Time-Dependent Changes in Dural Enhancement Associated With Spontaneous Intracranial Hypotension

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1 Neuroradiology/Head and Neck Imaging Original Research Neuroradiology/Head and Neck Imaging Original Research Peter G. Kranz 1 Timothy J. mrhein Kingshuk Roy Choudhury Teerath Peter Tanpitukpongse Linda Gray Kranz PG, mrhein TJ, Choudhury KR, Tanpitukpongse TP, Gray L Keywords: brain MRI, CSF leak, CT myelography, spontaneous intracranial hypotension DOI: /JR Received March 14, 2016; accepted after revision May 28, ll authors: Department of Radiology, Duke University Medical Center, ox 3808, Durham, NC ddress correspondence to P. G. Kranz (peter.kranz@duke.edu). JR 2016; 207: X/16/ merican Roentgen Ray Society Time-Dependent Changes in Dural Enhancement ssociated With Spontaneous Intracranial Hypotension OJECTIVE. The objective of our study was to determine whether the presence of individual imaging signs of spontaneous intracranial hypotension (SIH) is correlated with increasing duration of headache symptoms. Of particular interest is the relationship of symptom duration to dural enhancement because it is the most commonly identified imaging sign in patients with SIH. MTERILS ND METHODS. Eighty-nine patients with SIH who underwent pretreatment brain MRI and total-spine CT myelography and whose medical record included data on the duration of clinical symptoms were included in this cross-sectional retrospective study. rain imaging was reviewed for the presence of dural enhancement, brain sagging, and the venous distention sign. CT myelograms were assessed for CSF leak. If present, a leak was subcategorized as a high-flow or low-flow leak. Differences in headache duration between subjects with and those without individual imaging signs were compared. RESULTS. Subjects without dural enhancement on brain MRI had a longer average duration of symptoms than those with dural enhancement present (average symptom duration: 45.3 ± 59.0 [SD] vs 15.1 ± 33.0 weeks, respectively; p = 0.002). No difference in symptom duration was observed between subjects whose MRI studies showed and those whose MRI studies did not show brain sagging (p = 0.10) or the venous distention sign (p = 0.21). The presence of a CSF leak on CT myelography was not associated with symptom duration (p = 6) except in the subgroup of patients with low-flow leaks. CONCLUSION. Increasing symptom duration in SIH is associated with decreased prevalence of abnormal dural enhancement on brain MRI. ecause dural enhancement is considered a hallmark imaging feature of this condition, its absence may exacerbate the problem of underdiagnosis in chronic cases of SIH. S pontaneous intracranial hypotension (SIH) is an increasingly recognized cause of chronic headache. Diagnosis often depends on the detection of characteristic imaging abnormalities on brain MRI, the most common of which is diffuse, smooth dural contrast enhancement on contrast-enhanced imaging [1, 2]. This enhancement is thought to represent a physiologic response to CSF volume loss whereby intracranial vascular structures (including those within the dura) are forced to dilate to compensate for the total intracranial volume lost as a result of spinal CSF leakage [3]. lthough highly characteristic of SIH and explainable by the physiologic principles accompanying CSF leakage, dural enhancement is not present in approximately 20% of patients with SIH [4]. This fact is problematic when at- tempting to establish the diagnosis of SIH because other imaging markers of SIH such as MRI evidence of brain sagging, MRI evidence of the venous distention sign, and CT myelographic evidence of CSF leak are found less commonly than dural enhancement and are therefore less reliable indicators of the disease [4]. The absence of dural enhancement may therefore increase the likelihood of misdiagnosis, an already common problem in patients with SIH [5]. Identifying which patients are more likely to show variability in the presence of dural enhancement is therefore important. One potential clue to the variability in dural enhancement may lie with the mounting evidence suggesting that SIH is not a static process but, rather, is one in which the underlying physiology changes with time. For example, CSF pressure, which is often found to be abnormally low in patients with the dis- JR:207, December

C Fig. 1 57-year-old man with positional headache. rain imaging reveals common imaging abnormalities associated with spontaneous intracranial hypotension.

