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Incidence of Recurrent Intracerebral Hemorrhages in a Multiethnic South Asian Population
ARTICLE IN PRESS
Incidence of Recurrent Intracerebral Hemorrhages in a Multiethnic South Asian Population Liming Qiu, MBBS, MRCS (Ed),* Trisha Upadhyaya, MBBS,† Angela An Qi See, BPsych (Hons),* Yew Poh Ng, MBBS, MRCS (Ed), MMED (Surg), FRCS (Ed),* and Nicolas Kon Kam King, MBChB, MRCS (UK), PhD-DIC, FRCS (Ed)*
Introduction: Spontaneous primary intracerebral hemorrhage (ICH) accounts for approximately 25% of all strokes in Singapore. Incidence of recurrent ICH is not well studied, and previous studies have reported inconsistent findings in the rate and risk factors associated with ICH recurrences. We aimed to study the incidence of recurrent ICHs in Singapore and to identify the associated risk factors as well as pattern of ICH recurrence. Methods: A retrospective review of all consecutive admissions for intracerebral hemorrhage at the National Neuroscience Institute between January 2006 and November 2013 was performed. Imaging and computerized clinical records were reviewed. The demographic, clinical, and radiological characteristics of index and recurrent ICH were compared. Univariate analysis was performed using chi-square and Student’s t-test, and logistic regression was used to analyze the predictors of ICH recurrence. Results: In total, 1708 patients who survived the index ICH beyond 14 days were followed up for 6398 person-years. Sixty patients developed 68 recurrences of ICH, giving rise to an annual incidence rate of ICH recurrence of 1.1%. A history of previous ischemic stroke (P = .001) and index lobar location of ICH (P = .004) were significantly associated with the occurrence of ICH recurrences on multivariate analysis. The most common pattern on ICH recurrence was ganglionic–ganglionic (44.1%), followed by lobar–lobar (17.6%). Overall mortality of recurrent ICH was 17.6%. Conclusion: The average annual incidence rate of primary ICH recurrence in Singapore is 1.1%, and is associated with previous ischemic stroke and lobar location of index ICH. Key Words: Intracerebral hemorrhage—recurrent—incidence—risk factors. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.
From the *Department of Neurosurgery, National Neuroscience Institute, Singapore, Singapore; and †Department of Diagnostic Radiology, Singapore General Hospital, Singapore. Received August 4, 2016; revision received October 9, 2016; accepted October 31, 2016. Address correspondence to Liming Qiu, MBBS, MRCS (Ed), Department of Neurosurgery, National Neuroscience Institute, Singapore, 11 Jalan Tan Tock Seng, Singapore 308433. E-mail: [email protected]. 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.10.044
Introduction Spontaneous primary intracerebral hemorrhage (ICH) accounts for approximately 10%-15% of all strokes globally.1 The incidence has been reported to be higher in the Asian region.2 In Singapore, stroke accounts for the fourth leading cause of death and is the top cause of long-term disability, with approximately 24.2% of all strokes due to ICH.3-5 The 2 main reported causes of ICH include hypertension and cerebral amyloid angiopathy. The incidence of recurrent ICH is not well studied, and generally thought to be low (average 3.8%).6 However, previous studies have
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shown discrepancies in the patterns of recurrent ICH and their associated risk factors. We aimed to study the incidence of recurrent ICHs in Singapore, a multiethnic South Asian population, and to identify the associated risk factors as well as pattern of ICH recurrence.
