Venous Sinus Stenting Outcomes in Patients with Papilledema from Secondary Causes of Elevated Intracranial Pressure

ABSTRACT

Venous sinus stenting (VSS) has recently emerged as a promising intervention in patients with idiopathic intracranial hypertension (IIH) who fail medical therapy. Less is known on outcomes of VSS to manage papilledema from secondary causes of increased intracranial pressures (ICP), such as venous sinus thrombosis. A retrospective cohort study was conducted to evaluate the outcomes of VSS for four patients with papilledema from secondary causes of elevated ICP. A subset of 25 consecutive IIH patients with equivalent degrees of papilledema who underwent VSS served as a comparison group. Of the four patients with secondary causes of papilledema, three had increased ICP due to venous sinus thrombosis and one following surgical treatment of a spinal CSF-venous fistula. The median papilledema grade in patients with secondary causes of elevated ICP was 3.75 (range 3–4) at baseline, with only one (25%) having a significant sustained improvement in papilledema after VSS (overall post-stent median papilledema grade 2.5, range 0–3.5). In comparison, all 25 patients with IIH and grade ≥3 papilledema at baseline (median 4, range 3–5) had improvement of papilledema at least to grade 1 (median 1, range 0–1) at 3-month follow-up (p = .003 for secondary causes vs IIH). Three (75%) patients with secondary causes of elevated ICP and four (16%) IIH patients required additional procedures for residual raised intracranial pressure after initial VSS (p = .034). This study suggests that secondary causes of raised ICP may respond less to VSS than IIH patients with similar degrees of papilledema.

Introduction

Papilledema is defined as a swelling of the optic disc due to a pathologic elevation of intracranial pressure (ICP). Common etiologies of elevated ICP include space occupying lesions such as tumors or intracranial hemorrhage, disruption in the inflow or outflow of cerebrospinal fluid (CSF) due to venous sinus thromboses, and idiopathic intracranial hypertension (IIH).^1,2 In cases with secondary causes of increased ICP, standard of care is addressing the underlying pathology such as tumor resection with concurrent medical or surgical management of the ICP, while first-line therapies for IIH are lifestyle management with weight loss and ICP-lowering medications such as acetazolamide.^3,4 In cases of medication-refractory vision-threatening papilledema, procedural interventions such as optic nerve sheath fenestration and ventriculoperitoneal (VP) shunting have been the traditionally performed surgeries.⁵

Many recent publications have detailed the outcomes of venous sinus stenting (VSS) as a possible safe and efficacious intervention to relieve clinical symptoms and improve papilledema in cases of IIH requiring surgical intervention.^6–8 For example, Oyemade et al showed robust improvement of papilledema, significant improvement of retinal nerve fiber layer (RNFL) thickness, and improvement of symptoms such as headache and pulsatile tinnitus measured 3 months after the VSS procedure.⁹ These outcomes are especially relevant with increased utilization of VSS as an endovascular interventional treatment modality and evidence showing outcomes similar or better with VSS as compared to alternative surgical procedures in cases of refractory IIH.^10,11

Although VSS appears to be effective in IIH, its role in treating papilledema due to secondary causes of high ICP has not been well explored.⁶ Herein, we report the outcomes of VSS for patients with papilledema due to secondary causes of increased ICP and compare the ophthalmic outcomes to cases of IIH with similar degrees of papilledema.

Methods

Study population and design

This was a retrospective cohort study of all patients who underwent VSS at the Mayo Clinic, Rochester, Minnesota and Stanford Medical Center, Palo Alto, California, for papilledema refractory to medical management between May 2015 and February 2022. This study was approved by the Mayo Clinic and Stanford Medical Center institutional review boards and conducted in accordance with the Health Insurance and Portability and Accountability Act (HIPAA) and adhered to the tenets of the Declaration of Helsinki.

