Non-invasive Estimation of CSF Pressure Using MRI in Patients With Spontaneous Intracranial Hypotension
Phase: NA
Conditions: Intracranial Hypotension
Sponsor: Duke University

 
 
 
 
 
 
Non-invasive intracranial pressure estimation in intracranial 
hypotension using magnetic resonance imaging 
 
                      ClinicalTrials.gov ID # NCT03041441  
 
                                           12/16/2019 
 
 
 
               
 
 

Research Summary 
 
 
 
 
 
1. Protocol Title:  
Non-invasive intracranial pressure estimation in intracranial hypotension using magnetic 
resonance imaging  
 
 
2. Study Purpose:   
The purpose of this study is to estimate the intracranial pressure (ICP) in subjects with 
intracranial hypotension (a condition caused by spinal cerebrospinal fluid (CSF) leakage, 
often associated with low CSF pressure) using non-invasive MRI techniques, and to 
determine whether changes in estimated ICP are seen after treatment of this condition.   
 
 
3. Background & Significance:   
Spontaneous intracranial hypotension (SIH) is a secondary cause of headache that has 
historically suffered from under-diagnosis but is becoming increasingly recognized. 1 
Clinically, SIH is characterized by headaches that occur or worsen when sitting or 
standing and improve or resolve when lying down. In almost all cases, spinal 
cerebrospinal fluid (CSF) leaks are the causative etiology for the clinical syndrome.2  As 
a result of CSF leakage, the CSF pressure is often low in this condition.3 
 
Despite increasing recognition of the condition, there is still no single diagnostic test that 
can establish the diagnosis with a high degree of sensitivity. The most widely accepted 
criteria for the disease, the International Classification of Headache Disorders, Version 3 
(ICHD-3), incorporates criteria derived from clinical presentation, anatomic brain 
imaging, spine imaging, and CSF pressure measurement, with the latter 2 tests typically 
involving invasive procedures.  From the standpoint of diagnosis, it would clearly be 
advantageous to develop additional noninvasive diagnostic modalities that could help 
establish the diagnosis with a high degree of sensitivity.   
 
Treatment can also be challenging in intracranial hypotension.  The primary treatment 
modality, epidural blood patching, is not effective in all cases, and it is common for 
patients to require several epidural patching procedures before symptom relief is 
achieved.  Furthermore, successful treatment may be complicated by inappropriate 
elevations of intracranial pressure, termed ‘rebound intracranial hypertension,’ that may 
mimic symptoms of low pressure.4  Therefore, a non-invasive measurement of ICP would 
be useful for following post-treatment response and differentiating persistent intracranial 
hypotension form rebound intracranial hypertension.  
 
Recently, MRI sequences have been developed that may be able to estimate ICP in a non-
invasive fashion. The MRI-based method for measurement of ICP (MRICP method) is 
based on basic principles of the cranio-spinal CSF physiology: The mono-exponential 
relationship between intracranial volume and pressure leads to a linear relationship 

Research Summary 
 
 
 
 
between elastance (i.e., the derivative of pressure with respect to volume) and pressure. 
The MRI method utilizes well-established velocity encoding cine MR imaging to 
measure elastance from the ratio of volume and pressure changes during the cardiac 
cycle. The measurement of the momentary differences between the volumes of blood and 
CSF entering and leaving the cranium during the cardiac cycle provides an estimate of 
the intracranial volume change, and the pressure difference is estimated using the 
derivative of the CSF velocities. The method has been recently validated independently 
by a group in Munich by demonstrating significant correlation between shunt valve 
opening pressures and MRI derived ICP values in shunted patients with well-functioning 
shunts. 
 
The MRI measurement is obtained using 3-cine phase contrast scan with a total scan time 
of about 10 minutes. Therefore the MRICP method is well suited as an add-on for a 
diagnostic MRI study.  In this study the MRICP method will be utilized as a potential 
diagnostic tool diagnosis of intracranial hypotension, and as a tool to monitor treatment 
response.  
 
