Intracerebral hemorrhage (ICH) accounts for 6.5% to 19.6%

Transcription

1 Incidence and 10-Year Survival of Intracerebral Hemorrhage in a Population-Based Registry Simona Sacco, MD; Carmine Marini, MD; Danilo Toni, MD; Luigi Olivieri, MD; Antonio Carolei, MD, FAHA Background and Purpose The purpose of this study was to evaluate the incidence and prognosis of intracerebral hemorrhage. Methods We analyzed data referring to our prospective population-based registry, including patients with a first-ever stroke followed up to 10 years. Results In a 5-year period, we included 549 patients (247 men and 302 women; mean age SD, years) with an intracerebral hemorrhage. The crude annual incidence rate was 36.9 per (95% CI, 33.8 to 40.0), 32.9 per when standardized to the 2006 European population, and 15.9 per when standardized to the world population. The case-fatality rate was 34.6% (95% CI, 30.6 to 38.6) at 7 days; it increased to 50.3% (95% CI, 46.1 to 54.5) at 30 days and to 59.0% (95% CI, 54.9 to 63.1) at 1 year. Diabetes mellitus and posterior fossa hemorrhage were associated with an increased risk of 7- and 30-day mortality, whereas older age was associated with an increased risk of 30-day mortality only. At the Kaplan Meier analysis, the 10-year survival rate was 24.1% (95% CI, 20.1 to 28.1). Conclusions Intracerebral hemorrhage is characterized by a severe prognosis, mostly in the short term. Because of the high proportion of fatal events that occurs early after the stroke, it is mandatory to identify and apply specific therapeutic strategies for patients with intracerebral hemorrhage. (Stroke. 2009;40: ) Key Words:incidence intracerebral hemorrhage prognosis stroke Intracerebral hemorrhage (ICH) accounts for 6.5% to 19.6% of all strokes and is characterized by high mortality. 1,2 Several studies have been undertaken to evaluate the epidemiological characteristics of ICH, but data referring to the Italian population are scanty. 3 Moreover, data from a large and methodologically rigorous study may provide robust estimates. Definition of incidence rates, impact of known risk factors, and mortality are relevant to plan health services and to define national and international guidelines for the management of the disease. 4,5 Moreover, few studies included a long-term follow-up of such patients, particularly useful to understand the natural history of the disease. 6 None of those studies refer to the Italian population. The aim of our study is to assess incidence, risk factors, case-fatality rates, and 10-year survival of patients with ICH in a population-based stroke registry in central Italy. Methods Study Design and Population Incidence and 10-year prognosis of ICH were evaluated in patients included in a 5-year period (1994 to 1998) in the prospective, population-based L Aquila registry, which complies with epidemiological criteria for stroke incidence studies. 1,2,7 The study was approved by the institutional ethics committee and complies with national rules on informed consent of subjects involved in the study. Definitions of risk factors were detailed in a previous paper. 2 The L Aquila district is a delimited mountainous area of km 2 of the Abruzzo region in central Italy. 2 Globally, there are 108 towns, 97 rural and 11 urban. The resident population, estimated from the 1991 and 2001 census data, is (48% rural) and was calculated as the linear projection to the midstudy period based on the observed trend between 1991 and 2001 censuses. 3,8,9 The population remained stable across the study period with very little migration in and out of the district. The population is served by 8 public hospitals, 8 private hospitals, 233 general practitioners, and 89 on-call physicians. Medical care is completely free of charge, allowing easy access to medical services within the acute phase of stroke. Definitions Stroke was defined as rapidly developing signs of focal or global disturbance of cerebral function, lasting longer than 24 hours or leading to death, with no apparent cause other than that of vascular origin. 10 ICH (code 431, International Classification of Diseases, 9th Revision) was defined as a neurological deficit documented by brain CT or MRI showing the presence of an ICH. In the absence of brain neuroimaging or necropsy examination, a diagnosis of probable ICH was made in the presence of clinical manifestations reflecting increased intracranial pressure such as headache and vomiting, decreased alertness or coma, and gradual progression to death within Received April 16, 2008; final revision received June 9, 2008; accepted June 24, From the Department of Neurology (S.S., C.M., L.O., A.C.), University of L Aquila, L Aquila, Italy; and the Department of Neurological Sciences (D.T.), Università La Sapienza, Rome, Italy. Correspondence to Antonio Carolei, MD, FAHA, Clinica Neurologica, Dipartimento di Medicina Interna e Sanità Pubblica, Università degli Studi di L Aquila, Piazzale Salvatore Tommasi 1, L Aquila, Italy. a_carolei@yahoo.com 2009 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 Sacco et al Epidemiology of Intracerebral Hemorrhage hours of onset. 