ISSN: 1524-4628
Copyright © 2006 American Heart Association. All rights reserved. Print ISSN: 0039-2499. Online
Stroke is ...
Hypertensive Intracerebral Hemorrhage in Young People
Previously Unnoticed Age-Related Clinical Differences
Jose´ L. Ruiz-...
(nϭ105). The same inclusion criteria were applied for all patients.
The internal Ethics Committee of our hospitals approve...
with total dependence on others for activities of daily living.
Four (15.4%) of the 26 patients with suitable follow-up ex...
cohort and their older counterparts differed in the location
pattern of the brain hematomas. These differences in ICH
20. Jennett B, Bond M. Assessment of outcome after severe brain damage.
Lancet. 1975;1:480–484.
21. Aurell M. Screening fo...
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  1. 1. ISSN: 1524-4628 Copyright © 2006 American Heart Association. All rights reserved. Print ISSN: 0039-2499. Online Stroke is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514 DOI: 10.1161/01.STR.0000248766.22741.4b 2006;37;2946-2950; originally published online Nov 9, 2006;Stroke Fernando Barinagarrementería Padilla-Martínez, Jorge Villarreal-Careaga, Carlos Cantú, Antonio Arauz and José L. Ruiz-Sandoval, Samuel Romero-Vargas, Erwin Chiquete, Juan J. Age-Related Clinical Differences Hypertensive Intracerebral Hemorrhage in Young People: Previously Unnoticed located on the World Wide Web at: The online version of this article, along with updated information and services, is Reprints: Information about reprints can be found online at Street, Baltimore, MD 21202-2436. Phone 410-5280-4050. Fax: 410-528-8550. Email: Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, 351 West Camden Subscriptions: Information about subscribing to Stroke is online at by ERWIN CHIQUETE on November 29, 2006stroke.ahajournals.orgDownloaded from
  2. 2. Hypertensive Intracerebral Hemorrhage in Young People Previously Unnoticed Age-Related Clinical Differences Jose´ L. Ruiz-Sandoval, MD; Samuel Romero-Vargas, MD; Erwin Chiquete, MD, PhD; Juan J. Padilla-Martı´nez, MD; Jorge Villarreal-Careaga, MD; Carlos Cantu´, MD, MSc; Antonio Arauz, MD, MSc; Fernando Barinagarrementerı´a, MD Background and Purpose—Hypertensive intracerebral hemorrhage (ICH) in young people has been the object of only succinct analyses. Therefore, it is unclear whether extrapolation of the information obtained from older patients is also valid for the young. Here we describe young persons with hypertensive ICH and compare them with their older counterparts to determine whether age-related clinical differences exist. Methods—From 1988 to 2004, we studied 35 consecutive young patients with ICH (60% men; mean age, 33 years; range, 15 to 40 years) for whom the etiology of the brain hemorrhage was hypertension. For clinical comparisons, sex-matched persons with hypertensive ICH, aged Ͼ40 years, were randomly selected by a factor of 3:1 (nϭ105). Results—Essential hypertension was present in 26 (74%) young patients and secondary hypertension in 9 (26%), with renovascular hypertension being the most common cause (nϭ5, 55%). Compared with older patients, the young had higher blood pressures, smaller hemorrhage volumes, lower rates of ventricular extensions (for all, PϽ0.05), and different distribution pattern of ICHs (Pϭ0.05), without cerebellar and lobar locations. Thirty-day mortality was markedly lower in the young than in older persons (Pϭ0.001), nevertheless at the expense of more incapacitating disabilities. Conclusions—Young people presenting with hypertensive ICH differ in clinical characteristics and have a different prognosis when compared with their older counterparts. These findings suggest underlying age-related differences in disease pathogenesis. (Stroke. 