Does Impaired Glymphatic Drainage Cause Glymphedema? A Review Tailored to Neurocritical Care and Neurosurgery

Glymphatic Pathway

AbstractResearch into the glymphatic system reached an inflection point with steep trajectory in 2012 when it was formally recognized and named, but the historical roots for it are solid and deep, dating back to pioneers such as Cushing, Weed, and Dandy. We provide an overview of key discoveries of the glymphatic system, which promotes bulk flow of fluid and solutes throughout the brain parenchyma. We also discuss the lymphatic drainage of the central nervous system. Evidence is building that failure of the glymphatic system causes glymphedema in patients commonly managed by neurocritical care and neurosurgery specialists. We review research supporting this for decompressive craniectomy, subarachnoid hemorrhage, and normal-pressure hydrocephalus. We argue that it is time for a paradigm shift from the traditional model of cerebrospinal fluid circulation to a revised model that incorporates the glymphatic pathway and lymphatic clearance. These recent breakthroughs will inspire new therapeutic approaches to recognize, reverse, and restore glymphatic dysfunction and to leverage this pathway to deliver brain-wide therapeutics.

Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS

Frontiers in Neuroscience ◽

10.3389/fnins.2021.639140 ◽

2021 ◽

Vol 15 ◽

Author(s):

Gianfranco Natale ◽

Fiona Limanaqi ◽

Carla L. Busceti ◽

Federica Mastroiacovo ◽

Ferdinando Nicoletti ◽

...

Keyword(s):

Interstitial Fluid ◽

Lymphatic Vessels ◽

Normal Pressure ◽

Lymphatic Drainage ◽

Brain Parenchyma ◽

Waste Products ◽

Pathological Conditions ◽

Glymphatic Pathway ◽

The Brain

The classic concept of the absence of lymphatic vessels in the central nervous system (CNS), suggesting the immune privilege of the brain in spite of its high metabolic rate, was predominant until recent times. On the other hand, this idea left questioned how cerebral interstitial fluid is cleared of waste products. It was generally thought that clearance depends on cerebrospinal fluid (CSF). Not long ago, an anatomically and functionally discrete paravascular space was revised to provide a pathway for the clearance of molecules drained within the interstitial space. According to this model, CSF enters the brain parenchyma along arterial paravascular spaces. Once mixed with interstitial fluid and solutes in a process mediated by aquaporin-4, CSF exits through the extracellular space along venous paravascular spaces, thus being removed from the brain. This process includes the participation of perivascular glial cells due to a sieving effect of their end-feet. Such draining space resembles the peripheral lymphatic system, therefore, the term “glymphatic” (glial-lymphatic) pathway has been coined. Specific studies focused on the potential role of the glymphatic pathway in healthy and pathological conditions, including neurodegenerative diseases. This mainly concerns Alzheimer’s disease (AD), as well as hemorrhagic and ischemic neurovascular disorders; other acute degenerative processes, such as normal pressure hydrocephalus or traumatic brain injury are involved as well. Novel morphological and functional investigations also suggested alternative models to drain molecules through perivascular pathways, which enriched our insight of homeostatic processes within neural microenvironment. Under the light of these considerations, the present article aims to discuss recent findings and concepts on nervous lymphatic drainage and blood–brain barrier (BBB) in an attempt to understand how peripheral pathological conditions may be detrimental to the CNS, paving the way to neurodegeneration.

The Glymphatic System: A Review

Arquivos Brasileiros de Neurocirurgia Brazilian Neurosurgery ◽

10.1055/s-0038-1667052 ◽

2018 ◽

Vol 37 (03) ◽

pp. 190-195 ◽

Cited By ~ 1

Author(s):

Louise Oliveira ◽

Eberval Figueiredo ◽

Carlos Peres

Keyword(s):