, MR image shows venous distention sign (arrow), whereby borders of dominant transverse venous sinus are convex, rather than normal concave configuration, and result in rounded appearance of sinus.

ease, has been shown to rise with time even if CSF leakage is ongoing [6].

2 C Fig year-old man with positional headache. rain imaging reveals common imaging abnormalities associated with spontaneous intracranial hypotension., bnormal diffuse, smooth dural enhancement (arrowheads) is seen on axial contrast-enhanced T1-weighted image., MR image shows venous distention sign (arrow), whereby borders of dominant transverse venous sinus are convex, rather than normal concave configuration, and result in rounded appearance of sinus. C, MR image shows brain sagging with downward sloping of third ventricular floor, narrowing of suprasellar cistern, and descent of mammillary bodies (arrow) to level of dorsum sella. ease, has been shown to rise with time even if CSF leakage is ongoing [6]. Similarly, clinical symptoms often change with time as well, and many patients experience a reduction in the stereotypical orthostatic component of their headaches, which may evolve into nonorthostatic headaches [7]. Whether the imaging features of SIH, including dural enhancement, also change with time remains an unexplored question. The primary purpose of this investigation was to determine whether dural enhancement on MRI in patients with SIH is correlated with an increasing duration of clinical headache symptoms. We also sought to determine whether other imaging signs of SIH such as MRI evidence of brain sagging, MRI evidence of the venous distention sign, and CT myelographic evidence of CSF leak vary with symptom duration. Materials and Methods This investigation is a retrospective cross-sectional study of patients with SIH. Subjects were identified from a database search of patients with SIH treated at our institution between January 2006 and October 2014 that was performed as part of a separate investigation examining the relationship between the imaging signs of SIH and CSF pressure [4]. This study was approved by our local institutional review board and is compliant with HIP regulations. Subjects total of 99 subjects who met the criteria for SIH according to the criteria proposed by Schievink et al. [8] and whose pretreatment brain MRI studies were available in our institution s PCS were identified. ll subjects underwent CT myelography as part of their workup [9]. The duration of each patient s clinical symptoms was determined from the clinical history recorded in the electronic medical record; assessment of the duration of headache symptoms, including a specific starting date if possible, is part of the history obtained from patients at our institution using a standardized pretreatment questionnaire. Ten of these 99 patients (10%) were excluded because information about the duration of their clinical symptoms was not available in the medical record, resulting in a final study cohort of 89 subjects. Of these remaining subjects, 83 (93%) underwent pretreatment brain MRI performed with and without IV contrast material, and six (7%) underwent unenhanced brain MRI only. rain MRI protocols varied on a case-by-case basis because almost all pretreatment brain imaging examinations were performed at outside centers; however, the brain MRI examinations typically included axial fast spin-echo (FSE) unenhanced and contrast-enhanced T1-weighted images and either FSE or spoiled gradient-recalled coronal contrastenhanced T1-weighted images. Image nalysis The imaging studies were reviewed by a boardcertified radiologist who was in the second year of a neuroradiology fellowship to determine if the imaging signs of SIH were present or absent. If the imaging findings for a patient were thought to be equivocal, the imaging studies were reviewed by a second board-certified radiologist who has a certificate of added qualification in neuroradiology and extensive experience in treating patients with SIH. The presence of principal brain MRI signs of SIH (i.e., dural enhancement, brain sagging, and the venous distention sign) (Fig. 1) was assessed using previously described criteria [4]. Dural enhancement was graded as follows: absent, abnormal enhancement without dural thickening, or abnormal enhancement with dural thickening. The presence of pituitary engorgement was not assessed because we think that this sign is too subjective for reproducible analysis and is of lesser diagnostic significance in SIH. CT myelograms were designated as showing evidence of CSF leak if contrast material was seen outside the thecal sac. Leaks were further subcategorized as high-flow leaks or low-flow leaks using the following previously described criteria: leak was defined as a high-flow leak if leaked contrast material was seen spreading over more than one vertebral level and as a low-flow leak if leaked contrast material was seen spreading over one vertebral level or less [10]. Statistical nalysis Differences in symptom duration between subjects for whom individual brain MRI signs of SIH were present or absent were compared using a two-sided t test. For subjects with abnormal dural enhancement, differences in symptom duration based on the degree of dural abnormality were compared using the Mann-Whitney test. For CT myelographic findings, a two-sided t test was used to compare symptom duration between subjects with a CSF leak and those without a CSF leak. one-way NOV was used to further compare 1284 JR:207, December 2016