2006;37:2946-2950.) Key Words: aging Ⅲ intracerebral hemorrhage Ⅲ hypertension Ⅲ risk factors Ⅲ young people Intracerebral hemorrhage (ICH) accounts for 10% to 23% of strokes,1,2 with hypertension being the single most important risk factor in middle-aged and elderly persons.3–5 Current knowledge about hypertensive ICH in the young is derived mainly from studies on all-cause ICH, which have reported variable frequencies ranging from 11% to 64% and providing only brief conclusions about topography and prog- nosis.5–15 The other well-characterized clinical and radiolog- ical characteristics of middle-aged and elderly ICH patients are generally unknown for their younger counterparts. There- fore, extrapolation of the information obtained from older people might not be valid for young persons. In view of the scarce information on these issues, we aimed to analyze hypertensive ICH in young people, their hyperten- sion profile, clinical condition, and outcome. Also, to identify features that would suggest underlying age-related differences in disease pathogenesis, we compared the young patients with their older counterparts. Our hypothesis was that hypertensive ICH of the young differs in clinical characteristics and has a different prognosis, when compared with that seen in older people. Subjects and Methods Study Population and Design From January 1988 to December 2004, we analyzed 294 consecutive patients with symptomatic ICH who were Ͻ40 years old. From 1988 to 1998, the Instituto Nacional de Neurologı´a y Neurocirugı´a (Mexico City, Distrito Federal, Mexico) included 244 patients, and from 1999 to 2004, the Hospital Civil de Guadalajara Fray Antonio Alcalde (Guadalajara, Jalisco, Mexico) included 50 patients in the respective research databases. Of the 294 young patients, hyperten- sion was the cause of ICH in 35 (12%). To identify possible age-related clinical differences, sex-matched persons with hyperten- sive ICH, aged Ͼ40 years, were randomly selected by a factor of 3:1 Received April 22, 2006; final revision received July 17, 2006; accepted July 19, 2006. From the Department of Neurology and Neurosurgery (J.L.R.-S., S.R.-V., E.C., J.J.P.-M.), Hospital Civil de Guadalajara Fray Antonio Alcalde, and the Department of Neurosciences, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, and the Stroke Clinic (J.V.-C., C.C., A.A., F.B.), Instituto Nacional de Neurologı´a y Neurocirugı´a, Mexico City, Mexico. Dr Jorge Villarreal-Careaga is currently at the Hospital General de Culiaca´n; Culiaca´n, Mexico. Dr Carlos Cantu´ is currently at the Department of Neurology, Instituto Nacional de Ciencias Me´dicas y de la Nutricio´n Salvador Zubira´n, Mexico City, Mexico. Dr Fernando Barinagarrementerı´a is currently at the Department of Neurology, Hospital A´ ngeles de Quere´taro, Quere´taro, Mexico. Correspondence and reprint requests to Dr Jose´ Luis Ruiz-Sandoval, Servicio de Neurologı´a y Neurocirugı´a, Hospital Civil de Guadalajara Fray Antonio Alcalde, Hospital 278, Guadalajara, Jalisco, Me´xico CP44280. E-mail, or Dr Fernando Barinagarrementerı´a Aldatz, Neurologı´a, Hospital A´ ngeles, Quere´taro. Bernardino del Razo 21, Santiago de Quere´taro, Qro, Me´xico. E-mail © 2006 American Heart Association, Inc. Stroke is available at DOI: 10.1161/01.STR.0000248766.22741.4b 2946
  3. 3. (nϭ105). The same inclusion criteria were applied for all patients. The internal Ethics Committee of our hospitals approved the study, and informed consent was obtained from all patients or their closest relatives. Operational Definitions In all cases included, ICH was defined as a sudden, focal, neurolog- ical deficit with intraparenchymal hemorrhage seen on head com- puted tomography (CT) scans. Hypertensive status was defined as a patient history of hypertension, with or without treatment, or averaged readings of systolic blood pressure (SBP) Ͼ140 mm Hg or of diastolic (DBP) Ͼ90 mm Hg, sustained for Ͼ2 weeks after the hospital admission and confirmed during follow-up, if suitable.16 Other potential causes of ICH were excluded. The BP readings obtained at presentation to the Emergency Department were consid- ered for analyses to evaluate the discrete point of evolution of the ICH in which the first clinical evaluations and decisions were performed. Brain hemorrhage volume was calculated by analysis of CT scans according to the ABC/2 method.17 Obesity was defined as a body mass index Ն30 kg/m2 , smoking habit as the consumption of Ն5 cigarettes at least 2 days per week during 12 months or more, and alcoholism as Ͼ2 alcoholic drinks per day. Mean arterial pressure (MAP) was calculated from the BP measurement on admittance to the Emergency Department as follows: MAPϭDBPϩ0.412 (SBPϪDBP).18 Every young patient received an exhaustive clinical, radiological, and laboratory assessment for secondary hypertension. The Sokolow-Lyon criteria were used to define