Lymphatic Vessels ◽

Normal Pressure ◽

Therapeutic Interventions ◽

Glymphatic System ◽

Adult Body Mass ◽

System A ◽

Optimal Function ◽

Glymphatic Pathway ◽

The One

AbstractThe brain represents ∼ 2% of the adult body mass; conversely, it is responsible for 20% to 25% of the glucose and 20% of the oxygen consumption, receiving 15% of the cardiac output. This substantial metabolic rate is associated with a significant production of biological debris, which is potentially toxic. Therefore, a complex and efficient clearance system is required to prevent the accumulation of byproducts and ensure optimal function. However, until today, there is little knowledge about this topic. The glymphatic system, also known as perivascular pathway, is a recently described glial-dependent network that is responsible for the clearance of metabolites from the central nervous system (CNS), playing a role equivalent to the one played by the lymphatic vessels present in other organs. Studies have demonstrated that the glymphatic pathway has a paramount role in protein homeostasis, and that the malfunction of this system may be related to the development of neurodegenerative disorders such as Alzheimer disease and normal pressure hydrocephalus. They also showed that body posture, exercise and the state of consciousness influence the glymphatic transport. In this context, the understanding of this clearance system could not only clarify the pathophysiology of several diseases, but also contribute to future therapeutic interventions. In the present article, we will evaluate the glymphatic pathway, focusing on the factors that regulate its flow, as well as on its role in CNS physiology and in disease initiation and progression, including dementia, hydrocephalus, glaucoma and traumatic brain injury. Ultimately, this review also aims to encourage further research on novel therapeutic targets.

The Ocular Glymphatic Clearance System

10.1101/2019.12.29.889873 ◽

2019 ◽

Author(s):

Xiaowei Wang ◽

Nanhong Lou ◽

Allison Eberhardt ◽

Peter Kusk ◽

Qiwu Xu ◽

...

Keyword(s):

Optic Nerve ◽

Lymphatic Vessels ◽

Amyloid Β ◽

Lymphatic Drainage ◽

Murine Models ◽

Therapeutic Approaches ◽

Pupil Constriction ◽

Glymphatic Pathway ◽

High Metabolic Activity

AbstractDespite high metabolic activity, the retina and optic nerve head lack traditional lymphatic drainage. We here identified a novel ocular glymphatic clearance route for fluid and wastes via the proximal optic nerve. Amyloid-β (Aβ) was cleared from the vitreous via a pathway driven by the ocular-cranial pressure difference. After traversing the lamina barrier, intra-axonal Aβ was cleared via the perivenous space and subsequently drained to lymphatic vessels. Light-induced pupil constriction enhanced, while atropine or raising intracranial pressure blocked efflux. In two distinct murine models of glaucoma, Aβ leaked from the eye via defects in the lamina barrier instead of directional axonal efflux. The discovery of a novel pathway for removal of fluid and metabolites from the intraocular space prompts a reevaluation of the core principles governing eye physiology and provides a framework for new therapeutic approaches to treat common eye diseases, including glaucoma.One Sentence SummaryGlymphatic pathway clears ocular amyloid-β via optic nerve and fails in glaucoma.

Comorbidity in multiple sclerosis: Past, present and future

Clinical & Investigative Medicine ◽

10.25011/cim.v42i1.32383 ◽

2019 ◽

Vol 42 (1) ◽

pp. E5-E12 ◽

Cited By ~ 12

Author(s):

Ruth Ann Marrie

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Chronic Disease ◽

Disease Course ◽

Comorbid Conditions ◽

Therapeutic Approaches ◽

Neurologic Diseases ◽

Source Studies ◽

The Central Nervous System

Purpose: Multiple sclerosis (MS) is an inflammatory and degenerative condition affecting the central nervous system. Like many neurologic diseases, it is chronic and incurable, and confers a substantial burden on affected individuals, their families and society. Although many individuals suffering from a serious chronic disease also suffer from comorbid conditions, the important consequences of their interaction often receive little attention. This was particularly true for MS two decades ago. Broadening our perspective by better understanding the effects of comorbidity on an individual with a particular chronic disease offers us an opportunity to improve understanding of prognosis, personalize disease management, develop new therapeutic approaches and illuminate the pathophysiology of disease. Source: Studies examining the incidence, prevalence and outcomes related to comorbidity in MS will be discussed, along with areas requiring further investigation. Conclusion: Comorbidity is highly prevalent in MS throughout the disease course. Comorbid conditions, including depression, anxiety, hypertension, hyperlipidemia, diabetes and chronic lung disease, adversely affect a broad range of outcomes. Less is known about the effects of MS on outcomes related to these comorbid conditions. These findings highlight an urgent need to determine how to best prevent and treat comorbidity in MS.

