Idiopathic intracranial hypertension

Methods.

In a prospective study from April 2001 to October 2002, patients being evaluated for a possible diagnosis of IIH were referred for ATECO MRV at our institution. The diagnosis of IIH was established in each patient using the following criteria: headache; papilledema (confirmed by experienced neuro-ophthalmologist); CSF opening pressure greater than 20 cm of H₂O; normal CSF constituents; no history of prior condition or medication known to be associated with intracranial hypertension; normal gadolinium enhanced MRI of the brain; and no evidence of current or prior sinovenous thrombosis.

Image processing and review.

Source images from the ATECO MRV of each IIH and control patient were transferred to a commercially available 3D workstation (Advantage Windows, version 4.0; GE Medical Systems). Maximum intensity projection (MIP) images were created for each ATECO MRV data set as shown in figure 1. All identifying and demographic data were removed from the image. This segmented MIP was rotated in an incremental fashion providing 90 images (a MIP image every 4° through 360° of rotation). An MPEG cine loop was created for each rotating segmented MIP and was identified with a number (via digital randomizer) and archived to CD. Workstation image processing required approximately 5 minutes for each patient and was completed by J.N.S. Three neuroradiologists experienced in neurovascular imaging were the readers for this study (R.A.W., K.T.B., and D.J.M.). Readers were blinded to the nature of the patient (i.e., IIH vs control) and were asked to grade the patency of the transverse and sigmoid dural venous sinuses using the grading scale explained in figure 2 and termed the combined venous conduit score (CCS). The readers underwent a brief training session using examples of images of control and IIH patients not subsequently used in the study. The readers reviewed the cine loops of the patients in a randomized blinded fashion recording the CCS of each case. Viewing software allowed the reader to pause the cine loop and slowly review the images in a stepwise fashion when needed to ensure careful review. The CCS on each patient was determined by each of three readers independently and an averaged combined venous conduit score (ACCS) was calculated. Additionally, all MR venograms of IIH patients were reviewed by a single reviewer (R.I.F.) to determine the nature of the lumenal compromise. The stenoses were classified as due to either intralumenal obstruction or extralumenal compression using standard radiologic criteria i.e., extralumenal compression of a tube appears as a relatively long segment of smooth tapering of the opacified lumen where as intralumenal obstruction appears as a sharply demarcated acutely marginated filling defect within the opacified lumen. Institutional Review Board approval was obtained for all aspects of the study, and written informed consent was obtained for all control patients.

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Figure 1. Auto-triggered elliptic-centric-ordered three-dimensional gadolinium-enhanced MR venography of a control patient. (A) Lateral and (B) anteroposterior maximum intensity projections (MIPs) showing the sequence of tracings used to create the segmented MIPs obtained for each control and IIH patient. (C–E) Anteroposterior, left anterior oblique (LAO), and right anterior oblique (RAO) segmented MIPs. These are three selected images taken from the cine loop of 90 images that the readers reviewed.

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Figure 2. Schematic diagram of the system used for grading the patency of the transverse and sigmoid sinus. The grade for each right and left transverse-sigmoid conduit was determined separately and defined by the highest degree of stenosis encountered from the torcula to the distal sigmoid sinus and given a corresponding number from 0 to 4. 0 = discontinuity (gap) or aplastic segment; 1 = hypoplasia or severe stenosis within a segment of the conduit estimated as less than 25% of the cross sectional diameter of the lumen of the distal superior sagittal sinus; 2 = moderately stenosed segment of the conduit (25–50%), 3 = mildly narrowed segment (50–75%); and 4 = no significant narrowing seen (75–100%). The sum of the right and left provided the combined conduit score (CCS) and generally ranged from 2–8. (A) A normal situation in which each right and left conduit would score a 4 with a resultant CCS of 8, and (B, C, and D) schematic examples of a CCS of 4, 3, and 1.

Results.

Twenty-nine patients fulfilled the requisite criteria for IIH and also underwent ATECO MR venography at our institution (table). The average age of these patients was 37.2 years with a male to female ratio of 1:2.6. Figure 3 illustrates findings at ATECO MRV typical of the patients with IIH.

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Figure 3. Auto-triggered elliptic-centric-ordered three-dimensional gadolinium-enhanced MR venography findings in patients with IIH. LAO and RAO segmented maximum intensity projections on (A and B) Patient 77; (C and D) Patient 36; and (E and F) Patient 8. (A) Discontinuities (scored as = 0) are seen (arrows) in the right transverse sinus in (B). Examples of extralumenal compressive stenoses are seen (open arrows) in (B–F). Examples of intralumenal obstructions are seen bilaterally (arrowheads) in Patient 69 in (G and H).

A total of 82 control patients gave consent to undergo MRV examination, 21 of these patients had intracranial abnormalities (metastatic disease) and were excluded from the study. Two patients were excluded from the control population due technical failure (improper trigger delay) precluding the use of the MRV. The final control population consisted of 59 patients with an average age of 60.3 years and a male to female ratio of 1:0.9.