11,12 Secondary ICHs were diagnosed in the presence of ruptured aneurysms, arteriovenous malformations, tumors, venous thrombosis, trauma, anticoagulation, or other known causes of ICHs. Patients who could not be categorized as ischemic, hemorrhagic, or due to subarachnoid hemorrhage because of the absence of adequate clinical signs or symptoms, and confirmatory investigations were included among those with ill-defined or unclassified cerebrovascular events (International Classification of Diseases, 9th Revision codes 436 to 437). Codes of the Application of the International Classification of Diseases to Neurology were applied to patients who had brain neuroimaging. 13 Those cases were classified as lobar when the bleeding occurred in the frontal, temporal, parietal, or occipital lobes; deep when the bleeding involved subcortical structures; posterior fossa when the bleeding was located in the brainstem or in the cerebellum; and as intraventricular or multiple localized when appropriate. Recruitment and Follow-Up All events were identified by active monitoring of all inpatient and outpatient health services. In each clinical ward, all patients admitted for a cerebrovascular event were identified and examined by a senior physician. Thereafter, all patients were seen by a consulting neurologist to validate the event. To verify all admitted patients with stroke, 8 consulting neurologists screened the admission and discharge lists on a daily basis. Nearby hospitals were regularly monitored to identify those residents who had crossboundary medical care. The records of patients with dizziness, vertigo, confusion, seizures, headache, and transient global amnesia were also reviewed. Neuroradiology, neurophysiology, and neurosonology services were systematically checked. Regular contacts were also maintained with rehabilitation and long-term care services. The study purpose was explained in advance to all general practitioners and on-call physicians who were asked to refer all stroke cases or give information about patients evaluated at home. Death certificates were checked monthly, and clinical details of all patients who died with a diagnosis of stroke or with a diagnosis of probable ICH were reviewed. All cases were followed up with quarterly planned visits or with a structured telephone interview up to December 31, 2005; moreover, death certificates were checked to identify the causes of death of patients who died. Outcome events were represented by death from vascular or nonvascular causes. In particular, cerebral death was defined as death occurring within or after 30 days of the onset of signs or symptoms of the qualifying stroke or of a new stroke with clinically proven brain herniation in the absence of other intervening causes. Because patients were included in a population-based registry, during the study, no compulsory treatment was adopted, although strict adherence to current guidelines for medical and surgical treatment was encouraged. Statistical Analyses Incidence rates were standardized by age and sex with the direct method to the 2006 European population and to the 2005 world population. 14,15 Poisson regression analysis was performed to evaluate the linear relation between incidence rates of ICH and year of inclusion in the registry. Student t test was used to compare group means. Logistic regression analysis was used to evaluate the association between deep and lobar hemorrhages and prevalence of vascular risk factors. Survival after the stroke was estimated by the Kaplan Meier method and comparisons between groups were performed by means of the log rank test. Multivariate estimates of the hazard ratios (HRs) were calculated according to the Cox regression analysis. Two-sided values of P 0.05 were considered to indicate significance. All analyses were performed with the SPSS (Version 10.1). Results Of 4353 patients with a first-ever stroke, 53 (1.2%) had ill-defined or unclassified cerebrovascular events and 588 (13.5%) had an ICH. Of them, 561 (95.1%) patients were hospitalized, whereas 27 (4.9%) died at home. Thirty-nine (6.6%) patients were excluded from the study because medical history and brain neuroimaging indicated a secondary ICH. ICH was confirmed by brain neuroimaging (CT, 435 [93.8%]; MRI, 19 [4.1%]; and both, 10 [2.1%]) in 464 (84.5%) patients, whereas in the remaining 58 (10.6%) hospitalized patients not submitted to neuroimaging and in the 27 (4.9%) patients who died before hospitalization, a probable ICH was diagnosed according to our predefined criteria. Hence, the object of this study were 549 patients with ICH (mean SD age, years), of whom 247 (45.0%) were men (mean SD age, years) and 302 (55.0%) were women (mean SD age, years; P ). Patients with ICH confirmed by neuroimaging were younger than patients who were not submitted to neuroimaging ( versus years; P ). Crude annual incidence rate for a first-ever ICH was 36.9 per (95% CI, 33.8 to 40.0), 32.9 per when standardized to the 2006 European population, and 15.9 per when standardized to the world population. Age- and sex-specific incidence rates (Table 1) increased sharply with age in both sexes and were higher in women than in men; incidence rates were higher in men than in women in all age groups but older than 75 years of age. They were approximately 7 times higher in patients older than 85 years (309.8 per ) with respect to patients in the 55- to 64-year age group (41.8 per ) and 3 times higher with respect to patients in the 65- to 74-year age group (98.0 per ). During the study period, the incidence rate was 38.3 per in 1994, 38.6 per in 1995, 30.6 per in 1996, 36.0 per in 1997, and 41.0 per in 1998 at the Poisson regression analysis (slope 1.01; P 0.995). In the 464 patients with ICH confirmed by neuroimaging, the crude annual incidence rate was per , per when standardized to the 2006 European population, and per when standardized to the 2005 world population. According to the Application of the International Classification of Diseases to Neurology (Table 2) that was applied to the 464 patients with ICH confirmed by brain neuroimaging, 210 (45.3%) were lobar, 205 (44.2%) deep, 44 (9.4%) were in the posterior fossa (16 involved the brainstem and 28 the cerebellum), and 5 (1.1%) involved more than one ventricle (n 4) or were multiple localized (n 1). Proportions of lobar and deep hemorrhages were similar in the different age and sex groups. Arterial hypertension was present in 415 of 549 patients (75.6%) and was more common in patients with deep (83.3%) than in those with lobar (72.9%) hemorrhage (OR, 0.5; 95% CI, 0.3 to 0.9). As shown in Table 3, 190 patients (34.6%; 95% CI, 30.6 to 38.6) died within 7 days, 276 (50.3%; 95% CI, 46.1 to 54.5) within 30 days, and 324 (59.0%; 95% CI, 54.9 to 63.1) within 1 year. Most of the deaths that occurred within the first 7 days were cerebral (98.4%). Multivariate Cox regression analysis, including age, sex, and location of the hemorrhage as covariates (Table 4), showed an increased 7- and 30-day mortality associated with

3 396 Stroke February 2009 Table 1. Annual Incidence Rates (Per ) of First-Ever Primary ICH According to Age and Sex Population at Risk Group Patient, n (Person- Years), n Rate 95% CI Men 0 44 years years years years years years All (crude) All (European All (world Women 0 44 years years years years years years All (crude) All (European All (world Both 0 44 years years years years years years All (crude) All (European All (world Estimates include cases of probable ICH. diabetes mellitus (HR, 1.86 for 7-day mortality and 1.82 for 30-day mortality) and posterior fossa hemorrhage (HR, 1.89 for 7-day mortality and 1.69 for 30-day mortality), whereas age was associated with 30-day mortality only (HR, 1.18). On the opposite, the presence of hypercholesterolemia was associated with a lower 7-day mortality (HR, 0.55). Associations were the same after excluding from the analyses the 85 patients without brain neuroimaging. Table 2. ICD-9 and ICD-10 NA Codes of Primary ICH in 464 Patients With Available Brain Neuroimaging ICD-9 ICD I61.0 ICH in hemisphere, subcortical I61.00 Basal ganglia 71 I61.01 Thalamus 36 I61.02 Internal capsula 39 I61.07 Involving more than one 59 subcortical structure I61.1 ICH in hemisphere, cortical I61.10 Frontal 20 I61.11 Temporal 29 I61.12 Parietal 43 I61.13 Occipital 11 I61.17 Involving more than one lobe 101 I61.2 ICH in hemisphere, 6 unspecified I61.3 ICH in brainstem I61.30 Midbrain 3 I61.31 Pons 9 I61.37 Involving more than one 4 subdivision of brainstem I61.4 ICH in cerebellum I61.40 Cerebellar hemisphere 21 I61.41 Cerebellar tonsil 1 I61.42 Vermis 3 I61.47 Involving more than one 3 subdivision of cerebellum I61.5 ICH, intraventricular I61.57 Multiple ventricles 4 I61.6 ICH, multiple localized 1 ICD-9 indicates International Classification of Diseases, 9th Revision; ICD-10 NA, Application of the International Classification of Diseases to Neurology. As shown in the Figure, the overall 10-year survival was 24.1% (95% CI, 20.1 to 28.1), whereas, according to site of ICH, it was 31.6% in deep hemorrhages, 23.8% in lobar hemorrhages, and 34.3% in posterior fossa hemorrhages (P ; log rank test). Discussion In this study on a large cohort of patients prospectively included in the population-based L Aquila registry and followed up to 10 years, we found a proportion of ICHs (13.5%) similar to that reported in other registries and lower than that reported in the Japanese population. 