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

Abstract

Research 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.

Should individual timeline and serial CT/MRI panels of all patients be presented in acute brain insult cohorts? A pilot study of 45 patients with decompressive craniectomy after aneurysmal subarachnoid hemorrhage

“…Primary causes of ischemia include the tearing of small vessels by the burst of arterial blood, locally increased pressure, and brain herniation. Secondary causes of brain injury [ 79 ] include neuroinflammation [ 24 , 44 ], brain edema [ 116 ], microglial activation [ 10 ], leukocyte infiltration [ 57 , 117 ], perihematomal edema [ 76 ], impaired glymphatic drainage [ 2 ], delayed brain edema resolution [ 80 , 86 ], delayed blood clearance [ 71 , 73 ], and microemboli [ 12 , 79 ]. Iatrogenic causes include manipulation, temporary artery occlusion, and accidental branch or perforator occlusion during sIA occlusions.…”

The Anatomy and Physiology of the Glymphatic System and Its Role in Craniectomies and Syndrome of the Trephined

“…22 If severe enough, CSF may accumulate in the ventricular system causing communicating hydrocephalus 64 or pool in the interstitial fluid leading to intraparenchymal edema. 22…”

“…Others hypothesize neuronal dysfunction may be due to fluid accumulation in the brain parenchyma as a direct result of glymphatic dysfunction. 19 Though brain edema is not seen in all patients with SoT after craniectomy, it is an interesting idea supported by other authors and termed “glymphedema.” 22 More information is needed to understand the role of the glymphatic system in human with SoT and persistent neurologic dysfunction after DC.…”

The role of the astrocyte in subarachnoid hemorrhage and its therapeutic implications

“…The classic model of CSF circulation theory acknowledges that cerebrospinal fluid (CSF) is produced by the choroid plexus, circulated into the subarachnoid space, and absorbed through arachnoid villi ( 55 ). Any obstruction in this circulation may consequently lead to the accumulation of CSF in communicating hydrocephalus ( 55 ). However, a cerebral waste clearance system was discovered by Iliff et al.…”