Utility of Magnetic Resonance Imaging Features for Improving the Diagnosis of Idiopathic Intracranial Hypertension Without Papilledema

Objective: Revised diagnostic criteria for idiopathic intracranial hypertension (IIH) were proposed in part to reduce misdiagnosis of intracranial hypertension without papilledema (WOP) by using 3 or 4 MRI features of intracranial hypertension when a sixth nerve palsy is absent. This study was undertaken to evaluate the sensitivity and specificity of the MRI criteria and to validate their utility for diagnosing IIH in patients with chronic headaches and elevated opening pressure (CH + EOP), but WOP. Methods: Brain MRIs from 80 patients with IIH with papilledema (WP), 33 patients with CH + EOP, and 70 control patients with infrequent episodic migraine were assessed in a masked fashion for MRI features of intracranial hypertension. Results: Reduced pituitary gland height was moderately sensitive for IIH WP (80%) but had low specificity (64%). Increased optic nerve sheath diameter was less sensitive (51%) and only moderately specific (83%). Flattening of the posterior globe was highly specific (97%) but had low sensitivity (57%). Transverse venous sinus stenosis was moderately sensitive for IIH WP (78%) but of undetermined specificity. A combination of any 3 of 4 MRI features was nearly 100% specific, while maintaining a sensitivity of 64%. Of patients with CH + EOP, 30% had 3 or more MRI features, suggesting IIH WOP in those patients. Conclusion: A combination of any 3 of 4 MRI features is highly specific for intracranial hypertension and suggests IIH WOP when present in patients with chronic headache and no papilledema.

Clinical Research: Epidemiology Meets Neuro-Ophthalmology Section Editors: Heather E. Moss, MD, PhD Stacy L. Pineles, MD Utility of Magnetic Resonance Imaging Features for Improving the Diagnosis of Idiopathic Intracranial Hypertension Without Papilledema Robert M. Mallery, MD, Obeidurahman F. Rehmani, MD, John H. Woo, MD, Yin Jie Chen, MD, Sudama Reddi, MD, Karen L. Salzman, MD, Marco C. Pinho, MD, Luke Ledbetter, MD, Madhura A. Tamhankar, MD, Kenneth S. Shindler, MD, Kathleen B. Digre, MD, Deborah I. Friedman, MD, MPH, Grant T. Liu, MD Objective: Revised diagnostic criteria for idiopathic intracranial hypertension (IIH) were proposed in part to reduce misdiagnosis of intracranial hypertension without papilledema (WOP) by using 3 or 4 MRI features of intracranial hypertension when a sixth nerve palsy is absent. This study was undertaken to evaluate the sensitivity and specificity of the MRI criteria and to validate their utility for diagnosing IIH in patients with chronic headaches and elevated opening pressure (CH + EOP), but WOP. Methods: Brain MRIs from 80 patients with IIH with papilledema (WP), 33 patients with CH + EOP, and 70 control patients with infrequent episodic migraine were assessed in a masked fashion for MRI features of intracranial hypertension. Results: Reduced pituitary gland height was moderately sensitive for IIH WP (80%) but had low specificity (64%). Increased optic nerve sheath diameter was less sensitive (51%) and only moderately specific (83%). Flattening of the posterior globe was highly specific (97%) but had low sensitivity (57%). Transverse venous sinus stenosis was moderately sensitive for IIH WP (78%) but of undetermined specificity. A combination of any 3 of 4 MRI features was nearly 100% specific, while maintaining a sensitivity of 64%. Of patients with CH + EOP, 30% had 3 or more MRI features, suggesting IIH WOP in those patients. Conclusion: A combination of any 3 of 4 MRI features is highly specific for intracranial hypertension and suggests IIH WOP when present in patients with chronic headache and no papilledema. Journal of Neuro-Ophthalmology 2019;39:299-307 doi: 10.1097/WNO.0000000000000767 © 2019 by North American Neuro-Ophthalmology Society Department of Neurology (RMM), Brigham and Women's Hospital, Boston, Massachusetts; Department of Ophthalmology (RMM), Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; East Tennessee Medical Group-Neurology (OFR), Blount Memorial Hospital, Maryville, Tennessee; Department of Radiology (JHW, YJC), Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Texas Neurology Consultants (SR), Texas Health Resources, Plano, Texas; Department of Radiology (KLS, LL), University of Utah School of Medicine, Salt Lake City, Utah; Department of Radiology (MCP), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Ophthalmology (MAT, KSS, GTL), University of Pennsylvania Scheie Eye Institute, Philadelphia, Pennsylvania; Departments of