate the ICC; no interim analyses were performed. The ICC based on the first enrolled 
47 patients was 0.000059, much smaller than what was assumed (0.05) for the original sample size 
calculation. However, we expect this ICC estimate to change with more enrollments.  
Enrollment in the trial has increased over time and continues to do so (for example, 10 patients 
were enrolled in both November and December, 2017 and the total trial enrollment is now 83). 
However, when calculated at the time of the annual meeting at the end of November 2017, the 

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average accrual rate, calculated over the entire 19-month period of the study, was 6 patients per 
month. Thus, using the conservative projection of 6 patients per month over the course of an 
enrollment extension ending 12/1/2018, we expect the total number of subjects to be at least 145 
(73 + 12 x 6). (73 was the total enrollment when these calculations were made at the end of 
November; however, as noted above, 10 patients were recruited in December.) 
Based on the enrolled 47 patients in the database with complete data as of 11/28/17, the average 
cluster size is 2.9. If we assume each center enrolls 3 more patients over the enrollment extension, 
the average cluster size increases to 5.9. With the current ICC estimate of <0.01 and using the 
original estimates for the complication rates (17.8% in PFDD and 2.7% in PFD), with the projected 
sample size of 145, we can still reach 84% power by enrolling patients from 24 centers with 
an average cluster size of 6. The same power level can also be achieved by enrolling patients from 
30 centers with an average cluster size of 5. 
It should be noted that it is assumed that the average cluster size is 6 in all centers for these 
calculations. The design effect (DE) concept is used in cluster randomized trials to inflate the 
sample size of the study, compared to the traditional randomized trials [44]. When cluster size is 
fixed, DE = 1 + (m - 1) x ICC; where m is the average cluster size and ICC is the intraclass 
correlation coefficient. In other words, the sample size of the study can be calculated by traditional 
methods, and should be multiplied by the DE. Under the assumption that m = 6 and ICC = 0.01, 
DE becomes 1.05. To compare 17.8% vs 2.7% surgical complication rates for a (not clustered) 
randomized trial, with 84% power, and 0.05 type I error rate, we would need to enroll 136 patients 
total. This is also listed in the sample size calculator above under the “unadjusted box”. For a DE 
value of 1.05, this sample size should be multiplied by 1.05 to find the sample size of a cluster 
randomized trial to reach same power. Therefore, the sample size of the clustered randomized trial 
would be 136 x 1.05 = 142.8 ~143.   
 The variable cluster size is common in cluster randomized trials. Eldridge et al considered the 
effect of variable cluster size on the sample size calculation for cluster randomized trials [45]. 
They showed that the DE value can be calculated for variable class sizes. DE’ = 1 + {(cv2 +1) m -
1} x ICC; where cv is the coefficient of variation of cluster sizes (standard deviation of cluster 
sizes divided by the mean cluster size). The cv is 1.08 for our study. If we use the current average 
cluster size of m = 2.9, DE’ becomes 1.06. In other words, the sample size of the study should be 
inflated to 136 x 1.06 = 144.16~145 to reach 84% power. This assures us that our planned sample 
size of 145 patients will allow us to reach 84% power even if our cluster sizes will not be fixed at 
6.  
It should be noted that, as of March 6th 2018, only 1 of 100 enrolled patients was lost to follow-
up.  However, to account for a potential 2% loss to follow up on the 145 subjects needed (72 per 
group), we will recruit a minimum of 148 subjects total (74 per group) and up to 238, over the 
entire trial enrollment period, which is proposed to be extended to December 31, 2018. 
 
 
 Aim 1: Power Calculations 
For the purpose of sample size estimation, data from in the Park-Reeves Syringomyelia Research 
Consortium (PRSRC) were analyzed (ambispective enrollment, n=589 subjects with complete 
data); specifically, surgical complications ≤12 months were used to calculate the sample size. In 

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this dataset, surgical complications were noted in 17.8% of PFDD cases and 2.7% of PFD cases.  
This is consistent with reported values from a recent meta-analysis, where the rates for CSF-related 
complications for PFDD and PFD were 18.5% and 1.8%, respectively [27], as well data reported 
in case series [17, 25] and a systematic review [42].  We expect to observe a similar difference in 
PFDD versus PFD cases in the proposed study. Because of the clustered randomized nature of the 
trial, the intraclass correlation coefficient (ICC) should be taken into account. The ICC is defined 
as the proportion of the between cluster (PRSRC center) variation to the total variation. Since the 
cluster sizes are small (6 per center), and we have a large number of centers available for 
enrollment (48 total), the effect of ICC on sample size will be small. Thus, using the PRSRC values 
of 17.8% for PFDD and 2.7% for PFD, and assuming equal number of subjects per group and two-
sided type I error rate of 0.05, to reach 90% power, 36 centers averaging 6 subjects per center will 
be required for the trial assuming the ICC is 0.05. To account for 2% dropout rate, we will recruit 
48 centers with a cluster size averaging 6 subjects. Therefore, overall sample size of enrolled 
patients will be 148 patients, approximately 74 patients per procedure over the enrollment period. 
These numbers are achievable, as our data suggest there is  >500 potential study candidates across 
the 48-center network over two years. 
 
