The cerebral collateral circulation: Relevance to pathophysiology and treatment of stroke

Neuroendovascular procedures have led to breakthroughs in the treatment of ischemic stroke, intracranial aneurysms, and intracranial arteriovenous malformations. Due to these substantial successes, there is continuous development of novel and refined therapeutic approaches. Large animal models feature various conceptual advantages in translational research, which makes them appealing for the development of novel endovascular treatments. However, the availability and role of large animal models have not been systematically described so far. Based on comprehensive research in two databases, this systematic review describes current large animal models in neuroendovascular research including their primary use. It may therefore serve as a compact compendium for researchers entering the field or looking for opportunities to refine study concepts. It also describes particular applications for ischemic stroke and aneurysm therapy, as well as for the treatment of arteriovenous malformations. It focuses on most promising study designs and readout parameters, as well as on important pitfalls in endovascular translational research including ways to circumvent them.

https://journals.sagepub.com/doi/pdf/10.1177/0271678X19827446

Large animals in neurointerventional research: A systematic review on models, techniques and their application in endovascular procedures for stroke, aneurysms and vascular malformations:

Acute central nervous system injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide. Studies in animal models have grea...

Large animal models of stroke and traumatic brain injury as translational tools.

Large animal ischemic stroke models: replicating human stroke pathophysiology

Stroke is a debilitating condition which is also the second leading cause of death and disability worldwide. Despite the benefits and promises shown by numerous neuroprotective agents in animal stroke models, their clinical translation has not been a complete success. Hence, search for treatment options have directed researchers towards utilising stem cells. Mitochondria has a major involvement in the pathophysiology of stroke and a number of other conditions. Stem cells have shown the ability to transfer mitochondria to the damaged cells and to help revive cell energetics in the recipient cell. The present review discusses how stem cells could be employed to protect neurons and mitochondria in stroke and also the various mechanisms involved in neuroprotection.

Mitochondrial Dysfunction in Stroke: Implications of Stem Cell Therapy

Purpose of the Review To provide an up-to-date review of the incidence of stroke and large vessel occlusion (LVO) around the globe, as well as the eligibility and access to IV thrombolysis (IVT) and mechanical thrombectomy (MT) worldwide. Recent Findings Randomized clinical trials have established MT with or without IVT as the usual care for patients with LVO stroke for up to 24 hours from symptom onset. Eligibility for IVT has extended beyond 4.5 hours based on permissible imaging criteria. With these advances in the last 5 years, there has been a notable increase in the population of patients eligible for acute stroke interventions. However, access to acute stroke care and utilization of MT or IVT is lagging in these patients. Summary Stroke is the second leading cause of both disability and death worldwide, with the highest burden of the disease shared by low- and middle-income countries. In 2016, there were 13.7 million new incident strokes globally; ≈87% of these were ischemic strokes and by conservative estimation about 10%–20% of these account for LVO. Fewer than 5% of patients with acute ischemic stroke received IVT globally in the eligible therapeutic time window and fewer than 100,000 MTs were performed worldwide in 2016. This highlights the large gap among eligible patients and the low utilization rates of these advances across the globe. Multiple global initiatives are underway to investigate interventions to improve systems of care and bridge this gap.

https://n.neurology.org/content/neurology/97/20_Supplement_2/S6.full.pdf

Global Epidemiology of Stroke and Access to Acute Ischemic Stroke Interventions.

Large animal canine endovascular ischemic stroke models: A review

Yucatan micropigs have brain and spinal cord dimensions similar to humans and are useful for certain spinal cord injury (SCI) translational studies. Micropigs are readily trained in behavioral tasks, allowing consistent testing of locomotor loss and recovery. However, there has been little description of their motor and sensory pathway neurophysiology. We established methods to assess motor and sensory cortical evoked potentials in the anesthetized, uninjured state. We also evaluated epidurally evoked motor and sensory stimuli from the T6 and T9 levels, spanning the intended contusion injury epicenter. Response detection frequency, mean latency and amplitude values, and variability of evoked potentials were determined. Somatosensory evoked potentials were reliable and best detected during stimulation of peripheral nerve and epidural stimulation by referencing the lateral cortex to midline Fz. The most reliable hindlimb motor evoked potential (MEP) occurred in tibialis anterior. We found MEPs in f...