Ophthalmology and Neurology (KBD), University of Utah School of Medicine, Salt Lake City, Utah; Departments of Neurology and Neurotherapeutics and Ophthalmology (DIF), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Neurology (MAT, KSS, GTL), Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; and Division of Ophthalmology (GTL), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. L. Ledbetter receives royalties from Elsevier for being a contributing author of Diagnostic Imaging: Head and Neck, Third Edition. M. A. Tamhankar is a Principal Investigator for Quark Pharmaceuticals and is currently conducting a research study on studying the efficacy of an experimental drug in patients with nonarteritic ischemic optic neuropathy. K. S. Shindler is supported by NIH grant #EY015014, by a Research to Prevent Blindness Physician Scientist Award, by the F. M. Kirby Foundation, receives royalties for an article published in UpToDate, has served as a scientific advisory board member and received consulting fees from Noveome Biotherapeutics, Inc (formerly Stemnion, Inc.), and Noveome has provided unrestricted funds to the University of Pennsylvania to support research in K. S. Shindler's laboratory. K. B. Digre receives royalties from Springer for being an author of Lee and Digre; A Case-Based Guide to Eye Pain. She is supported in part by an Unrestricted Grant from Research to Prevent Blindness, New York, NY, to the Department of Ophthalmology & Visual Sciences, University of Utah. She is the president of the American Headache Society. D. I. Friedman has served on advisory boards for Alder BioPharmaceuticals, Amgen, Avanir, electroCore, Supernus, Teva Pharmaceuticals, and Zosano. She is on the speaker's bureau for Allergan, electroCore, Supernus, and Teva Pharmaceuticals, and has received grant support from Merck, Eli Lilly, and Autonomic Technologies, Inc. She is on the editorial boards of Neurology Reviews and Headache, and is a contributing author for MedLink Neurology and Medscape. She is a member of the Board of Directors of the American Headache Society. G. T. Liu receives royalties from Elsevier for being a coauthor of Liu, Volpe, and Galetta's Neuro-ophthalmology: Diagnosis and Management. The remaining authors have no conflicts of interests to disclose. Address correspondence to Robert M. Mallery, MD, Department of Neurology, Brigham and Women's Hospital, 60 Fenwood Road Boston, MA 02115; E-mail: [e-mail]. Mallery et al: J Neuro-Ophthalmol 2019; 39: 299-307 299 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology M RI features of intracranial hypertension inappropriate use of abbreviation include elevation of the optic nerve head, reduced pituitary gland height ("empty" or "partially empty" sella), distention of the perioptic subarachnoid space, tortuosity of the optic nerves, flattening of the posterior sclera of the globe, and transverse venous sinus stenosis (1-4). Cerebellar tonsillar descent suggestive of Chiari I malformation has been described (5), and skull base erosion can lead to enlargement of the sella turcica (6,7), widening of the foramen ovale (8), and formation of skull base encephaloceles (9,10). The 2013 revision of the diagnostic criteria for idiopathic intracranial hypertension (IIH) was proposed, in part, to reduce misdiagnosis of IIH without papilledema (IIH WOP) by using 3 of 4 MRI features of intracranial hypertension when a sixth nerve palsy (a neurologic sign of intracranial hypertension) is absent (Table 1) (11,12). Elevated lumbar puncture (LP) opening pressure (OP) of greater than 25 cm cerebrospinal fluid (CSF) in adults and greater than 28 cm CSF in sedated, obese children occurs incidentally in up to 10% of normal patients (13), which may lead to a misdiagnosis if other supportive evidence is not required. Headache phenotype is insufficient to distinguish IIH WOP from primary forms of chronic headaches including chronic migraine and chronic tension-type headache (14,15). The much higher prevalence of primary headache disorders compared with IIH in the general population magnifies the number of patients who could be misdiagnosed as having IIH WOP (16,17), exposing them to the complications associated with surgical treatments, such as CSF diversion, that are offered when medical therapy fails. This study was undertaken to determine whether the use of 3 of 4 MRI features in the diagnosis of IIH WOP is valid. We applied a standardized assessment of MRI features of intracranial hypertension to brain MRIs from multicenter cohorts of patients with IIH with papilledema (IIH WP), patients with chronic headache, elevated