Should Magnetic Resonance Venography be Performed Routinely in all Patients Undergoing Evaluation for Idiopathic Intracranial Hypertension?

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory Van Stavern, MD Should Magnetic Resonance Venography be Performed Routinely in all Patients Undergoing Evaluation for Idiopathic Intracranial Hypertension? Marc Dinkin, MD, Heather E. Moss, MD, PhD Patients with idiopathic intracranial hypertension (IIH) frequently present to the neuro-ophthalmologist before obtaining any neuroimaging studies. Although magnetic resonance imaging (MRI) of the brain with and without contrast is the recommended diagnostic imaging modality for IIH, some clinicians advocate routine inclusion of magnetic resonance venography (MRV), both to screen for venous sinus thrombosis and transverse sinus stenosis. Two experts debate whether MRV should be routinely included in the diagnostic work-up of patients with suspected IIH. Magnetic Resonance Imaging-Based Venous Assessment Should Be Performed In All Patients Who Present With Presumed IIH: Marc Dinkin, MD Opening statement Most women of child-bearing age with an elevated body mass index who present with papilledema and negative brain MRI will be diagnosed with IIH. The diagnostic criteria for IIH have evolved over the years, beginning with the Dandy criteria (initially requiring brain computed tomography and lumbar puncture) and evolving to the modified Dandy criteria, which include the addition of MRI to more definitively rule out mass lesions and other etiologies responsible for elevation in intracranial pressure (ICP). Whether or not MRV should be included in the routine evaluation of patients suspected of IIH remains controversial, but an analysis of its respective costs and benefits supports its use. MRV offers an opportunity to detect and quantify venous sinus stenosis that may be associated with IIH or may result from tumor compression. However, the primary reason to obtain an MRV in patients who are suspected of having IIH is to rule out cerebral venous sinus thrombosis (CVST). CVST is a rare condition of obstruction of the venous sinuses because of thrombotic occlusion, with an annual incidence of 3-4 per million (1) population and up to 7 per 100,000 hospital patients per year (2). Its primary manifestations include venous infarction and hemorrhage, leading to seizures and neurological deficits, and symptoms and signs of elevated ICP including papilledema and sixth Departments of Ophthalmology, Neurology and Neurosurgery (MD), Weill Cornell Medical College, New York, New York; and Departments of Ophthalmology, Neurology and Neurosurgery (HEM), University of Illinois at Chicago, Chicago, Illinois. The authors report no conflicts of interest. Address correspondence to Marc Dinkin, MD, Email: mjd2004@med. cornell.edu Dinkin and Moss: J Neuro-Ophthalmol 2015; 35: 431-437 nerve palsy. While 80% of patients recover with no permanent neurological sequelae, the remainder may be left with permanent disability, and an estimated 16%-28% die from associated cerebral edema and transtentorial herniation (3,4). In an estimated 37% of patients, the only manifestation is elevation in ICP, mimicking the clinical presentation of IIH (5). Some have argued that IIH-like CVST can be distinguished from IIH clinically based on the abrupt nature of presentation (6) but in a review of 624 adults with CVST, the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVST) found a subacute presentation in 55% and chronic in 7.2%. Thus, the acuteness of the clinical presentation cannot reliably be used to distinguish IIH-like CVST from actual IIH. And since up to 75% of CVST patients are women (likely attributable to an increased risk of CVST with oral contraceptives use (7) and during pregnancy (8)) and because the median age of CVST is much younger than that of arterial stroke (median age 37 in the ISCVST), these demographic features also do not offer a useful means of differentiation either. In 2006, Lin et al (9) reviewed the charts of 106 patients with papilledema who underwent MRI and MRV, where no mass lesion or meningitis was identified. Ten of these patients (9.4%) were found to have CVST of which four were obese females of child-bearing age, displaying the typical demographic profile of a patient with IIH. From this, we can conclude that a strategy of only searching for CVST in patients who do not fit the typical IIH phenotype would potentially lead to 4/106 (3.7%) patients left with undiagnosed CVST. Of note, only 1 patient in this series was diagnosed with MRI alone, whereas the remaining patients were diagnosed with MRI combined with MRV. 431 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point Magnetic resonance venography vs magnetic resonance imaging alone MRI alone may detect CVST, especially when there is associated intraparenchymal hemorrhage, but MRV obtained alongside MRI is the most widely accepted technique for diagnosing CVST and has been shown to correlate well with the results of conventional catheter angiography (10). There are 3 primary types of MRV: 1) a 2-dimensional time of flight (2D-TOF) with saturation of arterial flow, 2) phase contrast (PC) MRV, and 3) gadolinium-enhanced 3dimensional MRV (Gd-MRV). 