Progress in translational research on intracerebral hemorrhage: Is there an end in sight?
Introduction
Intracerebral hemorrhage (ICH) is a particularly devastating form of stroke with high mortality and morbidity (Keep et al., 2012, Qureshi et al., 2009). Relative to ischemic stroke, there have been few preclinical studies and clinical trials for the development of treatments for ICH. However, increased interest in ICH over the past decade has improved our knowledge of the underlying mechanisms of ICH-induced brain injury, which have been found to differ from those of ischemic stroke (Xi et al., 2006). These findings have led to the initiation of several ongoing clinical trials investigating ICH treatment.
This review aims to describe the underlying causes and natural history of ICH, as well as the animal models employed in its study. This is followed by a discussion of the systemic effects of ICH, focusing on immune and cardiac effects, areas that have been largely neglected in research on ICH. Current and potential clinical trials in ICH alone and with intraventricular extension are also discussed, of which the latter is particularly difficult to treat and is associated with higher mortality (Hanley, 2009).
Section snippets
Causes of bleeding
Spontaneous ICH, i.e., ICH that is not related to trauma, most frequently occurs secondary to hypertension, with up to 70% of patients with ICH having a history of hypertension (Mendelow et al., 2005). However, ICH may also result from bleeding associated with amyloid angiopathy, tumors, hemorrhagic conversion of ischemic stroke, dural venous sinus thrombosis, vasculitis and vascular malformations such as cavernous angiomas, arteriovenous fistulae, arteriovenous malformations, venous angiomas,
Hematoma enlargement
Post-ICH hematoma enlargement occurs in about one third of patients (Broderick et al., 1990, Brott et al., 1997, Fujii et al., 1994, Fujii et al., 1998, Kazui et al., 1996, Kazui et al., 1997). For example, in a study of hematoma enlargement in patients with ICH (n = 103) 38% of patients experienced a hematoma expansion within 20 h (Brott et al., 1997). Post-ICH hematoma enlargement causes a midline shift and accelerates neurological deterioration (Broderick et al., 1990, Zazulia et al., 1999). A
Overview
Experimental models of ICHs have been available since the 1960s and commonly involve the intracerebral injection of autologous blood, which is a straightforward and effective technique for producing ICH. This type of model has been developed in large animals (e.g., dogs, cats, pigs and monkeys) (Sussman et al., 1974, Takasugi et al., 1985, Wagner et al., 1996, Whisnant et al., 1963), by injecting blood into the frontal lobe. For small animals (e.g., rats and mice) blood is injected into the
Inflammatory and immune responses
ICH results in systemic inflammatory response. For example, in patients with hemorrhagic stroke, interleukin-2 levels in peripheral blood T lymphocytes were lower than in healthy controls, but no significant difference was observed between ICH and SAH groups (Zou et al., 1997). Experimental data from a murine model of ICH has shown that total neutrophils and lymphocytes are reduced but that monocytes are increased, and that this is related to hematoma size (Illanes et al., 2011). Immune cells
Therapeutic targets and ongoing clinical trials
All ongoing clinical trials have been summarized in a recent review paper (Keep et al., 2012). Below are major therapeutic targets and clinical trials.
Future directions
There has also been a marked increase in preclinical research into cerebral hemorrhage in the past decade, resulting in the identification of novel potential therapeutic targets (Keep et al., 2012) that are starting to form the basis of clinical trials (Selim et al., 2011). As with other neurological conditions, there are concerns over whether animal models recapitulate the human disease and whether preclinical efficacy will translate to the clinic. Determining the validity of preclinical
Conclusions
Our understanding of the mechanisms involved in ICH-induced injury have increased in the last two decades and there are now multiple, potentially pivotal, ongoing clinical trials, creating hope that effective treatments for these devastating forms of stroke may be discovered. The end may be in sight. However, it should be noted that others have thought this before and that ICH covers a spectrum of conditions dependent upon location and size of the hematoma. It is, therefore, likely that no one
Disclosures
None.
Acknowledgments
This work was supported by grants NS-034709, NS-057539, NS-073595, NS-079157, NS-084049 and NS-007222 from the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
References (265)
- et al.
Prosurvival and prodeath effects of hypoxia-inducible factor-1alpha stabilization in a murine hippocampal cell line
Journal of Biological Chemistry
(2005) - et al.
Rehabilitation after intracerebral hemorrhage in rats improves recovery with enhanced dendritic complexity but no effect on cell proliferation
Behavioural Brain Research
(2010) - et al.
Eaten alive! Cell death by primary phagocytosis: ‘phagoptosis’
Trends in Biochemical Sciences
(2012) - et al.
Intracerebral hemorrhage in a primate model: effect on regional cerebral blood flow
Surgical Neurology
(1988) - et al.
Endoscopic surgery for intraventricular hemorrhage (IVH) caused by thalamic hemorrhage: comparisons of endoscopic surgery and external ventricular drainage (EVD) surgery
World Neurosurgery
(2011) - et al.
Minocycline attenuates iron neurotoxicity in cortical cell cultures
Biochemical and Biophysical Research Communications
(2009) - et al.