LP OP, and no papilledema (CH + EOP), and control patients with infrequent episodic migraine. METHODS Approval from an ethical standards committee to conduct this study was received at the University of Pennsylvania, University of Utah, and University of Texas Southwestern Medical Center. Searches of the electronic medical record and radiology databases identified patients diagnosed at age 17 years or older within the following groups, who also had MRI studies performed and available for review: (i) definite IIH WP as defined by the revised diagnostic criteria (12); (ii) CH + EOP consisting of patients with chronic headache, LP OP .250 mm CSF, normal CSF composition, normal brain MRI, and no papilledema; and (iii) control patients with infrequent episodic migraine and fewer than 4 headache days per month. The threshold of 4 days per month was set to clearly distinguish these patients from those with chronic headache, defined as greater than 15 headache days per month by the International Headache Society International TABLE 1. Diagnostic criteria for pseudotumor cerebri syndrome* 1. Required for diagnosis of pseudotumor cerebri syndrome† A. Papilledema B. Normal neurologic examination except for cranial nerve abnormalities C. Neuroimaging: Normal brain parenchyma without evidence of hydrocephalus, mass, or structural lesion, and no abnormal meningeal enhancement on MRI, with and without gadolinium, for typical patients (female and obese), and MRI, with and without gadolinium, and magnetic resonance venography for others; if MRI is unavailable or contraindicated, contrast-enhanced CT may be used D. Normal CSF composition E. Elevated lumbar puncture opening pressure ($250 mm CSF in adults and $280 mm CSF in children [250 mm CSF if the child is not sedated and not obese]) in a properly performed lumbar puncture 2. Diagnosis of pseudotumor cerebri syndrome without papilledema In the absence of papilledema, a diagnosis of pseudotumor cerebri syndrome can be made if B-E from above are satisfied, and in addition, the patient has a unilateral or bilateral abducens nerve palsy In the absence of papilledema or sixth nerve palsy, a diagnosis of pseudotumor cerebri syndrome can be suggested but not made if B-E from above are satisfied, and in addition, at least 3 of the following neuroimaging criteria are satisfied i. Empty sella ii. Flattening of the posterior aspect of the globe iii. Distention of the perioptic subarachnoid space with or without a tortuous optic nerve iv. Transverse venous sinus stenosis *Termed idiopathic intracranial hypertension (IIH) when there is no secondary cause of intracranial hypertension. † A diagnosis of pseudotumor cerebri syndrome is definite if the patient fulfills criteria A-E. The diagnosis is considered probable if criteria A-D are met, but the measured CSF pressure is lower than specified for a definite diagnosis. Reproduced with permission from (12). CSF, cerebrospinal fluid. 300 Mallery et al: J Neuro-Ophthalmol 2019; 39: 299-307 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology Classification of Headache Disorders-3 beta (IHS ICHD-3b). Clinical records, LP procedure notes, radiology reports, and CSF analyses were reviewed to ensure proper group assignment. In addition, patients with IIH WP and CH + EOP had to have the presence or absence of papilledema documented by a neuro-ophthalmologist. Patients with evidence of optic nerve gliosis or atrophy were excluded from the CH + EOP group. MRI and Magnetic Resonance Venography Features of Intracranial Hypertension MRI sequences were reviewed by a neuroradiologist at each participating center using a defined protocol to ensure consistency in interpretations. The radiologists were masked to the clinical status of the patients to prevent bias. Moreover, each of the 4 MRI features was evaluated separately, so that the presence of one MRI finding would not influence the interpretation of another MRI finding. Pituitary gland height (PGH) was measured on mid-sagittal T1 images as the maximum orthogonal distance from the upper surface of the pituitary gland to the sellar floor (Fig. 1A) according to the method of Hoffmann et al (3). By measuring PGH on the mid-sagittal T1 image and taking the measurement orthogonal to the sellar floor, PGH represents the central height of the pituitary gland and is invariable to head tilt along the pitch axis. On T2 axial images, optic nerve sheath diameter (ONSD) was measured as the maximum width of the optic nerve sheath within the orbit measured perpendicular to the optic nerve (Fig. 1B), and flattening of the posterior sclera of the