Dilated Virchow-Robin spaces are a marker for arterial disease in multiple sclerosis

BACKGROUND Virchow-Robin spaces (VRS) have been associated with neurodegeneration and neuroinflammation. However, it remains uncertain to what degree non-dilated or dilated VRS reflect specific features of neuroinflammatory pathology. Thus, we aimed at investigating the clinical relevance of VRS as imaging biomarker in multiple sclerosis (MS) and to correlate VRS to their histopathologic signature. METHODS In a cohort study comprising 142 MS patients and 30 control subjects, we assessed the association of non-dilated and dilated VRS to clinical and magnetic resonance imaging (MRI) outcomes. Findings were corroborated in a validation cohort comprising 63 MS patients. Brain blocks from 6 MS patients and 3 non-MS controls were histopathologically processed to correlate VRS to their tissue substrate. FINDINGS In our actively treated clinical cohort, the count of dilated centrum semiovale VRS was associated with increased T1 and T2 lesion volumes. There was no systematic spatial colocalization of dilated VRS with MS lesions. At tissue level, VRS mostly corresponded to arteries and were not associated with MS pathological hallmarks. Interestingly, in our ex vivo cohort comprising mostly progressive MS patients, dilated VRS in MS were associated with signs of small vessel disease. INTERPRETATION Contrary to prior beliefs, these observations suggest that VRS in MS do not associate with an accumulation of immune cells. But instead, these findings indicate vascular pathology as a driver and/or consequence of neuroinflammatory pathology for this imaging feature. FUNDING NIH, Swedish Society for Medical Research, Swiss National Science Foundation and University of Zurich

The etiology and evolution of magnetic resonance imaging-visible perivascular spaces: Systematic review and meta-analysis

ObjectivesPerivascular spaces have been involved in neuroinflammatory and neurodegenerative diseases. Upon a certain size, these spaces can become visible on magnetic resonance imaging (MRI), referred to as enlarged perivascular spaces (EPVS) or MRI-visible perivascular spaces (MVPVS). However, the lack of systematic evidence on etiology and temporal dynamics of MVPVS hampers their diagnostic utility as MRI biomarker. Thus, the goal of this systematic review was to summarize potential etiologies and evolution of MVPVS.MethodsIn a comprehensive literature search, out of 1,488 unique publications, 140 records assessing etiopathogenesis and dynamics of MVPVS were eligible for a qualitative summary. 6 records were included in a meta-analysis to assess the association between MVPVS and brain atrophy.ResultsFour overarching and partly overlapping etiologies of MVPVS have been proposed: (1) Impairment of interstitial fluid circulation, (2) Spiral elongation of arteries, (3) Brain atrophy and/or perivascular myelin loss, and (4) Immune cell accumulation in the perivascular space. The meta-analysis in patients with neuroinflammatory diseases did not support an association between MVPVS and brain volume measures [R: −0.15 (95%-CI −0.40–0.11)]. Based on few and mostly small studies in tumefactive MVPVS and in vascular and neuroinflammatory diseases, temporal evolution of MVPVS is slow.ConclusionCollectively, this study provides high-grade evidence for MVPVS etiopathogenesis and temporal dynamics. Although several potential etiologies for MVPVS emergence have been proposed, they are only partially supported by data. Advanced MRI methods should be employed to further dissect etiopathogenesis and evolution of MVPVS. This can benefit their implementation as an imaging biomarker.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=346564, identifier CRD42022346564

İskemik İnme Hastalarında İskemik Lezyonun Karşı Hemisferinde Oluşan Serebral Hacim Kaybının İnme İlişkili İnflamasyon ile İlişkisi