findings as sugges- tive of left ventricular hypertrophy on the ECG.19 The patient’s functional status was evaluated at hospital discharge and during follow-up by using the Glasgow Outcome Scale.20 Data Analysis Pearson ␹2 and Fisher exact test were used to assess nominal variables in bivariate analyses. To compare quantitative variables distributed between the 2 groups, Student t test and the Mann- Whitney U test were performed for the distributions of parametric and nonparametric variables, respectively. Pearson correlation was used for continuous variables. All probability values were 2-sided and considered significant when PϽ0.05. The SPSS (SPSS Inc) v12.0 statistical package was used for all calculations and the process of randomization and selection of the comparison group. Results We studied 35 consecutive young patients with hypertensive ICH, 21 (60%) men and 14 (40%) women. MeanϮSD age was 33Ϯ6.2 years (range, 15 to 40 years). One (3%) patient was Ͻ20 years, 11 (31%) were between 21 and 30 years, and 23 (66%) were between 31 and 40 years. In addition to the head CT scan, nine (26%) patients also underwent magnetic resonance imaging and 14 (40%) were investigated further with conventional cerebral angiography. Three (8.6%) pa- tients had a history of prior ICH. Hypertension Profile Twenty-seven (77%) patients had known their hypertensive status at the time of ICH, and in 8 (23%) the diagnosis of hypertension was performed while hospitalized and con- firmed during follow-up. In the 27 patients with antecedent hypertension, the mean time from the diagnosis to ICH was 43 months (range, 1 month to 20 years); in 4 (15%) patients, this period was Ͻ1 year; in 16 (59%), 1 to 5 years; and in 7 (26%), Ͼ5 years. Twenty (74%) patients had received phar- macological treatment, and of them, only 7 (35%) declared to be at least 80% compliant with their antihypertensive regimen. The ICH volume was higher in patients without treatment than in those with antihypertensive medication (Table 1). By ECG records and chest films review, evidence of left ventricular hypertrophy was found in 28 (80%) patients. A secondary cause of hypertension was identified in 9 (26%) patients, renal artery stenosis being the cause in 5 (1 of them with Takayasu disease) and Cushing syndrome, aortic coarc- tation, primary aldosteronism, and pheochromocytoma in 1 case each. ICH Features and Outcome The brain hematomas were located in the putamen in 18 (51%) patients, the thalamus in 9 (26%), the pons in 5 (14%), and the medulla, midbrain, and caudate nucleus in 1 (3%) case each. Extension into the ventricular system occurred in 10 (29%) patients, 6 of them with hemorrhage in the thalamus, 3 in the putamen, and 1 in the caudate nucleus. The mean time of hospitalization was 14 days (range, 0 to 43 days). Twenty-five (71%) patients received medical treatment for ICH and 10 (29%), a neurosurgical procedure (hematoma evacuation in 4 and ventriculostomy alone in 5; 1 patient received both proce- dures). In-hospital death occurred in 8 (23%) patients, 6 (17%) were discharged with total dependence on others for daily activities, and 16 (46%) were discharged with severe and 5 (14%) with mild disabilities. No patient was discharged with complete recovery. The patients who survived to discharge lived for at least 30 days; therefore, both in-hospital and 30-day mortality was the same. MAP was higher in patients who had died than in survivors at 30 days (170.8 versus 144.9 mm Hg, respectively; Pϭ0.047). Twenty-six (96%) of the 27 survivors had at least 1 follow-up visit. The mean follow-up period was 18.7 months (range, 1 to 96 months). At the last follow-up visit, only 4 (15%) patients finally achieved total recovery, 13 (50%) remained with moderate dependence, and 6 (23%) remained TABLE 1. Clinical Characteristics and Outcome of the 35 Young Patients With Hypertensive ICH, According to Antihypertensive Treatment Characteristic Antihypertensive Treatment P*Present (nϭ20) Absent (nϭ15) Age, median (SD), y 33.3 (6.6) 33.4 (5.8) 0.93 Male, n (%) 10 (50) 11 (73) 0.16 BP profile at hospital admission SBP, mean (SD), mm Hg 197.55 (49.6) 172.93 (35.9) 0.11 DBP, mean (SD), mm Hg 125.20 (22.4) 126.00 (35.0) 0.93 MAP, mean (SD), mm Hg 155.01 (31.6) 145.34 (34.2) 0.39 ICH characteristics and outcome ICH volume, mean (SD), cm3 8.8 (6.7) 31.8 (12.2) 0.006 Irruption to ventricles, n (%) 7 (35) 3 (20) 0.33 Disabilities, n (%)† 12 (60) 10 (67) 0.46 Disabilities or death at 30 days, n (%) 18 (90) 12 (80) 0.40 30-day mortality, n (%) 6 (30) 2 (13) 0.42 *P value for differences between patients with and without antihypertensive treatment; Pearson ␹2 , Fisher’s exact test, Student t test, or Mann-Whitney U test, as appropriate. †A Glasgow Outcome Scale classification of II or III. Ruiz-Sandoval et al Hypertensive ICH in Young People 2947
