L’éculizumab est aujourd’hui approuvé dans le traitement de la neuromyélite optique (NMOSD). Le ravulizumab possède une demi-vie plus longue, ce qui permet un intervalle d’administration plus ...important.
L’objectif est d’évaluer, à travers l’étude de phase 3 CHAMPION-307, l’efficacité et la sécurité du ravulizumab chez des adultes atteints de neuromyélite optique positifs aux anticorps anti-aquaporine 4 (NMOSD AQP4+).
Patients adultes recevant du ravulizumab en intraveineuse en fonction de leur poids (dose de charge à j1 et dose d’entretien à j15 puis toutes les 8 semaines). Pour des raisons éthiques et en raison de la disponibilité de l’éculizumab et d’autres traitements, le bras placebo de PREVENT a été utilisé comme comparateur externe. Le critère d’évaluation principal était le délai d’apparition de la première poussée ainsi que la réduction du risque de poussée (RRR).
L’étude a atteint son critère d’évaluation principal avec 0 rechute (58 patients) dans le groupe ravulizumab (médiane de suivi 73,5 semaines) contre 20 (47 patients) dans le groupe placebo (médiane de suivi 36 semaines), ce qui représente 98,6 % de RRR pour le ravulizumab et un taux annualisé de poussée de 0,00 contre 0,42 pour le groupe Placebo. au total, 93,1 % d’évènements indésirables ont été observés dans le groupe ravulizumab contre 95,7 % dans le groupe Placebo.
Le ravulizumab administré toutes les 8 semaines a démontré son efficacité chez les patients NMOSD AQP4+ dans l’étude de Phase III Champion 307. En effet, aucune poussée n’a été observée dans le groupe traité contrairement au groupe Placebo externe de PREVENT. De plus, aucun nouveau signal de tolérance n’a été mis en évidence par le traitement dans cet essai.
Chez les patients atteints de NMOSD AQP4+, le ravulizumab a significativement réduit le risque de rechute et le profil de tolérance était conforme avec celui observé dans les autres indications.
Le spectre de la neuromyélite optique (NMOSD) est un ensemble des maladies inflammatoires du système nerveux central. Sa classification a été définie grâce à des biomarqueurs comme les ...anti-aquaporine4 (anti-AQP4).
Décrire les différentes manifestations cliniques, radiologiques et évolutives du NMOSD en fonction du statut sérologique AQP4 des patients.
C’est une étude descriptive et analytique menée au service de neurologie CHU Habib Bourguiba Sfax, Tunisie durant une période de 6 ans (2014–2020) incluant les patients suivis pour NMOSD définie selon les critères International Panel for NMO Diagnosis (IPND) de 2015. Nous avons défini deux groupes selon le statut des AQP4 : G1 séropositif et G2 séronégatif. Pour chaque groupe, nous avons déterminé les caractéristiques sociodémographiques, les manifestations cliniques, les aspects radiologiques et le profil évolutif.
Quinze patients étaient colligés dont 10 avaient des AQP4+. Une prédominance féminine était notée chez les 2 groupes avec un âge moyen de début de la maladie à 45,73 ans. La fréquence du tableau clinique de myélite et\ou de névrite optique était similaire entre les 2 groupes. Sur le plan radiologique : tous les patients du G1 ont une myélite aiguë longitudinale transversale étendue contrairement à 40 % des patients AQP4− (p<0,05). L’évolution était récurrente pour les deux groupes.
Conformément à la littérature, 2/3 des patients avaient des AQP4+. Ils avaient des lésions médullaires plus étendues, comparativement aux AQP4−. Par ailleurs, selon la littérature, les patients AQP4− présentaient un tableau de myélite combinée à une névrite optique plus que les patients AQP4+, ce qui n’était pas le cas dans notre cohorte
Conformément à la littérature, on a recensé 2/3 des patients ayant des AQP4+, qui avaient des caractéristiques différentes des patients AQP4− tel que des lésions médullaires plus étendues.
La neuromyélite optique de Devic (NMO) et les syndromes liés aux anti-myelin oligodendrocyte glycoprotein (MOG) sont des affections à médiation immunitaire. Nous rapportons deux cas de NMO et de ...MOGopathie associés à un cancer mammaire et gastrique.
Mme D.O., 45 ans présenta une névrite optique bilatérale sévère et une myélite aiguë transverse longitudinalement étendue, la recherche d’anticorps anti-aquaporine 4 (AQP4) était positive signant le diagnostic de neuromyélite optique de Devic, le bilan avait concomitamment retrouvé un adénocarcinome évolutif du sein gauche jusque là méconnu, un traitement par immunothérapie associé à un traitement carcinologique ont permis le contrôle des troubles neurologiques.