globe (FPG) was judged as any forward bowing or flattening of the globe at the site of insertion of the optic nerve relative to a circular arc superimposed over the posterior sclera (Fig. 1C) (1,3). Threshold values determined by Hoffmann et al (3) defined the presence of vertical compression of the pituitary gland and increased ONSD and were verified from our data using receiver operating curve analyses. A PGH of less than 4.8 mm on mid-sagittal T1 images was considered significant vertical compression, and FIG. 1. MRI features of intracranial hypertension. A. Mid-sagittal T1 MRI shows a "partially empty sella" with vertical compression of the pituitary gland. The pituitary gland height was the maximum orthogonal distance between the upper surface of the pituitary gland and the sellar floor. B. Axial T2 scan reveals prominence of the perioptic subarachnoid space surrounding the left optic nerve. The optic nerve sheath diameter was measured as the greatest width of the optic nerve sheath within the orbit perpendicular to the axis of the optic nerve. C. Axial T2 image demonstrates flattening of the posterior globe at the insertion of the right optic nerve and optic nerve sheath (arrowheads). The smear sign is also present (arrow). D. Time of flight MR venogram shows stenosis of a dominant right transverse sinus (arrowhead); the left transverse sinus is hypoplastic, but also demonstrates stenosis (arrow). Mallery et al: J Neuro-Ophthalmol 2019; 39: 299-307 301 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology a significant increase in ONSD was considered present if the mean ONSD (averaging right and left) was greater than 5.5 mm. The presence of transverse venous sinus stenosis (TSS) was assessed using magnetic resonance venography (MRV), if performed. Generally, as MRV studies would not have been performed in the control group (patients with episodic migraine), this MRV assessment was performed at a separate session from the MRI assessment (of PGH, ONSD, and FPG), so as not to inform the radiologist of the underlying diagnosis. The caliber of each transverse-sigmoid junction was graded using the modified venous conduit score on a scale of 0-2 (0 = less than 25% stenosis; 1 = 25-50% stenosis; and 2 = greater than 50% stenosis) (Fig. 1D) (3,18,19). TSS was defined as present if a grade of 2 was given for either the left or the right transverse-sigmoid junction. Transverse sinus hypoplasia was also graded on a scale of 0-2 (0 = less than 25% smaller than the contralateral side, 1 = 25-50% smaller than the contralateral side; and 2 = greater than 50% diffuse narrowing compared with the contralateral side). Statistical Analysis Statistical analysis was performed using STATA Version 14 (College Station, TX). Statistical significance was assumed at a = 0.05 (2-sided). Numerical and proportion data were expressed as mean values and 95% confidence intervals (CIs). The Shapiro-Wilk test assessed normality of continuous variables (mean ONSD and PGH). Welch's t test (the unpaired 2-sample t test assuming unequal variances) was used to make pairwise comparisons of group means. For non-normal continuous variables (LP OP only), the Wilcoxon rank-sum test was used to make pairwise comparisons of group medians. Wilson intervals were used to estimate binomial CIs of proportion data (20,21), and the Fisher exact test was used to make pairwise comparisons of proportion data between groups. A receiver operating characteristic (ROC) analysis was performed to evaluate the optimal threshold values for PGH and mean ONSD to maximize sensitivity and specificity for distinguishing between patients with IIH WP and controls. Sensitivity and Specificity Values of MRI Features For each patient group, the relative frequencies of the MRI features were calculated. As MRV was performed in a subset of patients in each group, the relative frequency of TSS in each group was defined as the proportion of patients with IIH WP who underwent MRV and were found to have TSS. Sensitivity and specificity values were calculated for the ability of each individual MRI feature to distinguish between IIH WP and controls. Sensitivity values were derived from the relative frequencies of the MRI features in the IIH WP group and defined as the percentage of IIH 302 WP patients with the feature. Specificity values were derived from the relative frequencies of the MRI features in the control group and defined as the percentage of control patients who did not have the feature. Two calculations of the relative frequency of at least 3 of 4 MRI features were derived for each patient group. The first relative