3 t test p = t test p = t test p = bsent Present Dural Enhancement symptom duration on the basis of leak subtype (i.e., no leak, high-flow leak, low-flow leak). The Fisher exact test was used to compare the prevalence of dural enhancement in patients who had received a prior epidural blood patch with that in patients who had not. nalysis was performed using statistical and computing software (R, version 3.0.2, The R Foundation); p values of < 0.05 were considered to be statistically significant. bsent Present rain Sagging bsent Present Venous Distention Sign C Fig. 2 ox-and-whisker plots comparing symptom duration in patients with spontaneous intracranial hypotension (SIH) and brain MRI signs suggestive of SIH. Upper and lower lines of boxes show first and third quartiles, respectively. Middle lines in boxes show median. Whiskers show minimum and maximum values, excluding outliers. = outliers. C, ox-and-whisker plots show symptom duration in SIH patients with and in those without brain MRI signs of SIH. rain MRI signs of SIH that were evaluated include dural enhancement (), brain sagging (), and venous distention sign (C). t test p = 6 bsent Present Leak on CT Myelography NOV p = Results The mean duration of headache symptoms was 2 months (range, 9 days 240 months; SD, 40.0 months). The distribution was skewed, however, with subjects having symptom duration of less than 1 year accounting for 67% of the population. s a result, the median duration of symptoms was only 6.0 months (95% CI, months). In the final study cohort, the mean age was 47.7 ± 13.9 (SD) years (range, years). Sixty patients (67%) were female subjects, and 29 patients (33%) were male subjects. prior blood patch had been attempted in 36 subjects (40%), whereas 53 subjects (60%) had not been treated previously. The prevalence of dural enhancement was not significantly different in the subgroup of patients who had received prior blood patch (89%) compared with the subgroup of those who had not (77%) (p = 0.25). Comparisons of symptom duration in patients with and those without brain MRI signs of SIH are shown in Figure 2. Significant differences in symptom duration were observed between subjects with dural enhancement on brain MRI compared with those without dural enhancement. The absence of dural enhancement was associated with a longer duration of symptoms than the presence of dural enhancement (average symptom duration, 45.3 ± 59.0 vs 15.1 ± 33.0 weeks, respectively; p = 0.002). For subjects with abnormal dural enhancement, a subgroup analysis based on the degree of abnormality (i.e., abnormal enhancement alone vs abnormal enhancement plus dural thickening) was not associated with a significant difference in symptom duration (p = 8). No difference in symptom duration was found between subjects showing and those not showing brain sagging on brain MRI (p = 0.10) or between subjects showing and those not showing the venous distention sign on brain MRI (p = 0.21). Of the 89 subjects, 37 (42%) showed no CSF leak, 45 (51%) had a high-flow leak, and seven (8%) had a low-flow leak on CT my- No Leak High-Flow Leak Low-Flow Leak CT Myelography Findings Fig. 3 ox-and-whisker plots comparing symptom duration and CT myelography findings in patients with spontaneous intracranial hypotension. Upper and lower lines of boxes show first and third quartiles, respectively. Middle lines in boxes show median. Whiskers show minimum and maximum values, excluding outliers. = outliers., ox-and-whisker plot shows symptom duration in patients with and in those without CSF leak on CT myelography., ox-and-whisker plot shows symptom duration in patients with CSF leak on CT myelography by subtype of CSF leak identified. Leak was defined as high-flow leak if leaked contrast material was seen spreading over more than one vertebral level and as low-flow leak if leaked contrast material was seen spreading over one vertebral level or less [10]. JR:207, December

