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MR Lymphatic Imaging in Idiopathic Intracranial Hypertention (LYMPHIMAGIIH)

Primary Purpose

Idiopathic Intracranial Hypertension

Status
Not yet recruiting
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
3T MRI with Gadobutrol injection
Sponsored by
Institut National de la Santé Et de la Recherche Médicale, France
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Idiopathic Intracranial Hypertension focused on measuring Dural venous stenoses, MRI, Vessel Wall Imaging, Headache, Papilledema

Eligibility Criteria

20 Years - 40 Years (Adult)FemaleAccepts Healthy Volunteers

Inclusion Criteria: For all participants: Age > 18 years and ≤ 40 years female gender Absence of previous neurosurgical or endovascular neurological history Participant able to express her consent Medical insurance For participants with IIH No required criterion of severity or evolution of IIH Definite diagnosis of IIH according to Dandy's modified criteria. All of the following criteria must be met and verified by medical reports or certificates from a neurologist, especially the value of the CSF opening pressure measured during the lumbar puncture must be clearly noted on the reports History of papilledema Normal neurological examination, except for paralysis of the VIth cranial nerve Neuroimaging: normal cerebral parenchyma without hydrocephalus, intracranial expansive process, or structural anomaly, and absence of meningeal contrast enhancement in MRI without and with contrast product. A venous angio-MRI is necessary in atypical patients; if MRI is unavailable or contraindicated, a brain scan without and with contrast product can be done in combination with a venous angioscan with contrast injection Normal CSF composition High CSF opening pressure (≥ 25 cm of water) obtained from a lumbar puncture performed in lateral decubitus For healthy volunteers No previous history of neurological or neurosurgical disorder Exclusion Criteria: For all participants Pregnant or breastfeeding woman Contraindication to cerebral MRI: metallic implant, pacemaker, artificial heart valve, cerebral vascular malformation, aneurysm clips, metallic fragments, artificial implants, peripheral or neural pacemaker, insulin pump, intravenous catheter, epilepsy , metallic contraceptive device, claustrophobia, refusal to be informed in case of abnormal MRI (with a significant medical abnormality) Hypersensitivity to the active substance of the contrast agent or to any of the excipients (Sodium calcobutrol, Trometamol, 1N hydrochloric acid (pH adjustment), Water for injections) lumbar puncture in the month preceding the brain MRI Neurological tumoral, degenerative, vascular, inflammatory or progressive pathology Renal or hepatic impairment MRI with gadolinium injection performed in the 7 days preceding the inclusion visit Person subject to a measure of legal protection (safeguard of justice, curatorship, guardianship), deprived of liberty by judicial or administrative decision For participants with IIH Participants with a probable but not definite diagnosis of IIH according to the Dandy modified criteria For healthy volunteers Chronic headaches (>15 days per month) Uncorrected and/or unlabeled visual symptoms (visual blurriness, diplopia, visual eclipses, papilledema, optic atrophy)

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Active Comparator

    Arm Label

    Patients with IIH

    Healthy volunteers

    Arm Description

    Female patients with IIH between 20 and 40 years old

    Female healthy volunteers between 20 and 40 years old

    Outcomes

    Primary Outcome Measures

    Morphometric study of the dural lymphatic network in patients with IIH vs controls
    Measurement of the dural lymphatic network volume (mm3) in patients with IIH vs controls

    Secondary Outcome Measures

    Characterization of lateral sinus stenoses using high resolution vessel wall imaging in patients with IIH
    Measurement of the volume of the dural lymphatic vessels at the transverse-sigmoid junction in patients with IIH vs control Measurement of the thickness of the parasinus at the transverse-sigmoid junction in patients with IIH vs control Measurement of the stenosis (ratio intraluminal diameter at the level of the stenosis and intraluminal diameter of the transverse sinus upstream) in patients with IIH Presence of intraluminal granulation in patients with IIH vs control Qualitative analysis of dural venous stenoses in patients with IIH
    Morphometric study of the cervical lymphatic network in patients with IIH vs controls
    Comparison of the volume of the cervical lymph nodes in patients with IIH vs controls
    Comparison of the volumes of the different compartments of the skull in patients with IIH vs controls
    Brain volume in patients with IIH vs controls Intraventricular CSF volume of the lateral ventricles in patients with IIH vs controls Intradural venous volume in patients with IIH vs controls

    Full Information

    First Posted
    February 28, 2023
    Last Updated
    March 9, 2023
    Sponsor
    Institut National de la Santé Et de la Recherche Médicale, France
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05762367
    Brief Title
    MR Lymphatic Imaging in Idiopathic Intracranial Hypertention
    Acronym
    LYMPHIMAGIIH
    Official Title
    MR Lymphatic Imaging in Idiopathic Intracranial Hypertension
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    March 10, 2023 (Anticipated)
    Primary Completion Date
    March 9, 2025 (Anticipated)
    Study Completion Date
    March 10, 2025 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Institut National de la Santé Et de la Recherche Médicale, France