frequency included all patients, and the second included only patients who underwent MRV. Patients could achieve at least 3 of 4 MRI features either by having all 3 contrast-enhanced MRI features (reduced PGH, increased ONSD, and FPG) or by having TSS on MRV in combination with 2 of the contrast-enhanced MRI features. Sensitivity and specificity values were estimated for the combination of at least 3 of 4 MRI features to distinguish between IIH WP and controls. Because some patients with IIH WP lacked MRVs, the proportion of all patients in the IIH WP group with at least 3 of 4 MRI features was expected to underestimate the true sensitivity. Therefore, the sensitivity of 3 of 4 MRI findings was calculated from the subset of patients with IIH WP who underwent MRV. As MRV was an uncommon imaging procedure in the control group, the relative frequency of at least 3 of 4 MRI features could likewise be underestimated, leading to an overestimation of specificity. Therefore, an estimate of the lower bound for the specificity of at least 3 of 4 MRI features was calculated with the assumption that all control patients would have had TSS. RESULTS MRIs that included T1 sagittal images, T2 axial images, and contrast-enhanced T1 axial images were identified in 70 control patients, 80 patients with IIH WP, and 33 patients with CH + EOP. MRVs were available for 45 patients with IIH WP, 14 patients with CH + EOP, and 3 control patients. The proportion of female patients was 66/70 (0.95) for the control group, 78/80 (0.98) for the IIH WP group, and 29/33 (0.88) for the CH + EOP group. The mean age was 37 (95% CI: 34-41) years for the control group, 32 (95% CI: 29-34) years for the IIH WP group, and 37 (95% CI: 33-40) years for the CH + EOP group. LP OP (cm CSF) was significantly increased in the IIH WP group (median: 36 cm, interquartile range [IQR]: 31-42 cm) compared with the CH + EOP group (median: 31 cm, IQR: 29-36 cm, P = 0.005). PGH and ONSD did not differ significantly from the normal distribution for any of the patient groups. PGH was significantly reduced in the IIH WP (mean: 3.5 mm, 95% CI: 3.1-3.8 mm, P , 0.001) and CH + EOP (mean: 3.6 mm, 95% CI: 3.0-4.1 mm, P , 0.001) groups compared with controls (mean: 5.3 mm, 95% CI: 4.9-5.7 mm) (Fig. 2A). Similarly, the mean ONSD was significantly increased in the IIH WP (mean: 5.2 mm, 95% CI: 5.0- 5.5 mm, P , 0.001) and CH + EOP (mean: 5.1 mm; 95% Mallery et al: J Neuro-Ophthalmol 2019; 39: 299-307 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology FIG. 2. Comparison of pituitary gland height (PGH) and optic nerve sheath diameter (ONSD) measurements between the study groups. A. Box plot reveals a reduction in PGH for the idiopathic intracranial hypertension with papilledema (IIH WP) (P , 0.001) and chronic headache and elevated opening pressure (CH + EOP) (P , 0.001) groups compared with controls. The threshold of 4.8 mm for significant reduction in PGH is shown. B. Box plot shows an increase in mean ONSD for the IIH WP (P , 0.001) and CH + EOP (P = 0.002) groups compared with controls. The threshold of 5.5 mm for significant optic nerve sheath distention is shown. C. Receiver operating characteristic (ROC) curve for PGH confirms that 4.8 mm is located at an inflection point and represents a reasonable cutoff value for prediction. D. ROC curve for ONSD shows that values greater than the threshold of 5.5 mm cause a disproportionate reduction in sensitivity for any gain in specificity. AUC, area under the curve. CI: 4.7-5.4 mm, P = 0.002) groups, each compared with controls (mean: 4.4 mm, 95% CI: 4.2-4.6 mm) (Fig. 2B). ROC analysis (Fig. 2C, D) showed that a threshold value of less than 4.8 mm for PGH was located at an inflection point on the ROC curve and gave a sensitivity of 80% and specificity of 64% for distinguishing patients with IIH WP from controls. A threshold value of greater than 5.5 mm for mean ONSD yielded a sensitivity of 46% and specificity of 89%. Threshold values greater than 5.5 mm caused a disproportionately greater drop in sensitivity than increase in specificity, and threshold values less than 5.5 mm greatly reduced sensitivity. Both threshold values maximized the number of patients that were correctly classified as having IIH WP and were accepted for the subsequent analysis. The area under the curve (AUC) for PGH was 0.80, and the AUC for mean ONSD was 0.73, suggesting that individually these MRI features have only moderate predictive value for distinguishing IIH WP from controls. Mallery et al: J Neuro-Ophthalmol 2019; 39: 299-307 Table 2 shows the relative frequencies of the individual