Primary balloon angioplasty of venous Sinus stenosis in idiopathic intracranial hypertension

Abstract

Background

Venous sinus stenosis (VSS) stenting has emerged as an effective treatment for patients with Idiopathic Intracranial Hypertension (IIH). However, stenting carries risk of in-stent stenosis/thrombosis and cumulative bleeding risk from long-term dual antiplatelet (DAPT) use. Thus, we investigated the potential safety and efficacy of primary balloon angioplasty as an alternative to stenting in IIH.

Methods

A prospectively maintained single-center registry of IIH patients undergoing endovascular procedures was queried. Inclusion criteria included patients with confirmed IIH and angiographically demonstrable VSS who underwent interventions from 2012- 2021. Patients were dichotomized into primary balloon angioplasty (Group A) and primary stenting (Group S), comparing clinical outcomes using bivariate analyses.

Results

62 patients were included with median age of 33 [IQR 26-37], 74% females. Group A (9/62) and Group S (53/62) had similar baseline characteristics. Papilledema improvement was higher in Group S at 6 weeks and 6 months (44 vs. 93, p = 0.002 and 44 vs. 92%, p = 0.004), with similar improvements across all symptoms. Group S had higher mean post-procedure venous pressure gradient change (8 vs. 3 mmHg, p = 0.02) and a lower CSF opening pressure at 6 months (23 vs. 36 cmH2O, p < 0.001). VPS rescue rate was higher in Group A (44 vs. 2%, p = 0.001). There was only one procedural complications; a subdural hematoma in Group A.

Conclusions

Primary VSS balloon angioplasty provides a marginal and short-lived improvement of IIH symptoms compared to stenting. These findings suggest a cautious and limited role for short-term rescue angioplasty in poor shunting and stenting candidates with refractory IIH.

Background

Cumulative evidence has demonstrated the efficacy of venous sinus stenosis (VSS) stenting for medically refractory idiopathic intracranial hypertension (IIH) patients.^1–5 The mechanistic underpinning underlying IIH remain poorly understood. However, poor CSF outflow is believed to be the basic defect leading to intracranial hypertension. ⁶ In the appropriate clinical circumstances, patients with VSS and a supraphysiological lesional gradient who undergo stenting achieve better CSF clearance and subsequent resolution of intracranial hypertension and clinical improvement.^6,7

Venous stenting offers an effective method of improving stenotic lesions with strong and continuous radial force. Nevertheless, it is not without risk. In particular, stents are susceptible to in-stent thrombosis or stenosis. ⁸ The need for chronic antiplatelet use confers a cumulative lifetime hemorrhagic risk in patients who are generally young and active. Balloon angioplasty has been a mainstay in arterial stenosis treatment with high success rates, limited complication rates and lower long term antiplatelet need.^9–12 While balloon angioplasty has been utilized in VSS patients, this is only as an adjuvant technique for improved stent apposition or for subsequent revisions thereof. Thus, we aimed to explore the safety and efficacy of primary balloon angioplasty versus stenting in IIH patients with VSS.

Methods

Patient populations and selection for treatment

This study is based on a prospective registry of all patients who underwent angiographic evaluation for symptomatic IIH at a single center from 2012 to 2021. The study was approved by our local institutional IRB approval number is HSC-MS-17-0524. All patients carried a diagnosis of idiopathic intracranial hypertension and had non-invasive imaging (CTV or MRV) demonstrating venous sinus stenosis (VSS). Lumbar puncture to ascertain opening pressure (OP) was performed immediately prior to angiography. Angiographic pressure measurements were undertaken only for patients with opening pressures > 20 cm H₂O and papilledema. We use the >20 cm H2O cutoff defined by the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) modified Dandy criteria to be inclusive in our treatment selection and we believe more representative of prior trial treatment populations. ¹³ Meaningful venous stenosis pressure gradient was defined as gradient >4 mmHg based on previously published minimal thresholds.^3,14,15 Patients were treated with either angioplasty or stenting if they had 1) signs of elevated intracranial pressure (ICP); 2) stenosis of a dominant transverse and/or sigmoid sinus; and 3) a pressure gradient >4 mm Hg across the stenotic segment of venous sinus. Consecutive patients were treated with angioplasty alone from 2012–2014 and then treated with stenting between 2012–2021. Repeat LP and angiography were performed at 6 months following the treatment procedure for most patients. In terms of objective clinical outcome measurements, papilledema was followed using ophthalmalogical dilated eye exams performed by expert neuro-ophthalmalogists at six weeks and six months. No interpolation was done for missing data.