Characterization of Motor and Somatosensory Evoked Potentials in the Yucatan Micropig Using Transcranial and Epidural Stimulation

Neuroimaging facilitates the translation of animal pre-clinical research to human application. The large porcine spinal cord is useful for testing invasive interventions. Ideally, the safety and efficacy of a delayed intervention is tested in pigs that have recovered sufficiently after spinal cord injury (SCI) to allow either deterioration or improvement of function to be detected. We set out to create moderate severity T9 injuries in Yucatan minipigs by conducting a bridging study adapting methods previously developed in infant piglets. The injury severity was varied according to two pneumatic impactor parameters: the piston compression depth into tissue or the velocity. To stratify locomotor recovery, a 10-point scale used in prior piglet studies was redefined through longitudinal observations of spontaneous recovery. Using hindlimb body weight support to discriminate injury severity, we found that end-point recovery was strongly bimodal to either non-weight-bearing plegia with reciprocating leg movements (<5/10) or recovery of weight bearing that improved toward a ceiling effect (≥ 8/10). No intermediate recovery animals were observed at 2 months post-injury. The ability of intra-operative ultrasound and acute magnetic resonance imaging (MRI) to provide immediate predictive feedback regarding tissue and vascular changes following SCI was assessed. There was an inverse association between locomotor outcome and early gray matter hemorrhage on MRI and ultrasound. Epicenter blood flow following contusion predicted recovery or non-recovery of weight-bearing. The depth of the dorsal cerebrospinal fluid space, which varied between animals, influenced injury severity and confounded the results in this fixed-stroke paradigm.

Dichotomous Locomotor Recoveries Are Predicted by Acute Changes in Segmental Blood Flow after Thoracic Spinal Contusion Injuries in Pigs

OBJECTIVE Thyroid disorder has been known to affect vascular function and has been associated with aortic aneurysm formation in some cases; however, the connection has not been well studied. The authors hypothesized that hypothyroidism is associated with the formation of cerebral aneurysms. METHODS The authors performed a retrospective case-control study of consecutive patients who had undergone cerebral angiography at an academic, tertiary care medical center in the period from April 2004 through April 2014. Patients with unruptured aneurysms were identified from among those who had undergone 3-vessel catheter angiography. Age-matched controls without cerebral aneurysms on angiography were also identified from the same database. Patients with previous subarachnoid hemorrhage or intracranial hemorrhage were excluded. History of hypothyroidism and other risk factors were recorded. RESULTS Two hundred forty-three patients with unruptured cerebral aneurysms were identified and age matched with 243 controls. Mean aneurysm size was 9.6 ± 0.8 mm. Hypothyroidism was present in 40 patients (16.5%) and 9 matched controls (3.7%; adjusted OR 3.2, 95% CI 1.3-7.8, p = 0.01). Subgroup analysis showed that men with hypothyroidism had higher odds of an unruptured cerebral aneurysm diagnosis than the women with hypothyroidism, with an adjusted OR of 12.7 (95% CI 1.3-121.9) versus an OR of 2.5 (95% CI 1.0-6.4) on multivariate analysis. CONCLUSIONS Hypothyroidism appears to be independently associated with unruptured cerebral aneurysms, with a higher effect seen in men. Given the known pathophysiological associations between hypothyroidism and vascular dysfunction, this finding warrants further exploration.

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Luis Guada

Papers

Global Epidemiology of Stroke and Access to Acute Ischemic Stroke Interventions.

Large animal canine endovascular ischemic stroke models: A review

Characterization of Motor and Somatosensory Evoked Potentials in the Yucatan Micropig Using Transcranial and Epidural Stimulation

Dichotomous Locomotor Recoveries Are Predicted by Acute Changes in Segmental Blood Flow after Thoracic Spinal Contusion Injuries in Pigs

Association of hypothyroidism with unruptured cerebral aneurysms: a case-control study