 
Aim 2: Non-Inferiority Margins and Power 
The non-inferiority margins for this trial were determined in conjunction with a panel of experts 
on CM+SM and related treatment (the Park-Reeves investigators), our non-physician stakeholder 
partners, and our patient partners, Gina Tramelli, Elizabeth O’Keefe, Lisa Reynolds, Sandy Spears, 
Sam Reeves, Dorothy Poppe, and Rich Labuda.  Using a clinical, Delphi-type approach [46] for 
the complex measure of clinical improvement, the research team agreed upon a non-inferiority 
margin of no more than 20% lower response for PFD from the PFDD group.  The clinical 
improvement rate for the PFDD group was provided as 78.6% in the Durham study [27].  Thus, 
with the sample size of 72 subjects per group (after an assumed 2% dropout), we concluded non-
inferiority of the PFD to PFDD with a margin of 0.17 units (α=0.05, 80% power). This corresponds 
to clinical improvement rate of 61.6% in the PFD group. It was shown in the Durham study that 
the clinical improvement following PFD was 64.6%. 
 
Determine if PFD provides non-inferior clinical improvement compared to PFDD (Non-inferiority Design) 
Outcome 
PFDD 
PFD 
Data 
Source 
Non-inferiority 
Margin 
α-level 
Subjects 
per group 
Power 
Clinical 
Improvement 
44/56 (78.6%) 
51/79 (64.6%) 
Durham 
[27] 
0.17 
0.05 
72 
80% 
For these calculations, the drop-out rate is assumed to be 2%, and the one-sided type I error rate is 0.05.  
 
After determination with the Delphi method, the non-inferiority margin was subsequently 
confirmed as appropriate using Rothman’s 95-95 approach [47, 48] and the FDA guidelines for 
selecting the non-inferiority margin for non-inferiority clinical trials [49].    Using these methods, 
the non-inferiority margin was estimated using the effect of the standard treatment (PFDD) from 
Durham’s meta-analysis [27], with the lower 1-sided 95% confidence interval for the random-
effects meta-analysis calculated to be used as a non-inferiority margin.  When the data from the 
PFDD group from the Durham study was used for the clinical improvement outcome, the 95% 
lower 1-sided confidence interval from the random effects model was calculated as 0.611.  In our 
proposal, we defined the non-inferiority margin as the difference between the rates. For the clinical 
improvement outcome, this corresponds to the non-inferiority margin of 0.786 – 0.611 = 0.175 

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units.  Therefore, our recommended non-inferiority margin of 0.17 units, for the clinical 
improvement outcome, is smaller than the FDA-recommended largest acceptable non-inferiority 
margin of 0.175 units. 
 
In contrast to clinical improvement, syrinx regression is an objectively measurable and easily 
quantifiable outcome.  It is measured by comparing syrinx size on MRI scans obtained before and 
after surgery.  When the effective sample size is 68 subjects per group, and assuming 89.1% syrinx 
regression rate in the PFDD group [27], the non-inferiority margin is 0.135 units to reach 81% 
power.  A non-inferiority margin of 0.135 units represents no more than 13.5% reduction from the 
PFDD group in terms of syrinx regression.  Note that a one-sided type I error rate of 0.05 was 
assumed, and the ‘Two group test of equivalence in proportions’ option in nQuery Advisor was 
used. 
 
Determine if PFD provides non-inferior syrinx regression compared to PFDD (Non-inferiority Design) 
Outcome 
PFDD 
PFD 
Data 
Source 
Non-inferiority 
Margin 
α-level 
Subjects 
per group 
Power 
Syrinx 
Regression 
261/293 
(89.1%) 
31/38 (81.2%) 
Durham 
[27] 
and PRSRC 
0.135 
0.05 
72 
81% 
For these calculations, the drop-out rate is assumed to be 2%, intra-class correlation coefficient is 0.05, and the one-
sided type I error rate is 0.05.  
 
Aim 3: Power Calculations 
Based on preliminary data using the Chiari Health Index in Pediatrics (CHIP)[50], we observed a 
0.12±0.16 unit improvement in Quality of Life (QOL) scores following PFDD.  Our sample size 
of 72/group (effective sample size of 68/group) will provide 82% power to detect a 0.20±0.16 unit 
improvement in CHIP QOL scores following PFD (α =0.05).  Both from an analytical standpoint 
and from the view of PRSRC investigators and our patient partners, this value represents both a 
significant and meaningful increase in QOL. 
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms  
The DCC will create source documents and disseminate them to all of the participating centers.  
Ultimately, the data on the source documents will be transcribed to an electronic database 
created by the DCC.   Similarly, imaging will be uploaded to a separate electronic platform, the 
Central Neuroimaging Database Archive (CNDA).  This platform is maintained and managed at 
Washington University-St. Louis. 
10.2 Data Management  
The DCC will monitor each site’s data and interpret the respective imaging.  The University of 
Iowa will oversee the DCC and process data in the following manner: 
o Data Management 
 Design and modify data dictionary (the information that is being collected) 
 Design and modify SQL Server database 
 Quality Control 
o Retrieval and Reports 