2D-TOF MRV benefits from a short acquisition time (5-8 minutes) and its spatial resolution. Absence of normal signal in the sinus suggests CVST, as do the indirect signs of collateral veins and visualization of emissary vessels. Its major disadvantage is a low sensitivity to blood flowing within the acquisition plane (coronal for MRV), potentially causing signal drop out that can mimic stenosis or thrombosis. PC MRV uses the fact that protons flowing through a magnetic field will demonstrate a phase shift, which is proportional to the velocity of flow. Thus, direction and speed of flow can be determined. PC MRV has the advantage of a greater ability to differentiate slow flow from true thrombosis. Gd-MRV demonstrates a flow-independent 3D image of the venous lumen and removes the in-plane drop out problem of 2D-TOF imaging. To maximize the flow of contrast during acquisition time, an autotriggered elliptic centric ordered (ATECO) system may be used, which begins acquisition after an 8 second delay. This method has been shown to provide greater visibility of the venous structures (complete in 92% of patients) (11). Finally, time-resolved contrast 3D MRV (also known as "contrast-enhanced 4D venography") creates subtracted images of the contrast bolus in the venous system similar to digital subtraction (catheter) venography. The false-positive rate of MRV alone, based on misinterpretation of a congenitally absent anterior superior sagittal sinus, prominent arachnoid granulations or blood flow in the direction of the imaging plane as CVST, can be reduced with the concomitant analysis of the conventional magnetic resonance images. The same can be said for the false-negative rate of MRV alone, which may be due to misinterpretation of the high signal of a subacute thrombus as normal flow. MRT has become increasingly sensitive at visualizing intra-arterial or intravenous thrombus. Indeed, a hyperintense thrombus may be noted on spin echo T1weighted MRI in CVST, and for that reason alone, a concomitant MRI is always useful in conjunction with MRV for the diagnosis of CVST. More recently, T2*SW (susceptibility-weighted) MRI has been shown to be more sensitive for the detection of CVST than T1, T2, and fluidattenuated inversion recovery imaging, and also for the intraparenchymal and subarachnoid blood, which may accompany CVST (12,13). However, T2 spin-echo sequences may produce false-negative results as the thrombus may seem hypointense in the acute period, mimicking normal flow, whereas contrast MRI may produce a false negative when contrast at the edge of a thrombus simulates a patent sinus. The addition of MRV to MRI helps to address these pitfalls. The various modalities were compared in a retrospective study of 39 patients with CVST, in which a neuroradiologist, masked to the patients' clinical condition, reviewed MRIs and MRVs (14). The sensitivity of MRV at onset was 95% vs only 84% for T1 spin-echo imaging. Of note, a magnetic susceptibility effect was seen on T2*SW imaging in 90% of patients at presentation. One study compared time-resolved contrast 3D MRV to TOF MRV and conventional MRI and found a significantly higher sensitivity (90%) and specificity (100%) for CVST as compared with TOF MRV (83% and 79%), T2-weighted MRI (75% and 97%), and gradient echo imaging (55% and 95%) (15). In short, inclusion of TOF and contrast-enhanced MRV, and also SW MRI, will improve the sensitivity for CVST when compared with conventional MRI alone, by up to 15%. Furthermore, in the real world, where radiologists are not always made aware of the clinical context, it is likely that the inclusion of MRV will further improve sensitivity for CVST simply by alerting the interpreting radiologist to the clinicians' suspicions for the condition. Magnetic Resonance Venography Should Not be Performed Routinely in All Patients Undergoing Evaluation for IIH: Heather E. Moss, MD, PhD, University of Illinois at Chicago Opening statement MRV has 2 potential applications in the evaluation of patients with suspected IIH. First, it is the gold standard