Introduction The relationship between degree of angiographic venous sinus stenosis and the trans-stenosis pressure gradient magnitude in idiopathic intracranial hypertension (IIH) is poorly understood. The present study aimed to assess the utility of angiography, venography, and non-invasive imaging (MRV or CTV) for the diagnosis and characterization of clinically significant VSS.
Methods Retrospective analysis of a prospectively collected database was performed to identify patients with medically refractory IIH who were evaluated by angiography and venous manometry for the presence of VSS with associated clinically significant pressure gradient. Angiographic stenosis was measured by two independent raters using novel methodology.
Results Thirty-seven patients met inclusion criteria for the study. In total, 70% of patients had clinically significant pressure gradients and were selected for stenting. The optimal percentage stenosis for detection of a significant pressure gradient was 34% stenosis on venous phase arteriography (sensitivity 0.81 and specificity 0.91) and 31% stenosis on venography (0.92 and 0.73). For every 10% increase in stenosis, an approximate increase in pressure gradient of 3.5 mmHg is seen. MRV/CTV had a calculated sensitivity of 0.42, and a negative predictive value of 22%.
Conclusion The degree of stenosis predictive of a clinically significant pressure gradient (30–35%) in the venous sinuses is considerably lower than the arterial stenosis at which pathologic hemodynamic alterations occur. While highly predictive of a venous pressure gradient when a stenosis is identified, non-invasive imaging does not appear to be a suitable diagnostic evaluation for the purpose of ruling out clinically significant cerebral VSS.
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Idiopathic intracranial hypertension (IIH), previously known as pseudotumor cerebri, is a syndrome occurring most commonly in women of childbearing age and characterized by increased intracranial pressure (ICP) without an intracranial mass. Recent studies have suggested cerebral venous sinus stenosis (VSS) and resultant cerebral venous hypertension as one possible causative etiology for the development of IIH.1–4 There is developing evidence supporting venous sinus stenting for patients with medically-refractory IIH secondary to VSS with an associated pressure gradient across the stenosis.5–9
Traditionally, non-invasive imaging such as magnetic resonance venography (MRV) has been used to screen for VSS in patients with clinical signs and symptoms consistent with IIH. Previous reports have utilized the presence of a radiographic stenosis on MRV as their indication to proceed with diagnostic cerebral arteriograms and venograms, with some studies citing a cut-off of 50% stenosis on venography to be considered for treatment.4 10 11 The management of patients who present with a clinical picture highly suggestive of IIH but without obvious lesion on MRV has remained challenging, with practice patterns varying by provider. To date, there have been no published reports linking the degree of VSS with the presence or magnitude of a pressure gradient.
At our institution, diagnostic angiography and venography with venous manometry are routinely performed to evaluate patients with medically refractory IIH and elevated intracranial pressure. Herein, we present the results of a prospective study investigating the diagnostic utility of non-invasive venous imaging, angiography, and venography for detecting the presence and degree of clinically significant pressure gradient associated with VSS.
Study design and sample
A prospective database of patients evaluated for IIH was retrospectively queried after obtaining institutional review board approval. Criteria for inclusion in the database were: presentation with clinical symptoms of IIH without evidence of intracranial mass lesion on imaging; a lumbar puncture opening pressure >20 cm H2O in the lateral decubitus position; and either medically-refractory symptoms or medication intolerance. All patients underwent diagnostic catheter angiography and venography with venous manometry.
Chart review of each patient was performed to identify demographic features (age, gender, and body mass index), presence of papilledema, visual symptoms or vision loss, presence of pulsatile tinnitus, and opening pressure on lumbar puncture. Additionally, pre-procedural non-invasive imaging radiology reports, specifically MRV and CT venography (CTV), were reviewed for the presence of VSS. Stenosis on radiology reports was specifically defined by the following words and phrases: ‘stenosis,’ ‘narrowing,’ and ‘focal changes in caliber.’
The presence and magnitude of venous sinus pressure gradients found on manometry as well as the details of intervention were noted for each patient. Significant venous sinus pressure gradients were defined as those of at least 8 mmHg, with a gradient of at least 6 or 7 mmHg determined to be significant in select cases where central venous pressures were normal or low and patients were felt to benefit from stenting.
Diagnostic angiography, venography, and venous sinus manometry were performed in all patients under minimal conscious sedation with fentanyl. The full details of the procedure have been described previously.12 In brief, the femoral artery and vein were accessed in all patients and 5F sheaths placed. Next, cerebral arteriography was performed first with a 5F diagnostic catheter in order to evaluate for the presence of venous sinus stenosis, venous outflow patterns, and rule out arteriovenous fistulae. Next, a 5F catheter was positioned in the right and/or left internal jugular veins near the jugular bulb. A 0.027 inch Rebar microcatheter (Medtronic, Minneapolis, MN, USA) was then navigated over a 0.014 inch microwire into the superior sagittal sinus and super-selective diagnostic venography was subsequently performed. Following venography, manometry was performed in the superior sagittal sinus, torcula, transverse sinus, transverse-sigmoid junction, sigmoid sinus, jugular vein, and superior vena cava-atrial junction (central venous pressure).