The two cohorts assessed include one group of patients found to have papilledema due to secondary causes of elevated intracranial pressure, such as venous sinus thrombosis, and a comparative group of consecutive IIH patients with similar degrees of papilledema that underwent VSS during the same time period, who were published in our group’s prior study on VSS for IIH.⁹ A diagnosis of IIH was determined using the modified Dandy criteria, including signs and symptoms of increased intracranial pressure, no focal neurological signs apart from abducens nerve palsy, elevated intracranial pressure with normal CSF constituents on lumbar puncture, and neuroimaging without a clear etiology for the increased ICP.¹²

Patients in both groups were only considered for VSS if they met one or more of the following criteria: symptoms refractory to standard medical therapy, failure of prior surgical management, or vision threatening papilledema. Patients who underwent cerebral venography received a venous sinus stent if the trans-stenotic pressure gradient was at least 8 mmHg. Patients were excluded from the study if their post-VSS follow-up was less than one month. The electronic medical records of the patients were reviewed for baseline, intraprocedural, and postprocedural clinical data. VSS was conducted with the same methodology as Oyemade et al.⁹

Outcomes and data points

The change in papilledema grade of the eye with the worse papilledema after VSS was recorded for each group. Grading was conducted during detailed ophthalmic evaluation of these patients by a neuro-ophthalmologist using the Frisen scale. In addition, improvement in symptoms, specifically headache and pulsatile tinnitus after VSS, change in best corrected visual acuity (BCVA), optic nerve RNFL and ganglion cell-inner plexiform layer (GC-IPL) thickness, and Humphrey visual field mean deviation pre- and post-procedurally were collected with ophthalmic outcomes focusing on the eye with worse papilledema. BVCA was measured using a Snellen chart (pin-hole VA if refraction was not done) and reported in LogMar. RNFL and GCL thickness were measured using Cirrus ocular coherence tomography (OCT). The optic disc cube 200  ×  200 Cirrus protocol covering a 6  ×  6 mm² area centered on the optic disc was used to determine RNFL thickness and a macular cube 512  ×  128 Cirrus protocol centered on the fovea was used to measure GC-IPL thickness. Visual field mean deviation was measured using a SITA standard 24–2 algorithm. The worse eye pre- and post-stenting was used for all comparisons.

Statistical analysis

All statistical tests were performed using Microsoft Excel. Continuous variables were presented as mean (SD, standard deviation), and compared using the student’s t-test and Mann – Whitney Rank Sum test. Categorical variables were presented as numbers and percentages and compared using the chi-square test and Fisher’s exact test. A p-value <.05 was considered statistically significant.

Results

Between May 2015 and February 2022, VSS was performed on 107 patients for raised ICP at both institutions. Of these patients, 17 patients were excluded from our study because their post-VSS follow-up was less than one month after their procedure and minimal follow-up data, leaving 90 patients for analysis. Of these 90 patients, 4 patients underwent VSS for papilledema from secondary etiologies of increased ICP. The median papilledema grade in patients with secondary causes of increased ICP was 3.75 (range 3–4) at baseline. Among the 90 patients that underwent VSS, 25 IIH patients had similar degrees of papilledema at baseline (grade ≥3 papilledema), which was used as a comparison group. The median age for the secondary etiology group was 58 years (range 42–88) and the IIH group was 29 years (range 23–68) (p < .001). One (25%) patient in the secondary etiology group was female compared to 22 (88%) patients in the IIH group (p = .004). Median BMI was 30.9 (range 23.7–46.7) in the secondary etiology group and 38 (range 22.8–55.2) in the IIH group (p = .219).

The clinical etiologies of increased ICP leading to VSS in patients without IIH were a spinal CSF venous fistula (1, 25%) and 3 (75%) venous sinus thrombosis: left transverse and superior sagittal sinus thromboses (1, 25%), dural venous sinus thrombosis of the transverse sinus (1, 25%), and superior sagittal sinus thrombosis (1, 25%). Three (75%) patients in the secondary etiology group had surgical procedures prior to VSS, all with optic nerve sheath fenestrations. Balloon angioplasty over the deployed venous sinus stent was conducted for 2 patients. No patients underwent other angiographic procedures. Of the patients with IIH, 2 (8%) had a surgical procedure prior to VSS, both being a ventriculoperitoneal (VP) shunt. The median opening pressure of the last LP before VSS in the secondary etiology group was 402 mmH₂O (range 290–510) and 360 mmH2O (range 235–580) in the IIH group (p = .657). Three (75%) patients in the secondary etiology group and 25 (100%) patients in the IIH group reported headaches. Three (75%) patients in the secondary etiology group and 23 (92%) patients in the IIH group reported pulsatile tinnitus.