Methods This study was approved by the Centralized Institutional Review Board (CIRB). The National Neuroscience Institute is the largest center for neurosurgical practice in Singapore, and serves about 70% of the Singaporean population. A retrospective review of a prospectively collected database of all consecutive admissions for ICH at the National Neuroscience Institute, Singapore, between January 1, 2006 and November 30, 2013 was performed. Imaging studies (computed tomography, magnetic resonance imaging scans) and electronic clinical records were reviewed to verify the diagnosis of ICH. Patient demographics, including age at presentation, gender, risk factors such as coexisting hypertension, dyslipidemia, diabetes mellitus, ischemic heart disease, atrial fibrillation, use of anticoagulant or antiplatelet agents, previous strokes, smoking history, and alcohol use, were obtained on admission. The patients’ blood pressure on admission, Glasgow Coma Scale (GCS) at presentation, location and laterality of ICH, size and associated mass effects were recorded for first and subsequent ICHs. The first ICH that occurred for each patient within the study period was defined as the index ICH. Secondary ICH due to aneurysms, vascular malformations, cerebral malignancy, hemorrhagic conversion of ischemic strokes and trauma were excluded. ICHs were divided into lobar, ganglionic (thalamus, putamen, caudate), cerebellar, brainstem, and intraventricular based on anatomical location. Time to each recurrence of ICH was recorded. The primary outcome measure was recurrence of ICH or death. Secondary outcome measure was the modified Rankin scale (MRS) on discharge. Poor clinical outcome was defined by MRS of 4 or more. The follow-up period was determined by the time from first presentation to readmission for recurrent ICH, death, or censorship on November 30, 2013. The demographic, clinical, and radiological characteristics of index and recurrent ICH were compared. The overall mortality of all index ICHs was 25% (n = 545), of which 89% (n = 485) occurred within the first 14 days. Thus, for analyses of recurrence, 485 patients who did not survive beyond 14 days after the index ICH were excluded. The analysis of data was divided into 2 parts. The first part of the analysis compared the baseline characteristics and radiological features at presentation of index ICHs, between patients who subsequently developed recurrent ICHs and those who did not, to identify the clinical risk factors and radiological predictors that can help to
prognosticate the risks of rebleeding. The second part of the analysis evaluated features of recurrent ICHs as compared to index ICHs to identify patterns of rebleeding. A total of 2286 cases of ICH were identified during the study period. Twenty-five patients were excluded due to wrong coding for subarachnoid hemorrhage or intraventricular hemorrhage, or incomplete data available. The final sample consisted of 60 patients with a total of 68 recurrences of ICH, and 1648 patients with single ICH who survived beyond 14 days. Data of these patients were used to determine variables predicting ICH recurrence.
Statistical Analysis All data analyses were performed using IBM SPSS Statistics for Macintosh, Version 22.0 (IBM Corp., Armonk, NY). Differences between characteristics of patients with single and recurrent ICHs were analyzed using chisquared tests and independent samples for categorical and continuous variables, respectively. Variables with a value of P < .05 in the univariate analyses were entered into multivariate analysis using logistic regression. Odds ratios were used to examine the association of these variables with the odds of recurrence for ICH. Statistical significance was taken as P < .05.
Results Incidence and Risk Factors The demographic and clinical characteristics of the patients who presented with index ICH are shown in Table 1. The total duration of follow-up for 1708 patients who survived the index ICH beyond 14 days was 6398 personyears. During this period, 60 patients had a total of 68 recurrences of ICH, giving rise to an annual incidence rate of ICH recurrence of 1.1% per year. Among 60 patients who had ICH recurrences, 4 patients had 2 recurrent ICHs and 1 patient had more than 2 recurrences. There was no significant difference in the age of patients (P = .79) or gender (P = .59) who had a single episode or recurrent ICHs. Racial distribution reflected the population racial distribution in Singapore. Hypertension was associated with both single and recurrent ICHs in 83.4% and 85.0% of patients, respectively. In univariate analysis, a premorbid history of previous ischemic stroke (P = .006), hyperlipidemia (P = .018), and the use of anticoagulation agent (P = .05) were significantly associated with the occurrence of ICH recurrences. In addition, lobar location of index ICH was associated with a higher risk of recurrence (P = .009). Presence of ischemic heart disease and atrial fibrillation, as well as the use of antiplatelet agents, were not significant risk factors for recurrence of ICH. A history of hyperlipidemia, diabetes mellitus, smoking, or alcohol drinking habits had no implication in the risk of ICH recurrence.
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Table 1. Characteristics of patients who had recurrent versus single ICH at first presentation
n Age, mean (SD), years Male, n (%) Ethnicity ratio (Chinese:Malay:Indian:Others) Comorbidities, n (%) Hypertension Hyperlipidemia Previous CVA Diabetes mellitus Cigarette smoking Antiplatelet use Ischemic heart disease Anticoagulant use Alcohol use Atrial fibrillation Location of ICH, n (%) Lobar Ganglionic Midline Multiple
Recurrent ICH
Single ICH
P value
60 61.9 (11.9) 34 (57) 48:6:4:2
1648 62.4 (14.3) 1001 (61) 1377:154:54:63
.79 .59 .55
51 (85) 40 (67) 20 (38) 17 (28) 11 (18) 11 (18) 6 (10) 5 (8) 4 (7) 3 (5)
1380 (84) 841 (51) 348 (21) 408 (25) 389 (24) 285 (17) 157 (9) 53 (3) 183 (11) 56 (3)
1.00 .018* .006* .54 .44 .86 .82 .050* .40 .47
17 (28) 32 (53) 1 (2) 1 (2)
241 (15) 1159 (70) 100 (6) 15 (1)
.009* .006* .26 .44
Abbreviations: CVA, cerebral vascular accident; ICH, intracerebral hemorrhage. *P < .05.