to exclude CVST, a condition that causes elevated ICP, and is an important consideration in the differential diagnosis of some patients with suspected IIH. However, while this is a serious diagnosis that requires directed management, it is not common in typical IIH patients and, therefore, does not need to be excluded in all suspected IIH patients. One 432 prospective series of 22 typical IIH patients who had MRV found venous sinus thrombosis in none (16). Second, MRV may be important for identifying patients with primary or secondary venous sinus stenosis, treatment of which is an emerging therapeutic option for IIH in select patients. However, this is only a consideration when nonmedical treatment options are being considered, which is not the case in most patients. There is little debate that MRV is an essential part of the evaluation of IIH in some patients. This group consists of Dinkin and Moss: J Neuro-Ophthalmol 2015; 35: 431-437 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point those individuals who are more likely to have CVST as a cause of headache and papilledema based on history of present illness or medical history. Historical features such as acute presentation of headache, particularly with crescendo symptoms, are concerning for possible CVST (17). Patients with risk factors for CVST or hypercoagulability, such as dehydration, pregnancy, infection, recent head trauma, history of cancer, or history of a clotting disorder, are more likely to have CVST (1,18). Finally, MRV is also essential for evaluation of patients who are less likely to have IIH based on their demographic, for example, males, prepubertal girls, older women, and nonobese women. There are patients in whom there is little debate that MRV need not be performed because of a very low probability of CVST. For example, a patient with stable papilledema and headache for 6 months who had normal brain MRI during this period is unlikely to have CVST. In a patient such as this, where the benefit of MRV is low, the risks may outweigh the benefits. Risks include those associated with gadolinium contrast, including allergic reactions and nephrogenic sclerosing dermopathy. Many patients find the duration and configuration of the magnetic resonance scanner to be uncomfortable and some require sedation, which carries inherent risks with it. Another consideration is cost, both to the medical system and to the patient. Brain MRI and MRV are 2 separate tests. Thus, completing both doubles the duration of testing time (from 30-60 minutes to 60-90 minutes) and doubles the testing cost (frome$4,000 toe$8,000). Patient charges vary based on insurance and authorization and can be in the $300-$550 for MRV without gadolinium for a patient who has coinsurance and has not met their deductible (this range includes self-pay, commercial, and Medicare/Medicaid). There can be an additional $150-$450 charge to the patient (depending on insurance provider) if MRV is performed both with and without contrast. These charges are in addition to those for MRI brain. Perhaps the most important consideration in deciding to not perform brain MRV in suspected IIH patients who have a low likelihood of CVST is the possibility of a false-positive study. This may lead to unnecessary treatment some of which may be invasive. There are many MRV protocols, which vary in sensitivity, specificity, and interrater reliability for the detection of CVST. Contrast-enhanced 3D MRV has greater diagnostic sensitivity and is less subject to artifact than 2D-TOF non-contrast-enhanced MRI (19). In my experience, some facilities do not use the most sensitive or specific protocols. Furthermore, expertise in MRV and CVST is necessary for a radiologist to accurately interpret the study (20). For example, transverse sinus thrombosis may be difficult to detect (17) because of the high prevalence of anatomic variants and artifacts in normal individuals (21-23), and distinct non-thrombotic venous abnormalities in IIH patients (24). The challenge is to determine criteria for which patients do not need an MRV to be performed. Chronicity of symptoms is likely the most important consideration. In a series of 1,876 patients referred to a headache clinic who were symptomatic for more than 4 weeks at the time of evaluation and had at least 3 months of follow-up, 4 had papilledema, 3 of which were diagnosed with IIH, and 1 was diagnosed with malignant glioma (25). None were diagnosed with CVST. Another perspective is provided by the ISCVST, in which over 600 patients with CVST were studied (26,27). Time from symptom onset to diagnosis was positively skewed with the median (7 days) being much