Very asymmetric papilledema in idiopathic intracranial hypertension (IIH) is an uncommon finding that can raise concern for alternate diagnoses, such as unilateral optic neuropathy. Few studies have systematically addressed the issue of asymmetric papilledema in IIH, and most are only case reports or small case series (1–11). The largest series of 38 patients focused specifically on visual function outcome (12), and only 1 study has detailed orbital imaging findings (13). Very asymmetric papilledema offers a unique opportunity to study factors proposed in the pathogenesis of papilledema. Although several mechanisms have been suggested to explain very asymmetric papilledema, such as optic nerve sheath defects and loss of lamina cribrosa compliance (1,6), its mechanism remains unclear.
Our aim was to describe the clinical and radiologic features of patients with IIH and very asymmetric papilledema and to characterize factors associated with this unusual presentation of IIH.
Our study was approved by the Emory University Institutional Review Board. Using our established database of patients seen in our center between 1989 and 2013, we identified all adult patients (age 18 years or older) with definite IIH according to the modified Dandy criteria (14). Although this study was a retrospective chart review, all patients were evaluated in a standardized fashion, and all had fundus photographs at presentation.
We first selected all patients with IIH from our IIH database, who had been recorded as having a ≥1 Frisén grade difference in papilledema between the 2 eyes at initial presentation. All fundus photographs were then unpaired and graded independently using the modified Frisén scale (15) in random order by 2 neuro-ophthalmologists (S.B. and B.B.B.), who were masked to the patients' clinical data. In case of disagreement, the third neuro-ophthalmologist (V.B.) was asked to grade the papilledema. We defined very asymmetric papilledema as a ≥2 modified Frisén grade difference between the 2 eyes and selected all patients with IIH with at least 2 grades of difference in their papilledema.
Demographic data of all patients with very asymmetric papilledema including age, gender, body mass index (BMI), and race were collected. Initial symptoms (visual loss, transient visual obscurations, diplopia, tinnitus, and headaches), Snellen visual acuity, intraocular pressure (IOP), automated visual fields, and cerebrospinal fluid (CSF) opening pressure (OP) were recorded.
We reviewed all brain imaging and selected those performed at our institution (either magnetic resonance imaging [MRI] or contrast-enhanced computed tomography [CT]). MRI was performed on either 3.0-T (Siemens Trio, Erlangen, Germany) or 1.5-T (Siemens Avanto, Erlangen, Germany or GE Signa, Milwaukie, WI) scanner using a standard head coil. The MRI protocol included a T2 sequence at a slice thickness of 5 or 3 mm. Patients received intravenous gadolinium contrast material at a standard dose (0.1 mmol/kg Multihance; Bracco Diagnostics Inc, Monroe Township, NJ), followed by postcontrast T1 axial and T1 sagittal volumetric images. The magnetic resonance venography (MRV) protocol included either a noncontrast MRV using an oblique sagittal 2D time-of-flight (TOF) technique or a contrast-enhanced MRV, which included an axial precontrast MRV mask, followed by repetition of the sequence after contrast administration. The precontrast MRV dataset was subtracted from the postcontrast dataset, and multiple oblique maximum intensity projections were generated from this subtracted dataset. The CT examination included orbital cuts and was performed on a 64 detector row scanner (GE Lightspeed VCT, Milwaukee, WI) using 70 mL iodinated contrast agent (Isovue 370; Bracco Imaging) with 5-mm slice reconstructions.
All MRI and CT examinations were reviewed by an experienced neuroradiologist (A.M.S.) blinded to the neuro-ophthalmic examination. Previously described orbital imaging findings associated with increased intracranial pressure were recorded on all patients with imaging. These findings included protrusion of the optic nerve head, flattening of the posterior sclera, increased perioptic nerve CSF (0: none; 1: mild; 2: moderate; 3: severe [measured at the level of maximal dilation of the orbital optic nerve sheath]), and vertical tortuosity of the intraorbital optic nerve. The presence of meningoceles, as defined by CSF containing structures outside the expected confines of the cranial vault, was recorded. The presence or absence and side of transverse sinus stenosis was evaluated from either the contrast-enhanced MRV, postcontrast T1 (16), 2D TOF MRI, postcontrast CT, or transverse sinus flow voids on T2 images when there was no contrast-enhanced image set. When possible, and before recording the radiologic findings, cross-sectional area of both the right and left optic canals were measured using either precontrast T1 volumetric 1 mm isotropic images, by reformatting into a coronal oblique plane orthogonal to the axis of each optic canal, or thin-section CT examination that was also reformatted in a similar fashion using images of 0.625 mm to obtain cross-sectional area (Fig. 1).
