MR Lymphatic Imaging in Idiopathic Intracranial Hypertention

Overview

In the brain and its borders, blood vessels coexist with lymphatic vessels exclusively in the dura mater, the outermost layer of meninges. Dural lymphatics are present in various vertebrate species, including humans, and a cluster of experimental studies in the mouse strongly suggest their relevance in the pathophysiology of chronic and acute neurological disorders in humans. Demonstrating this assumption is however still at stake and the lymphatic regulatory mechanisms involved remain poorly characterized. Our main objective is to assess dural lymphatics contribution to the pathophysiology of a rare neurological disorder: idiopathic intracranial hypertension (IIH). In IIH patients, intracranial hypertension causes severe headache and visual loss and is associated with a stenosis of dural sinuses and abnormal retention of fluids in the central nervous system. Angioplasty treatment by stent placement into venous sinuses is frequently followed by recurrent stenosis suggesting that, in addition to the blood vessels, the duro-lymphatic environment contributes to disease progression. Several studies have found hot spots of lymphatic uptake at confluence points between cerebral veins and dural sinuses. Based on this premise, the investigators predict a causal link between lymphatic and venous behavior around dural sinuses and the remodeling of dural lymphatics in neurovascular conditions such as IIH. Our approach will combine radiological observations from human patients with experimental analyses in mouse models. The investigators have recently developed a technique of high resolution vessel wall imaging to explore and compare the lymphatic networks between individuals. This advanced MR-imaging technique has been validated through a translational study comparing the lymphatic networks in mice and humans (Jacob et al. 2022, JExpMed). Using this tool, the investigators aim to monitor dural lymphatic and sinus wall abnormalities in patients with IIH. In this view, cohorts of IIH patients and controls without neurological disorders (n = 20/cohort) will be scanned by MRI to perform high resolution vessel wall imaging of the dural lymphatics, sinus and cerebral veins.

Fluid retention in idiopathic intracranial hypertension (IIH) (Lenck, Neurology 2018) preferentially occur at the "hot spots" of the dural lymphatic system described in mice (Ahn, Nature 2019; Ma, Nat Commun 2017; Louveau, Nat Neurosci. 2018). While the pathophysiological mechanisms of IIH are still unknown, dural venous stenoses are constant and endovascular treatment by stenting allow to decrease the intracranial pressure in most cases, suggesting a crucial role of these stenoses in the pathological process of IIH. However, the cause of dural venous sinsu stenoses are still unknown. IIH corresponds to a paradigmatic model of neurological disorder associating vascular and fluid dysfunction, since raised intracranial pressure and stenosis of the dural venous sinuses are in constant association. Dural venous stenoses are located at the transverse sinus-sigmoid sinus junction, a lymphatic reuptake point or 'hot spot', in mice. The pathological process leading to the progressive obstruction of the vein seems to directly affect the wall of the dural sinus and only secondarily its lumen (Lenck, Neurology 2018; Lenck, AJNR 2021; Lenck, Neurosurgery 2017; Kedra, JNNP 2021). Impaired lymphatic reuptake could also contribute to this pathology as suggested by the accumulation of fluid at the level of the cribriform plate, or at the Meckel's cave. Thus, the association between cerebral venous outflow obstruction and CSF accumulation in the dura mater at the hotspots of the lymphatic system suggests impaired dural lymphatic system and veno-lymphatic relationships in IIH. Since 2017, and the first demonstration by MRI of the dural lymphatics in humans by Absinta (Absinta, Elife. 2017), VWI (Vessel Wall Imaging) techniques have been significantly improved in terms of resolution allowing an analysis of the cerebral vessel wall (Xie et al. Magn Reson Med. 2016). These techniques were mainly developed in the context of arterial wall abnormalities but have never been applied to the study of the dural venous wall and its lymphatics. The 3D T1 SPACE (variable flip angle turbo spin echo) - DANTE (delay alternating with nutation for tailored excitation) sequence has been recently developed and allows to improve the suppression of the intravascular signal and consequently to improve the resolution of the vessel wall imaging (Xie et al. Magn Reson Med. 2016). In collaboration with Siemens, our team has further developed and improved this advanced VWI technique and performed a translational comparative study comparing the dural lymphatic network between humans and mice to validate its preliminary results (Jacob, J. Exp. Med 2022). This study allowed to characterize the entire dural lymphatic network with high resolution and in three dimensions, as well as its connections with the cervical lymph nodes in humans. Furthermore, the investigators firstly demonstrated the presence of a ventral lymphatic network around the cavernous sinus. Our results seem superior to previous radiological protocols for qualitative and large field analysis of the parasinus and its lymphatics. Image processing by dedicated segmentation software (3D-Slicer) allows a three-dimensional reconstruction of the veno-lymphatic network in humans but also its quantitative analysis. This represents a major scientific breakthrough allowing objective comparisons of these networks between pathologies. IIH is a still mysterious and poorly known entity at the frontiers of neurology, neurosurgery and ophthalmology. It affects young women of childbearing age and can lead to a major deterioration in the quality of life through headaches, visual impairment or even the blindness that it can cause. All available treatments (Acetazolamide, CSF diversion, venous stent) are active on the symptoms of the disease but do not target its cause. Their effectiveness is limited, they are invasive and associated with significant risks and adverse effects. More effective and less invasive therapies, directly targeting the biological cause of IIH, therefore represent a major medical challenge. However, a prerequisite before considering such approach is to understand the pathophysiological bases underlying IIH. Our project combines innovative experimental approaches in surgery and imaging on murine models with the previously described development of lymphatic imaging in humans in patients with IIH and controls. The ultimate goal of our research is to open therapeutic avenues with realistic potential to improve the prognosis of patients with IIH. In this study the investigators will enroll 20 female patients with IIH and 20 female healthy volunteers between 20 and 40 years old. Our primary objective is to compare the anatomy of the dural lymphatic network in patients with IIH compared to healthy subjects. Our secondary objectives are: * Characterization in high resolution VWI imaging of dural venous sinus stenoses in IIH * Morphometric study of the cervical lymphatic network in patients with IIH compared to healthy subjects. * Comparison of the volume of the different compartments of the skull between patients with IIH and healthy volunteers (cerebral volume, intraventricular CSF volume (lateral ventricles), intradural venous volume)