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    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.
    Detailed Description
    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)

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Idiopathic Intracranial Hypertension
    Keywords
    Dural venous stenoses, MRI, Vessel Wall Imaging, Headache, Papilledema

    7. Study Design

    Primary Purpose
    Diagnostic
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Model Description
    20 patients with IIH and 20 volunteers paired on age (20-40 yo) and gender will be prospectively enrolled in the study
    Masking
    InvestigatorOutcomes Assessor
    Masking Description
    MRI will be pseudo-anonymised and blindly analyzed
    Allocation
    Non-Randomized
    Enrollment
    40 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Patients with IIH
    Arm Type
    Experimental
    Arm Description
    Female patients with IIH between 20 and 40 years old
    Arm Title
    Healthy volunteers
    Arm Type
    Active Comparator
    Arm Description
    Female healthy volunteers between 20 and 40 years old
    Intervention Type
    Diagnostic Test
    Intervention Name(s)
    3T MRI with Gadobutrol injection
    Intervention Description
    MRI will be performed in all participants before and after Gadobutrol injection
    Primary Outcome Measure Information:
    Title
    Morphometric study of the dural lymphatic network in patients with IIH vs controls
    Description
    Measurement of the dural lymphatic network volume (mm3) in patients with IIH vs controls
    Time Frame
    Immediate
    Secondary Outcome Measure Information:
    Title
    Characterization of lateral sinus stenoses using high resolution vessel wall imaging in patients with IIH
    Description
    Measurement of the volume of the dural lymphatic vessels at the transverse-sigmoid junction in patients with IIH vs control Measurement of the thickness of the parasinus at the transverse-sigmoid junction in patients with IIH vs control Measurement of the stenosis (ratio intraluminal diameter at the level of the stenosis and intraluminal diameter of the transverse sinus upstream) in patients with IIH Presence of intraluminal granulation in patients with IIH vs control Qualitative analysis of dural venous stenoses in patients with IIH
    Time Frame
    Immediate
    Title
    Morphometric study of the cervical lymphatic network in patients with IIH vs controls
    Description
    Comparison of the volume of the cervical lymph nodes in patients with IIH vs controls
    Time Frame
    Immediate
    Title
    Comparison of the volumes of the different compartments of the skull in patients with IIH vs controls
    Description
    Brain volume in patients with IIH vs controls Intraventricular CSF volume of the lateral ventricles in patients with IIH vs controls Intradural venous volume in patients with IIH vs controls
    Time Frame
    Immediate

    10. Eligibility

    Sex
    Female
    Minimum Age & Unit of Time
    20 Years
    Maximum Age & Unit of Time
    40 Years
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    Eligibility Criteria
    Inclusion Criteria: For all participants: Age > 18 years and ≤ 40 years female gender Absence of previous neurosurgical or endovascular neurological history Participant able to express her consent Medical insurance For participants with IIH No required criterion of severity or evolution of IIH Definite diagnosis of IIH according to Dandy's modified criteria. All of the following criteria must be met and verified by medical reports or certificates from a neurologist, especially the value of the CSF opening pressure measured during the lumbar puncture must be clearly noted on the reports History of papilledema Normal neurological examination, except for paralysis of the VIth cranial nerve Neuroimaging: normal cerebral parenchyma without hydrocephalus, intracranial expansive process, or structural anomaly, and absence of meningeal contrast enhancement in MRI without and with contrast product. A venous angio-MRI is necessary in atypical patients; if MRI is unavailable or contraindicated, a brain scan without and with contrast product can be done in combination with a venous angioscan with contrast injection Normal CSF composition High CSF opening pressure (≥ 25 cm of water) obtained from a lumbar puncture performed in lateral decubitus For healthy volunteers No previous history of neurological or neurosurgical disorder Exclusion Criteria: For all participants Pregnant or breastfeeding woman Contraindication to cerebral MRI: metallic implant, pacemaker, artificial heart valve, cerebral vascular malformation, aneurysm clips, metallic fragments, artificial implants, peripheral or neural pacemaker, insulin pump, intravenous catheter, epilepsy , metallic contraceptive device, claustrophobia, refusal to be informed in case of abnormal MRI (with a significant medical abnormality) Hypersensitivity to the active substance of the contrast agent or to any of the excipients (Sodium calcobutrol, Trometamol, 1N hydrochloric acid (pH adjustment), Water for injections) lumbar puncture in the month preceding the brain MRI Neurological tumoral, degenerative, vascular, inflammatory or progressive pathology Renal or hepatic impairment MRI with gadolinium injection performed in the 7 days preceding the inclusion visit Person subject to a measure of legal protection (safeguard of justice, curatorship, guardianship), deprived of liberty by judicial or administrative decision For participants with IIH Participants with a probable but not definite diagnosis of IIH according to the Dandy modified criteria For healthy volunteers Chronic headaches (>15 days per month) Uncorrected and/or unlabeled visual symptoms (visual blurriness, diplopia, visual eclipses, papilledema, optic atrophy)
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Stephanie Lenck, MD
    Phone
    +33(0)142163594
    Email
    stephanie.lenck@icm-institute.org