In addition to estimation of ICP, the caliber and flow velocity through the dural venous 
sinuses will be studied.  It is well established that there is a relationship between the 
caliber of the intracranial dural venous sinuses and disorders of CSF pressure.   In 
particular, the caliber of the junction of the transverse and sigmoid sinuses has been 
found to be reduced in idiopathic intracranial hypotension (IIH) and increased in 
spontaneous intracranial hypotension, diseases characterized by high and low CSF 
pressures, respectively.5-8  This portion of the sinus has been hypothesized to be 
distensible owing to its lack of fixed dural margins, and may serve as a ‘barometer’ of 
intracranial pressure.   
 
As a secondary aim, therefore, we plan to study the caliber of the sinus and flow velocity 
through this portion of the sinus in subjects with SIH using non-contrast 3D phase-
contrast MR venography, a well-established sequence in current clinical use.  Our goals 
are to establish baseline measurements of cross sectional area and velocity, and to study 
how these parameters change following treatment of SIH with epidural blood patching.  
 
4. Design & Procedures: 
 
 
 
 
 
 
 
This is a prospective, single-arm proof-of-concept study with enrollment goal of 5 
subjects.  
 
4.1 Study summary 
Subjects with known intracranial hypotension who are scheduled to undergo standard-of-
care CSF pressure measurement using lumbar puncture prior to planned epidural patch 
treatment will first undergo a research MRI of the brain in order to estimate ICP. The 
imaging protocol is listed in Appendix 2.  Approximate scan time per session will be 20-
22 minutes. 
 

Research Summary 
 
 
 
 
Subjects will then undergo lumbar puncture according to the standard-of-care treatment 
plan.  Estimated values of CSF pressure derived from MRI will be compared to values 
measured during lumbar puncture. Patients will then undergo standard-of-care epidural 
patching. A repeat research MRI after epidural patching will be performed to assess for 
differences in pre- and post-treatment scans.  
 
 
4.2 Primary and secondary objectives 
The primary objective is compare CSF pressure measured by lumbar puncture as part of 
standard-of-care testing to ICP measurements estimated by the MRICP technique.  
 
Secondary objectives include: (1) assessment of change in estimated ICP prior to and 
following standard-of-care epidural patching and (2) evaluate changes in diameter and 
flow velocity through the transverse dural venous sinus prior to and following epidural 
blood patching.   
 
4.3 Pre-registration procedures 
Potential subjects will be identified from among patients referred to our department for 
evaluation/treatment of spontaneous intracranial hypotension.  Currently, our department 
is one of the few referral centers for this condition in the country, ensuring an active 
practice with high volumes of new patients suffering from this condition.  
 
Currently, our standard practice is to contact all patients by telephone for consultation 
prior to their visit to discuss the patient’s history, prior testing, and expectation for their 
upcoming visit.  This contract is made by one of 3 radiologists who perform epidural 
patching procedures, or the physician’s assistant associated with our practice.  Because 
many of our patients are referred from out of state, this provides an opportunity to 
establish a relationship with the provider, to determine what testing will be necessary, 
and to answer any patient questions about their trip. Patients typically arrive the day 
before the procedure, and are advised to stay locally1-2 days after their procedure.   
 
At completion of the this telephone consultation, patients meeting eligibility criteria will 
be asked by their provider if they would be willing to speak to a research coordinator to 
learn more about this study.  If they agree, they will be contacted separately by a trained 
clinical research coordinator to explain the study.  
 
 
4.4. Enrollment procedures 
 
If the patient decides to participate, the research coordinator will confirm eligibility and 
arrange for the research MRI to be performed within one day prior to the standard-of-care 
lumbar puncture (i.e. the same day as the procedure, prior to the scheduled procedure 
appointment, or the day before), and within one day following the epidural patch 
treatment. The lumbar puncture and the epidural patching are typically performed on 

Research Summary 
 
 
 
 
consecutive days.   On the day of the pre-treatment MRI, the research coordinator will 
meet with the patient prior to the scan to have the patient sign consent for the study.  
 
All subjects will undergo their scheduled medical procedures as planned regardless of 
their decision to participate or not participate in the study; no change to the medical care 
of the patient will be made as part of this study.  
 
 
4.5 Study procedures 
The main study procedures will consist of the pre-treatment MRI and post-treatment 
MRI. The study plan is presented in the schema in Appendix 1.  
 
No intravenous contrast material is used in the research sequence.  
 