All statistical analyses were performed with R: A language and environment for statistical computing (R Foundation for Statistical Computing, http://www.R-project.org). Continuous and ordinal variables were compared between groups using the Mann–Whitney U test. Pearson χ2 with Yates' continuity correction or Fisher exact test, as appropriate, were used to compare categorical variables. The eyes of patients with very asymmetric papilledema were compared using the Wilcoxon signed rank test for continuous variables and paired proportion test for categorical variables. These tests were 2 tailed, and significance was set at 5%.
Of the 559 adult patients with definite IIH seen over 24 years, 20 (3.6%; 95% confidence interval [CI], 2.3–5.6) had very asymmetric papilledema defined as a ≥2 modified Frisén grade difference between 2 the eyes at initial evaluation. Patients with very asymmetric papilledema were significantly older (39 vs 30 years; P < 0.001), had significantly lower CSF OP (35.5 vs 36 cm of water; P = 0.03), and were significantly more likely to be asymptomatic compared with patients with more symmetric papilledema (27% vs 3%; P < 0.001) (Table 1).
The highest-grade edema was on the right side in 9 of 20 patients (45%). Papilledema was strictly unilateral in 8 of 20 patients (40%) and was located on the right side in 3 of 8 patients (38%). When comparing the eye with the highest-grade edema to the fellow eye, visual fields were significantly worse (mean deviation, −3.0 vs −2.1 dB; P = 0.02), but visual acuities and IOPs were not different (Table 2).
Neuro-imaging (11 MRIs and 1 CT) was performed at our institution for 12 of 20 patients. Nine of 11 patients with MRI received intravenous gadolinium contrast material, and 3 of 11 patients had an MRV (contrast-enhanced MRV: 2/3 patients). The optic canal was smaller on the side of the lowest-grade edema in all 8 patients (100%, 7 MRIs and 1 CT) in whom it could be reliably evaluated (Table 2). The cross-sectional optic canal measurement was 14.9% smaller on average on the side of the lowest-grade edema (range: 2.5%–31.0%; P = 0.008) (Fig. 1). Asymmetric perioptic nerve CSF was reported in 6 of 12 patients (50%) and was always less prominent on the side of the lowest-grade edema (P = 0.01). Optic nerve protrusion into the globe and scleral flattening, both trended toward being more common on the side of the highest-grade edema (P = 0.07).
Our study confirms that very asymmetric papilledema is rare in IIH, occurring in less than 4% of patients with definite IIH. Interestingly, we showed that the bony optic canal was always smaller on the side of the lowest-grade edema.
Few reports (1–13) have dealt with asymmetric papilledema in IIH. Three studies reported its prevalence in a tertiary neuro-ophthalmic setting (1,11,12), and found heterogeneous results. Using the same definition of asymmetric papilledema, Wall and White (12) and the Idiopathic Intracranial Hypertension Treatment Trial (11) have shown that IIH with very asymmetric papilledema was uncommon (≈7.5%), but a smaller series of 6 patients (1) found a higher prevalence (23%). Surprisingly, our study found a much lower prevalence of 3.6%. Several factors may have contributed to these discrepancies. First, we believe that the high prevalence found by Lepore (1) should be interpreted cautiously because the sample was small (6/27 patients; 95% CI, 7.1–38.9) and no details regarding the definition of asymmetric papilledema were provided. Second, we had a strict definition of very asymmetric papilledema to emphasize the potential differences between symmetric and asymmetric papilledema in terms of demographics, clinical presentation, and radiologic features; therefore, we might have underestimated its prevalence.
Regarding patient demographics, we found that patients with IIH with very asymmetric papilledema were older compared with patients without asymmetric papilledema, which also was reported by Lepore (1). Lepore (1) suggested a possible loss of compliance in the aging lamina cribrosa, buffering the effect of the perioptic CSF pressure. However, he did not address how this would result in asymmetric papilledema. Wall and White (12) found an overrepresentation of men (29%); we also found a higher frequency of men (15%) among patients with very asymmetric papilledema, but this did not reach significance when compared with the group of patients with symmetric papilledema. In our study, race and BMI of patients with very asymmetric papilledema were similar to those with symmetric papilledema.
The clinical presentation of patients with IIH with very asymmetric papilledema seems to differ from that of patients with IIH with symmetric papilledema, with a high proportion of asymptomatic cases (27%) and a lower proportion of patients with headaches (35%) in the asymmetric papilledema group. In a previous series including patients from the same IIH database (17), we emphasized that men with IIH experience headache less often. Our higher frequency of men with very asymmetric papilledema, none of whom had headache, may account partially for this difference. In addition, although no correlation between headaches and CSF OP in IIH has been reported, the significantly lower CSF OP we found among patients with very asymmetric papilledema might have contributed to the difference in headache frequency. Regarding visual function, as previously reported (12), visual fields were significantly worse on the side of the highest-grade papilledema.