MRI features in each study group. In the control group, the most common MRI feature was reduced PGH, occurring in 25/70 patients (36%; CI: 26%-47%), but other MRI features were uncommon. Mean ONSD was increased in only 12/70 control patients (17%; CI: 10%-28%), and FPG was present in only 2/70 control patients (3%; CI: 1%- 10%). In the IIH WP group, reduced PGH and TSS were the most common MRI features occurring in 64/80 patients (80%; CI: 70%-87%) and 35/45 patients (78%; CI: 64%- 87%), respectively. Increased mean ONSD occurred in 41/80 patients with IIH WP (51%; CI: 40%-62%), and FPG occurred in 45/80 patients with IIH WP (57%; CI: 45%-67%). In the CH + EOP group, reduced PGH was the most common MRI feature, present in 27/33 patients (82%; 66%-91%). Increased ONSD was present in 14/33 CH + EOP patients (42%; CI: 27%-59%), FPG was present in 14/33 CH + EOP patients (42%; CI: 27%-59%), 303 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology TABLE 2. Relative frequency of patients in each group with the individual MRI features and with at least 3 of 4 features Feature PGH ,4.8 mm Sensitivity = 80% (70%-87%) Specificity = 64% (53%-74%) Mean ONSD .5.5 mm Sensitivity = 51% (40%-62%) Specificity = 83% (72%-90%) FPG Sensitivity = 57% (45%-67%) Specificity = 97% (90%-99%) TSS (unilateral or bilateral) Sensitivity = 78% (64%-87%) At least 3 of 4 features Sensitivity = 64% (50%-77%) Specificity upper bound = 100% (95%-100%) Specificity lower bound = 97% (90%-99%) Control IIH WP CH + EOP 25/70 = 0.36 CI = 0.26-0.47 64/80 = 0.80 CI = 0.70-0.87 27/33 = 0.82 CI = 0.66-0.91 12/70 = 0.17 CI = 0.10-0.28 41/80 = 0.51 CI = 0.40-0.62 14/33 = 0.42 CI = 0.27-0.59 2/70 = 0.03 CI = 0.01-0.10 45/80 = 0.57 CI = 0.45-0.67 14/33 = 0.42 CI = 0.27-0.59 0/3 35/45 = 0.78 CI = 0.64-0.87 38/80 = 0.48 CI = 37%-58% Patients with MRV: 29/45 = 0.64 CI = 0.50-0.77 4/14 = 0.29 CI = 0.12-0.55 10/33 = 0.30 CI = 0.17-0.47 Patients with MRV: 5/14 = 0.36 CI = 0.16-0.61 0/70 = 0.0 CI = 0.0-0.05 Assuming all controls have TSS on MRV: 2/70 = 0.03 CI = 0.01-0.10 Data shown are the sample proportions and 95% confidence intervals. Sensitivity and specificity values are shown for the ability of each individual MRI feature and the combination of at least 3 features to distinguish between IIH WP and controls. To account for the rarity of MRV in the control group, a lower bound for the specificity of at least 3 of 4 features was calculated. CH + EOP, chronic headache and elevated opening pressure without papilledema; FPG, flattening of the posterior sclera of the globe; IIH WP, idiopathic intracranial hypertension with papilledema; MRV, magnetic resonance venogram; ONSD, optic nerve sheath diameter; PGH, pituitary gland height; TSS, transverse venous sinus stenosis. and TSS was present in 4/14 CH + EOP patients (29%; CI: 12%-55%) that underwent MRV. Individual MRI features including reduced PGH, increased mean ONSD, and FPG were significantly present in the IIH WP group compared with controls (P , 0.001 for each, Fisher exact test). Sensitivity and specificity values for distinguishing patients with IIH WP from controls are shown for each individual MRI feature (Table 2). The specificity of TSS could not be determined because only 3 control patients underwent MRV. Figure 3A compares the number of patients in each group with 0, 1, 2, 3, or 4 MRI features of intracranial hypertension, and the proportion of patients in each group with at least 3 of 4 MRI features is shown Figure 3B and in Table 2. In the control group, 33/70 patients (47%; CI: 36%-59%) had no MRI features present, and 35/70 patients (50%; CI: 39%-61%) had 1 MRI feature present. Multiple MRI features were present in only 2/70 control patients, each having 2 MRI features (reduced PGH and increased ONSD in one patient and reduced PGH and FPG in another patient). In the IIH WP group, multiple MRI features were common, with 2 or more features present in 68/80 patients (85%; CI: 76%-91%) and 3 or more MRI features present in 38/80 patients (48%; CI: 37%- 58%). Multiple MRI features occurred with an intermediate frequency in the CH + EOP group with 2 or more MRI features present in 18/33 patients (55%; CI: 38%-70%), 304 and 3 or more MRI features present in 10/33 patients (30%; CI: 17%-47%). The presence of at least 3 of 4 MRI features had a sensitivity of 64% (CI: 50%-77%); 3 or 4 MRI features were present in 29/45 patients with IIH WP who underwent MRV and had assessment of all 4 MRI features. The upper bound for the specificity of at least 3 of 4 MRI features was 100% (CI: 95%-100%) because none of the control patients had 3 or 4 MRI