Central nervous system (CNS) and immune system are in a two-way relationship with a delicate homeostatic balance. This relationship is disrupted following CNS insults, such as ischemic stroke. The introduction of cerebral parenchyma-specific antigens into the systemic circulation after stroke, triggers a natural and adaptive immune response directed towards the focal ischemic tissue. As a protective reaction, mechanisms involving the hypopituitary adrenal axis, the sympathetic nervous system, the parasympathetic nervous system induce an immune-depressive response in the peripheral immune system; however, this leads to an infection prone state in stroke patients. It is considered that these intimate cascades of inflammation, immune-depression and infection are associated with neuro-glial loss in cerebral tissue in the long term. In this study, our aim was to determine whether cerebral volume loss occurs in the unaffected hemisphere contralateral to the ischemic hemisphere, and identify factors associated with this possible volume loss. A total of 31 patients with ischemic stroke were enrolled into the study; parameters including clinical features, laboratory values (complete blood count, erythrocyte sedimentation rate, C-reactive protein, procalcitonin), heart rate variability, and development of infections following stroke were collected in all patients. Contralateral hemisphere volume was determined by voxel-based morphometry on admission and follow-up magnetic resonance imaging (MRI). The contralateral hemisphere volume decreased by a median (IQR) of 2.53% (0.63-5.72) on images obtained after a median follow-up of 73 (52-114) days (p <0.001). The monthly volume reduction was 1.26% (0.00-2,53). Baseline NIH stroke scale score, infarct volume, neutrophil count, neutrophil / lymphocyte ratio, SAPS II score and pneumonia or urinary tract infection during admission constituted factors significantly associated with monthly volume loss in the contralateral hemisphere (p <0.05). When various combinations of variables related to stroke severity (NIH stroke scale score, infarct volume, SAPS II score) and inflammatory response (neutrophil/lymphocyte ratio, development of infections) were assessed in multivariate regression models, both variable groups remained independently associated with monthly volume loss. These findings suggest that cerebral volume loss is not limited to the symptomatic hemisphere in ischemic stroke patients and this volume loss is related to stroke severity and impaired CNS-immune system homeostasis.Santral sinir sistemi (SSS) ve immun sistem iki yönlü bir ilişki içerisinde olup bu ilişki homeostatik bir denge içerisindedir. İskemik inme gibi SSS’de hasar yaratan süreçlerde bu iki yönlü ilişki bozulmaktadır. İnme sonrası serebral parankime özgü antijenlerin sistemik dolaşıma girmesi fokal iskemik dokuya karşı doğal ve adaptif immun yanıtın tetiklenmesine neden olur. Bu yanıtın baskılanmasına karşı koruyucu bir süreç olarak hipopituiter adrenal aks, sempatik sinir sistemi, parasempatik sinir sistemi aracılı mekanizmaların devreye girmesi ile periferik immun sistem üzerinde immun depresyon cevabı oluşur; ancak bu cevap inme hastalarının sistemik enfeksiyonlara yatkın hale gelmesine neden olmaktadır. İnflamasyon, immunodepresyon, enfeksiyon kaskadlarının içe içe geçtiği bu döngülerin uzun dönemde serebral dokuda nöro-glial kayıp ile ilişkili olduğu düşünülmektedir. Bu çalışmanın amacı iskemik inme sonrası sağlam, kontralateral hemisferde olası serebral atrofi gelişimi olup olmadığı ortaya koymak ve hacim kaybı ile ilişkili faktörleri belirlemektir. Çalışmaya 31 iskemik inme hastası dahil edilerek klinik, laboratuvar (tam kan sayımı, eritrosit sedimentasyon hızı, C-reaktif protein, prokalsitonin), kalp hızı değişkenlik analizi, inme sonrası izlemde enfeksiyon gelişimi ile ilgili veriler toplandı. Başvuru ve takip manyetik rezonans görüntüleme (MRG) incelemelerinde voksel bazlı morfometrik ölçüm metodolojisi ile kontralateral hemisfer hacim değerleri hesaplandı. Başvuru sonrası ortanca (ÇAA) 73 (52-114) gün sonra alınan görüntülerde, sağlam hemisferde bazal incelemeye göre tüm izlem süreci boyunca %2,53 (0,63-5,72) ve aylık olarak %1,26 (0,00-2,53) azalma saptandı (p<0,001). İkili karşılaştırmalarda aylık sağlam hemisfer hacim kaybı ile ilişkili faktörler olarak başvuru NIH inme skoru, enfarkt hacmi, nötrofil sayısı, nötrofil/lenfosit oranı, SAPS II skoru ve izlemde pnömoni veya idrar yolu enfeksiyonu gelişimi bulundu (p<0,05). İnme şiddeti (NIH inme skoru, enfarkt hacmi, SAPS II skoru) ve inflamatuar cevap (izlemde infeksiyon gelişmesi, başvuru nötrofil/lenfosit oranı) ile ilgili değişkenlerin çeşitli kombinasyonları çok değişkenli regresyon modelinde değerlendirildiğinde, her iki grup faktörün aylık volüm kaybı ile ilişkisinin sebat ettiği görüldü. Bu bulgular, iskemik inme hastalarında serebral hacim kaybının enfarktın etkilendiği hemisferle sınırlı kalmadığını ve bu hacim kaybının inme şiddeti ve inme sonrası SSS immun sistem homeostazının bozukluğu ile ilişkili olabileceğine işaret etmektedi