4 elography. Comparisons of symptom duration related to CT myelographic findings are shown in Figure 3. lthough there was no overall difference in symptom duration between patients with no leak and those with a leak (p = 6), there was a significant difference (p = 0.003) when the data were segmented by leak subtype. ased on a one-way NOV analysis, the duration of symptoms of subjects with high-flow leaks was shorter relative to baseline (i.e., the no-leak group), but this difference was not statistically significant (p = 0.17). However, subjects with low-flow leaks were symptomatic 40.9 weeks (mean) longer than baseline (no-leak group), a difference that was highly statistically significant (p = 0.01). Discussion Our investigation shows that the dural enhancement seen in patients with SIH becomes less prevalent over time after the onset of symptoms. The mean duration of headache symptoms for subjects with dural enhancement present was 15.1 weeks compared with 45.3 weeks for those with no dural enhancement. Conversely, other less common imaging findings including brain sagging and the venous distention sign do not show similar time-dependent variability, but these signs are less frequently found in SIH overall. The presence or absence of a CSF leak on CT myelography was not associated with differences in symptom duration in general, with the exception of the low-flow subtype of leaks. These findings have implications when considering the diagnosis of SIH, particularly in patients with symptoms of longer duration. Dural enhancement is the single most common imaging sign found in patients with SIH [4] and therefore is often relied on as a major indicator of the condition. Failure to account for the time-dependent decrease in the prevalence of dural enhancement could potentially contribute to underdiagnosis, which is already a known problem [5]. Specifically, patients with chronic SIH whose imaging studies no longer show dural enhancement would be less likely to be recognized as suffering from the condition. This problem of underdiagnosis could be further compounded by the fact that the headache phenotype in SIH also can change with chronicity, evolving from positional headaches into nonspecific headache symptoms that are less stereotypical of the condition. These changes may result in decreasing headache severity or the disappearance of the positional component of the headache altogether and transformation into chronic daily headache [7, 11]. The headache pattern may evolve into a so-called second-half-of-theday headache in which the orthostatic component is evident only over a longer period of time upright [12] despite ongoing CSF leakage detectable on CT myelography. Thus, as the clinical symptoms become less clearly indicative of a diagnosis of SIH, the likelihood of suggestive imaging abnormalities may also decrease, further hindering diagnosis. The observation that the prevalence of dural enhancement changes with time contributes to the growing body of evidence that the physiology associated with SIH is not static and that various compensatory mechanisms may contribute to variations in the clinical and imaging presentation of the condition over time. Defining these changes and how to detect them could lead to improvements in the management of patients currently diagnosed with SIH and could potentially lead to a further broadening of the diagnostic criteria as more variation is recognized. Evidence of physiologic compensatory mechanisms in SIH has been suggested by several prior observations. First, SIH is associated with identifiable anatomic changes in the caliber of the veins in the intracranial compartment and within the spinal canal; these changes are consistent with the tenets of the Monro-Kellie doctrine that requires the vascular space to expand as the CSF volume decreases [3]. Second, CSF pressure is only weakly correlated with other objective indicators of CSF volume depletion such as brain imaging findings of venous distention and brain sagging and is not significantly correlated with dural enhancement or CT myelographic evidence of CSF leakage [4]. These observations point to the influence of compensatory physiologic processes that can help maintain CSF pressure in some patients despite ongoing CSF volume loss. Finally, CSF pressure in patients with SIH shows a statistically significant increase with the increasing duration of symptoms independent of the presence or absence of CT myelographically detectable CSF leakage, again suggesting that the physiologic changes induced by SIH vary in a manner that is partially time-dependent [6]. The observation of time-dependent changes in dural enhancement in this current investigation further reinforces this body of evidence. Specifically, our results suggest that compensatory mechanisms mitigate the effects of CSF volume depletion over time and result in a decrease in the dilatation of blood vessels within the dura, as necessitated by the Monro-Kellie doctrine. This decreased vasodilatation manifests as a decrease in dural enhancement on MRI. Our investigation also found that the likelihood of finding a CSF leak on CT myelography was independent of symptom duration except in patients with low-flow leaks. Therefore, in general, it cannot be concluded that the decreased prevalence of dural enhancement with time is caused by spontaneous cessation of CSF leaks. With regard to the low-flow leaks, it is possible that some of the subjects in our study cohort had leaks that initially started out as more rapid but that slowed over time because of partial containment of the leak. ecause there is no single test that functions as the reference standard for the diagnosis of SIH, the decreased prevalence of hallmark imaging signs such as dural enhancement poses challenges for diagnosing SIH in patients who present for evaluation later in the course of their symptoms. This diagnosis is doubly challenging if the clinical symptoms also are changing with time. It is possible, perhaps even likely, that some patients diagnosed with other chronic headache syndromes such as new daily persistent headache actually suffer from an occult presentation of SIH. These patients may exhibit different clinical or imaging features than subjects with so-called classic, or stereotypical, presentations of SIH. Defining how broad the disease spectrum may be and defining how to best establish the diagnosis in these patients remain important avenues for future investigation. Limitations of this study include our location at a tertiary referral center, which could have the potential to introduce spectrum bias. However, most of our subjects had not been treated elsewhere previously, and thus our sample would likely be representative of SIH patients in general. We do not have retrospective data regarding headache severity, which could be a theoretic covariate that could change with time. However, there are no data, to our knowledge, to suggest that the severity of headache influences the imaging signs of SIH such as dural enhancement. In conclusion, we found that dural enhancement is less likely to be present as symptom duration increases in patients with SIH. s a result, SIH may be less likely to be diagnosed accurately in patients with long JR:207, December 2016