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 Assist in preparation of data quality reports 
 Assist in preparation of progress reports 
o Design and Analysis 
 Consult with investigators in design and analysis of research questions 
10.3 Quality Assurance  
10.3.1 Training 
All pediatric neurosurgeons involved in the study have completed both an accredited neurosurgery 
residency and a 1-year subspecialty fellowship in pediatric neurosurgery at a program accredited 
by the Accreditation Council for Pediatric Neurosurgery Fellowships (ACPNF) ) or by The 
American Osteopathic Association (AOA) and are either certified or eligible for certification by 
both the American Board of Neurological Surgeons (ABNS) and the American Board of Pediatric 
Neurological Surgery (ABPNS) or the American Osteopathic Board of Surgery (AOBS).  Prior to 
participating in the study, each pediatric neurosurgeon must submit documentation verifying that 
s/he has performed ≥20 PFDD/PFD cases at the level of attending pediatric neurosurgeon or that 
that s/he performed ≥5 PFDD/PFD cases in the year preceding the participation in the study; and 
3) review two videos showing the study-approved operative technique for PFDD and PFD in step-
wise fashion.  As detailed in the videos, PFDD and PFD both begin with a midline posterior 
suboccipital incision extending from the level of the inion inferiorly.  Suboccipital craniectomy ± 
cervical laminectomies are performed based upon the level of tonsillar position on the pre-
operative MRI.  The posterior atlanto-occipital membrane and any additional constricting epidural 
bands are then dissected off the dura and bisected.  For PFD, the operation is complete (dural 
scoring or splitting is permitted), and wound closure is initiated.  For PFDD, the dura is then incised 
and retracted for microsurgical dissection. Intradural maneuvers are performed at the surgeon’s 
discretion based on the intra-operative findings, but may include exploration/fenestration of an 
arachnoid veil, lysis of adhesions, or tonsillar reduction.  Following the intradural dissection, the 
duraplasty is performed with autologous graft or dural substitute, and the wound is closed in 
standard fashion.  Dural opening without subsequent dural closure is not permitted for PFDD or 
PFD. Periodic quality assurance checks will be performed by reviewing a subset of operative notes 
from randomly selected participating surgeons. 
 
The DCC will have a representative train each participating site’s research personnel how to collect 
data on source documents; transcribe them to the electronic database; and instructions on how to 
upload imaging to the Central Neuroimaging Data Archive.  Training will be documented and 
must be completed before access is granted to the respective portal. 
10.3.2  Quality Control Committee  
The DSMB is responsible for monitoring accrual of study subjects, adherence to the study 
protocol, assessment of data quality, performance of individual clinical sites, review of serious 
adverse events and other subject safety issues, and review of formal interim statistical analyses of 
treatment efficacy.  The DCC will send reports relating to these topics to DSMB members 10 
days prior to each DSMB meeting.   
 
Members of the DSMB will include a pediatric neurosurgeon with relevant expertise in CM+SM, 
a neuroradiologist, a biostatistician, a clinical ethicist, and a patient partner (Sandy Spears).   

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10.3.3  Metrics 
Primary Outcome: measured as a binary (yes/no) variable. The presence of any of the following 
items will be considered as a poor outcome (harm to patients): 
o Intra-operative Complication 
 Vascular injury resulting in dissection or stroke 
 Intracranial hemorrhage requiring return to surgery for evacuation 
 Neurological injury (new cranial nerve deficit, weakness, sensory loss, 
bowel or bladder dysfunction) 
 Death 
o Complication ≤12 (+/- 2 months) months after initial PFDD or PFD 
 Pseudomeningocele: extradural and/or subcutaneous fluid collection 
resulting in discomfort or pain, limitation of movement, or CSF leak.  
Radiological evidence of fluid collection alone is not sufficient for 
diagnosis of pseudomeningocele. 
 CSF leak 
 Hydrocephalus: requires external drainage, shunting, or endoscopic 3rd 
ventriculostomy 
 Infection: clinical diagnosis that may include fever, wound drainage, 
dehiscence, or elevated laboratory parameters in association with antibiotic 
treatment ± surgical debridement. 
 Chemical (or aseptic) meningitis: clinical diagnosis prompting medical 
treatment (e.g. steroids); lumbar puncture and analysis of CSF cell profile 
not required but will be tracked if available. 
 Cervical instability 
 Cerebellar ptosis with intractable headaches 
o Need for surgical procedures for complication management ≤12 (+/- 2 months)  
months after initial PFDD or PFD 
 External drainage for the following: 
 Hydrocephalus 
 CSF leak 
 Pseudomeningocele 
 Infection 
 Shunt malfunction/infection 
 Simple over-sewing of wound for CSF leak 
 Surgical revision in operating room for the following: 
 CSF leak 
 Infection 
 Pseudomeningocele 
 Lumbar puncture and steroids for the following: 
 Chemical meningitis 
 True meningitis 
 Implantation of ventriculo-peritoneal or other permanent shunt or 
endoscopic 3rd ventriculostomy for hydrocephalus. 
 Cervical collar and/or fusion for cervical instability 
 Cerebellopexy for cerebellar ptosis 
 