Of the patients in the secondary etiology group, 1 (25%) patient was stented in the right transverse sinus, 1 (25%) was stented in the right transverse sinus/sigmoid sinus junction, 1 (25%) was stented in the left transverse-sigmoid sinus junction, and 1 (25%) was stented in the superior sagittal sinus. In the IIH group, 22 (88%) had stenting of the right transverse/sigmoid sinuses and 3 (12%) had stenting of the left transverse/sigmoid sinuses. The median pre-procedure pressure gradient across the stented segment was 41 (range 30–61) mmHg in the secondary etiology group and 25 (range 13–60) mmHg in the IIH group (p = .110).

In the patients with secondary causes of elevated ICP, the median papilledema grade of the worse eye was 3.75 (range 3–4) at baseline, with only one (25%) (a patient with venous sinus thrombosis) having a significant sustained improvement in papilledema after VSS (median papilledema grade 2.5, range 0–3.5, p = .37) (Figure 1). Of note, one patient improved to grade 2 after VSS, but had worsening to grade 3.5 due to a thrombosis of the stent. In the IIH group, the median papilledema grade of the worse eye pre-VSS was 4 (range 3–5), and 1 (range 0–1) post-VSS (p < .001) (Table 1, Figure 2).

Figure 1.

Papilledema grade before and after VSS in patients with secondary etiologies of elevated ICP.

Table 1.

Change in grade of papilledema and Re-intervention rate after VSS.

	Patients with Secondary Etiologies	Patients with IIH
Median papilledema grade pre-VSS, Frisen Scale (range)	3.75 (3–4)	4 (3–5)
Median papilledema grade post-VSS, Frisen Scale (range)	2.5 (0–3.5)	1 (0–1)
Change in papilledema grade of worst eye post-VSS, n (%) Improved No Change Worsened	2 (50) (p = .37)* 2 (50) 0 (0)	23 (100) (p < .001) 0 (0) 0 (0)
Patients needing additional procedures post-VSS, n (%)	3 (75)	4 (16)

*One patient experienced thrombosis of venous sinus stent and subsequently underwent angioplasty after initial improvement of papilledema after stenting.

Figure 2.

Papilledema grade before and after VSS in patients with IIH.

Median logMAR BCVA of the worse eye pre-VSS was 0.49 (Snellen equivalent 20/60) (range 0.1–1.4) in the secondary etiology group and 0 (Snellen equivalent 20/20) (range 0–0.3) in the IIH group. The median logMAR BCVA post-VSS was 0.36 (Snellen equivalent 20/50) (range 0.1–1.18) (p = .43) and 0 (Snellen equivalent 20/20) (range  − 0.12–0.18) (p = .006) in the secondary etiology and IIH groups respectively.

Median mean visual field mean deviation of the worse eye pre-VSS was  − 6.54 (range  − 6.99 –  − 0.6) in the secondary etiology group and  − 3.72 (range  − 9.15 –  − 0.35) in the IIH group, and  − 12.22 (range  − 19.04 –  − 5.4) (p = 1.00) and  − 2.48 (range  − 4.15–0.33) (p = .003) in the secondary etiology and IIH groups respectively post-VSS.

Median average RNFL thickness of the worse eye pre-VSS was 234 (range 166–318) in the secondary etiology group and 290 (range 113–588) in the IIH group, and 196 (range 104–199) (p = 1.00) and 96.5 (range 71–158) (p < .001) in the secondary etiology and IIH groups respectively post-VSS.

Median average GCL thickness of the worse eye pre-VSS was 74 (range 74–74) in the secondary etiology group and 78 (range 65–92) in the IIH group, and 73 (range 73–73) (p = 1.00) and 74.5 (range 62–87) (p = .002) in the secondary etiology and IIH groups respectively post-VSS.

After VSS, 2 (50%) patients in the secondary etiology group and 21 of 24 (87.5%) patients in the IIH group had refractory headaches, while 3 (75%) patients in the secondary etiology group and 8 out of 24 (33.3%) patients in the IIH group had persistent pulsatile tinnitus.

Three (75%) patients in the secondary etiology group required additional procedures for raised ICP following VSS with one requiring repeat VSS of another vessel, one requiring a VP shunt, and one requiring optic nerve sheath fenestration. Only 4 (16%) patients in the IIH group required additional procedures following VSS (3 with stenting of another vessel, 1 requiring repeat stenting due to stent stenosis).

There were no post-procedural complications in the secondary etiology group. One patient in the IIH group had a post-procedural complication, experiencing a generalized tonic-clonic seizure.