The research MRI technologists will screen the subject for contraindications to MRI, 
according to established departmental protocol. Because completion of diagnostic brain 
MRI is required generally required by our service prior to referral of patients as part of 
standard-of-care procedure, and brain MRI imaging findings positive for intracranial 
hypotension serve as inclusion criteria (see section 5.1), it is anticipated that all patients 
will have undergone MRI scanning without complication prior to enrollment, and 
therefore few if any patients will be expected to have contraindications to MRI scanning.  
 
 
5. Selection of Subjects:  
5.1 Subjects and eligibility 
 
Subjects will be identified and approached using the procedures describe in Section 4.3 
and 4.4 above.  
 
 
5.2 Inclusion & Exclusion criteria 
Inclusion criteria will consist of the following: 
 Known diagnosis of intracranial hypotension, established by the following 
criteria: the presence of orthostatic headache, and one or more of the following 
criteria: prior CSF opening pressure ≤6 cmH20, demonstration of an active spinal 
CSF leak on prior spine imaging, or cranial MRI changes of intracranial 
hypotension.9 
 Ability to provide informed consent. 
 Expected ability to complete standard-of-care procedures (lumbar puncture and 
epidural patching) 
 
Exclusion criteria will consist of the following: 
 Known contraindication to MRI (pacemaker, MRI incompatible hardware, etc.) 

Research Summary 
 
 
 
 
 Severe claustrophobia or other condition requiring the need for anxiolysis, 
sedation, or any other medication for MRI scanning 
 Inability or expected inability to complete study interventions as scheduled  
 Any known contraindication to standard-of-care procedures (e.g. coagulopathy, 
allergic reaction to required medication, lack of vascular access, etc.) 
 
6. Subject Recruitment & Compensation: 
 
 
 
 
 
 
There is no subject compensation in this study.  
 
 
 
 
 
 
 
 
 
 
7. Consent Process: 
Once patients have agreed to participate and arrive at Duke University Medical Center 
prior to their MRI scan, study personnel will approach eligible subjects in a location 
sufficient to provide for private and confidential discussion. Written informed consent 
will be obtained on the date of their procedure using standard IRB-approved consent 
processes.  
 
The subject will be given time to read the consent and discuss alone or with 
family/friends present. The consent will be signed only after all questions are answered. 
There will be no time limit for potential subjects to consider participation. The study 
personnel will take as much time as needed to answer all questions and thoroughly 
review the consent form with potential subject. This will likely take between 5 and 15 
minutes. Participants who do not read or are blind will have the consent form read to 
them in the presence of a witness. Subjects who withdraw consent or otherwise become 
ineligible for the study after enrollment may be withdrawn.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. Subject’s Capacity to Give Legally Effective Consent: 
Subjects must be capable of providing informed consent to participate in this study. 
 
 
 
 
 
 
 
 
 
 
 
 
9. Study Interventions :  
 
The study intervention will consist of the pre-intervention and post-intervention MRI, as 
detailed above.  Scans will be performed without the need for intravenous contrast.  
 
 
 
 
 
 
 
 
 
 
 
 
10. Risk/ Benefit Assessment:  
 
 
 
 
 
 
The risk to the subject from undergoing a non-contrast MRI study is minimal.  The major 
risk is entering the magnetic field with an implanted non-MRI compatible device or 
hardware, or other ferromagnetic metallic object.  This risk will be mitigated through the 
use of standard MRI screening techniques performed by the MRI technologist 
immediately prior to the scan.  Again, because patients will have undergone MRI 
scanning of the brain as part of the standard diagnostic workup for intracranial 
hypotension, it is anticipated that few if any patients will have contraindicated hardware 
or metallic devices.  Another risk is the risk of anxiety or claustrophobia associated with 
MRI scanning, which is screened for routinely by MRI technologists and will also be 
assessed by the research coordinator consenting patients for the study prior to enrollment.  

Research Summary 
 
 
 
 
 
Another potential risk associated with any research that involves data storage is the 
potential risk is loss of confidentiality. This will be minimized by adherence to the 
research data security plan (RDSP). Because this technique is investigational, no direct 
benefit to the subject can be promised.  
 
