A Randomized Trial of CT Fluoroscopy-guided Targeted Autologous Blood and Fibrin Glue Patching for Treatment

Spontaneous intracranial hypotension (SIH) is a condition caused by non-iatrogenic spinal CSF leaks that classically presents with orthostatic headaches. These headaches, in conjunction with other presenting symptoms such as nausea, diplopia, tinnitus, and cognitive deficits, often result in profound disability. SIH is considerably underreported due to pervasive misdiagnosis. Thus, while the estimated annual incidence is reported to be 5 in 100,000, the actual number is likely considerably greater.

The current standard-of-care treatment for SIH cases that are refractory to conservative measures (i.e. bed rest and hydration) is percutaneous epidural blood patching (EBP) of the spinal CSF leak. Percutaneous EBP can be performed in several ways: 1) with or without imaging guidance, 2) targeted to a site of known or suspected CSF leak or non-targeted, and 3) with or without the addition of fibrin glue sealant.

The leading theory for the mechanism behind percutaneous EBP treatment of SIH is that it creates a durable seal of the CSF leak resulting in normalization of CSF hydrodynamics and a resultant diminution in symptoms. Fibrin glue, a sealant used for treatment of unintended durotomies during neurosurgery, is thought to improve the likelihood of a successful patch over patches containing blood alone. Therefore, imaging-guided targeted delivery of patching material containing both blood and fibrin glue directly to the site of CSF leak, a novel therapy, is presumed to be the optimal therapy. For this reason, this procedure has become standard-of-care at many tertiary-care institutions over the past several years.

Our group has extensive experience with CT fluoroscopy-guided targeted blood and fibrin glue patching of proven CSF leaks in SIH patients. However, significant uncertainty remains with regard to the efficacy of this procedure due to a paucity of outcomes data and the absence of any prospective RCTs. In fact, nearly all of the current evidence for the treatment of SIH is found in the form of retrospective chart reviews. Given the growing recognition of SIH, the fact that a known subset of patients will have spontaneous resolution of symptoms, and the absence of clear evidence to guide treatment, there is a critical need to evaluate the efficacy of targeted patching with blood and fibrin glue with a prospective RCT. Fulfilling this unmet need forms the basis for this proposal. While determining the efficacy of the other types of EBPs is also important, we aim to begin by evaluating the efficacy of the presumed optimal therapy.

• TISSEEL (Drug): TISSEEL is a fibrin sealant indicated for use as an adjunct to hemostasis in adult and pediatric patients (>1 month of age) undergoing surgery when control of bleeding by conventional surgical techniques (such as suture, ligature, and cautery) is ineffective or impractical. TISSEEL is effective in heparinized patients

Primary outcomes

• Change in Median (Headache Impact Test-6) HIT-6 Score From Baseline [Baseline, 1 month]: Absolute change in median HIT-6 score from pre-procedural baseline to 1 month post procedure for each group. The HIT-6 consists of six items: pain, social functioning, role functioning, vitality, cognitive functioning, and psychological distress. The patient answers each of the six related questions using one of the following five responses: "never", "rarely", "sometimes", "very often", or "always". These responses are summed to produce a total HIT-6 score that ranges from 36 to 78, where a higher score indicates a greater impact of headache on the daily life of the respondent.