  4. 4. with total dependence on others for activities of daily living. Four (15.4%) of the 26 patients with suitable follow-up experi- enced rebleeding during this period, 1 of them with a history of prior ICH. Among the 3 patients without a history of ICH, the pattern of recurrence was ganglia-ganglia in 2 and brain stem– ganglia in 1. The patient with prior ICH presented with 2 rebleeding episodes during an 8-month outpatient follow-up, and all hematomas were located in the basal ganglia. This 39-year- old man had an abdominal pheochromocytoma and was dis- charged in a vegetative state after the last event. Young Versus Older Patients Compared with older patients, the young had a higher frequency of alcoholism and fewer cases of diabetes mellitus (Table 2). Notably, the BP readings were higher in the young than in older persons (Table 2); however, there were smaller volumes of the hematomas and fewer cases of ventricular involvement. Thirty-day mortality was markedly lower in young patients than in the older, nevertheless at the expense of a high number of cases with incapacitating disabilities (Table 2). Compared with older persons, the young had a different pattern of ICH location, with more brainstem hematomas and without the occurrence of lobar or cerebellar ICH (the Figure). Discussion Hypertensive ICH in young people is relatively uncommon when other putative causes are excluded by an exhaustive investigative protocol. We observed few cases before the third decade of life, which underscores the association of age with both hypertension and brain hemorrhage. Hypertension Profile of the Young The frequency of secondary hypertension in our young cohort was higher than that reported for hypertensive persons with- out ICH.21 Because the screening protocol for secondary hypertension is not systematically practiced in our centers for all persons, we could not determine the frequency of second- ary hypertension in the older group. Nevertheless, secondary hypertension causing ICH might be more frequent in young people than it is in older persons, an issue that, however, needs more study. Moreover, despite the relatively short period between the diagnosis of hypertension and the occur- rence of ICH in the young cohort, we found features of target-organ damage commonly attributed to chronic expo- sure to hypertension.22 Clinical and Radiological Age-Related Differences At admission to the Emergency Department, the young had higher BP readings than the older patients. The reason for this aggravated BP profile in the young at hospital presentation might be due to either to hyperactivity of the autoregulation mechanisms of perfusion in response to brain damage23–25 or a distinct pattern of hypertension of the young (ie, secondary hypertension), compared with older patients. The young TABLE 2. Risk Factors, Clinical Characteristics, and Outcome of 35 Young Patients and 105 Sex-Matched Persons With Hypertensive ICH and >40 Years Variables All Patients Persons Aged Persons Aged P* Յ40 Years (nϭ35) Ͼ40 Years (nϭ105) Age, median (range), y 57 (18–99) 35 (18–40) 65 (42–99) Ͻ0.001 Male, n (%) 84 (60) 21 (60) 63 (60) Ͼ0.99 Risk factors Obesity, n (%) 62 (44) 18 (51) 44 (42) 0.33 Alcoholism, n (%) 23 (16) 10 (29) 13 (12) 0.02 Smoking habit, n (%) 29 (21) 5 (14) 24 (23) 0.28 Diabetes mellitus, n (%) 29 (21) 3 (9) 26 (25) 0.04 Previous ICH, n (%) 17 (12) 3 (9) 14 (13) 0.45 BP profile at hospital admission SBP, mean (SD), mm Hg 160.86 (68.1) 187 (45.3) 152.15 (72.3) 0.008 DBP, mean (SD), mm Hg 97.32 (41.1) 125.54 (28) 87.91 (40.5) Ͻ0.001 MAP, mean (SD), mm Hg 123.50 (51.1) 150.86 (32.6) 114.38 (52.9) Ͻ0.001 ICH characteristics and outcome ICH volume, mean (SD), cm3 32.9 (32.4) 20.3 (15.3) 34.1 (33.4) 0.03 Irruption to ventricles, n (%) 74 (53) 10 (29) 64 (61) 0.001 Surgical treatment, n (%)† 67 (48) 10 (29) 57 (54) 0.008 Severe disabilities, n (%)‡ 48 (34) 22 (81) 26 (56) 0.03 30-day mortality, n (%) 67 (48) 8 (23) 59 (56) 0.001 Severe disabilities or 30-day mortality, n (%) 115 (82) 30 (86) 85 (81) 0.52 *P value for differences between patients aged Յ40 years and older patients; Pearson ␹2 , Fisher’s exact test, Student t test, or Mann-Whitney U test, as appropriate. †Hematoma evacuation, ventriculostomy, or both. ‡A Glasgow Outcome Scale classification of II or III. 2948 Stroke December 2006