1,16,17 We also found a 32.9 per European standardized annual incidence rate of ICH that was similar to rates reported in comparable studies. 1,16 24 We might speculate that the per standardized annual incidence rate, referring to patients with ICH confirmed by neuroimaging, underestimates the real burden of the disease. Variations in incidence rates are commonly attributed to different methodology, demographics, and ethnic characteristics of the studied populations as well as to differences in the management of risk factors and

4 Sacco et al Epidemiology of Intracerebral Hemorrhage 397 Table 3. Seven-, 30-Day, and 1-Year Case-Fatality Rates in Patients With ICH 7-Day 30-Day 1-Year Type n Percent 95% CI n Percent 95% CI n Percent 95% CI ICH confirmed by neuroimaging (n 464) Lobar (n 205) Deep (n 210) Posterior fossa (n 44) Intraventricular or multiple localized (n 5) Probable ICH without brain neuroimaging (n 85) All ICH (n 549) health conditions. 13,16 24 As shown by the Poisson regression analysis, no significant incidence change could be detected, reflecting stability of the population and adherence to guidelines of primary prevention within the 5-year study period. However, we cannot exclude that changes of the incidence rates might have occurred after the end of the inclusion period so that the reported rates might not correspond to the current figure. We also found that lobar (45.3%) and deep (44.2%) hemorrhages were equally represented, whereas posterior fossa hemorrhages in the brainstem (3.4%) and in the cerebellum (6.0%) were far less frequent. The high proportion of lobar hemorrhages might be, at least in part, attributed to the old age of patients included in the present study. As expected, arterial hypertension was the most common risk factor for ICH, being present in over three fourths of our patients. Its prevalence was higher in patients with deep (83.3%) than in those with lobar (72.9%) hemorrhage, but not as much as 2-fold more common in the former than in the latter as reported in a recent review. 25 However, since those studies cumulatively included a total of 601 patients, we think that our 464 patients with brain neuroimaging could provide a useful contribution to the issue. Our case-fatality rate for ICH was among the highest ever reported as a predictable consequence of the higher mean age of our patients. 1,17,18 Moreover, because all patients diagnosed as probable ICH died early, we cannot exclude that their inclusion may have biased the fatality rates. However, casefatality rates were also high in patients with ICH confirmed by neuroimaging but lower than in the comparable studies. 21,22 The higher mortality of patients with probable ICH with respect to patients with ICH confirmed by neuroimaging might have depended on their older age and on the burden of comorbidities. In our study, factors accounting for mortality in the short term after ICH were represented by diabetes mellitus, posterior fossa location of the bleeding, and older age, but not arterial hypertension. Hypercholesterolemia was related to a lower 7-day mortality, a figure not easily explainable, which adds to the controversial issue of the relationship between cholesterol levels and risk of brain hemorrhage As shown by the Kaplan Meier analysis, we found a 24.1% (95% CI, 20.1 to 28.1) survival at 10 years. This proportion was lower than the 31% (95% CI, 17% to 45%) reported in a comparable study, whose estimate was characterized by a wider CI; we cannot exclude that the better long-term survival might be attributed to the younger age. 6 Our series represents the largest group of patients with ICH followed up to 10 years. However, the study has some Table 4. Factors Associated With 7- and 30-Day Mortality in Patients (n 549) With Primary ICH (Multivariate Cox Regression Analysis) 7-Day 30-Day HR 95% CI P Value HR 95% CI P Value Age* Men Arterial hypertension Diabetes mellitus Cigarette smoking Hypercholesterolemia Coronary heart disease Chronic atrial fibrillation Peripheral arterial disease Deep hemorrhage 1 1 Lobar hemorrhage Posterior fossa hemorrhage *For each 10-year increase of age. Deep hemorrhage considered as the reference group.