 
 
 
 
 
 
 
 
11. Cost to the subject:  
There will be no cost to the subjects 
 
12. Data Analysis & Statistical Considerations: 
 
 
 
As detailed above, the primary outcome measure is a comparison of ICP estimated with 
MR technique and the CSF pressure measured by lumbar puncture.  Comparative 
statistics will be used for this analysis; the selection of appropriate statistical methods 
will depend on the normality of the data. It is anticipated that the main statistics will be 
descriptive and univariate comparisons.  More advanced statistical techniques requiring 
support of a statistician are not anticipated, but if required by the data at the time of 
analysis, will be determined in consultation with the departmental statistician as 
necessary.  
 
13. Data & Safety Monitoring:  
 
 
 
 
 
 
 
   
Physical risks associated with the non-contrast MRI are minimal, as noted above. Any 
unexpected adverse events during the MRI will be addressed according to standard 
practice and departmental guidelines.  Given the small number of subjects and 
exploratory nature of the data, no data monitoring committee will be used for this study.  
The risk of loss of confidentiality will be mitigated through the adherence to the RDSP.   
 
 
 
14. Privacy, Data storage & Confidentiality:  
 
 
 
 
 
  
Every effort will be made to ensure confidentiality of the patients included in this study.  
Other data stored within Duke University Health System will be maintained in an IRB 
approved electronic storage format, as outlined in the RDSP.  
 
Efforts will be made to protect the confidentiality of all medical records and other 
personal information to the extent required by law. However, we cannot guarantee 
absolute confidentiality. Patients will be advised in the consent process that the limited 
data set from their MRI will be sent to an outside institution for data analysis.  Medical 
records of study participants are stored and kept according to legal requirements. They 
may be subject to inspection by the U.S Food and Drug administration and /or other 
regulatory authorities. A copy of this consent form will be put in the subject’s medical 
record. All data will be considered confidential, and individuals will not be identified in 
any report or publication occurring as a result of this study.  
 
 
 
 
 
15. References: 

Research Summary 
 
 
 
 
1. 
Mokri B, Posner JB. Spontaneous intracranial hypotension: the broadening clinical and imaging 
spectrum of CSF leaks. Neurology 2000;55:1771-1772 
2. 
Kranz PG, Luetmer PH, Diehn FE, et al. Myelographic Techniques for the Detection of Spinal CSF 
Leaks in Spontaneous Intracranial Hypotension. AJR Am J Roentgenol 2016;206:8-19 
3. 
Schievink WI. Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension. Jama 
2006;295:2286-2296 
4. 
Kranz PG, Amrhein TJ, Gray L. Rebound Intracranial Hypertension: A Complication of Epidural 
Blood Patching for Intracranial Hypotension. American Journal of Neuroradiology 2014 
5. 
Rohr A, Dorner L, Stingele R, et al. Reversibility of venous sinus obstruction in idiopathic 
intracranial hypertension. AJNR Am J Neuroradiol 2007;28:656-659 
6. 
Simister R, Bowler JV, Wilson PL, et al. Transverse venous sinus stenosis and intracranial 
hypertension: evidence for which comes first. J Neurol 2008;255:601-603 
7. 
Farb RI, Forghani R, Lee SK, et al. The venous distension sign: a diagnostic sign of intracranial 
hypotension at MR imaging of the brain. AJNR Am J Neuroradiol 2007;28:1489-1493 
8. 
Farb RI, Vanek I, Scott JN, et al. Idiopathic intracranial hypertension - The prevalence and 
morphology of sinovenous stenosis. Neurology 2003;60:1418-1424 
9. 
Schievink WI, Dodick DW, Mokri B, et al. Diagnostic criteria for headache due to spontaneous 
intracranial hypotension: a perspective. Headache 2011;51:1442-1444 
Appendix 1 – Schema 

Research Summary 
 
 
 
 
 
 
 

Research Summary 
 
 
 
 
Appendix 2 – Summary of MRI brain protocol 
 
Sequence   
 
 
 
Approximate scan time 
1.  3D T1  (for pre & post registration)   5min   
2.  sag FSE T2   
 
 
 
3min 
3.  3d phase-contrast MRV  
 
4-5 min 
4.  MRICP protocol  
 
 
8-10 min 
 
   
 
 
 
 
Total : 20-23 min 
 
NB: all scans are performed without IV contrast administration.