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Secondary Outcomes: 
o Treatment Efficacy, measured ≤6 weeks, 3-6 months, and 12 (+/- 2 months)  
months after surgery: 
 Status of clinical symptoms 
 Status of neurological findings 
 Syrinx diameter (in mm) 
 Spinal alignment (coronal and sagittal Cobb angles) 
 Need for revision of PFDD or PFD 
o Quality of life, measured ≤6 weeks, 3-6 months, and 12 (+/- 2 months)  months 
after surgery: 
 Chiari Health Index in Pediatrics (CHIP) 
 HUI-3.  
10.3.4 Protocol Deviations 
Protocol deviations will be reported to the local IRB per the respective institution’s 
guidelines. 
10.3.5 Monitoring 
The DCC will monitor data quality primarily through the use of remote monitoring 
activities. Remote monitoring involves detailed review of the data entered by the Clinical 
Center and consultations with the Clinical Center investigator and/or research 
assistant/coordinator to review safety and data quality. This may require uploading de-
identified copies of specific parts of the medical record, patient study file, regulatory 
documentation, or other source documents to the DCC staff who will review those 
materials against the data recorded in the electronic data capture system. This helps assure 
protocol compliance and accurate data collection. The DCC may conduct more remote 
monitoring activities early in the trial to assure protocol compliance and identify any 
training issues that may exist. Safety of subjects will be monitored and ensured in 
accordance with the DSMB plan. The medical record and study files (including informed 
consent, permission, and assent documents) must be made available to authorized 
representatives of the DCC, upon request, for source verification of study documentation. 
In addition, medical information and data generated by this study must be available for 
inspection upon request by representatives of the IRB for each study site. 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
Candidates for participants in the proposed study, “Posterior Foss Decompression with or 
without Duraplasty for Chiari type I Malformation with Syringomyelia” are between the 
ages of day-of-life 1 through 21 years.  Children are a vulnerable population, and it is 
critical that their protection be given the utmost consideration. We will conduct our 
research under the most stringent guidelines, the Good Clinical Practice (GCP) 
guidelines.  In a multi-institutional study setting, the protection of children becomes more 
complex and involves multiple research institutions with their respective institutional 
review boards (IRBs), the funding agency (PCORI), the data safety monitoring board 
(DSMB), Park-Reeves Syringomyelia Research Consortium (PRSRC) investigators, and 
the PRSRC Research Advisory Board, which will serve as the study steering committee It 
is paramount that the PI and the DCC ensure that these entities work in collaboration to 

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protect pediatric subjects and verify that the study is fully compliant with all regulatory 
and ethical requirements and policies. 
 
Patient partner and mother of a CM+SM patient, Sandy Spears, will serve as a patient 
representative on the study’s Data Safety and Monitoring Board.  In doing so, she will 
help to ensure that the safety and rights of study participants is protected throughout the 
duration of the study. 
  
The DCC will provide training for clinical site investigators and designees regarding study 
procedures and GCP.  The following measures are designed to protect against risk. 
 
Risk due to loss of confidential information 
Risk due to loss of confidential information is mitigated by several factors.  All 
evaluation forms and reports will be identified only by a coded number to maintain 
patient confidentiality.  All records will be kept in a locked/password protected 
computer.  Clinical information will not be released without the written permission of 
the parent or legal guardian, except as necessary for monitoring by the funding agency, 
the DCC, or other governmental regulatory bodies.  Specifics pertaining to this study 
for risks due to loss of confidential information are detailed below. 
 
PRSRC Registry Electronic Database (EDB) 
Data for this study will be entered into the electronic database system maintained by 
the DCC.  The server facility is locked and separately secured from the remainder of 
the DCC.  Its entry and exit access to the building is monitored by cameras, additional 
key codes, and security personnel year round.  The DCC coordinates its network 
infrastructure and security with the ITC (Information Technology Center) information 
systems at Washington University-St. Louis.  This provides effective firewall 
hardware, automatic network intrusion detection, and the expertise of dedicated 
security experts working at the University.  Network equipment includes multiple 
firewalls, routers, and high-speed switches.  User authentication is centralized with four 
Windows 2012R2 domain servers.  Communication over public networks is encrypted 
with virtual point-to-point sessions using secure socket layer (SSL) or virtual private 
network (VPN) technologies.  Both access methods providing at least 128 bit 
encryption.  All DCC Web-based systems use the SSL protocol to transmit data 
securely over the internet.  Direct access to DCC machines is only available while 
physically located in the DCC offices, or via a VPN client.  All network traffic is 
monitored for intrusion attempts, security scans are regularly run against the servers, 
and IT staff is automatically notified of intrusion alerts.  Security is maintained with 
Windows 2012R2 user/group domain-level security.  Users are required to change their 
password every 90 days, and workstations time out after 5 minutes of inactivity.  All 
files are protected at group and user levels.  Database security is handled in a similar 
manner with group-level access to databases, tables, and views in Microsoft SQL 
Server.   
 
The investigators and staff of the DCC are fully committed to the security and 
confidentiality of data collected for the study.  All personnel involved with the DCC 

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have signed confidentiality agreements concerning data encountered in the course of 
their daily work.  All personnel (including administrative staff) have received Human 
Subjects Protection and Health Information Portability and Accountability Act 
(HIPAA) education.  All users are required to sign specific agreements concerning 
security, confidentiality, and use of our information systems before access is provided. 
 
Centralized Neuroimaging Data Archive (CNDA) 
The Centralized Neuroimaging Data Archive (CNDA) is an imaging informatics 
platform that provides secure data management services for Washington University – 
St. Louis and collaborating investigators.  The CNDA’s services include automated 
archiving of research imaging studies from all of the University’s scanners, automated 
quality control and image processing routines, and secure web-based access to acquired 
and post-processed data. The CNDA currently stores over 60,000 individual sessions, 
representing data from a wide range of multi-site and in-house studies.  It also manages 
thousands of non-imaging experiments, including neuropsychological, clinical, 
biomarker, and behavioral data.  The CNDA is built on XNAT [51, 52], a widely used 
open source imaging informatics platform designed to facilitate common data 
management and productivity tasks for neuroimaging and associated data. Notable 
features include: 1) support for a range of image upload/download methods, including 
DICOM, web services, and web browsers; 2) an extensible data model that simplifies 
the incorporation of new data types by automatically generating the necessary database 
tables and relations, user interface components, and search engine plug-ins; 3) quality 
control modules and audit trails, including a virtual quarantine that houses uploaded 
data until authorized users have validated them and a complete history profile that 
tracks all changes made to the managed data; 4) a secure web-based user interface for 
data entry and access; 5) a sophisticated search engine that builds queries across data 
types; 6) an online image viewer that supports a number of common neuroimaging 
formats, including DICOM and Analyze; and 7) a pipeline engine for automating image 
processing routines.   
 