5 398 Stroke February 2009 Figure. Kaplan Meier survival curves over 10 years (logarithmic scale) in patients with deep (light grey line), lobar (dark grey line), or posterior fossa (black line) ICH (P ; log rank test). Data referring to all hemorrhages (dotted line) are given as reference and include cases of probable ICHs. limitations despite the methodology we adopted matched the required criteria for comparable population-based stroke studies. 1 Studies aimed to assess the epidemiology of ICH need to identify all incident cases, including also patients treated at home or those who die before or shortly after hospital admission without performing brain neuroimaging. 1,2 However, although hospital-based studies are mainly biased by the exclusion of the most severe cases, population-based studies, which include also patients who die prematurely before a confirmatory brain neuroimaging, are at risk of including cases without the disease of interest. Hence, we may have included some patients with secondary ICH, subarachnoid hemorrhage, hemorrhagic transformation of a cerebral infarction, ischemic stroke, or even nonstroke cases. However, had we excluded those patients (15.5%), we might have underestimated both incidence and case-fatality rates of ICH. Obviously, our study may have missed asymptomatic cases. In any case, the adoption of strict and predefined diagnostic criteria should have minimized any inclusion bias. On the other hand, the large number of included patients, the large proportion of patients who underwent neuroimaging, and the 10-year follow-up give strength to our data. In conclusion, our population-based study shows that ICH is characterized by a severe prognosis mostly in the short term. Because of the high proportion of fatal events that occurs early after the stroke, it is mandatory to identify and apply specific therapeutic strategies for patients with ICH. Source of Funding This study was supported by a grant (CNR CT04) from the Consiglio Nazionale delle Ricerche, Rome, Italy. None. Disclosures References 1. Feigin VL, Lawes CMM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol. 2003;2: Carolei A, Marini C, Di Napoli M, Di Gianfilippo G, Santalucia P, Baldassarre M, De Matteis G, di Orio F. High stroke incidence in the prospective community-based L Aquila registry ( ). First year s results. Stroke. 1997;28: Marini C, Triggiani L, Cimini N, Ciancarelli I, De Santis F, Russo T, Baldassarre M, di Orio F, Carolei A. Proportion of older people in the community as a predictor of increasing stroke incidence. Neuroepidemiology. 2001;20: Sacco RL, Adams R, Albers G, Alberts MJ, Benavente O, Furie K, Goldstein LB, Gorelick P, Halperin J, Harbaugh R, Johnston SC, Katzan I, Kelly-Hayes M, Kenton EJ, Marks M, Schwamm LH, Tomsick T; American Heart Association; American Stroke Association Council on Stroke; Council on Cardiovascular Radiology and Intervention; American Academy of Neurology. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37: Stroke Prevention and Educational Awareness Diffusion. Italian Guidelines for Stroke Prevention and Management: Syntheses and Recommendations. Milan, Italy: Stroke Prevention and Educational Awareness Diffusion; Hardie K, Hankey GJ, Jamrozik K, Broadhurst RJ, Anderson C. Ten-year survival after first-ever stroke in the Perth Community Stroke Study. Stroke. 2003;34: Sudlow CL, Warlow CP. Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke. 1997;28: Istituto Centrale di Statistica. Popolazione e abitazioni. 13 Censimento generale della popolazione e delle abitazioni, 20 ottobre 1991, Fascicolo provinciale 66, L Aquila, Roma, 1993: ISTAT. 14 o censimento generale della popolazione e delle abitazioni, 21 ottobre Available at: misc.jsp?p 2. Accessed September 1, World Health Organization. Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death, 9th Revision, Vol 1. Geneva: World Health Organization; Mohr JP, Caplan LR, Melski JW, Goldstein RJ, Duncan GW, Kistler JP, Pessin MS, Bleich HL. The Harvard Cooperative Stroke Registry: a prospective registry. Neurology. 