Treatment procedure protocols

Measurement of venous pressure gradient

A 7F Envoy MPC guide catheter (Cerenovus^™, Raynham, MA) was placed in the targeted distal jugular vein with sigmoid sinus junction and a 0.027-inch Marksman or Phenom microcatheter (Medtronic Neurovascular, Irvine, CA) was then advanced to into the superior sagittal sinus. Mean venous pressure manometry measurements at superior sagittal sinus, confluence, transverse sinus, and sigmoid sinus were obtained through the microcatheter. This was repeated immediately following angioplasty or stent placement.

Balloon angioplasty

A 7 mm × 20 mm Aviator angioplasty balloon (Cardinal Health, Dublin, OH) was advanced over an Asahi Black 0.014-inch microwire (Asahi Intecc, Irvine, CA) and centered at the site of venous sinus stenosis. The balloon was inflated to dilate the venous sinus and held for approximately 10 s before being deflated. Once the balloon was deflated and removed, angiography was repeated to demonstrate radiographic improvement.

Venous sinus stent placement

Patients were given aspirin 325 mg and clopidogrel for 7 days prior to the procedure. Aspirin activity was confirmed with an ARU assay (350–450), and clopidogrel activity was confirmed by a PRU assay (80–180) prior to treatment. A Precise Pro RX^™ self-expandable 8 mm by 40 mm stent (Cardinal Health, Dublin, OH) was deployed to straddle the region of venous stenosis. Adjuvant balloon angioplasty was performed at the discretion of the interventionalist for purposes of stent opening and apposition using the technique described above. Angiography was repeated after stent placement to confirm restoration of the venous sinus lumen.

Outcomes measures

Clinical outcome measures were maintained prospectively in the registry. Primary outcomes were defined as improvement in clinical symptoms at 6 weeks and 6 months. Secondary outcomes were improvement in venous gradient immediately post-intervention, improvement in opening pressure at 6 months, and rate of VPS rescue. Safety outcomes were defined as any procedural complication (both groups) or post-treatment stent thrombosis or restenosis (Group S).

Statistical analysis

All clinical data was obtained prospectively. Baseline demographic, clinical characteristics, and clinical outcomes of Group A and Group S were compared using Student's t-test for continuous variables, and Fisher's exact test for categorical variables. A p-value of less than 0.05 was considered statistically significant. Statistical analysis was performed using Stata Statistical Software: Release 15 (StataCorp LLC, College Station, TX).

Results

A total of 62 patients were identified that met the clinical criteria for intervention. Nine consecutive patients underwent angioplasty alone (Group A), and 53 patients underwent venous sinus stenting, with or without angioplasty (Group S). Baseline demographic and clinical information is presented in Table 1. Median patient age was 33 years [IQR 26-37] within the complete cohort. In total, 46 patients (74%) were female and average BMI was 35 ± 7, neither of which differed significantly between treatment cohorts. Average CSF opening pressure was 35 ± 11 cmH₂O, average venous sinus pressure gradient was 10 ± 6 mmHg, and 34 patients (55%) were taking acetazolamide prior to the procedure. No patients included in this study underwent placement of a ventriculoperitoneal shunt prior to endovascular treatment. Comparison of baseline demographic and presenting clinical characteristics did not yield any statistically significant differences between treatment groups.

Table 1.

Baseline characteristics by treatment group.