The CNDA is widely used to support studies that include geographically dispersed data 
acquisition sites and analysis teams.  Example studies include the Dominantly Inherited 
Alzheimer Network (DIAN), a 15-site study of inherited Alzheimer’s disease that 
includes PET, MR, neuropsychological, clinical, and tissue data; the Park-Reeves 
Syringomyelia Research Consortium a 36-site study of Chiari malformation and 
syringomyelia in subjects under 21 years of age, including MR, CT and CR data; and 
INTRUST, a 10-site study of traumatic brain injury and post-traumatic stress disorder 
in combat veterans.  Scans are uploaded using a user friendly web-based tool that 
removes identifiers from the image file metadata and transfers the files to the CNDA 
over an encrypted protocol. 
 
The CNDA implements a number of features and procedures to ensure the security and 
integrity of the data it hosts and full HIPAA compliance. All data coming into and out 
of the CNDA are transmitted over secure channels using SSL.  All data are stored on a 
level 5 RAID device with disaster recovery and offsite backup. Snapshots of the 
relational database are taken nightly, enabling reconstruction of the database from any 

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time point in the study.   Access to study data is restricted to authorized users who are 
assigned specific access privileges (create, read, edit, delete) according to their role in 
the study.  All logins and access to data are tracked in the internal audit system. 
 
The CNDA offers a number of features to monitor and maintain the quality of 
acquired data.  As data are uploaded to the system, sequence details (e.g. flip angle, 
repetition time) can be validated against a study specific protocol to ensure that the 
acquisition is compliant. Noncompliant scans are flagged in the system for immediate 
follow-up.  Automated image analysis routines are then executed to determine overall 
image quality specific to the acquisition type.  For fMRI, for example, signal to noise 
and subject movement histograms are generated.  The CNDA also supports 
radiological evaluation and manual quality assessments that can be optionally used by 
studies. The output from these routines is available to users in web-based reports and 
is flagged when key values fall outside acceptable limits. 
 
 
11.1 Institutional Review Board (IRB) Review  
This protocol and the informed consent document and any subsequent modifications will 
be reviewed and approved by the IRB or ethics committee responsible for oversight of the 
study.   
11.2 Informed Consent Forms 
The consent form will include the following: 
o Purpose statement 
o Participant commitment 
o Costs 
o Risks 
o Benefits 
o Disclosure of alternative 
o Statement of confidentiality 
o Study contact information 
 
When a clinical site investigator and/or research coordinator identifies a candidate for the 
study, patient eligibility will be confirmed, and the study investigator or coordinator will 
approach the individual to offer participation. After a thorough discussion to inform the 
patient and family of the rationale and objectives of the study and the risks, benefits, and 
alternatives to participation, written informed consent will be obtained from a parent or 
legal guardian (patient <18 years of age) or the patient themselves (patient ≥18 years of 
age).  Additionally, assent will be obtained for patients of appropriate age, according to 
individual institutional practices.  If study participation is declined, then all clinical care 
will be provided to the child in accordance with institutional practice and judgment.   
11.3 Participant Confidentiality  
Each center will be responsible for coding data prior to entry in the PRSRC database.  Each 
center will be required to demonstrate IRB approval from their own university or 

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institution.  The electronic database and CNDA is password-protected.  For subjects 
enrolled at Washington University-St. Louis, we will maintain a key with the de-
identification and coding information in a locked office. 
 
All records related to a participant’s research will be stored in locked filing cabinets or on 
computers protected with passwords. The participant’s identity on these records will be 
indicated by a case number rather than by name, and the information linking these case 
numbers with the participant’s identity will be kept separate from the research records. The 
participant will not be identified by name in any publication of the research results. 
 
All data collected will be entered into the PRSRC Registry Electronic Database (EDB). 
This EDB was created in 2011 and has been used for collection of prospective, multicenter 
clinical and radiographic patient data since 2012.   PRSRC privacy and confidentiality 
principles have been maintained in accordance with the PCORI Standards for Data 
Registries, HIPAA regulations, Good Clinical Practice guidelines, and the Washington 
University-St. Louis Human Research Protection Office.  Each PRSRC site and PRSRC 
ancillary site shares a detailed data use agreement with Washington University-St. Louis.  
Prior to accessing the PRSRC Registry EDB, PRSRC investigators and coordinators from 
each site must demonstrate IRB approval by their own institution and undergo an online 
training and privacy/confidentiality module.  A coded, limited data set may then be entered, 
with the key to the code maintained at each collaborating site. This information will only 
be kept onsite at each institution and will only be available to key personnel of this study, 
data monitors and IRB officials as needed. At the conclusion of the study, the de-identified 
data will be retained indefinitely by the P.I. The data with PHI will be destroyed at the 
conclusion of the study. The PRSRC, PCORI, this institution, the Principal Investigator, 
and his/her staff will comply with any and all laws regarding the privacy of such 
information.  
11.4 Study Discontinuation  
The study may be discontinued at any time by the Principal Investigator, David Limbrick, 
MD, PhD; the IRB, the OHRP, the FDA, or other government agencies as part of their 
duties to ensure that research participants are protected.  
12. COMMITTEES 
Below are the list of committees involved with the research study.  See appendix II. 
o Dissemination Committee 
o PRSRC Research Advisory Board 
o PRSRC Research Team 
o Study Steering Committee 
o Data Safety and Monitoring Board 
o Adjudication Committee 
13. PUBLICATION OF RESEARCH FINDINGS  
A Dissemination Committee has been created to monitor the efficacy of efforts aimed at disseminating 
study progress and research results.  This committee will include Drs. Limbrick (study PI) and 