Multivariate analysis using logistic regression model using selected variables with P < .05 in univariate analysis showed that previous ischemic stroke and lobar location of ICH were independent predictive factors for ICH recurrence. Patients with previous ischemic stroke were 10.2 times more likely to have a recurrence of ICH (P = .001), whereas lobar location of index ICH had an adjusted odds ratio of 8.1 for recurrence of ICH (P = .004). Of 20 patients with a previous history of ischemic stroke, 15 of them were lacunar infarction and the remaining 5 were unknown due to missing data or stroke in a different institution. The use of anticoagulation agent and history of hyperlipidemia tended to increase risk of ICH recurrence, but did not reach statistical significance. The average time interval between index ICH and recurrent ICH was 20.9 (±17.4) months. Recurrent ICHs occurred at a lower mean systolic blood pressure (SBP). The median GCS on presentation of index ICH was 14, and recurrent ICH was 12 (Table 2).
Patterns of Index and Recurrent Intracerebral Hemorrhage The distribution of index and recurrent ICHs, as well as pattern of ICH recurrence, is shown in Figure 1. In this study, index and recurrent ICHs displayed similar patterns of occurrence, with the hematoma predominantly found in ganglionic regions, followed by lobar, brainstem, and cerebellar areas (Fig 1A). ICH location in midline structures such as the brainstem was associated with early mortality in the first 14 days. None of the patients who
eventually developed ICH recurrences had index ICH in midline structures, such as the brainstem. Overall, recurrent ICHs occurred at a lower blood pressure when compared to index ICH (161 mmHg versus 176 mmHg, P < .001) but were significantly larger in size mL (25.2 versus 16.3 mL, P = .001) (Table 2). A subgroup analysis showed that lobar– lobar ICH occurred at a mean SBP of 148 mmHg, compared to 165 mmHg in ganglionic–ganglionic recurrences (Table 3). Among the 68 recurrent ICHs, 30 (44.1%) occurred in the same side and 27 (39.7%) occurred in the same anatomical location as the index ICH. Forty-four percent (n = 30) of ICH recurrences occurred in the ganglionic–ganglionic in pattern. This was followed by lobar–lobar, ganglionic– lobar, or lobar–ganglionic and other patterns (Fig 1B). The mean age of patients who had lobar–lobar pattern of recurrent ICH was on average more than 10 years older than the ganglionic–ganglionic pattern of ICH recurrence (Table 3). The volume of hematoma was also significantly larger in lobar recurrences when compared to ganglionic–ganglionic recurrences (50.1 mL versus 18.7 mL, P = .004). A known history of hypertension was significantly associated with the development of ganglionic–ganglionic recurrences of ICH (83% versus 58%, P < .001). The time to ICH recurrences did not differ between ganglionic–ganglionic and lobar–lobar pattern of recurrences (P = .86).
Clinical Outcomes The mean follow-up period for all patients was 45.8 (±28.5) months. The overall mortality of all index ICHs was 25%. There were 12 mortalities (17.6%) among the
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Table 2. Clinical and radiological characteristics of recurrent compared to single ICH
n Age, mean (SD), years SBP, mean (SD), mmHg Size of ICH, mean (SD), mL Median GCS at presentation Mortality, n (%) MRS on discharge, n (%) 0 1 2 3 4 5 Median MRS Poor outcome (MRS >3), n (%) Time to recurrence, mean (SD), months Follow-up, mean (SD), months
Recurrent ICH
Single ICH
P value
68 64.1 (12.2) 161 (32) 25.2 (31.4) 12.5 12 (18)
1648 62.4 (14.3) 176 (33) 16.3 (21.6) 14 545 (25)
.32 <.001* .001* – .157
1 (1.5) 5 (7.5) 3 (4.5) 12 (17.9) 25 (37.3) 10 (14.9) 4 47 (69) 20.9 (17.4) –
69 (4.2) 178 (10.8) 111 (6.7) 131 (7.9) 785 (47.6) 311 (18.9) 4 1159 (70) – 45.8 (28.5)
–
.34
Abbreviations: GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage; MRS, modified Rankin scale; SBP, systolic blood pressure at presentation. *P < .05.