	Angioplasty (n = 9)	Stent (n = 53)	p-value
Age, y, mean (SD)	29 (7)	32 (9)	0.4
Female sex, n (%)	9/9 (100)	37 (70)	0.1
BMI, mean (SD)	33 (6)	36 (7)	0.3
Opening pressure, cm H2O, mean (SD)	42 (15)	35 (10)	0.1
Venous sinus pressure gradient, mmHg, mean (SD)	13 (7)	10 (6)	0.1
Prior Diamox use, n (%)	6/9 (67)	28/53 (53)	0.5
Shunt prior to endovascular intervention, n (%)	0/9 (0%)	0/53 (0%)	n/a

Data analyzed by Student's t-test for continuous variables, or Fisher's exact for categorical variables.

Patients were seen in follow up at standardized times post-procedure, allowing for comparison of clinical outcomes at six weeks and six months as primary outcome (Table 2). A greater proportion of patients in Group S had resolution of headache at six weeks (44% vs. 92%, p = 0.002), and this difference was sustained at six months (22% vs. 94%, p < 0.001), as compared to Group A. Tinnitus also resolved in a greater proportion of patients in Group S at six weeks (44% vs. 94%, p = 0.001) and at six months (44% vs. 92%, p = 0.003) of follow up. Finally, subjective visual impairment resolved in a significantly greater proportion of patients in Group S at the six weeks (50% vs. 92%, p = 0.002) and six month (25% vs. 91%, p < 0.001) time points. Papilledema had resolved at six weeks in a greater proportion of patients in Group S (93%) as compared to Group A (44%, p = 0.002); this result was sustained at 6 months (44% vs. 92%, p = 0.004).

Table 2.

Clinical outcomes by groups.

	Angioplasty (n = 9)	Stent (n = 53)	p-value
Post-op pressure gradient, mmHg, mean (SD)	10 (7)	1 (2)	<0.001
Change in pressure gradient, mmHg, mean (SD)	3 (3)	8 (6)	0.02
Post-op opening pressure, cm H2O, mean (SD)	36 (7)	23 (7)	0.0008
Change in opening pressure, cm H2O, mean (SD)	6 (4)	13 (10)	0.2
Symptom improvement, n (%)	6 weeks | 6 months	6 weeks | 6 months	6 weeks | 6 months
Headache	4/9 (44) | 2/9 (22)	49/53 (92) | 49/52 (94)	0.002 | <0.001
Tinnitus	4/9 (44) | 4/9 (44)	47/50 (94) | 45/49 (92)	0.001 | 0.003
Visual disturbance	4/8 (50) | 2/8 (25)	46/50 (92) | 48/53 (91)	0.009 | <0.001
Papilledema	4/9 (44) | 4/9 (44)	43/46 (93) | 40/44 (92)	0.002 | 0.004
VPS rescue, n (%)	4/9 (44%)	1/53 (2%)	0.001

Data analyzed by Students’ t-test for continuous variables, or Fisher's exact for categorical variables. For symptom improvement data, analysis was performed comparing symptom improvement in patients undergoing angioplasty alone versus stenting at two different time points, and p-value is reported for comparison of the two treatment groups at both time points.

The secondary outcome of pressure gradient across the lesion immediately following intervention was found to be 10 ± 7 mmHg versus 1 ± 2 mmHg (p < 0.001) in Group A and Group S, respectively. The change in pressure gradient from pre-intervention to post-intervention was 3 ± 3 mmHg in Group A and 8 ± 6 in Group S (p = 0.02). Rates of post-procedure ventriculoperitoneal shunt placement was 44% (4/9 patients) in Group A, and two percent (1/53 patients); this difference was statistically significant (p = 0.001). Stenting was performed as a rescue technique in only one patient in Group A.

There was one observed periprocedural complication within 24 h in a Group A patient. This patient had diffuse bilateral transverse venous sinus and sigmoid sinus critical stenosis required multiple balloon angioplasties throughout the entire length of these segments of venous sinus. An infratentorial subdural hematoma occurred post-procedure, which required surgical evacuation. There were no periprocedural complications in the Group S patients. In the available 6 month follow up angiography for Group S patients, there was 2 stent interface stenoses without thrombosis in a single patient with bilateral stents not requiring retreatment.

Discussion

Our present work describes our early experience with angioplasty alone versus stenting (with or without angioplasty) for symptomatic venous sinus stenosis by analysis of a prospectively collected clinical database. In our patient population, patients who underwent angioplasty alone, without placement of an intravenous stent, performed worse by both objective and subjective clinical parameters. Patients undergoing angioplasty without stent placement were significantly more likely to have a clinically significant pressure gradient across the region of stenosis post-intervention, and had a significantly lower change in pressure gradient. They also had a significantly higher CSF opening pressure at six-month follow up (36 ± 7 vs. 23 ± 7, p = 0.0008).

IIH is believed to be caused by a deficient clearance of CSF resulting in abnormal accumulation leading to intracranial hypertension. ⁶ The mechanistic underpinnings of IIH remain poorly understood. Fundamentally, VSS has been both shown to persist in patients with resolved intracranial hypertension through pharmacologically driven decreased CSF production and resolve in others with CSF removal^16–18 This highlights our limited understanding of the progression and causes of IIH, specifically as it relates to VSS. Recent evidence suggests that in some cases VSS plays a significant role as either a primary or a secondary mechanism of impaired outflow. As such, VSS stenting has gained traction with reproducible success across multiple centers showing improvement in intracranial hypertension and symptom burden in a select group of patients with coexisting IIH and VSS. ⁵ The predominant theory behind this treatment is that stent assisted restoration of venous sinus outflow improves CSF clearance. Venous sinus stenting carries some short- and long-term risk including bleeding from prolonged DAPT treatment, in-stent stenosis or thrombosis or rarely allergic reactions. In certain patients, the allergic reaction or bleeding risk may be prohibitive. Thus, we sought to understand if VSS angioplasty could provide a similar effect without the need for stent placement.

Compared to the sustained benefit of stenting, balloon angioplasty appears to have a clinically meaningful but short-lived effect on improving IIH symptoms. Previous histologic studies of angioplastied human arteries demonstrate splitting of atheromatous plaques that can extend down to the muscular tunica media. ¹⁹ Shearing of the muscular fibers is believed to be important in the sustained success of balloon angioplasty. The media muscular layer is a significant determinant of arterial lumen compared to the smaller contribution from the thinner venous muscular layer; this difference may be a plausible explanation of the observed limited efficacy of venous angioplasty to sustain lumen dilation. Hence, while not standard of care, balloon angioplasty may represent a short-term rescue alternative in patients with refractory symptoms who are poor surgical candidates for shunting and have absolute contraindications to antithrombotics required for stenting. Importantly, angioplasty does not preclude future stenting.

Our study has several limitations including its non-randomized nature of the study and the limited number of angioplasty cases performed. However, using a standardized approach to the procedures as well as the clinical follow up is a relative strength. While non-randomized, our study was done in consecutive experiences meaning angioplasty was the only treatment option offered to patients in the early study period of 2012–2014 and then only stenting thereafter. This, diminished selection bias significantly. In addition, only one out of nine patients had follow up angiography in the angioplasty group compared to the majority of stented individuals. This was driven mostly by clear evidence of failure in four out of nine cases requiring VPS placement and one out of nine requiring optic sheath fenestration, as well as two out of nine with clinical improvement and lack of equipoise for an angiogram with possible risks. While there are multiple angioplasty with stent combination experiences, this represents the largest and only to date with primary angioplasty treatment without stenting, to the best of our knowledge.

Conclusions

Our study suggests that VSS stenting is superior and longer lasting than primary angioplasty in IIH. Angioplasty may offer a last resort, short-term alternative in IIH symptoms refractory patients who are poor shunt or stent candidates, but should not be used as first line therapy.