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Shannon (Co-PI), Dr. Tuite (Site PI and key personnel), as well as Haley Vance (Co-I, certified 
pediatric nurse practitioner-acute care, non-physician stakeholder) and Elaine Kennedy (Co-I, certified 
pediatric nurse practitioner, non-physician stakeholder) and the leaders of our patient advocacy group 
partners, Mr. Labuta and Ms. Poppe (both Co-Is).  The Dissemination Committee will also include 
patient partners and Co-Is, Ms. Reynolds and Ms. Tramelli.  Finally, as study results become available, 
the PRSRC will convene a consensus conference to discuss the results and their implications for 
clinical practice and patient education, and to draft evidenced-based guidelines for the surgical 
treatment of CM+SM. 
 
A data sharing procedure has been developed by the research team in accordance with PCORI 
guidelines to facilitate the use of these data by other researchers.  All code books, statistical 
programming code, and a cleaned, de-identified copy of the final data set will be made available to 
other researchers if requested within 9 months of the final analysis.  Likewise, datasets will be 
provided to any peer-reviewed journal requesting this information in support of manuscripts that 
resulted from the project. Researchers requesting access to the data will be directed to the Washington 
University Chiari website (https://chiari.wustl.edu)  where a description of the available data and the 
data release policy will be posted.  The researchers will then submit a short proposal (no more than 5 
pages) to Dr. Limbrick, principal investigator.  This proposal would then be reviewed by the PI, the 
research team and patient partners.  If there are concerns about confidentiality arising from the project, 
data will not be released.  Assuming that confidentiality can be maintained, the committee will make 
every effort to share data and will only deny requests under the following conditions: 
1. The central purpose of the study is not research or evaluation. 
2. The research goals are not feasible using the current study data. 
3. The proposed research involves data that may compromise the privacy or confidentiality of 
individuals, providers or institutions. 
4. The data processing necessary to produce the requested files places an unusually heavy burden 
on the data processing staff. 
5. The requestors have not demonstrated the necessary experience and expertise required to carry 
out the proposed research. 
 
If there are specific concerns raised during the review process, the reviewer’s comments will be sent 
to the requestor and the requestor will be given the opportunity to respond to these comments and 
resubmit his/her proposal. Any manuscripts or publications that result from the use of PRSRC data by 
other research teams will be reviewed by the PRSRC investigators to insure patient and provider 
confidentiality.  This last review is not intended for scientific purposes, only to protect confidentiality. 
 
 
 
 
 
 
 
 
 
 
 

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14. SUPPLEMENTS/APPENDICES 
Appendix I 
 
Participating Sites 
Sites 
Principal Investigators 
All Children's Hospital 
Tuite, Gerald, and Jallo, George 
Arkansas Children’s Hospital/University of 
Arkansas School of Medicine 
Albert, Greg 
Arnold Palmer Hospital-Orlando Health 
Olavarria, Greg 
Boston Children's Hospital 
 Scellig, Stone 
Children's Healthcare of Atlanta 
Chern, Joshua 
Children’s Hospital at Dartmouth-Hitchcock/ 
Dartmouth Geisel School of Medicine 
Bauer, David 
Children’s Hospital Colorado 
 O’Neill, Brent 
Children’s Hospital of Birmingham 
Johnston, James 
Children’s Hospital of New York-
Presbyterian/ Weill Cornell/Cornell 
University Medical College 
Greenfield, Jeffrey 
Children’s Hospital of Phoenix 
Adelson, David 
Children’s National Medical Center 
Keating, Robert 
Children’s Hospital of Philadelphia 
 Heuer, Greg 
Cincinnati Children’s Hospital 
 Mangano, Francesco 
Columbia University 
Anderson, Richard 
Dell (Seton) Children’s Medical Center 
George, Timothy, and Tyler-Kabara, 
Elizabeth 
Gillette Children’s Hospital Minnesota 
Graupman, Patrick 
John Hopkins Children’s Center/ Johns 
Hopkins School of Medicine 
Jackson, Eric 
Levine Children’s Hospital/Carolinas Medical 
Center 
Wait, Scott 
Los Angeles Children’s Hospital 
 McComb, J. Gordon 
Lurie Children’s Hospital of Chicago 
Alden, Tord 
Mayo Clinic Children’s Hospital 
Daniels, David 
Miami Children’s Hospital 
 Bhatia, Savjiv, Ragheb, John 
MUSC Children’s Hospital/Medical 
University of South Carolina School of 
Medicine 
Eskandari, Ramin 
Oregon Health & Science University 
Selden, Nathan 
Pennsylvania State University 
Iantosca, Mark 
Pittsburgh Children’s Hospital 
Tamber, Mandeep, and Greene, Stephanie 
Primary Children’s Hospital 
Brockemeyer,Doug 
St. Louis Children’s Hospital 
Limbrick, David 
Seattle Children’s Hospital 
Ellenbogen, Richard 
Stanford University 
Grant, Gerald 
Texas Children’s Hospital 
 Whitehead, Bill 

