Research
Research funded by the Spinal CSF Leak Foundation
Spinal CSF Leak Foundation, as a patient-led organization, actively supports research in spontaneous intracranial hypotension (SIH). While we have seen an accelerated rate of publication in recent years, there remain many gaps in published research. Narrowing these gaps will fuel increased awareness and understanding of SIH among health professionals, lead to improvements in diagnostic testing and treatment, and improve patient outcomes. We want to see every patient with SIH receive a prompt diagnosis and the best of diagnostic testing and treatments. This research will also benefit those with spinal cerebrospinal fluid leaks secondary to medical procedures.
Foundation Research Grants
Here are research grants we have awarded.
Grant Details
Principal Investigator: Deborah I. Friedman, MD, MPH
Institution: UT Southwestern Medical Center
Project: Quality of Life in Patients with Headache from Suspected or Confirmed Spontaneous Intracranial Hypotension (SIH): A Pilot Study
Date of Award: February 2022
About this project:
The impact of Spontaneous Intracranial Hypotension (SIH) on quality of life has never been systematically investigated or documented in the medical literature. SIH has a profound impact on physical, mental, and spiritual well-being that is comparable to, or more severe than, other neurologic disorders producing similar symptoms. The objective of this pilot study is to quantify the various aspects of quality of life (QOL) in SIH and compare them to published data from other neurologic conditions producing similar symptoms and affecting a similar population, such as pseudotumor cerebri syndrome (idiopathic intracranial hypertension), multiple sclerosis, and migraine. We then will use the data to extend the study to incorporate a larger patient population, nationally or internationally.
Update (June 2022):
“Our pilot quality of life (QOL) study included 106 patients from our practice at UT Southwestern who had either confirmed (using ICHD-3 diagnostic criteria) or suspected (based on clinical symptoms, responses to blood patches) spinal CSF leaks. All participants completed self-administered, standardized questionnaires on line including measures of general QOL (SF-36), depression (PHQ-9), anxiety (PHQ-9), spiritual well-being (FACIT-Sp-12) and headache disability (HIT-6) and were then invited to participate in an interview assessing suicidality (C-SSRS). Overall, general QOL was poor with average scores 30 points lower than the general population in physical health, social functioning and pain domains. The average depression score was in the mild to moderate range but almost half of respondents scored in the moderate range or worse. 75% of participants scored in the most severe category for headache disability. Of the 59 participants who completed the C-SSRS, over half expressed a wish to be dead and 25% had suicidal behavior. There was no difference in these outcomes between the group with definite leaks compared to those with suspected leaks. We continue to analyze the data in more detail.” —Deborah Friedman, MD, MPH (Principal Investigator), Victor Liaw (Medical Student), Morgan McCreary, PhD (Biostatistician)
Update (June 2023):
The paper has been accepted for publication in the journal Neurology, and Dr. Friedman and her team recently presented a poster with some of their findings. Overall, the study’s conclusion was: “SIH is associated with severe headache pain and high rates of depression, anxiety, and suicidality. Improved identification and treatment of SIH are imperative to improve patients’ quality of life.”
Dr. Friedman notes that, to her knowledge, this study is the first in headache medicine to include a measurement of spirituality in assessment of quality of life. Her team used a questionnaire called FACIT-Sp-12 (Functional Assessment of Chronic Illness Therapy—Spiritual Well-Being Scale), which is designed to assess spiritual well-being in individuals. The questionnaire consists of 12 items that participants respond to based on their personal experiences and feelings. It measures different aspects of spirituality such as inner peace, comfort, having a sense of purpose in life, finding strength in faith or spiritual beliefs, and feeling hopeful about the future despite illness. In Dr. Friedman’s study, participants experiencing symptoms of spinal CSF leak scored much worse on this assessment compared to other groups—including people with cancer and AIDS. It’s a striking example of just how severely spinal CSF leak can affect a person’s well-being.
Grant Details
Principal Investigator: Peter G. Kranz, MD
Institution: Duke University Medical Center
Project: Imaging Differentiation of Spontaneous Intracranial Hypotension and Chiari I Malformation
Date of Award: November 2018
Publication Date: October 2021
Differentiation of Chiari malformation type 1 and spontaneous intracranial hypotension using objective measurements of midbrain sagging.