Brain lymphatic drainage system – visualization opportunities and current state of the art

Complex Issues of Cardiovascular Diseases ◽

10.17802/2306-1278-2020-9-3-81-89 ◽

2020 ◽

Vol 9 (3) ◽

pp. 81-89

Author(s):

G. S. Yankova ◽

O. B. Bogomyakova

Keyword(s):

Neurodegenerative Diseases ◽

Immune Surveillance ◽

Lymphatic Vessels ◽

Drainage System ◽

Lymphatic Drainage ◽

Waste Products ◽

Glymphatic System ◽

Age Related ◽

The Brain

The lymphatic drainage system of the brain is assumed to consist of the lymphatic system and a network of meningeal lymphatic vessels. This system supports brain homeostasis, participates in immune surveillance and presents a new therapeutic target in the treatment of neurological disorders.The article analyzes and systematizes data on the brain lymphatic drainage system. The key components of this system are considered: recently described meningeal lymphatic vessels and their relationship with the glymphatic system, which provides perfusion of the central nervous system with cerebrospinal and interstitial fluids. The lymphatic drainage system helps to maintain water and ion balances of the interstitial fluid and to remove metabolic waste products, assists in reabsorption of macromolecules. Disorders in its work play a crucial role in age-related changes in the brain, the pathogenesis of neurovascular and neurodegenerative diseases, as well as injuries and brain tumors. The review also presents the results of human studies concerning the presence, anatomy and structure of meningeal lymphatic vessels and the glymphatic system. The discovery of the brain lymphatic drainage system has not only changed our understanding of cerebrospinal fluid circulation, but also contributed to understanding the pathology and mechanisms of neurodegenerative diseases.

Prospects in treatment of multiple sclerosis: near future

I P Pavlov Russian Medical Biological Herald ◽

10.23888/pavlovj2020283377-390 ◽

2020 ◽

Vol 28 (3) ◽

pp. 377-390

Author(s):

Gennadii E. Sheiko ◽

Anna N. Belova ◽

Maksim N. Kudykin

Keyword(s):

Multiple Sclerosis ◽

Modern Science ◽

Therapeutic Approaches ◽

New Methods ◽

Unclear Etiology ◽

Near Future ◽

The Given ◽

Methods Of Treatment

Multiple sclerosis (MS) is a widespread dysimmune-neurodegenerative disease of the central nervous system of unclear etiology. Despite significant achievements in the therapy of MS, the level of progressing disability and early mortality remains alarmingly high. The main aim of the given review is to give a detailed description of new promising medical drugs for treatment of MS. In the article the data of preclinical and clinical trials are given, presumptive mechanisms of the medical drugs under development are described. Development of new therapeutic approaches in treatment of MS is of great interest in modern science. The given review highlights new methods of treatment that are now undergoing clinical trialы and will probably come to the clinical practice in the near future.

Cortical and meningeal pathology in progressive multiple sclerosis: a new therapeutic target?

Reviews in the Neurosciences ◽

10.1515/revneuro-2018-0017 ◽

2019 ◽

Vol 30 (3) ◽

pp. 221-232 ◽

Cited By ~ 2

Author(s):

Berenice Anabel Silva ◽

Carina Cintia Ferrari

Keyword(s):