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The Children’s Hospital at OU Medical 
Center/ Oklahoma University College of 
Medicine 
 Mapstone, Timothy, Gross, Naina 
Nationwide Children’s Hospital 
Leonard, Jeffrey 
University of Florida HSC-Jacksonville 
Aldana, Philipp 
University of Iowa 
Menezes, Arnold 
University of Michigan 
Maher, Cormac 
University of Texas – Houston 
Shah, Manish 
University of Minnesota 
Guillaume, Dan 
University of Vermont Children’s Hospital/ 
University of Vermont College of Medicine 
Durham, Susan 
University of Wisconsin 
Iskandar, Bermans 
Vanderbilt University 
Shannon, Chevis and Wellons, Jay 
Wake Forest University 
Couture, Daniel 
 
 
 
 
Appendix II 
PRSRC Dissemination Committee 
Dr. David Limbrick 
PI 
Dr. Chevis Shannon 
Co-PI 
Ms. Haley Vance 
Nurse Practitioner 
Ms. Elaine Kennedy 
Nurse Practitioner 
Mr. Rick Labuda 
Patient Partner 
Ms. Dorothy Poppe 
Patient Partner 
Ms. Lisa Reynolds 
Patient Partner 
Mrs. Gina Tramelli 
Patient Partner 
 
PRSRC Research Advisory Board 
Ralph Dacey Jr, MD 
Washington University 
Robert Dauser, MD 
Baylor University 
Bermans Iskandar, MD 
Univ. of Wisconsin-Madison 
Lawrence Lenke, MD 
Columbia University 
Robert McKinstry, MD, PhD 
Washington University 
Arnold Menezes, MD 
University of Iowa 
W. Jerry Oakes, MD 
University of Alabama 
Sandra Reeves Spears 
Houston, Texas 
James Torner, PhD 
University of Iowa 
 
PRSRC Research Team 
Dr. David Limbrick 
PI 
Dr. Chevis Shannon 
Co-PI 
Dr. James Torner 
Co-PI 
Dr. Emine Bayman 
Co-PI 

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Dr. T.S. Park 
Co-PI 
Dr. Michael Kelly 
Co-PI 
Ms. Haley Vance 
Co-PI 
Ms. Elaine Kennedy 
Co-PI 
 Ms. Thanda Meehan 
Co-PI 
Mr. Samuel Reeves 
Patient Partner 
Ms. Lisa Reynolds 
Patient Partner 
Mrs. Gina Tramelli 
Patient Partner 
Mr. Rick Labuda 
Patient Partner 
Ms. Dorothy Poppe 
Patient Partner 
Dr. Jacob Greenberg 
Clinician/Research Consultant 
Ms. Angela Eschmann 
Clinician/OR Nurse Consultant 
Ms. Toni Goelz 
Clinician/Physical Therapist Consultant 
 
 
 
Steering Committee 
Ralph Dacey Jr, MD 
Washington University 
Lawrence Lenke, MD 
Columbia University 
Robert McKinstry, MD, PhD 
Washington University 
Arnold Menezes, MD 
University of Iowa 
Sandra Reeves Spears 
Houston, Texas 
James Torner, PhD 
University Of Iowa 
Gerald Tuite, MD 
All Children’s Hospital/ 
Univ. of South Florida College of Medicine 
Taryn Bragg, MD 
Bermans Iskandar, MD 
American Family Children’s Hospital/ 
Univ. of Wisconsin School of Medicine 
Daniel Guillaume, MD 
Amplatz Children's Hospital/ 
Univ. of Minnesota School of Medicine 
Benjamin Warf, MD 
Boston Children’s Hospital/ 
Harvard Univ. School of Medicine 
Daniel Couture, MD 
Alexander Powers, MD 
Brenner Children’s Hospital 
Wake Forest Univ. School of Medicine 
Joshua Chern, MD, PhD 
Children’s Healthcare of Atlanta/ 
Emory Univ. School of Medicine 
James Johnston, MD 
W. Jerry Oakes, MD 
Children’s Hospital of Birmingham/ 
Univ. of Alabama-Birmingham 
Todd Hankinson, MD, MBA 
Children’s Hospital of Colorado/ 
Univ. of Colorado School of Medicine 
Stephanie Greene, MD 
Children’s Hospital of Pittsburgh/ 
Univ. of Pittsburgh School of Medicine 
Bruce Kaufman, MD 
Children’s Hospital of Wisconsin/ 
Medical College of Wisconsin 
Manish Shah, MD 
Children’s Memorial Hermann Hospital/ 
Univ. of Texas School of Medicine 