Jessica L. Houk MD, Timothy J. Amrhein MD, Linda Gray MD, Michael D. Malinzak MD, PhD, and Peter G. Kranz MD
J Neurosurg. 2021 Oct 29:1-8. doi: 10.3171/2021.6.JNS211010. Epub ahead of print. PMID: 34715671.
OBJECTIVE: Chiari malformation type 1 (CM-1) and spontaneous intracranial hypotension (SIH) are causes of headache in which cerebellar tonsillar ectopia (TE) may be present. An accurate method for differentiating these conditions on imaging is needed to avoid diagnostic confusion. Here, the authors sought to determine whether objective measurements of midbrain morphology could distinguish CM-1 from SIH on brain MRI.
METHODS: This is a retrospective case-control series comparing neuroimaging in consecutive adult subjects with CM-1 and SIH. Measurements obtained from brain MRI included previously reported measures of brain sagging: TE, slope of the third ventricular floor (3VF), pontomesencephalic angle (PMA), mamillopontine distance, lateral ventricular angle, internal cerebral vein–vein of Galen angle, and displacement of iter (DOI). Clivus length (CL), an indicator of posterior fossa size, was also measured. Measurements for the CM-1 group were compared to those for the entire SIH population (SIHall) as well as a subgroup of SIH patients with > 5 mm of TE (SIHTE subgroup).
RESULTS: Highly significant differences were observed between SIHall and CM-1 groups in the following measures: TE (mean ± standard deviation, 3.1 ± 5.7 vs 9.3 ± 3.5 mm), 3VF (−16.8° ± 11.2° vs −2.1° ± 4.6°), PMA (44.8° ± 13.1° vs 62.7° ± 9.8°), DOI (0.2 ± 4.1 vs 3.8 ± 1.6 mm), and CL (38.3 ± 4.5 vs 44.0 ± 3.3 mm; all p < 0.0001). Eight (16%) of 50 SIH subjects had TE > 5 mm; in this subgroup (SIHTE), a cutoff value of < −15° for 3VF and < 45° for PMA perfectly discriminated SIH from CM-1 (sensitivity and specificity = 1.0). DOI showed perfect specificity (1.0) in detecting SIH among both groups. No subjects with SIH had isolated TE without other concurrent findings of midbrain sagging.
CONCLUSIONS: Measures of midbrain sagging, including cutoff values for 3VF and PMA, discriminate CM-1 from SIH and may help to prevent misdiagnosis and unnecessary surgery.
ABBREVIATIONS: 3VF = slope of the third ventricular floor; CL = clivus length; CM-1 = Chiari malformation type 1; CVF = CSF-venous fistula; DOI = displacement of iter; LVA = lateral ventricular angle; MPD = mamillopontine distance; PMA = pontomesencephalic angle; SIH = spontaneous intracranial hypotension; TE = tonsillar ectopia; VHA = venous hinge angle.
DOI link: https://doi.org/10.3171/2021.6.JNS211010
Online Publication Date: 29 Oct 2021
Grant Details
Principal Investigator: Peter G. Kranz, MD
Institution: Duke University Medical Center
Project: Clinical Outcomes Following Surgical Ligation of Cerebrospinal Fluid Venous Fistula in Patients with Intracranial Hypotension: A Prospective Case Series
Date of Award: March 2018
Publication Date: May 2019
Clinical Outcomes Following Surgical Ligation of Cerebrospinal Fluid-Venous Fistula in Patients With Spontaneous Intracranial Hypotension: A Prospective Case Series.
BACKGROUND: Cerebrospinal fluid-venous fistula (CVF) is a recently described cause of spontaneous intracranial hypotension (SIH). Surgical ligation of CVF has been reported, but clinical outcomes are not well described.
OBJECTIVE: To determine the clinical efficacy of surgical ligation for treatment of CVF.
METHODS: Outcomes metrics were collected in this prospective, single-arm, cross-sectional investigation. Inclusion criteria were as follows: diagnosis of SIH, demonstration of CVF on myelography, and surgical treatment of CVF. Pre- and postoperative headache severity was assessed with the Headache Impact Test (HIT-6), a validated headache scale ranging from 36 (asymptomatic) to 78 (most severe). Patient satisfaction with treatment was measured with Patient Global Impression of Change (PGIC).