Multiple Sclerosis ◽

Progressive Multiple Sclerosis ◽

Cortical Lesions ◽

Therapeutic Approaches ◽

Meningeal Inflammation ◽

Relapsing Remitting ◽

Therapeutic Alternatives ◽

Ms Pathogenesis

Abstract Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease that involves an intricate interaction between the central nervous system and the immune system. Nevertheless, its etiology is still unknown. MS exhibits different clinical courses: recurrent episodes with remission periods (‘relapsing-remitting’) that can evolve to a ‘secondary progressive’ form or persistent progression from the onset of the disease (‘primary progressive’). The discovery of an effective treatment and cure has been hampered due to the pathological and clinical heterogeneity of the disease. Historically, MS has been considered as a disease exclusively of white matter. However, patients with progressive forms of MS present with cortical lesions associated with meningeal inflammation along with physical and cognitive disabilities. The pathogenesis of the cortical lesions has not yet been fully described. Animal models that represent both the cortical and meningeal pathologies will be critical in addressing MS pathogenesis as well as the design of specific treatments. In this review, we will address the state-of-the-art diagnostic and therapeutic alternatives and the development of strategies to discover new therapeutic approaches, especially for the progressive forms.

Review of a new concept of glaucoma pathogenesis based on the glymphatic theory of cerebrospinal fluid circulation

Research Results in Pharmacology ◽

10.3897/rrpharmacology.6.53634 ◽

2020 ◽

Vol 6 (3) ◽

pp. 1-7

Author(s):

Aleksandr A. Dolzhikov ◽

Olga A. Shevchenko ◽

Anna S. Pobeda ◽

Anna A. Peresypkina ◽

Irina N. Dolzhikova ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Optic Nerve ◽

Ganglion Cells ◽

Brain Parenchyma ◽

Cribriform Plate ◽

Fluid Circulation ◽

Cerebrospinal Fluid Circulation ◽

Glymphatic System ◽

In Vivo Experiments

General aspects of glaucoma: Glaucoma is a heterogeneous multi-factorial disease that is one of the main causes of blindness, along with degeneration of retinal ganglion cells and optic nerve atrophy. Theories of pathogenesis: There are three theories of glaucoma pathogenesis: biomechanical, vascular, and biochemical. Basic theory of the glymphatic system: The classical knowledge of cerebrospinal fluid circulation has been revised, and in 2012 a new concept of glial-perivascular – glymphatic perfusion of the brain parenchyma was introduced. Due to experimental and clinical studies, it is approved by many scientists, especially in relation to Alzheimer’s disease (AD), in which amyloid pathology is the result of dysfunction of the para-/perivascular transport/cleansing pathways. Features of the optic nerve and the cribriform plate: The cribriform plate forms a barrier at the border of intraocular (IOP) and intracranial (ICP) pressures, thus affecting the para-/periarterial flow of cerebrospinal fluid to the optic nerve and retina, as well as the para-/perivenous cleansing outflow. Morphofunctional evidence of an ocular glymphatic system: The presence of an ocular glymphatic system is confirmed by in vivo experiments with the transfer of labeled substances through para-/perivascular structures from the ventricular or subarachnoid space to the optic nerve and by postmortem morphology. Clinical evidence for the glymphatic system hypothesis: There is some clinical, including case-based, and epidemiological evidence for similarities between glaucomatous optic nerve/retinal injuries and AD, since both occur in the form of improper secretion of neurotoxic metabolites, and both are often diagnosed together.

Rabies

10.1093/med/9780199937837.003.0155 ◽

2017 ◽

Author(s):

Alan C. Jackson

Keyword(s):

Central Nervous System ◽

Clinical Course ◽

Multiple Organ ◽

Medical Complications ◽

Therapeutic Approaches ◽

Acute Viral Infection ◽

Animal Bites ◽

Rabies Pathogenesis

Rabies is an acute viral infection involving the central nervous system with distinctive clinical features reflecting early brainstem involvement, including hydrophobia. This infection is usually transmitted by animal bites, typically from dogs or wildlife, including bats. There is a progressive clinical course to coma and the disease is virtually always fatal. When rabies is treated aggressively there are usually multiple medical complications, including multiple organ failure. Therapeutic attempts have been disappointing and new approaches need to be taken in the future. An improved understanding of rabies pathogenesis might lead to important insights into the development of new therapeutic approaches.