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Robert Keating, MD 
Children’s National Medical Center/ 
George Washington U. School of Medicine 
Karin Bierbrauer, MD 
Francesco Mangano, DO 
Cincinnati Children’s Hospital/ 
Univ. of Cincinnati School of Medicine 
Cormac Maher, MD 
CS Mott Children’s Hospital 
University of Michigan School of Medicine 
Lissa Baird, MD 
Nate Selden, MD 
Doernbecher Children’s Hospital 
Oregon Health & Science University 
Herbert Fuchs, MD, PhD 
Duke Children’s Hospital 
Duke Univ. School of Medicine 
Paul Klimo, MD 
LeBonheur Children’s Hospital/ 
Univ. Tennessee School of Medicine 
J. Gordon McComb, MD 
Mark Krieger, MD 
Los Angeles Children’s Hospital/ 
USC School of Medicine 
Gerald Grant, MD 
Lucile Packard Children’s Hospital 
Stanford University School of Medicine/ 
Tord Alden, MD 
Lurie Children’s Hospital of Chicago/ 
Northwestern Univ. Medical School 
David Daniels, MD 
Mayo Eugenio Litta Children’s Hospital 
Mayo Clinic College of Medicine 
Toba Niazi, MD 
John Ragheb, MD 
Miami Children’s Hospital/ 
University of Miami School of Medicine 
Richard Anderson, MD 
Morgan Stanley Children’s Hospital/ 
Columbia University College of Physicians 
and Surgeons 
Jay Wellons, MD 
Chevis Shannon, MBA, MPH, DrPH 
Monroe Carrell Jr. Children’s Hospital 
Vanderbilt University School of Medicine 
Jeffrey Leonard, MD 
Nationwide Children’s Hospital/ 
The Ohio State Univ. College of Medicine 
Mark Iantosca, MD 
Penn State Hershey Children’s Hospital/ 
Pennsylvania State School of Medicine 
David Adelson, MD 
Phoenix Children’s Hospital/ 
Barrow Neurological Institute 
Doug Brockmeyer, MD 
Primary Children’s Hospital/ 
Univ. of Utah School of Medicine 
Jeffrey Ojemann, MD 
Richard Ellenbogan, MD 
Seattle Children’s Hospital/ 
Univ. of Washington School of Medicine 
Prithvi Naryan, MD 
St. Christopher Children’s Hospital 
David Limbrick, MD, PhD 
St. Louis Children’s Hospital/ 
Washington Univ. School of Medicine 
William Whitehead, MD 
Robert Dauser, MD 
Texas Children’s Hospital/ 
Baylor Univ. School of Medicine 
Greg Albert, MD 
Arkansas Children’s Hospital/ 
Univ. of Arkansas School of Medicine 
David Bauer, MD 
Children’s Hospital at Dartmouth-Hitchcock 
Dartmouth Geisel School of Medicine 

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Jeffrey Greenfield, MD 
Children’s Hospital of New York-
Presbyterian/Weill Cornell/ 
Cornell University Medical College 
Michael Partington, MD 
Gillette Children’s Hospital 
Minnesota 
Eric Jackson, MD 
Johns Hopkins Children’s Center 
Johns Hopkins School of Medicine 
Scott Wait, MD 
Levine Children’s Hospital/ 
Carolinas Medical Center 
Ramin Eskandari, MD 
MUSC Children’s Hospital/ 
Medical Univ. of South Carolina 
School of Medicine 
Amanda Yaun, MD 
The Children’s Hospital at OU Medical 
Center 
Oklahoma Univ. College of Medicine 
Susan Durham, MD 
Univ. of Vermont Children’s Hospital 
Univ. of Vermont College of Medicine 
 
 
 
Data Safety and Monitoring Board 
 
 
 
 
Name 
Position 
Affiliation 
Role 
Philippe Mercier 
Pediatric 
Neurosurgeon 
St. Louis University 
Chair 
Ken Schechtman 
Biostatistician 
Washington University 
Member  
Alison Antes 
Clinical/research 
ethicist 
Washington University 
Member 
Sandy Spears 
Patient Partner 
Patient/Family Partner 
Member 
Alex Weil 
Pediatric 
Neurosurgeon 
CHU Sainte-Justine 
Hospital 
Member 
Tammy Bethel-
Anderson 
Data Monitor 
Washington University 
Executive 
Secretary (non-
voting member) 

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Adjudication Committee 
 
 
 
 
 
Name 
Position 
Affiliation 
Role 
Patrick McDonald 
Pediatric 
Neurosurgeon 
Winnipeg Children’s 
Hospital 
Chair 
Sumit Pruthi 
Pediatric 
Neuroradiologist 
Monroe Carrell Children’s 
Hospital 
Vanderbilt University 
Member 
Michael Levy 
Pediatric 
Neurosurgeon 
Rady Children’s Hospital 
UCSD School of Medicine 
Alternate 
Tim Vogel 
Pediatric 
Neurosurgeon 
North Jersey Brain and 
Spine Center/ Hackensack 
University Medical Center 
Alternate 
Gary Tye 
Pediatric 
Neurosurgeon 
Virginia Commonwealth 
University 
Alternate 
Anthony Wang 
Pediatric 
Neurosurgeon 
UCLA Medical Center 
Alternate 
Sandeep Sood 
Pediatric 
Neurosurgeon 
Pediatric Neurosurgery 
Group, Detroit Michigan & 
Wayne State University 
Alternate 
Krystal Tomei 
Pediatric 
Neurosurgeon 
UH Rainbow babies & 
Children’s Hospital 
Case Western Reserve 
University 
Alternate 
Jay Rivera-
Cambria 
Pediatric 
Neurosurgeon 
University of Utah/Primary 
Children’s Hospital 
Alternate 
Dale Swift 
Pediatric 
Neurosurgeon 
UT Southwestern  
Alternate 
Catherine A. 
Mazzola 
Pediatric 
Neurosurgeon 
New Jersey Pediatric 
Neuroscience Institute 
Alternate 
John Collins 
Pediatric 
Neurosurgeon 
New Jersey Pediatric 
Neuroscience Institute 
Alternate 
Alex Weil  
Pediatric 
Neurosurgeon 
CHU Sainte-Justine and 
Center hospitalier de 
l'Université de Montréal 
Alternate 

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Appendix III 
 
Screening Log 
 
Institution:_______________________ 
PI:______________________________ 
Site Number:__________ 
 
Instructions: 
Column 1: Enter subject number (start with 001, 002, 003, etc.). 
Column 2: Document reason not consented even though eligible. 
Column 3: The researcher entering this information acknowledges with his/her initials.