less than the mean of 14.5 days. Seventy-five percent of patients with CVT were diagnosed less than 16 days after symptom onset in this cohort. Together, these studies suggest that the likelihood of CVST diagnosis decreases with increasing duration of stable symptoms. It is important to remember that not performing MRV does not imply lack of evaluation for CVST. This is because brain MRI has limited sensitivity for CVT, which, in a population with low CVST prevalence, can translate to substantial negative predictive value. One study found that the multiple non-MRV sequences had sensitivities between 33% and 67% for CVT detection (28). Although these might seem low, in the authors' population of patients with MRVs performed for clinical indications, the negative predictive value exceeded 95% for all non-MRV sequences studied. It is therefore appropriate that recent guidelines for the diagnosis of IIH advise performing brain MRI in all patients and brain MRV only in select patients (29). Rebuttal-Dr. Dinkin Dr. Moss makes several excellent points regarding the assessment of patients with IIH-like presentations with MRV. As she makes clear, the incidence of CVST among patients with classic demographic features of IIH is low. The prevalence of CVST in the study quoted may offer false reassurance, however, given the small patient cohort (n = 22) of that study. Based on the 3.7% prevalence in the study of 106 patients by Lin et al (9), less than 1 patient Dinkin and Moss: J Neuro-Ophthalmol 2015; 35: 431-437 with presumed IIH and typical features would be expected to have CVST among a group of 22. So the question is whether it is worthwhile to obtain an MRV if it only would benefit 3.7% of the patients. While that is a low number, the decision to test for an entity should not only be based on a pretest probability of a positive result but also on the consequences of missing the diagnosis. In this case, severe vision loss, neurologic disability, and death could result 433 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point from missing the diagnosis of CVST, justifying acquisition of MRV despite the low possibility of a thrombosis. I agree with Dr. Moss that an MRV really is not essential in patients who have had symptoms of elevated ICP and stable papilledema for 6 months or have optic atrophy at presentation. But this is no more the standard IIH presentation than a thin male with papilledema. The recommendation to obtain an MRV really should apply to patients who present with acute or subacute symptoms, where there is a real possibility of acute CVST. Furthermore, although none of the 1,876 patients in the study by Sempere et al (25) (which included only patients with greater than 4 weeks of symptoms) were found to have CVST, only 4 of the patients had papilledema, so little can be concluded about the rate of CVST among patients with headache and papilledema from this study. Magnetic resonance venography risks Dr. Moss is also correct in identifying potential inconveniences and even risk resulting from obtaining an MRV. These include 1) extra time spent in the scanner 2) risk of false-positive results, 3) risk of contrast reaction, and 4) expense, ranging from an additional $500-600 per MRV. Time in the scanner Regarding time in the scanner, it is difficult to quantify the harm of these extra minutes spent in the scanner, but for the average non-claustrophobic patient, it is incomparable with the risk of permanent neurological deficits from missing CVST. The time of a standard MRI with and without contrast is already 40 minutes, whereas an MRV (without MRA) adds only an additional 10-15 minutes (potentially even shorter); total imaging time of ATECO contrast MRV has been reported to be 2 minutes and 24 seconds (30). Those patients with severe claustrophobia will need sedation or an open MRI facility anyway for the MRI of brain. Contrast reaction Regarding contrast reactions, a standard TOF MRV does not require contrast. And although contrast-enhanced MRV may offer greater accuracy, patients with presumed IIH should undergo contrast-enhanced MRI anyway, so there is no increased risk with the addition of contrast MRV. False-positive results The risk of false-positive results is real, but as stated above, it is reduced with concomitant MRI. For example, absence of the anterior portion of the superior sagittal sinus on MRV might mimic CVST, but if one looks at the coronal spin-echo images, one would see that the sinus is not occluded but is instead small (31). Furthermore, although loss of signal may occur when the direction of blood flow is within the imaging plane on TOF MRV, this artifact too can be