Discussion

While VSS is associated with significant improvement in papilledema for IIH in most cases, our study suggests that VSS may be less effective for secondary causes of raised ICP. Only 1 of 4 patients with papilledema from secondary etiologies had a significant sustained improvement in the papilledema after VSS (Figure 1). In comparison, all 25 IIH patients with similar degrees of papilledema (grade ≥3 papilledema) had improvement in papilledema at least to grade 1 (Table 1, Figure 2). This may be because of differences in the underlying pathophysiology of the raised ICP in these two groups.

A likely factor contributing to raised ICP in some cases of IIH is abnormalities in the venous sinus flow dynamics. Over 90% of patients with IIH have bilateral transverse sinus stenosis, typically at the junction of the transverse and sigmoid sinuses.¹³ Whether or not the stenosis is intrinsic (does not resolve with normalization of ICP) or extrinsic compression from the raised ICP (resolved with normalization of ICP), it is felt to be a contributor to the pathophysiology of IIH.⁶ One theory regarding extrinsic compression is that an incident event, such as weight gain, leads to an increase in ICP, which causes extrinsic compression of the transverse sinus that leads to a further increase in ICP and compression of the transverse sinus creating a positive feedback loop and resulting in IIH.¹⁴ VSS may interrupt this positive feedback and may explain the reported significant success in VSS procedures to treat medically refractory IIH.^9,15–17

In patients with increased ICP and papilledema without IIH, there is a secondary cause of the raised ICP. If the feedback loop of venous sinus stenosis raising ICP is not driving papilledema, then VSS is not surprisingly a less effective treatment for papilledema. Instead, treatment directed at the secondary cause of raised ICP may be more effective in treating the pathology at hand and resolving papilledema. The other explanation for less efficacy in our cohort with secondary etiologies is that the ICP was higher in these cases, making it so VSS alone was not sufficient to treat the pressure. We tried to control for ICP by picking an IIH comparison group with equal degrees of papilledema (≥3 Friesen grade), but papilledema grade does not always directly correlate with ICP. Of note, these two groups also had similar opening pressures on LP, but this is also not a perfect measure of ICP.

Although the utility of VSS in patients with secondary causes of elevated ICP compared to its use in IIH specifically has not been well studied, prior publications suggest that VSS can sometimes be effective for secondary causes. Li et al evaluated VSS in patients with cerebral venous sinus thrombosis – related stenosis and found resolution of papilledema in 12 of 15 (80%) of patients.¹⁸ Hunt et al also documented improvement of papilledema and visual acuity after VSS in two cases of cerebral venous sinus thrombosis.¹⁹ Lastly, Levitt et al. found VSS to be helpful in symptomatic venous sinus stenosis in a variety of secondary etiologies, including venous sinus thrombosis (n = 3), meningitis (n = 2), and tumor invasion of the dural venous sinus (n = 1), but it was not helpful in congenital hydrocephalus (n = 2).²⁰ Although evidence is sparse regarding established guidelines or indications for VSS use outside of IIH, these prior studies indicate that VSS may be effective in some secondary pathologies. Our study builds upon this prior work by directly comparing use of VSS in patients with papilledema from IIH versus those with papilledema from secondary causes, with our analysis suggesting that VSS for secondary causes of vision-threatening papilledema may not be as effective as it is in IIH.

Limitations of our study include its retrospective nature. Furthermore, 75% of patients in this series with secondary etiologies of raised ICP had already failed optic nerve sheath fenestration, suggesting a degree of severity that might help explain the lower efficacy of this series as compared to that of what Li et al and Levitt et al have described prior. This contrasts with only 8% of the patients in this study with IIH requiring surgical intervention prior to VSS. However, this confounder was attempted to be normalized by comparing patients with equal degrees of papilledema in the non-IIH and IIH groups. Lastly, the small size of the secondary etiology group limits the study’s generalizability and larger studies will be required to confirm our findings.

Conclusions

Our study comparing ophthalmic outcomes of VSS in patients with papilledema due to secondary etiologies of elevated ICP to patients with comparable papilledema secondary to IIH suggests lower efficacy of VSS in patients with raised ICP from secondary causes. Larger retrospective and prospective studies are needed to further characterize the utility of VSS in patients with secondary causes of elevated ICP.

Funding Statement

Statement: NIH P30 026877 (HM), unrestricted grant from Research to Prevent Blindness (HM), Gift to support research from Pierce the Darkness.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data available upon reasonable request