Mme T.K., 40 ans présenta un syndrome sensitif des quatre membres associé à un signe de Lhermitte, l’IRM cérébrale et médullaire ont mis en évidence une image en hyperT2 flair de la région bulbo-medullaire. Le diagnostic de MOGopathie a été retenu sur la positivité des anticorps anti-MOG, le bilan étiologique permit la découverte d’un cancer gastrique métastatique évolutif.
Si de rares cas de NMO ont été occasionnellement décrits en association avec un cancer, principalement une néoplasie du sein, de la thyroïde et des tumeurs neuroendocrines, aucun cas de MOG+ n’ a été décrit associé à un cancer chez l’adulte ou chez l’enfant.
les anti-aquaporines 4 peuvent refléter dans certains cas de NMO une réponse immunitaire paranéoplasique, pourrait-il en être de même pour les anti-MOG ? L’utilité clinique de rechercher un cancer dans ces deux entités reste justifiée.
Summary
The term ‘neuromyelitis optica’ (‘Devic's syndrome’, NMO) refers to a syndrome characterized by optic neuritis and myelitis. In recent years, the condition has raised enormous interest among ...scientists and clinical neurologists, fuelled by the detection of a specific serum immunoglobulin (Ig)G reactivity (NMO‐IgG) in up to 80% of patients with NMO. These autoantibodies were later shown to target aquaporin‐4 (AQP4), the most abundant water channel in the central nervous system (CNS). Here we give an up‐to‐date overview of the clinical and paraclinical features, immunopathogenesis and treatment of NMO. We discuss the widening clinical spectrum of AQP4‐related autoimmunity, the role of magnetic resonance imaging (MRI) and new diagnostic means such as optical coherence tomography in the diagnosis of NMO, the role of NMO‐IgG, T cells and granulocytes in the pathophysiology of NMO, and outline prospects for new and emerging therapies for this rare, but often devastating condition.
Neuromyelitis optica (NMO) is a disabling autoimmune astrocytopathy characterized by typically severe and recurrent attacks of optic neuritis and longitudinally extensive myelitis. Until recently, ...NMO was considered an acute aggressive variant of multiple sclerosis (MS), despite the fact that early studies postulated that NMO and MS may be two distinct diseases with a common clinical picture. With the discovery of a highly specific serum autoantibody (NMO‐IgG), Lennon and colleagues provided the first unequivocal evidence distinguishing NMO from MS and other central nervous system (CNS) inflammatory demyelinating disorders. The target antigen of NMO‐IgG was confirmed to be aquaporin‐4 (AQP4), the most abundant water channel protein in the CNS, mainly expressed on astrocytic foot processes at the blood–brain barrier, subpial and subependymal regions. Pathological studies demonstrated that astrocytes were selectively targeted in NMO as evidenced by the extensive loss of immunoreactivities for the astrocytic proteins, AQP4 and glial fibrillary acidic protein (GFAP), as well as perivascular deposition of immunoglobulins and activation of complement even within lesions with a relative preservation of myelin. In support of these pathological findings, GFAP levels in the cerebrospinal fluid (CSF) during acute NMO exacerbations were found to be remarkably elevated in contrast to MS where CSF‐GFAP levels did not substantially differ from controls. Additionally, recent experimental studies showed that AQP4 antibody is pathogenic, resulting in selective astrocyte destruction and dysfunction in vitro, ex vivo and in vivo. These findings strongly suggest that NMO is an autoimmune astrocytopathy where damage to astrocytes exceeds both myelin and neuronal damage. This chapter will review recent neuropathological studies that have provided novel insights into the pathogenic mechanisms, cellular targets, as well as the spectrum of tissue damage in NMO.
Stroke is the second leading cause of death and the third leading cause of disability globally. Edema is a hallmark of stroke resulting from dysregulation of water homeostasis in the central nervous ...system (CNS) and plays the major role in stroke-associated morbidity and mortality. The overlap between cellular and vasogenic edema makes treating this condition complicated, and to date, there is no pathogenically oriented drug treatment for edema. Water balance in the brain is tightly regulated, primarily by aquaporin 4 (AQP4) channels, which are mainly expressed in perivascular astrocytic end-feet. Targeting AQP4 could be a useful therapeutic approach for treating brain edema; however, there is no approved drug for stroke treatment that can directly block AQP4. In this study, we demonstrate that the FDA-approved drug trifluoperazine (TFP) effectively reduces cerebral edema during the early acute phase in post-stroke mice using a photothrombotic stroke model. This effect was combined with an inhibition of AQP4 expression at gene and protein levels. Importantly, TFP does not appear to induce any deleterious changes on brain electrolytes or metabolic markers, including total protein or lipid levels. Our results support a possible role for TFP in providing a beneficial extra-osmotic effect on brain energy metabolism, as indicated by the increase of glycogen levels. We propose that targeting AQP4-mediated brain edema using TFP is a viable therapeutic strategy during the early and acute phase of stroke that can be further investigated during later stages to help in developing novel CNS edema therapies.