1978;28: Yatsu FM, Becker C, McLeroy KR, Coull B, Feibel J, Howard G, Toole JF, Walker MD. Community Hospital-based Stroke Programs: North Carolina, Oregon, and New York. I: Goals, objectives, and data collection procedures. Stroke. 1986;17: World Health Organization. Application of the International Classification of Diseases to Neurology (ICD-10 NA). II ed. Geneva: World Health Organization; EUROSTAT. Population and social conditions. Available at: eurostat.ec.europa.eu/portal/page?_pageid 0, ,0_ &_ dad portal&_schema PORTAL. Accessed September 1, Population Division of the Department of Economic and Social Affairs of the United Nations Secretariat, World Population Prospects: The 2006 Revision and World Urbanization Prospects: The 2005 Revision. Available at: Accessed May 28, Giroud M, Gras P, Chadan N, Beuriat P, Milan C, Arveux P, Dumas R. Cerebral haemorrhage in a French prospective population study. J Neurol Neurosurg Psychiatry. 1991;54: Kitamura A, Nakagawa Y, Sato M, Iso H, Sato S, Imano H, Kiyama M, Okada T, Okada H, Iida M, Shimamoto T. Proportions of stroke subtypes among men and women or 40 years of age in an urban Japanese city in 1992, 1997, and Stroke. 2006;37: Rothwell PM, Coull AJ, Silver LE, Fairhead JF, Giles MF, Lovelock CE, Redgrave JN, Bull LM, Welch SJ, Cuthbertson FC, Binney LE, Gutnikov SA, Anslow P, Banning AP, Mant D, Mehta Z for the Oxford Vascular Study. Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study). Lancet. 2005;366: Thrift AG, Dewey HM, Macdonell RA, McNeil JJ, Donnan GA. Incidence of the major stroke subtypes: initial findings from the North East Melbourne stroke incidence study (NEMESIS). Stroke. 2001;32:

6 Sacco et al Epidemiology of Intracerebral Hemorrhage Anderson CS, Chakera TM, Stewart-Wynne EG, Jamrozik KD. Spectrum of primary intracerebral haemorrhage in Perth, Western Australia, : incidence and outcome. J Neurol Neurosurg Psychiatry. 1994; 57: Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project Incidence, case fatality rates and overall outcome at one year of cerebral infarction, primary intracerebral and subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 1990;53: Kolominsky-Rabas PL, Sarti C, Heuschmann PU, Graf C, Siemonsen S, Neundoerfer B, Katalinic A, Lang E, Gassmann KG, von Stockert TR. A prospective community-based study of stroke in Germany the Erlangen Stroke Project (ESPro): incidence and case fatality at 1, 3, and 12 months. Stroke. 1998;29: Labovitz DL, Halim A, Boden-Albala B, Hauser WA, Sacco RL. The incidence of deep and lobar intracerebral hemorrhage in whites, blacks, and Hispanics. Neurology. 2005;65: Feigin V, Carter K, Hackett M, Barber PA, McNaughton H, Dyall L, Chen MH, Anderson C, for the Auckland Regional Community Stroke Study Group. Ethnic disparities in incidence of stroke subtypes: Auckland Regional Community Stroke Study, Lancet Neurol. 2006;5: Jackson CA, Sudlow CLM. Is hypertension a more frequent risk factor for deep than for lobar supratentorial intracerebral haemorrhage? J Neurol Neurosurg Psychiatry. 2006;77: Counsell C, Boonyakarnkul S, Dennis M, Sandercock P, Bamford J, Burn J, Warlow C. Primary intracerebral haemorrhage in the Oxfordshire Community Stroke Project. Cerebrovasc Dis. 1995;5: Tatu L, Moulin T, El Mohamad R, Vuillier F, Rumbach L, Czorny A. Primary intracerebral hemorrhages in the Besançon stroke registry. Initial clinical and CT findings, early course and 30-day outcome in 350 patients. Eur Neurol. 2000;43: Thrift AG, McNeil JJ, Forbes A, Donnan GA. Three important subgroups of hypertensive persons at greater risk of intracerebral haemorrhage. Hypertension. 1998;31: Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in men screened for the multiple risk factor intervention trial. N Engl J Med. 1989;320: Suh I, Jee SH, Kim HC, Nam CM, Kim IS, Appel LJ. Low serum cholesterol and haemorrhagic stroke in men: Korea Medical Insurance Corporation Study. Lancet. 2001;357: The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355: