Diffusion-Weighted Imaging Reveals Impaired Glymphatic Clearance in Idiopathic Intracranial Hypertension

Abstract

Background and purpose: The pathophysiology underlying idiopathic intracranial hypertension (IIH) remains incompletely understood. While one theory postulates impaired cerebral glymphatic clearance in IIH, there is a paucity of methods to quantify glymphatic activity in human brains. The purpose of this study was to use advanced diffusion-weighed imaging to evaluate the glymphatic clearance of IIH patients and how it may relate to clinical severity.

Materials and methods: DWI was used to separately evaluate the diffusivity along the cerebral perivascular spaces and lateral association and projection fibers, with the degree of diffusivity used as a surrogate for glymphatic function (diffusion tensor image analysis along the perivascular space. Patients with IIH were compared with normal controls. Glymphatic clearance was correlated with several clinical metrics, including lumbar puncture opening pressure and Frisen papilledema grade (low grade: 0-2; high grade: 3-5).

Results: In total, 99 patients with IIH were identified and compared with 6 healthy controls. Overall, patients with IIH had significantly lower glymphatic clearance based on DWI-derived diffusivity compared with controls (P = .005). Additionally, in patients with IIH, there was a significant association between declining glymphatic clearance and increasing Frisen papilledema grade (P = .046) but no correlation between opening pressure and glymphatic clearance (P = .27). Furthermore, healthy controls had significantly higher glymphatic clearance compared with patients with IIH and low-grade papilledema (P = .015) and high-grade papilledema (P = .002). Lastly, patients with IIH and high-grade papilledema had lower glymphatic clearance compared with patients with IIH and low-grade papilledema (P = .005).

Conclusions: Patients with IIH possess impaired glymphatic clearance, which is directly related to the extent of clinical severity. The DWI-derived parameters can be used for clinical diagnosis or to assess response to treatment.

FIG 1.

ROI by using atlas-based ALPS index. Top row: The projection (superior and posterior corona radiata, magenta) and association (superior longitudinal fasciculus, yellow) fibers were defined by the labels of the ICBM DTI-81 Atlas. Bottom row: Gray-scale maps of X, Y, and Z diffusion with ROIs.

FIG 2.

A, Association between lumbar puncture opening pressure and Frisen papilledema grade in patients with IIH. B, Association between glymphatic function (ALPS index) and Frisen papilledema grade. The glymphatic clearance on the x-axis is declining moving left to right. C, Association between glymphatic clearance and lumbar puncture opening pressure in patients with IIH. D, Box-and-whisker plot showing difference in glymphatic clearance between patients with IIH and low Frisen grade papilledema (0–2) and lower opening pressure (<50th percentile in cohort) compared with patients with IIH and high Frisen grade papilledema (3–5) and higher opening pressure (≥50th percentile). * indicates P < .05.

FIG 3.

A, Box-and-whisker plot showing glymphatic clearance and how it relates between controls and patients with IIH and varying Frisen papilledema grades. B, Box-and-whisker plot showing difference in glymphatic clearance between controls and patients with IIH and low-grade papilledema (Frisen grade 0–2) and high-grade papilledema (Frisen grade 3–5). * indicates P < .05; ** indicates P < .01.

FIG 4.

ROC curve analysis assessing the diagnostic performance of the ALPS index between patients with IIH versus controls and between patients with IIH and less-severe (Frisen papilledema grade 0–1) and more-severe (Frisen papilledema grade 2–5) disease.