features. Two of the 70 control patients (neither of which underwent MRV) had 2 of 4 features. Therefore, the lower bound for the specificity of at least 3 of 4 MRI features was 97% (CI: 90%-100%) (Table 2). DISCUSSION Objective criteria for diagnosing IIH WOP are essential to reduce false-positive diagnoses that may expose patients with other primary headache disorders to medical and procedural risks, and ultimately delay appropriate treatment (22). Measurement of a single LP OP can be inaccurate. Diagnostic specificity relies on demonstrating sustained/ chronic elevated intracranial pressure (ICP), but an LP OP measurement represents a single point in time, may be obtained at the nadir of a CSF pressure wave, may be falsely decreased by a CSF leak caused by multiple attempts to withdraw spinal fluid or by hyperventilation, or may be falsely elevated related to patient pain, Valsalva, or Mallery et al: J Neuro-Ophthalmol 2019; 39: 299-307 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology FIG. 3. Distribution of individual MRI features per group and the proportion with at least 3 of 4 features. A. Dot plot shows the distribution of the number of MRI features in each group. Multiple MRI features of intracranial hypertension were common in patients with IIH WP (68/80), but rare in control patients (2/70). B. Bar chart showing the proportion and 95% CI of patients in each group with at least 3 of 4 MRI features. For the IIH WP and CH + EOP groups, the proportion of patients with at least 3 of 4 features is shown for all patients and for those who underwent MRV and had all 4 imaging features assessed. The sensitivity of 3 of 4 MRI features for distinguishing IIH WP from controls is 64% (CI: 50%-77%). The proportion of control subjects with 2 of 4 MRI features (2/70) is shown by the open square, and the CI shown for the controls assumes that these subjects also had TSS on MRV. At least 3 of 4 MRI features were identified in 30% (CI: 17%-47%) of all patients with chronic headache and elevated opening pressure without papilledema (CH + EOP) and 36% (16%-61%) of patients with CH + EOP who underwent MRV. CH + EOP, chronic headache and elevated opening pressure without papilledema; IIH WP, idiopathic interval hypertension with papilledema; MRV, magnetic resonance venogram; TSS, transverse venous sinus stenosis. inappropriate positioning. In addition, the current cutoff values that define significant elevation in LP OP fall below the OP measured in up to 10% of normal patients (13). The high rates of primary chronic headache disorders in comparison with IIH also pose diagnostic challenges. Chronic migraine and chronic tension-type headache (defined by the IHS ICHD-3b) have prevalence of 1.8%-3.3% (1,800- 3,300 per 100,000) and 1.6%-3.0% (1,600-3,000 per 100,000) in the general population, respectively (23). IIH occurs with a historical incidence of 1-1.9 per 100,000 (16,24). One report indicated an increase in incidence of IIH to 1.7-3.0 per 100,000 of the general population correlating with the rising rates of obesity, and the incidence of IIH in obese women of childbearing age approaches 19-22 per 100,000 (16,17). Mitigating this effect, migraine and other primary headache disorders may also be associated with obesity (25), and IIH WOP accounts for only a small percentage (approximately 5.7%) of IIH cases (26). Thus, a false-positive diagnosis of IIH WOP is vastly more likely to occur than a true-positive diagnosis when using LP OP without other objective criteria. Our data suggest that MRI features of intracranial hypertension may detect a subset of patients with IIH WOP among those with CH + EOP (30% of all CH + EOP patients in our study). As shown in Figure 3, the presence of 3 MRI features to distinguish between patients with IIH WP and controls maintained a moderate degree of sensitivity (64%) and was highly specific. The lower bound of our specificity estimate was 97% (CI: 90%-99%), calculated by assuming that both control patients who had 2 of 3 contrast-enhanced MRI features also had TSS. The rate of Mallery et al: J Neuro-Ophthalmol 2019; 39: 299-307 TSS in normal patients has previously been estimated at 4%-7% (3,27), suggesting that the specificity of at least 3 of 4 findings is nearly 100%, a necessity for distinguishing a rare disorder such as IIH WOP from the more common primary headache disorders that lead to chronic headache. No individual feature of intracranial hypertension had sufficient specificity to be diagnostic for raised ICP, and all individual features had only moderate sensitivity. Reduced PGH was the most sensitive individual