RESULTS: Twenty subjects were enrolled, with mean postoperative follow-up at 16.0 ± 9.7 mo. All CVFs were located in the thoracic region (between T4 and T12). Pretreatment headache severity was high (mean HIT-6 scores 65 ± 6). Surgical treatment resulted in marked improvement in headache severity (mean HIT-6 change of -21 ± -9, mean postoperative HIT-6 of 44 ± 8). Of subjects with baseline headache scores in the most severe category, 83% showed a major improvement in severity (transition to the lowest 2 severity categories) after surgery. All subjects (100%) reported clinically significant levels of satisfaction with treatment (PGIC score 6 or 7); 90% reported the highest level of satisfaction. There were no short- or long-term complications or 30-d readmissions.
CONCLUSION: Surgical ligation is highly effective for the treatment of SIH due to CVF. Larger controlled trials with longer follow-up period are indicated to better assess its long-term efficacy and safety profile.
PMID: 31134267
DOI: 10.1093/ons/opz134
Grant Details
Principal Investigator: Kerry Knievel, DO
Co-investigator: Lea Alhilali, MD
Institution: Barrow Neurological Institute
Project: Quantitative Analysis of Thecal Sac Volume and Morphology as a Diagnostic Tool in Intracranial Hypotension
Date of Award: November 2018
Progress report:
In this study, which is still underway, Dr. Kerry Knievel and Dr. Lea Alhilali of the Barrow Neurological Institute hypothesize that in some patients, spontaneous intracranial hypotension (SIH) “may result more from an increase in the size of the CSF space or increased compliance from connective tissue insufficiency, rather than from significant changes in CSF volume. Detecting these changes in thecal sac volume and compliance in SIH patients could aid in diagnosis in the significant number of patients in which myelography fails to detect a leak, as well as advance our understanding of the underlying pathophysiology.” The study seeks to determine whether or not “differences in thecal sac volume and quantitative shape features (sphericity, convexity, compactness) are sensitive and specific indicators of SIH in patients without detectable leak, improving diagnosis and treatment in this critical SIH population.” Dr. Knievel recently updated the Foundation on the study’s progress so far, noting that while they are still recruiting the remainder of the patients and normal controls to complete the study, on an interim data analysis they were able to find a statistically significant difference in the volume of the thecal sac in patients with SIH compared to normal controls using MRI for volume analysis.
Update (June 2022):
Dr. Knievel and her colleagues presented their early results, including an abstract, paper, and poster, at the American Headache Society’s annual meeting in June. Here is their abstract:
Title: Quantitative analysis of thecal sac volume and morphology as a diagnostic tool in SIH
SUMMARY: Quantitative volumetric analysis of the thecal sac can detect enlargement of the thecal sac in spontaneous intracranial hypotension (SIH) patients that may aid in diagnosis of this disorder.
BACKGROUND: The exact mechanism underlying spontaneous intracranial hypotension (SIH) remains unclear; however, the importance of underlying connective tissue pathology has been established in both clinical and laboratory studies. Given the association with connective tissue abnormalities, SIH may result in increased thecal sac size or thecal sac compliance from connective tissue insufficiency. As a result, the thecal sac of SIH patients may have a different volumetric and morphometric signature than subjects without SIH symptoms. The purpose of this study was to develop a new diagnostic tool based on the thecal sac volumetric and morphometric signatures of SIH from quantitative volume and shape analysis.
METHODS: SIH patients and age, gender, and BMI matched controls were prospectively recruited from December 1, 2020 to March 1, 2022. All subjects underwent volumetric MR imaging of the entire spine A semi automated segmentation method was used to extract 3D volumetric models of thecal sac for each subject. Comparison of total thecal sac volume as well as regional volumes were compared between subjects and controls with a paired t-test. Thecal sac models for controls and patients were then averaged among each cohort to create a single average model for each group from the labelmap representations. Subsequently, a signed model to model distance function was used to compute and visualize the correspondent vectors that quantify the localized differences between the models of the average thecal sac for controls and SIH patients. These vectors quantify the differences in shape along the thecal sac anatomy between the two groups.