The etiology and evolution of magnetic resonance imaging-visible perivascular spaces: Systematic review and meta-analysis

OBJECTIVES: Perivascular spaces have been involved in neuroinflammatory and neurodegenerative diseases. Upon a certain size, these spaces can become visible on magnetic resonance imaging (MRI), referred to as enlarged perivascular spaces (EPVS) or MRI-visible perivascular spaces (MVPVS). However, the lack of systematic evidence on etiology and temporal dynamics of MVPVS hampers their diagnostic utility as MRI biomarker. Thus, the goal of this systematic review was to summarize potential etiologies and evolution of MVPVS. METHODS: In a comprehensive literature search, out of 1,488 unique publications, 140 records assessing etiopathogenesis and dynamics of MVPVS were eligible for a qualitative summary. 6 records were included in a meta-analysis to assess the association between MVPVS and brain atrophy. RESULTS: Four overarching and partly overlapping etiologies of MVPVS have been proposed: (1) Impairment of interstitial fluid circulation, (2) Spiral elongation of arteries, (3) Brain atrophy and/or perivascular myelin loss, and (4) Immune cell accumulation in the perivascular space. The meta-analysis in patients with neuroinflammatory diseases did not support an association between MVPVS and brain volume measures [R: -0.15 (95%-CI -0.40-0.11)]. Based on few and mostly small studies in tumefactive MVPVS and in vascular and neuroinflammatory diseases, temporal evolution of MVPVS is slow. CONCLUSION: Collectively, this study provides high-grade evidence for MVPVS etiopathogenesis and temporal dynamics. Although several potential etiologies for MVPVS emergence have been proposed, they are only partially supported by data. Advanced MRI methods should be employed to further dissect etiopathogenesis and evolution of MVPVS. This can benefit their implementation as an imaging biomarker

Perivascular spaces and their role in neuroinflammation.

It is uncontested that perivascular spaces play critical roles in maintaining homeostasis and priming neuroinflammation. However, despite more than a century of intense research on perivascular spaces, many open questions remain about the anatomical compartment surrounding blood vessels within the CNS. The goal of this comprehensive review is to summarize the literature on perivascular spaces in human neuroinflammation and associated animal disease models. We describe the cell types taking part in the morphological and functional aspects of perivascular spaces and how those spaces can be visualized. Based on this, we propose a model of the cascade of events occurring during neuroinflammatory pathology. We also discuss current knowledge gaps and limitations of the available evidence. An improved understanding of perivascular spaces could advance our comprehension of the pathophysiology of neuroinflammation and open a new therapeutic window for neuroinflammatory diseases such as multiple sclerosis

Neuroinvasive Listeriosis Could Petechial Hemorrhages be a Diagnostic Clue?

Introduction:Listeria monocytogenes-related central nervous system infections may involve the cerebral parenchyma. Meningitis and meningoencephalitis are the most commonly seen forms and mainly affect immunocompromised patients; however, a less frequent form, rhombencephalitis, can occur in otherwise healthy people. Early treatment with appropriate antibiotic therapy is crucial for this otherwise fatal disorder. However, it is not always possible to rapidly establish the diagnosis because of varying presentations and discrepancies in diagnostic tests.Case Report:Herein we report 3 cases of listerial infections involving the central nervous system parenchyma, with versatile diagnostic challenges and related possible solutions and radiologic hints to overcome similar issues in the future.Conclusions:We point out the importance of nonconventional magnetic resonance imaging techniques in the diagnosis, as we detected petechial hemorrhages in the brain parenchyma in all cases, which can be a diagnostic clue