Over 2.3 million people suffer hemorrhagic forms of stroke (intracerebral hemorrhage [ICH] and subarachnoid hemorrhage) worldwide every year; two-thirds survive with permanent disabilities.1 Unlike its ischemic counterpart, the incidence and morbidity of hemorrhagic stroke have not declined over recent decades, and rates are substantially rising in Asia, and low- and middle-income countries.1 There is considerable need for effective therapies to improve outcomes from hemorrhagic stroke, in particular for its most common subtype, ICH.
Intracerebral hemorrhage is the second most common subtype of stroke. In recent decades our understanding of intracerebral hemorrhage has improved. New risk factors have been identified; more knowledge has been obtained on previously known risk factors; and new imaging techniques allow for in vivo assessment of preclinical markers of intracerebral hemorrhage. In this review the latest developments in research on intracerebral hemorrhage are highlighted from an epidemiologic point of view. Special focus is on frequency, etiologic factors and pre-clinical markers of intracerebral hemorrhage.
ICH occurs both sporadically and as part of familial syndromes. Monogenic disorders associated with ICH or microscopic bleeding, such as hereditary cerebral amyloid angiopathy, CADASIL, and collagen type IV A1–associated vasculopathy, demonstrate the potent effect of rare mutations. Dissecting the more complex genetics of sporadic ICH, however, will likely require defining multiple common DNA variants with weaker effects. Advances in high-throughput genotyping technology, computational and analytic methodologies, and large-scale collaborative efforts have already led to the identification of new genetic risk factors for dozens of common diseases. Such whole-genome association studies are being undertaken in sporadic ICH.
Whereas the age-standardized frequency of all stroke has decreased in the past decades, this decrease has primarily been driven by ischemic stroke. Data on temporal trends for intracerebral hemorrhage are conflicting with some studies reporting a decrease in intracerebral hemorrhage in the last two decades, whereas other studies show stable numbers in the same time period, and yet other studies show an increase. Given the temporal trends in risk factors for intracerebral hemorrhage, one explanation for the conflicting results across studies is that the number of intracerebral hemorrhages due to hypertension has decreased in time due to better treatment, but is offset by an increase in number of intracerebral hemorrhages related to warfarin use.
Potential treatments to be further evaluated for cessation or control of bleeding during the hyperacute phase include the use of clotting factors to promote hemostasis, targeted treatment to reverse anticoagulation-associated ICH, and consistent approaches to blood pressure (BP) control in the setting where ICH is first diagnosed.
Potential approaches include surgical aspiration of the clot with or without local thrombolysis, and the use of drugs to accelerate the removal of the toxic hemoglobin degradation products and iron or drugs that can impact other noniron mediators of secondary brain injury.3
Potential approaches include the use of osmotherapy, specific drugs targeting the pathophysiological pathway of edema formation, nonpharmacological strategies such as temperature regulation, or surgical treatments such as craniectomy or placement of an external ventricular drain in cases of developing hydrocephalus.
Currently available therapies for enhancing recovery after ICH are derived from ischemic stroke and traumatic brain injury. There are no specific treatments or therapies for ICH patients.
Prevention of ICH would have the greatest impact on its burden. This can be achieved by improved monitoring and treatment of hypertension and easy-to-comply-with antihypertensive regimens; the use of imaging and genetic biomarkers to identify those at high risk for ICH; and better delineation of the competing risks between prevention of ICH and cerebral and cardiovascular ischemia in patients requiring anticoagulation or statin therapy. There is also a need for better clarification of the pathological features, natural history, risk factors, and biomarkers (multiomics) of cerebrovascular pathologies predisposing to hemorrhage in young and old patients.
Much of the epidemiologic research on intracerebral hemorrhage has concentrated on identifying risk factors for intracerebral hemorrhage. Not only do risk factors provide etiologic insights into disease, but in case of modifiable risk factors, these can also become targets for preventive or therapeutic strategies. Moreover, risk factors can be utilized for their predictive or diagnostic value. This latter notion also brings forth an important methodological consideration in epidemiologic studies on intracerebral hemorrhage. Clinically, intracerebral hemorrhage is usually subtyped according to location into lobar or deep intracerebral haemorrhage.
Apart from the aforementioned risk factors, for which associations are robust and have been established, there are several other putative risk factors for which a solid body of evidence is emerging.
Regular physical activity has been suggested to be protective of intracerebral hemorrhage, though studies have not shown conclusive evidence. Dietary factors have been implicated in intracerebral hemorrhage, although it is still unclear which dietary constituents drive this association.
Emerging evidence further shows that poor kidney function is a novel risk factor for stroke, including intracerebral hemorrhage. This risk is not only restricted to patients with overt kidney disease, but seemingly extends to the general population. However, it is worth noting that not all studies find associations between markers of kidney disease and intracerebral hemorrhage. This shows the need for further studies on this relationship.
Intracerebral hemorrhage is a multi-factorial disease caused by several interacting and overlapping risk factors and etiologies. Hypertension remains the most important risk factor followed by cerebral amyloid angiopathy. However, the increased use of anticoagulants poses new challenges to better prevent intracerebral hemorrhage as complication. Emerging risk factors have also been identified providing new pathways for further research. New imaging techniques will in coming years be assessed for their ability to identify persons at an increased risk of intracerebral hemorrhage, which will substantially improve pre-clinical risk-stratification.
However, despite these advances, intracerebral hemorrhage still poses a substantial burden on healthcare systems. More worryingly, over the last decades the incidence and prognosis of intracerebral hemorrhage have remained stable. This indicates that there is still a long way to go before we have a full understanding of intracerebral hemorrhage. Epidemiologic research will continue to be one of the cornerstones in research on intracerebral hemorrhage.