RESULTS: 28 SIH patients (mean age 45.9 years, mean BMI 27.7, 57% male) and 28 controls (mean age 44.4 years, mean BMI 26.8, 57% male) were recruited. There was no significant difference between the groups in terms of gender (p=1.0), height (p=0.69), weight (p=0.53), BMI (p=0.68), or age (p=0.74). The thecal sac was significantly larger in SIH patients (mean 131.7 cc, 95%CI 108.1-155.3) than in controls (mean 116.5 cc, 95%CI 105.1-127.9, p<0.0001). Thecal sac volume had excellent discrimination for detecting SIH (AUC=0.91, 95%CI 0.83-0.98, p<0.0001). A volume greater than 122 cc was 82% sensitive and 82% specific for SIH, while a volume greater than 126 cc was diagnostic of SIH. Regional analysis demonstrated no significant difference in the cervical thecal sac volume between SIH patients and controls (25.8 and 25.7 cc, respectively, p=0.95), while the thoracic volume was slightly higher in SIH patients than controls (61.6 and 57.8 cc, respectively, p=0.02), and the lumbar volume was notably higher (46.6 and 33.0 cc, respectively, p<0.0001). Model to model distance vector analysis demonstrated that this difference was predominantly in the lower lumbar thecal sac (Figure 1).
CONCLUSION: SIH patients demonstrate a significantly larger thecal sac than controls and the thecal sac volume can be used to effectively diagnose these SIH patients. The enlargement of the thecal sac in SIH patients predominantly occurs in the lower lumbar region, in the same location where dural ectasia occurs in patients with connective tissue disease.
Grant Details
Principal Investigator: Fawad A. Khan, MD
Institution: Ochsner Clinic Foundation
Project: Optic Nerve Head Imaging with Enhanced Depth Imaging Optical Coherence Tomography in Patients with Intracranial Hypotension – A Pilot Study
Date of Award: November 2019 (Award announcement)
Progress report:
As most diagnostic tests for SIH are invasive and often carry significant risks, researchers are interested in establishing more non-invasive methods of identifying SIH. Dr. Khan noted in his comments about this pilot study that since intracranial hypotension can affect the eye, an emerging technique called enhanced depth imaging optical coherence tomography, used in the evaluation of eye diseases, may be one way to test for SIH non-invasively. “This diagnostic test uses ultrasound technology and is not invasive. It allows high‐resolution images of the lamina cribrosa and is superior to magnetic resonance imaging (MRI) and other imaging tests of the eye. Enhanced depth imaging optical coherence tomography is also safer in comparison to the widely used lumbar puncture (spinal tap) in the evaluation of intracranial hypotension. We are committed to investigating the use of enhanced depth imaging optical coherence tomography, a potentially safe and rapid test that can provide data to help in the diagnosis of intracranial hypotension and, possibly, determine the success of therapies.”
Dr. Khan was able to provide the Foundation with the following update: “The COVID-19 restrictions placed on our site during 2020 caused a delay in enrollment for our study. However, we were able to successfully resume enrollment in March 2021, and are slated to complete enrollment by the end of 2021. Our goal is to complete our analysis and present the data at the upcoming neuro-ophthalmology national meeting in early 2022. This will be followed by a formal manuscript detailing the findings.”
Grant Details
Principal Investigator: Timothy Amrhein, MD
Institution: Duke University Medical Center
Project: Development of a Novel Flexible Needle for Targeted Epidural Blood Patch of Ventral CSF Leaks
Date of Award: November 2019 (Award announcement)
Progress report:
Dr. Amrhein initially proposed this study to develop a new flexible needle for epidural blood patching, which could increase the effectiveness and safety of targeting ventral and lateral spinal CSF leaks via epidural blood patch. He recently updated us on his progress:
“Foundation support has allowed for further optimization of this novel patching needle design. New iterations have been tested in cadavers and we are now able to achieve optimal epidurograms (coverage of the ventral epidural space) in 96.8% of needle placements, which is vastly superior to the 47% achievable with standard needles. This work is ongoing and the preliminary data obtained through generous Foundation funding has led to a successful application for a Duke Clinical and Translational Science Institute (CTSI) Translational Accelerator Grant, which will allow for final needle design optimization and initiation of regulatory discussions with FDA in preparation for clinical testing. The CTSI grant, awarded in conjunction with the NIH National Center for Advancing Translational Sciences, provides Dr. Amrhein and his team with an additional $123,954 of funding to study “a flexible needle for the delivery of therapeutics in spatially constrained anatomy.”