5 standing SIH given the importance placed on brain imaging in the diagnostic evaluation of the condition. Further investigation of the time-dependent changes in the clinical presentation and physiologic changes accompanying SIH is warranted. References 1. Pannullo SC, Reich J, Krol G, Deck MD, Posner J. MRI changes in intracranial hypotension. Neurology 1993; 43: Fishman R, Dillon WP. Dural enhancement and cerebral displacement secondary to intracranial hypotension. Neurology 1993; 43: Mokri. The Monro-Kellie hypothesis: applications in CSF volume depletion. Neurology 2001; 56: Kranz PG, Tanpitukpongse TP, Choudhury KR, mrhein TJ, Gray L. Imaging signs in spontaneous intracranial hypotension: prevalence and relationship to CSF pressure. JNR 2016; 37: Schievink WI. Misdiagnosis of spontaneous intracranial hypotension. rch Neurol 2003; 60: Kranz PG, Tanpitukpongse TP, Choudhury KR, mrhein TJ, Gray L. How common is normal cerebrospinal fluid pressure in spontaneous intracranial hypotension? Cephalalgia 2015 Dec 17 [Epub ahead of print] 7. Mokri. Spontaneous low pressure, low CSF volume headaches: spontaneous CSF leaks. Headache 2013; 53: Schievink WI, Dodick DW, Mokri, Silberstein S, ousser MG, Goadsby PJ. Diagnostic criteria for headache due to spontaneous intracranial hypotension: a perspective. Headache 2011; 51: Kranz PG, Gray L, Taylor JN. CT-guided epidural blood patching of directly observed or potential leak sites for the targeted treatment of spontaneous intracranial hypotension. JNR 2011; 32: Kranz PG, Luetmer PH, Diehn FE, mrhein TJ, Tanpitukpongse TP, Gray L. Myelographic techniques for the detection of spinal CSF leaks in spontaneous intracranial hypotension. JR 2016; 206: Mokri. Spontaneous CSF leaks: low CSF volume syndromes. Neurol Clin 2014; 32: Leep Hunderfund N, Mokri. Second-half-ofthe-day headache as a manifestation of spontaneous CSF leak. J Neurol 2012; 259: JR:207, December

While some patients with SIH recover without intervention

While some patients with SIH recover without intervention ORIGINAL RESEARCH P.H. Luetmer K.M. Schwartz L.J. Eckel C.H. Hunt R.E. Carter F.E. Diehn When Should I Do Dynamic CT Myelography? Predicting Fast Spinal CSF Leaks in Patients with Spontaneous Intracranial