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•The drug trifluoperazine (TFP) effectively reduces cerebral edema during the acute phase in post-stroke mice.•This effect was combined with an inhibition of AQP4 expression at gene and protein levels.•TFP affects brain energy metabolism, as indicated by the increase of glycogen levels.•Targeting AQP4-mediated brain edema using TFP can be a viable therapeutic strategy in stroke.
Objectives
Recent evidence has associated mood disorders with blood‐brain barrier (BBB)/ neurovascular unit (NVU) dysfunction, and reduction in blood vessels coverage by the water channel aquaporin‐4 ...(AQP4) immunoreactive astrocytes. Lithium is an established treatment for mood disorders, yet, its mechanism of action is partially understood. We investigated the effects of lithium on BBB integrity and NVU‐related protein expression in chronic mild stress (CMS) rat model of depressive‐like behavior.
Methods
Male Wistar rats were exposed for 5 weeks to unpredictable mild stressors with daily co‐administration of lithium chloride to half of the stressed and unstressed groups. Sucrose preference and open field tests were conducted to validate the depressive‐like phenotype, and dynamic contrast‐enhanced MRI analysis was utilized to assess BBB integrity in brain regions relevant to the pathophysiology of depression. Hippocampal AQP4 and claudin‐5 expression were studied using immunofluorescence, western blot, and enzyme‐linked immunosorbent assays.
Results
Lithium administration to the stressed rats prevented the reductions in sucrose preference and distance traveled in the open field, and normalized the stress‐induced hippocampal BBB hyperpermeability, whereas lithium administration to the unstressed rats increased hippocampal BBB permeability. Additionally, lithium treatment attenuated the decrease in hippocampal AQP4 to glial fibrillary acidic protein immunoreactivity ratio in the stressed rats and upregulated hippocampal claudin‐5 and BDNF proteins expression.
Conclusions
Our findings suggest that lithium administration in a rat CMS model of depressive‐like behavior is associated with attenuation of stressed‐induced hippocampal BBB/NVU disruption. These protective effects may be relevant to the mode of action of lithium in depression.
Background:
MOG antibody and AQP4 antibody seropositive diseases are immunologically distinct subtypes of neuromyelitis optica spectrum disorders (NMOSD) with similar clinical presentations. MRI ...findings can be instrumental in distinguishing MOG antibody disease from AQP4 antibody NMOSD.
Objectives:
The aim of this study is to characterize the neuroradiological differences between MOG antibody disease and AQP4 antibody NMOSD with the aim to distinguish between the two entities.
Methods:
This is a retrospective study of 26 MOG and 25 AQP4 seropositive patients in which MRI features of the brain, spinal cord, and orbit were compared.
Results:
The majority of the abnormal findings in the MOG cohort were located on orbital MRIs, while spinal cord magnetic resonance (MR) abnormalities were more common in the AQP4 cohort. Brain abnormalities showed some overlap, but cortical gray/juxtacortical white matter involvement was distinct to MOG patients, while area postrema involvement was a rare feature.
Conclusion:
Cortical gray/juxtacortical white matter lesions on brain MRI might help distinguish MOG antibody disease from AQP4-positive NMOSD. These findings could be of value in distinguishing the two entities as early as the first presentation.
Abstract Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear ...whether glymphatic transport affects the distribution of soluble Aβ in Alzheimer's disease (AD). In wild type mice, we show that Aβ40 (fluorescently labeled Aβ40 or unlabeled Aβ40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, Aβ42 was mostly restricted to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to Aβ40. Interestingly, pretreatment with Aβ40 in the CSF, but not Aβ42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-β deposits, glymphatic transport was reduced, due to the accumulation of toxic Aβ species, such as soluble oligomers. CSF-derived Aβ40 co-localizes with existing endogenous vascular and parenchymal amyloid-β plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal Aβ accumulation. Importantly, glymphatic failure preceded significant amyloid-β deposits, and thus, may be an early biomarker of AD. By extension, restoring glymphatic inflow and ISF clearance are potential therapeutic targets to slow the onset and progression of AD.
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