A total of 88 patients were randomized and reviewed by each of the three readers. Pairwise agreement between the three readers for their blinded grading of the CCS in each patient (IIH or control) was evaluated using the weighted kappa statistic.7 Evaluation of agreement between readers one and two yielded a kappa value of 0.73; between readers one and three a kappa value of 0.66; and between readers two and three a kappa value of 0.67. The overall level of agreement between all three readers was evaluated using Kendall’s coefficient of concordance which measured 0.90 indicating excellent agreement across the readers for grading the CCS.8 A receiver–operator characteristic (ROC) curve (a commonly used tool to evaluate the performance of a diagnostic test9) was constructed for each reader as well as for the average of the three readers. The area under the curve and its associated standard error were computed using the equivalence to the Mann–Whitney U test (figure 4).9 The area under each ROC curve ranged from 0.93–0.97. The distribution of the ACCS for the control and IIH patients is shown in figure (E)1 on the Neurology Web site (go to www.neurology.org). Sensitivity and specificity were computed using a range of values for the ACCS. An ACCS value of below 5.0 best discriminated between normal and abnormal venous conduits. With the exception of two patients (false negatives), all IIH patients had an ACCS of less than 5.0. Four control patients (false positives) had an ACCS of less than 5.0. An ACCS of less than 5.0 in a patient with an otherwise normal MRI of the brain indicated the presence of IIH with a sensitivity 93% and specificity of 93%. The cause of sinovenous stenosis in patients with IIH was due to an apparent intralumenal filling defect in 13 transverse sinuses vs an extralumenal compression seen in 45. A scatter-plot and Pearson’s correlation were used to assess the relationship between CSF opening pressure and ACCS (figure 5). No apparent correlation between the ACCS and the CSF pressure was found.

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Figure 4. ROC curves generated for each reader and the overall combined curve (bolded) a portion of the calculated data used to generate these curves is displayed in the table below. The “threshold” (cut off) is the reader’s CCS for which all scores equal to and below it indicated presence of IIH. Sensitivity and specificity for that “threshold” are shown. The “threshold” for the averaged combined venous conduit score is also shown in the “overall” row.

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Figure 5. A scatter plot showing the relationship between CSF opening pressure and averaged combined venous conduit score (ACCS). The correlation between CSF opening pressure and ACCS is low (r = 0.12) and not significant. There is one outlying point that seems unusual (arrow) however, even without this point, the correlation is not much higher (r = 0.25) and still not significant.

Discussion.

It is well recognized that dural sinus thrombosis can cause clinical presentation similar to if not identical to IIH and thus diagnostic studies (particularly MRV) have become routine in the workup of these patients to exclude underlying venous sinus pathology.1 Recently, poorly understood forms of venous pathology such as giant arachnoid granulations10 and congenital stenosis11,12⇓ have been implicated in the etiology of IIH syndrome. The current study indicates that it is precisely these forms of questionable venous pathology that represent the “usual” findings in the venous system of patients with IIH, these patients have dural venous sinuses that are anatomically different than those of normal controls. Previous imaging studies that examined the venous outflow of the brain in IIH have inconsistently demonstrated stenoses or anomalies in the transverse dural sinuses similar to the ones shown here.12-14⇓⇓ Using the ATECO MRV technique, we have shown that these stenoses are seen consistently in more than 90% of IIH patients. This discrepancy underscores the limitations of the previous methods of venography namely catheter angiography and time-of-flight MR venography (TOF MRV). Digital subtraction angiography (DSA) is usually performed in two static planes making it difficult to fully appreciate the transverse sigmoid junctions. For proper intracranial venography with DSA, injection of the aortic arch with large quantities of contrast is required to ensure simultaneous complete filling of all the intracranial venous pathways. Only in this way can filling defects within the dural sinuses be truly defined, i.e., true filling defects seen following a selective arterial injection would commonly be misinterpreted as unopacified blood flowing into the dural sinus from an adjacent, uninjected, arterial territory.15 Only after performing rotational angiography with three-dimensional reconstruction could the quality of DSA approach the MR venography obtained in this study. In the past, DSA was performed to exclude other pathologies of intracranial disease and not specifically to interrogate the venous system, and, thus, subtle venous outflow findings were likely overlooked.12