Angiographic stenosis measurement
Two fellowship-trained neurointerventionists independently reviewed venous phase arteriography (most commonly right internal carotid artery injection) as well as venography for all patients. The two raters first agreed on a uniform methodology for assessing VSS. This consisted of the observer measuring the smallest diameter of the affected transverse sinus in the lateral projection (most commonly in the proximal transverse sinus near the transverse-sigmoid sinus junction) as well as the normal diameter of the transverse sinus in the anterior-posterior projection for both arteriography and venography (figure 1). Percent stenosis was calculated using the formula: 1 – (smallest diameter/normal diameter).
All analyses were conducted using R: A language and environment for statistical computing, R Foundation for Statistical Computing, Version 3.3.2 (Vienna Austria) and RStudio: Integrated Development for R., Version 1.1.383 (RStudio, Inc., Boston, MA, USA). Descriptive statistics were calculated such that mean (SD) were used for normally distributed variables and median(range) for nonparametric data. For all analyses, 2-tailed hypothesis testing was used with P<0.05 interpreted for statistical significance. Prior to conducting analyses, histograms and boxplots of continuous outcome variables were studied to assess normality. In order to create a composite score for percent stenosis, the reliability between raters for smallest and normal diameter scores for both arteriography and venography were examined by calculating the intra-class correlation coefficient (ICC). Once these scores were deemed highly reliable, a composite percent stenosis score was calculated by taking the average of both raters’ percent stenosis scores within subject. These composite scores were then used as predictors of significant gradient. Receiver operating characteristic curves (ROC) were constructed to estimate the sensitivity and specificity of percent stenosis (arteriography and venography) to predict significant gradient. The optimal cut-point value was chosen using the Youden index such that sensitivity and specificity were as high as possible while still remaining balanced.
To investigate the degree to which percent stenosis for arteriography could predict gradient pressure, a linear regression was performed and residuals examined for fit. Fit was deemed good at stenosis percentages below 60 with greater deviation in residuals at higher levels acknowledged.
A total of 38 patients were identified for inclusion in the study. One patient was excluded from the retrospective analysis secondary to angiographic evidence of chronic venous sinus thrombosis and multiple dural arteriovenous fistulae, leaving 37 total patients for analysis. All patients underwent diagnostic angiography, venography, and manometry. Overall, 33 (89%) of the patients were female. The mean age was 33.8 (10.3) years. Within the cohort, the mean BMI was 38.2 (8.2) kg/m2. A total of 26 patients (70%) had significant pressure gradients and 24 underwent subsequent venous sinus stenting. The overall mean pressure gradient was 15 (10.5) mmHg. Of the 26 patients, 21 had pressure gradients of 8 mmHg or greater (80.8%), and five patients had a measured gradient of 6–7 mmHg and stenting was recommended. Of the two patients that did not undergo stenting, one had a severe nickel allergy, and another was denied insurance approval.
Non-invasive imaging: sensitivity, specificity, and predictive value
Fifteen patients had a MRV or CTV performed prior to referral. Overall, nine of 15 patients had no evidence of VSS on MRV based on the radiologist interpretation. However, seven of these nine patients were found to have a significant pressure gradient on venous manometry with a median of 16 (7, 37) mmHg. All six patients with positive MRV or CTV were found to have a significant pressure gradient on venous manometry. The median pressure gradients measured for the MRV positive and negative cohorts were 12 mmHg and 16 mmHg respectively.
MRV/CTV had a calculated sensitivity of 0.42, a specificity of 1.0, a positive predictive value (PPV) of 100%, and a negative predictive value (NPV) of 22% for detecting significant venous sinus pressure gradient on manometry.
Measurement of angiographic stenosis
All diagnostic angiography and venography was reviewed by two independent observers and stenosis calculated as described in the Methods section. Venographic measurements were technically successful in all but one patient, who had such significant stenosis that retrograde venous flow was not visualized because the ipsilateral sinus was functionally occluded while the microcatheter was traversing the stenosis (figure 2A).
There was a high reliability between rater’s scores of percent stenosis in both arteriography and venography. The intra-class correlation coefficients for the observers were 0.99 (95% CI 0.96 to 0.99) for arteriography and 0.99 for venography (95% CI 0.97 to 0.99). The optimal percentage stenosis for detection of a significant pressure gradient was 34% stenosis on arteriography versus 31% stenosis on venography (figure 3).