Secondary outcomes

• Change in Median HIT-6 Score From Baseline [Baseline, 2 weeks, 4 months]: Absolute change in median HIT-6 score from pre-procedural baseline to 2 weeks and 4 months post procedure for each group. The HIT-6 consists of six items: pain, social functioning, role functioning, vitality, cognitive functioning, and psychological distress. The patient answers each of the six related questions using one of the following five responses: "never", "rarely", "sometimes", "very often", or "always". These responses are summed to produce a total HIT-6 score that ranges from 36 to 78, where a higher score indicates a greater impact of headache on the daily life of the respondent.
• Reduction in Median Migraine Disability Assessment (MIDAS) Score From Baseline [Baseline, 2 weeks, 1 month, 4 months]: The MIDAS questionnaire assesses headache-related disability. Patients answer five questions, scoring the number of days, in the past 3 months, where their activity was limited due to headache. A higher score indicates greater headache-related disability. This tool has been shown to be internally consistent, highly reliable, valid, and correlates with physicians' clinical judgment. MIDAS Scale Range: 0 - 270
• Change in Median NRS Score From Baseline [Baseline, 2 weeks, 1 month, 4 months]: The pain numerical rating scale (NRS) is a well-validated tool for quantitatively assessing patients' pain. The NRS asks patients to rate their current pain intensity on an 11-point scale ranging from 0 ("no pain") to 10 ("worst possible pain"). It has been found to be a valid measure of pain intensity with minimum clinically important difference noted to be a change of 2 points. The investigators will use NRS averaged over the past 24 hours for all time points in this trial. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus statement indicates that an NRS reduction of 30% (or 2 points) is associated with a meaningful or moderately important improvement in pain. Further, IMMPACT also indicates that an NRS reduction of 50% (or 4 points) is associated with a substantial improvement in pain. The investigators will follow their consensus recommendations and explicitly report these two categories of pain relief.
• Change in Median EQ-5D (European Quality of Life-5 Dimensions) Score From Baseline [Baseline, 2 weeks, 1 month, 4 months]: The EQ-5D is a standardized measure of health status that provides a simple, generic measure of health for clinical appraisal. It is well-validated for health status measurement and for quality-of-life in headache. Scores on the EQ-5D were calculated using the United States 3L, time trade off (TTO) valuation technique. Scores range from 0 to 1, with 1 indicating perfect health.
• Change in Median WPAI (Work Productivity and Activity Impairment) Score From Baseline [Baseline, 2 weeks, 1 month, 4 months]: The WPAI is a validated instrument with good test-retest reliability used extensively in health research that quantifies impairment in daily activities and work productivity. Scores on the WPAI range from 0 - 100% with higher percentages indicating greater impact on work productivity and more severe activity impairment.
• Change in PGIC (Patient Global Impression of Change) Score From Baseline [Baseline, 2 weeks, 1 month, 4 months]: PGIC is a validated 7-point Likert-type scale assessing a patient's overall impression of improvement after intervention. Scores range from 1 - 7 (1: no change or worsening of condition; 2: almost the same, hardly any change at all; 3: a little better, but no noticeable change; 4: somewhat better, but the change has not made any real difference; 5: moderately better, and a slight but noticeable change; 6: better and a definite improvement that has made a real and worthwhile difference; 7: a great deal better, and a considerable improvement that has made all the difference) with higher scores indicating greater improvement.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Adult patients meeting International Classification of Headache Disorders 3rd Edition (ICHD-3) criteria for a diagnosis of SIH (Table 1) who have had a contrast-enhanced brain MRI and a myelogram confirming the presence of a CSF leak will be recruited from the Duke Radiology spine intervention clinic \[25\]

Exclusion Criteria:

* recent (i.e., < 2 weeks) blood patch
* contraindication or inability to undergo the procedure
* inability to provide informed consent
* expected inability to complete follow-up assessment
* a contraindication to receiving contrast material (precluding an epidurogram)
* contraindication to receiving fibrin glue (i.e., allergy).

Participant flow

Outcome results

• Change in Median (Headache Impact Test-6) HIT-6 Score From Baseline (Primary), Median, score on a scale: Targeted Epidural Patching of CSF Leaks With Autologous Blood and Fibrin Glue -12 (-16 to -7); Simulated Patching Procedure -7 (-13 to -1)
• Change in Median HIT-6 Score From Baseline (Secondary), Median, units on a scale: Targeted Epidural Patching of CSF Leaks With Autologous Blood and Fibrin Glue -5.5 (-10 to 0.5); Simulated Patching Procedure -7 (-17 to -3)
• Reduction in Median Migraine Disability Assessment (MIDAS) Score From Baseline (Secondary), Median, units on a scale: Targeted Epidural Patching of CSF Leaks With Autologous Blood and Fibrin Glue -25 (-55 to 6); Simulated Patching Procedure 16 (-35 to 100)
• Change in Median NRS Score From Baseline (Secondary), Median, units on a scale: Targeted Epidural Patching of CSF Leaks With Autologous Blood and Fibrin Glue -0.5 (-1.5 to 1); Simulated Patching Procedure -1 (-3 to 0)
• Change in Median EQ-5D (European Quality of Life-5 Dimensions) Score From Baseline (Secondary), Median, units on a scale: Targeted Epidural Patching of CSF Leaks With Autologous Blood and Fibrin Glue 0.1 (0 to 0.2); Simulated Patching Procedure 0.1 (-0.1 to 0.3)
• Change in Median WPAI (Work Productivity and Activity Impairment) Score From Baseline (Secondary), Median, units on a scale: Targeted Epidural Patching of CSF Leaks With Autologous Blood and Fibrin Glue 1.3 (-16.9 to 13.5); Simulated Patching Procedure -0.3 (-8.8 to 3.6)
• Change in PGIC (Patient Global Impression of Change) Score From Baseline (Secondary), Median, score on a scale: Targeted Epidural Patching of CSF Leaks With Autologous Blood and Fibrin Glue 3.5 (3 to 4.5); Simulated Patching Procedure 2 (1 to 4)

Adverse events

Time frame: Adverse event data were collected immediately after the initial procedure, immediately after any crossover procedures (performed at the 2-month time point), and also at 1 week after any procedure (initial or crossover).

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2017-10-26)