  5. 5. cohort and their older counterparts differed in the location pattern of the brain hematomas. These differences in ICH location might be related to the effect of the aging process on the cerebral blood vessels.26–28 Thus, on one hand, more ICHs located in deep regions of the brain were observed in young persons, and on the other, more lobar hematomas were found in older people. Regarding this issue, the important role of cerebral amyloid angiopathy in hypertensive ICHs of lobar location has been demonstrated.27 However, the sample size included in the present report may be underpowered to detect some differences, and on the contrary, may exaggerate other small disparities between the young and older patients. Further studies are necessary to confirm our findings. Also, it remains to be defined whether the length of exposure to hypertension, the type of antihypertensive medication, and the management of associated risk factors can influence ICH location. We could not find any correlation between hematoma size and BP readings, and despite having a higher MAP, the young had smaller hematomas and a lower rate of ventricular extensions than did the older patients. These findings suggest that the vascular disease and parenchymal degeneration observed with the aging process are important factors that may contribute to the more catastrophic effect of ICH in older people.29 Our observations are in agreement with recent evidence of the negative effect of aging on ICH-induced brain injury.30,31 We hypothesize that the aging process may imply changes in brain plasticity, diminishing the strength of the brain tissue that normally acts as a restriction wall to the extension of the hematoma. However, other factors can also affect the volume and extension of ICHs. It has been shown that some altered coagulation markers not routinely measured in clinical practice are associated with the rapid expansion of hypertensive hemorrhages.32 In summary, hypertensive ICH in the young differs in several features from that of older patients, which in turn suggests underlying distinctions in disease pathogenesis. Our findings warrant further investigation on the influence of the aging process in hypertensive ICH. Disclosures None. References 1. Dennis MS, Burn JP, Sandercock PA, Barnford JM, Wade DT, Warlow CP. Long-term survival after first-ever stroke: the Oxfordshire Com- munity Stroke Project. Stroke. 1993;24:796–800. 2. Lavados PM, Sacks C, Prina L, Escobar A, Tossi C, Araya F, Feuerhake W, Galvez M, Salinas R, Alvarez G. Incidence, 30-day case-fatality rate, and prognosis of stroke in Iquique, Chile: a 2-year community-based prospective study (PISCIS project). Lancet. 2005;365:2206–2215. 3. Brott T, Thalinger K, Hertzberg V. Hypertension as a risk factor for spontaneous intracerebral hemorrhage. Stroke. 1986;17:1078–1083. 4. Thrift AG, McNeil JJ, Forbes A, Donnan GA. Three important subgroups of hypertensive persons at greater risk of intracerebral hemorrhage. Hypertension. 1998;31:1223–1229. 5. Feldmann E, Broderick JP, Kernan WN, Viscoli CM, Brass LM, Brott T, Morgenstern LB, Wilterdink JL, Horwitz RI. Major risk factors for intracerebral hemorrhage in the young are modifiable. Stroke. 2005;36: 1881–1885. 6. Jacobs BS, Boden-Albala B, Lin IF, Sacco RL. Stroke in the young in the Northern Manhattan Stroke Study. Stroke. 2002;33:2789–2793. 7. Marini C, Totaro R, De Santis F, Ciancarelli I, Baldassarre M, Carolei A. Stroke in young adults in the community-based L’Aquila registry: incidence and prognosis. Stroke. 2001;32:52–56. 8. Bevan H. Sharma K. Stroke in young adults. Stroke. 1990;21:382–386. 9. Leno C. A prospective study of stroke in young adults in Cantabria, Spain. Stroke. 1993;24:792–795. 10. 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