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    31341278
    Citation
    Ahn JH, Cho H, Kim JH, Kim SH, Ham JS, Park I, Suh SH, Hong SP, Song JH, Hong YK, Jeong Y, Park SH, Koh GY. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature. 2019 Aug;572(7767):62-66. doi: 10.1038/s41586-019-1419-5. Epub 2019 Jul 24.
    Results Reference
    background
    PubMed Identifier
    30201744
    Citation
    Lenck S, Radovanovic I, Nicholson P, Hodaie M, Krings T, Mendes-Pereira V. Idiopathic intracranial hypertension: The veno glymphatic connections. Neurology. 2018 Sep 11;91(11):515-522. doi: 10.1212/WNL.0000000000006166.
    Results Reference
    background
    PubMed Identifier
    29127332
    Citation
    Ma Q, Ineichen BV, Detmar M, Proulx ST. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat Commun. 2017 Nov 10;8(1):1434. doi: 10.1038/s41467-017-01484-6.
    Results Reference
    background
    PubMed Identifier
    30224810
    Citation
    Louveau A, Herz J, Alme MN, Salvador AF, Dong MQ, Viar KE, Herod SG, Knopp J, Setliff JC, Lupi AL, Da Mesquita S, Frost EL, Gaultier A, Harris TH, Cao R, Hu S, Lukens JR, Smirnov I, Overall CC, Oliver G, Kipnis J. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat Neurosci. 2018 Oct;21(10):1380-1391. doi: 10.1038/s41593-018-0227-9. Epub 2018 Sep 17.
    Results Reference
    background
    PubMed Identifier
    33414232
    Citation
    Lenck S, Nicholson P. Cerebral Venous Wall Diseases: The Other Side of the Picture. AJNR Am J Neuroradiol. 2021 Jan;42(2):297-298. doi: 10.3174/ajnr.A6914. Epub 2021 Jan 7. No abstract available.
    Results Reference
    background
    PubMed Identifier
    27218234
    Citation
    Lenck S, Vallee F, Labeyrie MA, Touitou V, Saint-Maurice JP, Guillonnet A, Tantot A, Crassard I, Bernat AL, Houdart E. Stenting of the Lateral Sinus in Idiopathic Intracranial Hypertension According to the Type of Stenosis. Neurosurgery. 2017 Mar 1;80(3):393-400. doi: 10.1227/NEU.0000000000001261.
    Results Reference
    background
    PubMed Identifier
    34168084
    Citation
    Kedra A, Lahlouh M, Shotar E, Chenoune Y, Boistard L, Boussac A, Shor N, Savatovsky J, Hage R, Touitou V, Nicholson P, Clarencon F, Piotin M, Blanc R, Lenck S. Global collapse of the dural sinuses after venous stenting in idiopathic intracranial hypertension. J Neurol Neurosurg Psychiatry. 2021 Dec;92(12):1363-1364. doi: 10.1136/jnnp-2020-325717. Epub 2021 Jun 24. No abstract available.
    Results Reference
    background
    PubMed Identifier
    28971799
    Citation
    Absinta M, Ha SK, Nair G, Sati P, Luciano NJ, Palisoc M, Louveau A, Zaghloul KA, Pittaluga S, Kipnis J, Reich DS. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Elife. 2017 Oct 3;6:e29738. doi: 10.7554/eLife.29738.
    Results Reference
    background
    PubMed Identifier
    26152900
    Citation
    Xie Y, Yang Q, Xie G, Pang J, Fan Z, Li D. Improved black-blood imaging using DANTE-SPACE for simultaneous carotid and intracranial vessel wall evaluation. Magn Reson Med. 2016 Jun;75(6):2286-94. doi: 10.1002/mrm.25785. Epub 2015 Jul 8.
    Results Reference
    background
    PubMed Identifier
    35776089
    Citation
    Jacob L, de Brito Neto J, Lenck S, Corcy C, Benbelkacem F, Geraldo LH, Xu Y, Thomas JM, El Kamouh MR, Spajer M, Potier MC, Haik S, Kalamarides M, Stankoff B, Lehericy S, Eichmann A, Thomas JL. Conserved meningeal lymphatic drainage circuits in mice and humans. J Exp Med. 2022 Aug 1;219(8):e20220035. doi: 10.1084/jem.20220035. Epub 2022 Jul 1.
    Results Reference
    background

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    MR Lymphatic Imaging in Idiopathic Intracranial Hypertention

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