avoided by reviewing contrast-enhanced MRV. 434 There is no question that MRV should only be acquired when the neuroradiologist is equipped to interpret the study and understands the potential pitfalls in interpretation. The best balance of sensitivity and specificity will occur when MRV and MRI (preferably with T2*SW imaging) are both acquired and analyzed together. Analysis of morbidity, mortality, and cost The expense of obtaining an MRV in all patients presenting with possible IIH does add up as one contemplates all the additional MRVs performed in patients with papilledema who fit the criteria for an IIH patient. The cost of MRV can vary considerably from state to state and between radiological suppliers but I found an asking price of $1,300 in a New York City Park Avenue practice with a maximum payment by Medicare of $520. Many insurance companies model their payment scales after Medicare, but let us assume a higher actual payment of $800. Assuming an incidence rate of IIH of 2 per 100,000 (32), and a population of 320 million in the United States, an estimated 6,400 patients are diagnosed with IIH in the country each year. Assuming that we would all perform MRV on the male patients with new onset papilledema because they are not typical IIH patients, and a female:male ratio of 10:1 (33), incorporating MRV in the work-up of "typical" IIH patients would lead to an additional 8/9 of 6,400 = 5,688 MRVs per year, yielding an additional cost of 5,688 · $800 = $4.5 million per year. However, when we compare this expense to the expense related to the morbidity that could result from missing CVST (forgetting about patient suffering for a moment), it is easily justified. Assuming that 3.7% of the patients who present with an IIH-like picture actually harbor CVST (9), there would be an estimated 6,400 · 3.7% = 236 patients annually in the US harbor CVST and present with IIH-like symptoms. Assuming an increased sensitivity of 15% by including MRV and T2* imaging specifically aimed at ruling out CVST, an estimated 236 · 15% = 35 more patients would be correctly diagnosed per year. The benefits of treatment of CVST are difficult to quantify as a large randomized trial vs placebo would be unethical because it has become the standard of care. However, in 1 small, patient-blinded, randomized controlled trial, 60% of the patients in the control arm were left with neurological deficits and 20% died, whereas only 20% in the treatment group were left with "slight" neurological deficits and none died (34). Assuming that treatment could reduce the risk of neurological disability by 40%; then, this would mean: 35 patients diagnosed with CVST because of the inclusion of MRV and SW MRI, and 40% reduction in the rate disability from treatment = 14 patients per year spared lifetime disability. Assuming loss of employment due to disability with median annual income currently $52,000 and an expected 30 years of working (retirement age 67 years; mean age of CVST 37 years), that is Dinkin and Moss: J Neuro-Ophthalmol 2015; 35: 431-437 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point $1,560,000 of lost income per patient · 14 patients = $21,840,000, a much higher value than the $4.5 million cost of the 5,688 additional MRVs per year. Now, if you include the direct medical costs of caring for these 14 patients, basing it on the annual cost of medical care of patients after ischemic and hemorrhagic strokes (35), which was estimated in Finland in 2007 (likely underestimating 2015 US costs) to be $32,900, multiplied by an estimated 30 years of medical care until retirement age, that adds an additional $987,000 per patient, or $13,818,000. Thus, the total cost in terms of lost employment and added health care costs to the US society of missing 35 cases of CVST by failing to obtain an MRV and MRI T2* is estimated at $21,840,000 (employment) + $13,818,000 (health care costs) = $35,658,000. It is apparent that inclusion of modalities to rule out CVST in the typical IIH patient will save lives, prevent disability, and when accounting for the financial burden of the morbidity and mortality prevented by finding the diagnosis in the rare patients who are positive is even cost effective in the long term. Assessment of venous sinus stenosis Over the last 14 years, it has become evident that most patients with IIH demonstrate stenosis at the junction of the transverse and sigmoid sinuses either unilaterally or bilaterally, leading to the hypothesis that this stenosis may play a role in the pathophysiology of the elevated ICP. Specifically, such stenosis was observed in 90% of IIH patients vs only 6.7% of controls using ATECO MRV (36). Beginning with the first stent placement by Higgins et al (37) and culminating in a large retrospective review of 52 patients treated with stents in 2011 (38), there is a growing body of evidence supporting a role for venous stenting as an option for IIH patients who are refractory to medications and in which a significant pressure gradient exists across the stenosis. In the patient who is suspected of having IIH, but in whom the results of ophthalmoscopy are equivocal (papilledema vs drusen, for example), and lumbar puncture is borderline (e.g., opening pressure of 22 cm of water), the identification of venous sinus stenosis can help support a diagnosis of IIH, along with other clinical and radiological features. Despite the positive retrospective data supporting venous stenting as safe and effective, it remains a procedure with little prospective or controlled data and is best reserved for patients with visionthreatening, medically refractory IIH. Dr. Moss is correct in stating that most patients will not require such a procedure, but in practice, I find it helpful to know early on if a patient might be a candidate for stenting should they become refractory to medications. In summary, I recommend a careful assessment of the cerebral venous system, preferably with a combination of contrast-enhanced MRV along with a contrast MRI that includes T2*SW imaging, in all patients who present with the symptoms and signs of presumed IIH, to increase the sensitivity for the possibility of CVST and help lessen the morbidity and mortality of that disease. The associated risks and costs of such an assessment are low when compared with the risk and long-term costs of missing the diagnosis. An added benefit to careful venous assessment is the identification of venous sinus stenosis which can help support the diagnosis of IIH in questionable cases and could have implications for therapy with venous sinus stenting in medically refractory cases. Rebuttal-Dr. Moss I agree wholeheartedly with Dr. Dinkin that the presentation of CVST can overlap with IIH, that MRV is the gold standard for diagnosing it, and that directed therapy is necessary for CVST to mitigate risk of substantial morbidity or mortality. For these reasons, it is imperative that every physician who is evaluating a patient with papilledema must consider CVST as a "can't miss diagnosis" in the same way that they consider tumor as a "can't miss diagnosis." It is also imperative that physicians consider immediate and downstream risks of all diagnostic tests that they order. Diagnostic testing is a complement to, not a replacement for, careful clinical evaluation and judgment. In the case of papilledema and possible CVST, clinical evaluation and previous diagnostic testing determine pretest probability of CVST. If this is low, as it is for patients with documented long-standing papilledema, chronic headaches, and normal brain MRI brain, the potential benefit of MRV to make a diagnosis of CVST is low, and the risks of MRV, including complications, false diagnosis, inadequate study and cost become relevant and worthy of consideration. When the risks exceed the benefit for a particular patient, MRV need not be performed in that patient. Conclusions The sensitivity and resolution of MRV have increased over the past decade, and further advances in neuroimaging should continue to improve the technical aspects of this Dinkin and Moss: J Neuro-Ophthalmol 2015; 35: 431-437 diagnostic technique. The authors have presented compelling arguments both for and against the routine inclusion of MRV in the work-up of IIH. All neuro-ophthalmologists 435 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point should have a low threshold for ordering MRV in patients who have a high risk of CVST. The decision to include MRV in most suspected IIH patients should include factors, such as the technical quality of the test at the specific facility, the skill of the interpreting neuroradiologist, the time and cost of the testing, and the degree to which the presence or absence of transverse sinus stenosis influences diagnosis and management. REFERENCES 1. Stam J. Thrombosis of the cerebral veins and sinuses. N Engl J Med. 2005;352:1791-1798. 2. Daif A, Awada A, al-Rajeh S, Abduljabbar M, al Tahan AR, Obeid T, Malibary T. Cerebral venous thrombosis in adults. A study of 40 cases from Saudi Arabia. Stroke. 1995;26:1193-1195. 3. Patil VC, Choraria K, Desai N, Agrawal S. Clinical profile and outcome of cerebral venous sinus thrombosis at tertiary care center. J Neurosci Rural Pract. 2014;5:218-224. 4. Coutinho JM, Zuurbier SM, Stam J. 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