Role of the glymphatic system and perivascular spaces as a potential biomarker for post-stroke epilepsy

Abstract

Stroke is one of the most common causes of acquired epilepsy, which can also result in disability and increased mortality rates particularly in elderly patients. No preventive treatment for post-stroke epilepsy is currently available. Development of such treatments has been greatly limited by the lack of biomarkers to reliably identify high-risk patients. The glymphatic system, including perivascular spaces (PVS), is the brain's waste clearance system, and enlargement or asymmetry of PVS (ePVS) is hypothesized to play a significant role in the pathogenesis of several neurological conditions. In this article, we discuss potential mechanisms for the role of perivascular spaces in the development of post-stroke epilepsy. Using advanced MR-imaging techniques, it has been shown that there is asymmetry and impairment of glymphatic function in the setting of ischemic stroke. Furthermore, studies have described a dysfunction of PVS in patients with different focal and generalized epilepsy syndromes. It is thought that inflammatory processes involving PVS and the blood-brain barrier, impairment of waste clearance, and sustained hypertension affecting the glymphatic system during a seizure may play a crucial role in epileptogenesis post-stroke. We hypothesize that impairment of the glymphatic system and asymmetry and dynamics of ePVS in the course of a stroke contribute to the development of PSE. Automated ePVS detection in stroke patients might thus assist in the identification of high-risk patients for post-stroke epilepsy trials. PLAIN LANGUAGE SUMMARY: Stroke often leads to epilepsy and is one of the main causes of epilepsy in elderly patients, with no preventative treatment available. The brain's waste removal system, called the glymphatic system which consists of perivascular spaces, may be involved. Enlargement or asymmetry of perivascular spaces could play a role in this and can be visualised with advanced brain imaging after a stroke. Detecting enlarged perivascular spaces in stroke patients could help identify those at risk for post-stroke epilepsy.

Keywords: blood-brain barrier; glymphatic system; neuroinflammation; perivascular spaces; post-stroke epilepsy.

FIGURE 1

This figure illustrates the neurovascular unit that permits bidirectional exchange between microvessels and neurons. The unit consists of arteries in the subarachnoid space, which penetrate into the brain parenchyma, surrounded by CSF, forming the perivascular space (PVS) as much as neurons and astrocytes. PVSs extend from arterioles to capillaries to venules and are shaped by the basal lamina's extracellular matrix, which allow a continuity of the fluid space between arterioles and venules. The boundary of the PVSs is formed by astrocytic endfeet, expressing aquaporin‐4 (AQP4).

FIGURE 2

MRI T1‐weighted images that show ePVS burden in a patient with behavioral variant fronto‐temporal dementia. The left image shows manual segmentation of ePVS highlighted in red. In the right image, automated segmentation of ePVS using the Multimodal Autoidentification of Perivascular Spaces (MAPS) algorithm is highlighted in green with a slightly higher number of ePVS (27 vs. 24) becoming visible using MAPS. However, the manual counts and automated segmentations show a weak correlation, likely due to poor image quality and motion artifacts. The dataset's scans resemble typical clinical practice quality, featuring low contrast‐to‐noise ratios (CNR). MAPS performs better with higher‐quality datasets boasting higher CNR. Thus, future research should optimize ePVS segmentation for clinical practice‐standard scan qualities.

FIGURE 3

The figure visualizes the hypothesized bidirectional relationships and positive feedback mechanisms between glutamate, amyloid‐beta, and tau whereby amyloid‐beta increases presynaptic glutamate, further exacerbating excitotoxicity, and increasing accumulation of both amyloid‐beta and tau. Amyloid‐beta and tau are in a bidirectional relationship whereby increases in amyloid‐beta increase phosphorylated tau and vice versa. Meanwhile, phosphorylated tau also increases NMDA‐mediated receptor stimulation and excitotoxicity.

FIGURE 4

The impairment of the glymphatic system by neurotoxic waste products: This figure highlights the pathway of neurodegeneration and how excess tau leads to the collapse of PVS.

FIGURE 5

The Interplay of ePVS Asymmetry and Post‐Stroke Epileptogenesis. This figure provides a comprehensive view of the intricate relationship between enlarged perivascular spaces (ePVS) asymmetry and the development of post‐stroke epilepsy (PSE). It integrates three key hypotheses: 1. Failed Recovery of Glymphatic Clearance after a Stroke: The figure explores the hypothesis that impaired glymphatic clearance mechanisms following a stroke may contribute to ePVS formation and subsequently influence post‐stroke epileptogenesis. 2. Correlation of Asymmetry of ePVS and Seizure Onset Zone (SOZ): It highlights the correlation between the asymmetry of ePVS distribution and the localization of the SOZ, shedding light on the potential significance of ePVS patterns in the context of epilepsy development. 3. Longitudinal Changes of ePVS Over Time and Their Relationship with Post‐Stroke Epileptogenesis: The figure addresses the dynamic nature of ePVS by examining how longitudinal changes in ePVS burden may be associated with the onset and progression of post‐stroke epileptogenesis. In essence, the figure serves as a visual guide to understanding the multifaceted interplay of these hypotheses in the context of ePVS asymmetry and its relevance to PSE.