The most interesting result from our study is that the bony optic canals were consistently smaller on the side of the lowest-grade papilledema. The pathophysiology of CSF dynamics in IIH is not fully understood (18). The lack of a clear relationship between the degree of papilledema and the CSF OP (14,19) suggests that an underlying mechanism may sometimes prevent the optic disc from swelling in some cases of IIH. The pathogenesis of papilledema depends on the translaminar pressure gradient at the optic nerve head, and therefore on the balance between the CSF pressure in the perioptic subarachnoid spaces and the IOP. Hayreh (20) showed that high CSF pressure in the perioptic subarachnoid spaces or low IOP cause identical microscopic changes and axonal flow stasis. However, our study and others (2,7,13) have shown that asymmetric IOP, although reported in anecdotal cases (3,5,10), is not the primary mechanism of asymmetric papilledema. We believe that, in the absence of optic atrophy (20), asymmetric papilledema is most likely related to asymmetric transmission of the CSF pressure to the lamina cribrosa (21).
Two mechanisms for asymmetric transmission of the CSF pressure along the perioptic subarachnoid spaces previously have been proposed, namely asymmetric structural changes either in the lamina cribrosa (1) or along the optic nerve sheath (6). These mechanisms remain debated. Our study shows compelling data regarding the role of asymmetry of the bony optic canals in the genesis of very asymmetric papilledema. It is well known that the orbital portion of the perioptic subarachnoid spaces shows distension in IIH (22,23). A study of 15 patients with IIH, 10 with IIH, failed to demonstrate asymmetric distension of the perioptic subarachnoid spaces in patients with unilateral papilledema, but no details regarding the grading of papilledema were provided (13). We included only very asymmetric papilledema to identify obvious potential differences between the 2 eyes. We showed that asymmetric distension of the perioptic subarachnoid spaces occurred in half of our cases, always less prominent on the side of the lowest-grade edema, suggesting that the CSF pressure may be lower in the perioptic subarachnoid spaces on the side of the lowest-grade edema. Possibly, our imaging or grading system might not have been sensitive enough to capture subtle asymmetry in the remaining 50% of cases with symmetric perioptic CSF.
The concept of compartmentation of the perioptic subarachnoid spaces (4,24,25), in which the perioptic subarachnoid spaces are partially separated from the suprasellar cisternal spaces, seems more likely to explain asymmetric papilledema. Although the orbital portion of the perioptic subarachnoid spaces is able to distend under increased CSF pressure, the intracanalicular portion, the narrowest (4,19), is characterized by tight relationships between the surrounding bone and the optic nerve (24). Because of its unique anatomy, the region of the optic canal plays a crucial role in CSF flow dynamics between the suprasellar cistern and the perioptic subarachnoid spaces. We have demonstrated that the bony optic canal was always smaller on the side of the lowest-grade edema. This anatomic configuration probably allows CSF pressure to be less easily transmitted along the optic nerve on the side of the smaller canal, thereby resulting in lower local intraorbital CSF pressure and less optic disc edema. However, longitudinal data on the optic canal diameter in patients with IIH are needed to better understand whether this asymmetry in size is congenital or results from bony erosion related to longstanding CSF hypertension, as described in other skull base locations with chronic IIH (26,27). The fact that we and others (1) have found that patients with IIH with asymmetric papilledema are older than other patients with IIH may support an acquired etiology.
Despite our small sample, there seems to be a definite relationship between the severity of papilledema and the cross-sectional area of the optic canal, suggesting that asymmetric papilledema may result from asymmetries in the bony optic canal. Our study lends further support to the concept of compartmentation of the perioptic subarachnoid spaces developed by Killer and Subramanian (24) and suggests that the bony optic canal may be a “bottleneck” interfering with the CSF flow between the perioptic subarachnoid spaces and the suprasellar cistern. Whether the asymmetry in size of the optic canal is congenital or acquired requires further study.
STATEMENT OF AUTHORSHIP
Category 1: a. Conception and design: S. Bidot, V. Biousse, A. M. Saindane, B. B. Bruce, and N. J. Newman; b. Acquisition of data: S. Bidot, A. M. Saindane, and B. B. Bruce; c. Analysis and interpretation of data: S. Bidot, V. Biousse, A. M. Saindane, B. B. Bruce, and N. J. Newman. Category 2: a. Drafting the article: S. Bidot, A. M. Saindane, and B. B. Bruce; b. Revising it for intellectual content: S. Bidot, V. Biousse, A. M. Saindane, B. B. Bruce, and N. J. Newman. Category 3: a. Final approval of the completed article: S. Bidot, V. Biousse, A. M. Saindane, B. B. Bruce, and N. J. Newman.
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