feature (80%) but had low specificity (64%). Despite using the available clinical MRI protocols, our results were similar to the results of Hoffmann et al (3), validating our use of a threshold value to determine significant reduction in PGH, and also fit with our clinical experience that a reduction in PGH can be a finding in normal patients. Increased mean ONSD was less sensitive (51%) and only moderately specific (83%) for identifying IIH WP. FPG was the most specific individual feature (90%-99% specific), but still had low sensitivity (57%), consistent with previous studies (2,3). FPG was also the most subjective of the MRI features and prone to error in patients with misshapen globes from high myopia or staphyloma. Interestingly, despite the absence of papilledema, the mean ONSD and the proportion of patients with globe flattening were increased in patients with CH + EOP compared with controls. This validates the use of these MRI features in patients without papilledema and suggests that although raised ICP is transmitted by the CSF within the ONS of these patients and may even distort the posterior globe, a structural difference at the optic nerve head or site of the ONS insertion at the posterior globe may mitigate the effects of raised ICP on axoplasmic flow within the 305 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology optic nerve. Alternatively, the ICP threshold for developing papilledema versus globe flattening or distention of the ONS may vary among individuals. In our study, TSS was of moderate sensitivity (78%) and of uncertain specificity given the lack of MRV available in the control group. In a report of 25 patients, Hoffmann et al (3), who used an equivalent grading system, found a sensitivity of 36% and specificity of 96%, but contrastenhanced MRV combined with a more complex scoring system for grading the patency of the transverse and sigmoid venous outflow may each have a sensitivity and specificity of up to 93% (18). In a study of patients with chronic tensiontype headache that had bilateral TSS on MRV, 4/14 (30%) patients had an LP OP less than 20 cm CSF, and 7/13 (54%) patients had an LP OP within the revised normal range of 25 cm CSF or less (27). Based on these data, TSS is still too nonspecific to be used in isolation as criteria to distinguish between patients with primary chronic headache disorders and IIH WOP. Within the limitations of our study, which include its retrospective nature and reliance on available MRI and MRV sequences, we demonstrated the utility of MRI features for identifying some patients with IIH WOP among patients with chronic headache. For the clinician evaluating a patient with chronic headache in which IIH WOP is a consideration, the presence of at least 3 of 4 MRI features of intracranial hypertension, as defined in our study, would be a clear indication for performing a LP to assess the OP and the CSF constituents. However, when fewer than 3 MRI features are present, chronically raised ICP is less certain. An additional prospective study using a standard MRI protocol that includes high-resolution, thin-cut orbit and sellar images, MRV in all patients, and optical coherence tomography to more objectively define the presence or absence of papilledema will help to better refine our predictions. Further study may also consider the correlation between the salience (severity of the abnormality) of individual MRI features and diagnostic specificity to improve the ability to predict the presence of IIH WOP in patients not meeting the MRI criteria described here. In conclusion, our study examines MRI features of intracranial hypertension in the largest cohort of patients with IIH WP to date and represents the first study to evaluate MRI features of intracranial hypertension in patients with CH + EOP, a group that includes patients with IIH WOP. Our results validate that the presence of 3 of 4 MRI features of intracranial hypertension is suggestive of IIH WOP when present in patients with chronic headache, no papilledema, and elevated LP OP (12). STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: R. M. Mallery, J. H. Woo, Y. J. Chen, M. A. Tamhankar, K. S. Shindler, K. B. Digre, D. I. Friedman, and G. T. Liu; b. Acquisition of data: R. M. Mallery, O. F. Rehmani, J. H. Woo, Y. J. Chen, S. Reddi, K. L. Salzman, M. C. Pinho, L. 306 Ledbetter, K. B. Digre, D. I. Friedman, and G. T. Liu; c. Analysis and interpretation of data: R. M. Mallery, O. F. Rehmani, J. H. Woo, M. A. Tamhankar, K. S. Shindler, K. B. Digre, D. I. Friedman, and G. T. 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