New concepts regarding cerebral vasospasm: glial-centric mechanisms

Abstract

Purpose Poor outcome in patients with cerebral vasospasm following subarachnoid hemorrhage remains a serious clinical problem. The current management with focus on the cerebrovascular constriction accounts for the use of ''triple-H'' therapy (hypertension, hypervolemia, and hemodilution) to enhance cerebral blood flow through constricted vessels. Recent work suggests that spreading depression (a stereotypical response of cerebral cortical tissue to noxious stimuli with subsequent oligemic blood flow) occurs in patients with cerebral vasospasm. A narrative review was conducted to examine the relationship between spreading depression and subarachnoid hemorrhage and to identify the anesthetic effects on the propagation of spreading depression. Principal findings Following review of the literature, an underlying mechanism is advanced that cerebral vasospasm is not primarily a problem of the cerebral vasculature but a consequence of glial cell dysfunction following spreading depression -a glial-centric cause for vasospasm. Such a mechanism for vasospasm becomes manifest when spreading depression waves transition to peri-infarct depolarization waves -with protracted ischemic blood flow in compromised tissue. The extracellular microenvironment with high potassium and low nitric oxide tension can account for conducting vessel narrowing. Conclusions The implication for clinical management is discussed supposing glial cell dysfunction is an underlying mechanism responsible for the vascular spasm. RésuméObjectif Les mauvais pronostics chez les patients manifestant un vasospasme ce´re´bral a`la suite d'une he´morragie sous-arachnoı¨dienne demeurent un proble`me clinique majeur. La prise en charge actuelle se concentre sur la constriction vasculaire ce´re´brale, ce qui explique le recours au traitement dit des « trois H » (hypertension, hypervole´mie et he´modilution) dans le but d'ame´liorer le de´bit sanguin ce´re´bral dans les vaisseaux contracte´s. Des recherches re´centes sugge`rent qu'une de´pression propage´e (une re´action typique du tissu cortical ce´re´bral aux stimuli nociceptifs, laquelle est suivie d'un de´bit sanguin re´duit) survient chez les patients manifestant un vasospasme ce´re´bral. Un compte-rendu narratif a e´te´entrepris afin d'examiner la relation entre la de´pression propage´e et l'he´morragie sous-arachnoı¨dienne ainsi que d'identifier les effets des anesthe´siques sur la propagation de la de´pression propage´e. Constatations principales Apre`s avoir passe´en revue la litte´rature sur le sujet, l'hypothe`se d'un me´canisme sous-jacent est avance´e, selon laquelle le vasospasme ce´re´bral n'est pas un proble`me principalement lie´a`la vasculature ce´re´brale mais plutôt la conse´quence d'un dysfonctionnement des cellules gliales apre`s une de´pression propage´e -en d'autres mots, le vasospasme est cause´principalement au niveau glial. Ce me´canisme qui provoque le vasospasme est manifeste lorsque les vagues de de´pression propage´e se changent en vagues de de´polarisation autour de l'infarct...

Cortical Spreading Depolarization and Delayed Cerebral Ischemia; Rethinking Secondary Neurological Injury in Subarachnoid Hemorrhage

“…Reversed glutamate transport sees astrocytes release glutamate instead of clearing glutamate from the ECF [ 3 , 29 , 30 , 31 , 32 , 33 , 34 ]. Glutamate released from injured or lysed cells eventually washes over nearby survivors to start this injurious cycle anew [ 8 , 27 , 35 ]. As ECF glutamate and potassium concentrations continue to rise, simultaneous opening of multiple channel types and marked conductance rises occur with CSDs.…”

“…As ECF glutamate and potassium concentrations continue to rise, simultaneous opening of multiple channel types and marked conductance rises occur with CSDs. ATP-dependent, voltage-gated, iontophoretic, and hemichannels are activated [ 8 , 36 ], leading to further excitotoxicity, neuroinflammation, and apoptosis [ 37 ].…”

“…Management of DCI to date has focused on vasospasm as the main cause [ 8 ], with recommendations including a trial of hypertension (presuming the aneurysm is secured), maintenance of euvolemia, and intra-arterial vasodilators administered locally. However, guideline recommendations against prophylactic balloon angioplasty [ 124 ] again point towards more complex phenomena than vasospasm.…”

“…Historically, it was noted that up to 70% of SAH patients showed evidence of delayed radiographic vasoconstriction. Delayed onset vasospasm was therefore thought to be the culprit of DCI [ 8 ]. Unfortunately, treatments focusing solely on the reversal of observable vasospasm were incompletely effective.…”