The percent stenosis as measured on venography was compared with the percent stenosis measured on arteriography (figure 4). The measures correlated similarly throughout the spectrum of stenosis with a Pearson’s correlation coefficient r=0.82 (95% CI. 67 to 0.90). There was no obvious biasing effect of measuring stenosis with venography compared with angiography.
Diagnostic utility of angiographic stenosis
The calculated sensitivity and specificity for a cut-point of 34% stenosis on arteriography to predict a significant pressure gradient is 0.81 (95% CI. 65 to 92) and 0.91 (95% CI. 73 to 1.0) respectively. Using 31% stenosis on venography, the sensitivity and specificity are 0.92 (95% CI. 80 to 1.0) and 0.73 (95% CI. 46 to 91) respectively. The receiver operator characteristic (ROC) curve is shown along with the positive and negative predictive values for both arteriogram and venogram respectively (figure 3C).
Regression analysis for stenosis as measured by arteriogram compared with the magnitude of the pressure gradient across the stenosis is shown in figure 5. The percent stenosis was chosen because the minimum measured diameter of a stenosis was less well correlated with changes in the magnitude of the pressure gradient rather than the percent stenosis of the segment. For every 10% increase in stenosis, an approximate increase in pressure gradient of 3.5 (SE 0.7) mmHg is seen.
For this prospective study, all patients who presented with medically intractable IIH were evaluated with diagnostic cerebral angiography and venography as well as venous manometry regardless of prior non-invasive venographic imaging. This is the first study to correlate angiographic venous sinus measurements to physiologic venous outflow obstruction determined by venous manometry. During catheter angiography, a stenosis of 30%–35% was determined to be the optimal threshold for sensitivity and specificity in detecting symptomatic venous sinus outflow obstruction. In addition, this study demonstrated a correlation between percent stenosis and magnitude of pressure gradient, with a 10% increase in stenosis yielding a 3.5 mmHg increase in the pressure gradient. Non-invasive venographic imaging had a very poor negative predictive value for a significant pressure gradient, with over 75% of patients with negative MRVs harboring clinically significant pressure gradients across the transverse sinus.
Venous pathology presents unique considerations that challenge the treatment norms for arterial stenosis. The calculated venous stenosis cut-point of approximately 30%–35% is significantly lower than seen in arterial stenoses, where stenosis is not considered hemodynamically significant when less than 50%. This is likely due to physical and rheological properties of the venous system that are distinct from that of the arterial system. Veins are compliant, owing to the relatively low presence of elastic and muscular fibers in the venous tunica media, which can make them more susceptible to external compression than arteries. The phenomenon of external compression causing venous congestion is referred to as May–Turner syndrome in the lower extremity circulation. A similar mechanism has been implicated in the development of the venous congestion associated with IIH, with the transverse sinus stenosis associated with IIH representing a type of Starling resistor.13 14 According to this theory, the transverse sinus diameter is influenced by intraluminal pressure but also by elevated intracranial (extramural) pressures, generating a positive feedback loop wherein elevated ICP leads to further venous sinus stenosis, resultant venous congestion, and further elevation of ICP.15 16 Recent case reports have implicated this mechanism of VSS following large volume lumbar punctures or placing a lumbar shunt, with subsequent decreases in the degree of VSS or trans-stenosis pressure gradient after CSF diversion.14 17
In addition to the increased compliance of the venous system, the endoluminal anatomy can vary significantly. The cerebral venous sinuses are traditionally thought of as large tubes with one true lumen, however this is not always the case. In certain patients, not only can intra-luminal webs impede flow, but the sinus can have multiple channels for venous blood flow.18 Additionally, the ability of the venous system to use collateral venous outflow pathways makes assessment of venous congestion by strictly anatomic assessment incomplete, as multiples routes of flow can develop to alleviate venous congestion at one area of stenosis (figure 2A).
Owing to the compliance and complexity of endoluminal venous anatomy and collateral pathways, the difficulty in defining anatomic criteria for treatment of chronic central or peripheral venous stenoses is well reported by our counterparts in the vascular surgery literature.13 19–21 Diagnostic criteria which have been referenced include degree of anatomic stenosis on venography, presence of collateralization, and presence of webs or synechiae.21 Previous reports in the area of central and peripheral venous stenosis highlight the difficulty in consistently and accurately measuring the degree of stenosis with conventional venography, and authors note that conventional venogram has a poor sensitivity for detecting intravenous webs.19 20 These reports also highlight the lack of a correlation between the anatomic degree of stenosis with the hemodynamic significance of the stenosis. They note that many patients with apparently high-grade stenoses had no pressure gradients across the lesions in contrast to patients who appeared to have relatively insignificant stenoses that were found to have large pressure gradients that benefited from treatment.19 20 The authors concluded the presence of a pressure gradient, as well as physiologic compensation via collateralization across the stenosis, seemed most significant in predicting treatment response.13 19–21
Based on previous experiences articulated in the literature with treating venous stenosis at other locations throughout the body, it is clear that diagnosing and treating VSS requires a different paradigm than does treating its arterial counterpart.19–21 With respect to the cerebrovascular system, the management of arterial and venous stenosis is concerned with two separate phenomena: in the arterial system patients are treated to ensure maximum post-stenotic flow to maintain cerebral perfusion, whereas in the cerebral venous system the goal is to alleviate pre-stenotic pressure and resultant venous congestion. The low cut-point stenosis of 30%–35% on catheter angiography provides further evidence for this difference and seemingly validates the IIH paradigm of physiology-based assessment and treatment focusing on pressure gradient rather than strictly anatomic criteria.
