'Malignant' Middle Cerebral Artery Territory Infarction

Hacke, Werner

doi:10.1001/archneur.1996.00550040037012

Cited by 1,229 publications

(966 citation statements)

References 38 publications

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“…Early mortality in acute ischemic stroke is associated with initial clinical stroke severity, the size of the infarct and subsequent cerebral edema 71, 72, 73. Mechanism which CN‐105 reduced early mortality were likely through decreasing overall infarct size, as observed in our study, and also through decreasing cerebral edema by maintaining BBB integrity.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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ObjectiveAt present, the absence of a pharmacological neuroprotectant represents an important unmet clinical need in the treatment of ischemic and traumatic brain injury. Recent evidence suggests that administration of apolipoprotein E mimetic therapies represent a viable therapeutic strategy in this setting. We investigate the neuroprotective and anti‐inflammatory properties of the apolipoprotein E mimetic pentapeptide, CN‐105, in a microglial cell line and murine model of ischemic stroke.MethodsTen to 13‐week‐old male C57/BL6 mice underwent transient middle cerebral artery occlusion and were randomly selected to receive CN‐105 (0.1 mg/kg) in 100 μL volume or vehicle via tail vein injection at various time points. Survival, motor‐sensory functional outcomes using rotarod test and 4‐limb wire hanging test, infarct volume assessment using 2,3,5‐Triphenyltetrazolium chloride staining method, and microglial activation in the contralateral hippocampus using F4/80 immunostaining were assessed at various time points. In vitro assessment of tumor necrosis factor‐alpha secretion in a microglial cell line was performed, and phosphoproteomic analysis conducted to explore early mechanistic pathways of CN‐105 in ischemic stroke.ResultsMice receiving CN‐105 demonstrated improved survival, improved functional outcomes, reduced infarct volume, and reduced microglial activation. CN‐105 also suppressed inflammatory cytokines secretion in microglial cells in vitro. Phosphoproteomic signals suggest that CN‐105 reduces proinflammatory pathways and lower oxidative stress.Interpretation CN‐105 improves functional and histological outcomes in a murine model of ischemic stroke via modulation of neuroinflammatory pathways. Recent clinical trial of this compound has demonstrated favorable pharmacokinetic and safety profile, suggesting that CN‐105 represents an attractive candidate for clinical translation.

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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“…A profound and morbid example can be seen in the development of "malignant edema" in patients after large vascular territory ischemic stroke [20]. A multi-organ system treatment algorithm is the standard of care, with hyperosmotic therapy, in the form of mannitol and hypertonic saline, being the mainstays of traditional pharmacologic treatment.…”

Section: Osmotherapymentioning

confidence: 99%

Novel Treatment Targets for Cerebral Edema

2012

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Cerebral edema is a common finding in a variety of neurological conditions, including ischemic stroke, traumatic brain injury, ruptured cerebral aneurysm, and neoplasia. With the possible exception of neoplasia, most pathological processes leading to edema seem to share similar molecular mechanisms of edema formation. Challenges to brain-cell volume homeostasis can have dramatic consequences, given the fixed volume of the rigid skull and the effect of swelling on secondary neuronal injury. With even small changes in cellular and extracellular volume, cerebral edema can compromise regional or global cerebral blood flow and metabolism or result in compression of vital brain structures. Osmotherapy has been the mainstay of pharmacologic therapy and is typically administered as part of an escalating medical treatment algorithm that can include corticosteroids, diuretics, and pharmacological cerebral metabolic suppression. Novel treatment targets for cerebral edema include the Na(+)-K(+)-2Cl(−) co-transporter (NKCC1) and the SUR1-regulated NC Ca-ATP (SUR1/TRPM4) channel. These two ion channels have been demonstrated to be critical mediators of edema formation in brain-injured states. Their specific inhibitors, bumetanide and glibenclamide, respectively, are well-characterized Food and Drug Administration-approved drugs with excellent safety profiles. Directed inhibition of these ion transporters has the potential to reduce the development of cerebral edema and is currently being investigated in human clinical trials. Another class of treatment agents for cerebral edema is vasopressin receptor antagonists. Euvolemic hyponatremia is present in a myriad of neurological conditions resulting in cerebral edema. A specific antagonist of the vasopressin V1A-and V2-receptor, conivaptan, promotes water excretion while sparing electrolytes through a process known as aquaresis.Keywords Cerebral edema . Hyponatraemia . Osmotherapy . NKCC1 . SUR1/TRPM4 . Vaptan . Glyburide Overview of Perturbations in Brain Fluid HomeostasisCerebral edema in the neurointensive care setting can occur with a heterogenous group of neurological diseases, which typically fall under the categories of metabolic [1, 2], infectious [3], neoplastic [4], cerebrovascular [5][6][7], and traumatic [8,9] brain injury. Irrespective of the inciting process, cerebral edema results in the pathological accumulation of fluid in the brain's intracellular and extracellular spaces. This occurs secondary to alterations in the complex interplay between 4 distinct fluid compartments within the cranium; fluid is present within: 1) the blood in the cerebral blood vessels, 2) the cerebrospinal fluid in the ventricular system and subarachnoid space, 3) the interstitial fluid of the brain parenchyma, and 4) the intracellular fluid of the neurons and glia. These fluid compartments are not isolated, and specific movements of solutes and water from one compartment to another occur under normal conditions. When dysregulation of this normally tightly controlled fluid balance...

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“…Patients with 2 of 3 clinical factors (gaze preference, hemiplegia, or hemi-neglect) and evidence of acute cortical infarction on initial computed tomographic scan were highly correlated with the later development of worsening consciousness from edema. In the 1996 study by Hacke et al [64], patients who had "malignant" MCA infarct develop were found to deteriorate between days 2 and 5. Furthermore, most patients in this study died as a result of transtentorial herniation ipsilateral to the region of ischemia.…”

Section: Surgical Therapiesmentioning

confidence: 98%

Care of the Stroke Patient: Routine Management to Lifesaving Treatment Options

2011

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The management of the acute ischemic stroke patient spans the time course from the emergency evaluation and treatment period through to the eventual discharge planning phase of stroke care. In this article we evaluate the literature and describe what have become standard treatments in the care of the stroke patient. We will review the literature that supports the use of a dedicated stroke unit for routine stroke care which has demonstrated reduced rates of morbidity and mortality. Also reviewed is the use of glycemic control in the initial setting along with data supporting the use of prophylactic treatments options in order to aide in the prevention of life threatening medical complications. In addition, lifesaving treatments will be discussed in light of new literature demonstrating reduced mortality in large hemispheric stroke patients undergoing surgical decompressive surgery. Both medical and surgical treatment options are discussed and compared.

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'Malignant' Middle Cerebral Artery Territory Infarction

Cited by 1,229 publications

References 38 publications

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Novel Treatment Targets for Cerebral Edema

Care of the Stroke Patient: Routine Management to Lifesaving Treatment Options

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