Heme oxygenase activity and hemoglobin neurotoxicity are attenuated by inhibitors of the MEK/ERK pathway
Neuropharmacology
(2009) - et al.
Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study
Lancet Neurology
(2012) - et al.
Time course of plasma leptin concentrations after acute spontaneous basal ganglia hemorrhage
World Neurosurgery
(2010) - et al.
The complement cascade as a therapeutic target in intracerebral hemorrhage
Experimental Neurology
(2009)
Myocardial dysfunction associated with brain death: clinical, echocardiographic, and pathologic features
Journal of Heart and Lung Transplantation
Intracerebral hemorrhage: pathology of selected topics
Moderate, rapidly induced hypertension as a cause of intraventricular hemorrhage in the newborn beagle model
Journal of Pediatrics
Acute inflammatory reaction following experimental intracerebral hemorrhage
Brain Research
Cerebrovascular neurosurgery in 2012
Journal of Clinical Neuroscience
Inflammatory response to intraventricular hemorrhage: time course, magnitude and effect of t-PA
Journal of the Neurological Sciences
Hematoma size as major modulator of the cellular immune system after experimental intracerebral hemorrhage
Neuroscience Letters
Response to external ventricular drainage in spontaneous intracerebral hemorrhage with hydrocephalus
Neurology
Advances in the management of intracerebral hemorrhage
Nature Reviews Neurology
Natural history and imaging prevalence of cavernous malformations in children and young adults
Journal of Neurosurgery Pediatrics
Effects of early intensive blood pressure-lowering treatment on the growth of hematoma and perihematomal edema in acute intracerebral hemorrhage: the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT)
Stroke
Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage
New England Journal of Medicine
Risk factors for intracerebral hemorrhage in the general population: a systematic review
Stroke: A Journal of Cerebral Circulation
Intraventricular hemorrhage in premature infants: mechanism of disease
Pediatric Research
Intracerebral hemorrhage in pregnancy: frequency, risk factors, and outcome
Neurology
Experimental intracerebral hemorrhage in the mouse: histological, behavioral, and hemodynamic characterization of a double-injection model
Stroke: A Journal of Cerebral Circulation
Cerebral hemorrhage and edema following brain biopsy in rats: significance of mean arterial blood pressure
Journal of Neurosurgery
Brain edema: a classification based on blood-brain barrier integrity
Cerebrovascular and Brain Metabolism Reviews
Elevated blood pressure causes larger hematoma in a rat model of intracerebral hemorrhage
Translational Stroke Research
The molecular mechanisms that promote edema after intracerebral hemorrhage
Translational Stroke Research
Very early edema growth with ICH
Stroke
Ultra-early evaluation of intracerebral hemorrhage
Journal of Neurosurgery
Early hemorrhage growth in patients with intracerebral hemorrhage
Stroke
Intracranial haemorrhage induced at arterial pressure in the rat. Part 1: Description of technique, ICP changes and neuropathological findings
Neurological Research
The intracerebral haemorrhage acutely decreasing arterial pressure trial: ICH ADAPT
International Journal of Stroke
Fingolimod reduces hemorrhagic transformation associated with delayed tissue plasminogen activator treatment in a mouse thromboembolic model
Stroke: A Journal of Cerebral Circulation
Oxidative markers in spontaneous intracerebral hemorrhage: leukocyte 8-hydroxy-2′-deoxyguanosine as an independent predictor of the 30-day outcome
Journal of Neurosurgery
Role of iron in brain injury after intraventricular hemorrhage
Stroke: A Journal of Cerebral Circulation
The insula and cerebrogenic sudden death
Archives of Neurology
Use of a spectrophotometric hemoglobin assay to objectively quantify intracerebral hemorrhage in mice
Stroke: A Journal of Cerebral Circulation
Consequences of intraventricular hemorrhage in a rabbit pup model
Stroke: A Journal of Cerebral Circulation
Citicoline treatment for experimental intracerebral hemorrhage in mice
Stroke: A Journal of Cerebral Circulation
Reversible left ventricular dysfunction associated with raised troponin I after subarachnoid haemorrhage does not preclude successful heart transplantation
Heart
Experimental intracerebral hemorrhage in rats. Magnetic resonance imaging and histopathological correlates
Stroke
Effect of fucoidan treatment on collagenase-induced intracerebral hemorrhage in rats
Neurological Research
Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation
Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism
The spot sign score in primary intracerebral hemorrhage identifies patients at highest risk of in-hospital mortality and poor outcome among survivors
Stroke
Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes
Neurology
Exacerbation of perihematomal edema and sterile meningitis with intraventricular administration of tissue plasminogen activator in patients with intracerebral hemorrhage
Neurosurgery
Frontal bur hole through an eyebrow incision for image-guided endoscopic evacuation of spontaneous intracerebral hemorrhage
Journal of Neurosurgery
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2022, Journal of Stroke and Cerebrovascular DiseasesCitation Excerpt :Intraventricular hemorrhage (IVH) is a subtype of cerebral hemorrhagic stroke, which is often characterized as an influx of blood into the brain ventricles, which usually happens as an extension of intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH).1-5