Over the last decade, MR has become the modality of choice for examining the venous system in patients suspected of having IIH to exclude venous sinus thrombosis. TOF MR angiography has been the most popular technique of MR venography to date despite the well documented limitations of the technique specifically the artifactual signal loss that occurs at predictable locations in the venous system due to in-plane flow and turbulence.6,16⇓ Ironically, the transverse and sigmoid sinuses are locations in the dural venous sinuses routinely plagued by such artifacts (figure 6). Thus, with TOF MRV, the important region of the distal transverse sinus would commonly be obscured whether normal, stenosed, or thrombosed. We believe this pitfall of earlier MRV techniques has been a source of great confusion in trying to define the role of MRV in IIH.17 The areas of lumenal stenosis within the dural sinuses associated with IIH that are described here could not be appreciated until the development of a new form of venography, namely ATECO MRV. The technique of ATECO MR angiography and venography has been shown to be superior to TOF techniques in large part due to its flow insensitivity and dramatically decreased artifactual signal loss.6

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Figure 6. ATECO vs TOF MRV. (A) LAO and (B) RAO segmented maximum intensity projections (MIPs) of an ATECO MRV of a control patient demonstrating good visualization of the right (arrows) and left (open arrows) transverse and sigmoid sinuses. Note the lack of artifactual signal loss. (C and D) are corresponding oblique-segmented MIPs from a TOF MRV in the same patient obtained at the same MR exam. Note the substantial artifactual loss of signal over the proximal right transverse sinus (curved arrow) and most of the left transverse sinus (arrowheads).

The observation of narrowed venous conduits in patients with IIH provides us with a relatively sensitive and specific imaging criterion for the diagnosis of this disease. The narrowed distal transverse sinuses of IIH shown here likely relate to the disease process; whether this is a primary or secondary relationship is uncertain. A theory of congenital venous conduit stenosis has been postulated as the occasional primary cause of a pseudotumor syndrome. In this theory the resulting chronic low-grade venous hypertension is in turn transmitted to the CSF to cause elevated pressure.11 A theory of venous stenosis as a primary cause of IIH is made even more seductive when one considers the potential treatment of the disease with percutaneous angioplasty and intravascular stent. Alternatively, the finding of venous conduit narrowing may be secondary as has been recently suggested by other authors.13,18⇓ In a recent manometric study, pressure gradients were demonstrated across the distal transverse sinuses in 19 of 21 patients with IIH, these gradients were mitigated by removal of CSF.13 The transverse sinuses were not imaged as part of that study however the author’s description of the location of the pressure gradients matches the location of the stenotic regions demonstrated in this current study. Let us for a moment assume that IIH is caused by edematous brain or perhaps dysfunctional CSF flow initially unrelated to venous obstruction. The apparent narrowing of the transverse sinuses would be easily explained based on intracranial compartmental accommodation. The Monroe-Kellie doctrine mandates that in the confined intracranial space the vascular compartment will give way to an expanding parenchymal or CSF compartment.19 As more accommodation is required, a threshold is exceeded above which the overall intracranial pressure is elevated, and the patient becomes symptomatic. Interestingly, with this theory, the two types of narrowing encountered in our study can be explained: 1) the long smooth tapered narrowing of external compression caused by brain parenchyma (see figure 3E); and 2) the acutely marginated apparent intralumenal filling defect of an enlarged, partially obstructing, intralumenal arachnoid granulation swollen by elevated CSF pressures (see figure 3G). This theory suggests that the stenosis is a consequence of and not the cause of the elevated intracranial pressure. The explanation for the finding of an intracranial, intravascular pressure gradient across the transverse sinus stenosis is not readily apparent. Perhaps the elevated intracranial pressure in IIH is due to two interrelated components, this possibility has been considered by other authors.13,20⇓ The first component is the primary (unknown) abnormality of IIH that is present over a variable period of time prior to patient presentation. During this time the dural walls of the transverse sinuses slowly stretch and collapse yielding to the extralumenal pressure. As the distal transverse sinus continues to narrow it eventually exceeds a threshold and creates a flow limiting stenosis and resultant pressure gradient (the second component). This results in a surge in intracranial pressure that brings the patient to presentation. The anatomy of the distal transverse sinus in some way likely predisposes it to this phenomenon. One may anticipate that a properly placed, self-expanding, intravascular stent would elevate the collapsed walls of the distal transverse sinus and would alleviate the exacerbating role of the venous hypertension and return the patient to their pre-presentation state. This may have been the case in a recent report of a patient with IIH who underwent stenting of a distal transverse sinus. In this report, at three week follow-up, the patient had a mild persistent headache however her papilledema had resolved, and her CSF opening pressure had dramatically decreased (but was still mildly elevated).21 In this scenario, stenting the sinus may have decreased the patient’s symptoms however the primary cause of IIH would remain unknown and untreated. The results presented here demonstrate that over 90% of patients with IIH have transverse sinuses that appear stenotic compared with those of normal patients. Patients with IIH and these dural sinus narrowings should no longer be considered the exception but rather the rule for this disease. Our ability to visualize the venous outflow of the brain has been dramatically improved with the advent of ATECO MR venography. Combining this technique of MR venography with a novel grading system for dural sinus patency provides us with a high performance noninvasive imaging test for IIH and may offer potential insight into the pathophysiology of this disease.