The low percent stenosis threshold and the difficulty of using diameter measurements with gold standard digital subtraction angiography to accurately predict the presence of symptomatic stenosis calls into question the utility of non-invasive venographic imaging in determining patient candidacy for diagnostic venography. In this study, non-invasive venographic imaging had a sensitivity of only 42% and a negative predictive value of 22%. So while MRV or CTV may be helpful in suggesting the presence of a significant pressure gradient prior to venography, the absence of VSS on MRV/CTV provides little useful information. Technical factors such as the anatomic angulation of the transverse-sigmoid junction as well as the low flow state of the cerebral sinuses make the interpretation of non-invasive imaging difficult and variable among radiologists. Often, the radiologist’s interpretations which accompanied outside imaging were highly variable in terms of description of potential findings. Using MRV to screen IIH patients for candidacy for diagnostic venography is likely to incorrectly rule out a large percentage of patients that would potentially benefit from venous sinus stenting. We therefore recommend venous manometry as the gold standard of evaluation regardless of previous anatomic imaging results because of its ability to provide physiologic information concerning the nature of the pressure gradient.
This study has several important limitations. First, the sample size is small, with data from only 37 patients comprising the cohort. Given this small size, the study was not sufficiently powered to allow evaluation of other important factors associated with the presence of a pressure gradient. However, it is important to note that most series in stenting for IIH are small, with the vast majority being less than 50 patients. Second, referral patterns and radiology interpretation of non-invasive venographic imaging at our center (and referring hospitals) may not be generalizable to other centers. Importantly, the investigators did not independently grade MRV or CTV images but instead used official radiology reports to identify the presence or absence of stenosis, which may introduce measurement bias. Additionally, pooling non-invasive imaging modalities (MRV and CTV) may not account for differences in diagnostic utility among the two techniques. A larger study is needed to accurately assess the diagnostic utility of these non-invasive imaging modalities. Additionally, this study is potentially prone to measurement bias specifically with angiographic measurements. There is no published, uniformly agreed on measurement technique for measuring transverse sinus stenosis and therefore a novel method was developed and agreed on by the two independent reviewers ahead of time. This methodology was developed to not only standardize measurements among readers but also provide a simple means of measuring stenosis that could be obtained from basic angiographic views (anteroposterior and lateral) so that it would be reproducible by other others. Finally, it is our practice to offer stenting in patients with marginal pressure gradients (6–7 mmHg) in select cases where the pressure gradient is thought to be contributing significantly to the patient’s elevated intracranial pressure (five patients in this series). This practice is not uniform across centers – importantly, the 8 mmHg gradient threshold for candidacy suggested by Ahmed et al was an arbitrarily selected value and a number of studies have reported successful stenting in patients with pressure gradients as low as 4–6 mmHg.3 22–25
In patients with a high clinical suspicion for IIH, the degree of stenosis predictive of a clinically significant pressure gradient (34% and 31% on venous phase arteriography and venography respectively) is lower than would be predicted based on the arterial literature. The treatment goals as well as vessel behavior are different for cerebral venous sinus stenosis as compared with arterial pathologies, and as such, physiologic measurement of the pressure gradient associated with stenosis remains the most important evaluation in determining the clinical significance of cerebral venous sinus stenosis. Non-invasive imaging has poor sensitivity and low negative predictive value and does not appear to be a suitable diagnostic evaluation for the purposes of ruling out clinically significant cerebral venous sinus stenosis.
Contributors JW (conception, design, data collection, data analysis, manuscript preparation), RG (data collection, manuscript preparation), GG (data collection), CA (design, data analysis), JS (conception, design, data collection, manuscript preparation), SW (conception, design, data collection, manuscript preparation), KF (conception, study design, data collection, data analysis, manuscript preparation).
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Ethics approval Wake Forest Baptist Health IRB.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Unpublished data is available upon request from the corresponding author.
Correction notice Since this article was first published online, the author name Garret P Greenway has been updated to read Garret P Greeneway.