recurrent ICHs (Table 2). Subgroup analysis suggested that most of the mortalities occurred in the ganglionic– ganglionic pattern of ICH recurrences (20%), and none were from the lobar–lobar group (P = .16). Although recurrent ICHs had an overall lower mortality rate, most patients still had a poor clinical outcome, with 64.9% of patients having an MRS of 4 or 5 (Table 3). In lobar recurrences, although patients tended to survive with larger volumes of ICH, they also had high clinical disability, with all patients being incapacitated after the recurrent ICH. Overall, clinical morbidity of recurrent ICHs was comparable to index ICH, with a lower all-cause mortality rate.
Discussion There is relative paucity in the literature regarding recurrent ICH, and the incidence of recurrent ICH is generally perceived to be low.6 Previous studies have reported differences in the incidence of ICH recurrences, as well as in the pattern and factors associated with recurrences.6-9 Lobar hemorrhages, 10-12 age, 13,14 male gender, 13 hypertension,15 previous ischemic stroke,16 and use of anticoagulation agent 13 have all been implicated with recurrence of primary ICH in previous studies, but results have been inconsistent across studies. Most Asian population had a predominance of ganglionic pattern of ICHs9,17-19 whereas Western studies showed more heterogenous patterns of ICH recurrences, with higher rates of lobar–lobar hemorrhages11,20,21 (Table 4).
The present study is the first series of patients with recurrent ICHs in Singapore. The annual incidence of ICH recurrence in our series is 1.1%, which is lower in comparison to previous studies (1.7%-12%, average 4.1%). In Asia, previously reported recurrence rate was between 1.8% and 11%.19 The most common pattern of ICH recurrence in this study was ganglionic–ganglionic, reflecting the results of previous studies done in Asia, namely Japan,15,18 South Korea,17,22 and Taiwan.7,9,19 Lobar–lobar pattern of ICH recurrence happened in 17.6% of all ICH recurrences in our study, significantly lower than reported rates in the Western population10,14 (Table 4). Congruent to previous studies, hypertension and amyloid angiopathy likely account for the 2 primary causes of primacy ICH in Singapore. This is reflected in the high proportion of hypertensive patients in both primary and recurrent ICHs. The distribution of ICH also reflects the predilection of hypertensive ICH to deep ganglionic regions. Epidemiological studies of strokes showed a higher incidence of primary hypertensive ICH in Asian countries, suggesting a more important role of hypertension in ICH in the Asian population. The differences found between ganglionic–ganglionic and lobar–lobar ICH patterns in our study support the notion that the lobar–lobar ICH recurrences were more likely due to amyloid angiopathy. These ICHs with lobar predilection tended to occur in those of older age and have lower mean blood pressure, higher volume of ICH, and lower mortality rates. The annual incidence rate of recurrent ICHs in our study is lower than previous reports, when compared to Asian
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Figure 1. (A) Intracerebral hemorrhage (ICH) distribution in index and recurrent ICHs by laterality and anatomical location. (B) Pattern of ICH recurrence.
countries where ganglionic–ganglionic patterns of ICH recurrences predominate. This may be the result of strict monitoring and control of blood pressure in these patients. In Singapore, 23.5% of the general adult population
have hypertension, with 67.4% having good blood pressure control.23 Patients who develop complications of hypertension such as ICH are regularly followed up every 3 months in the community clinics or general practitioners,
Table 3. Characteristics of ganglionic–ganglionic and lobar–lobar ICH recurrences
n Age, mean (SD), years Median GCS at presentation Known hypertension, n (%) SBP, mean (SD), mmHg Size of ICH, mean (SD), mL Mortality, n (%) Poor outcome (MRS 4-5), n (%) Time to recurrence, mean (SD), months
Ganglionic–ganglionic
Lobar–lobar
P value
30 61.9 (11.6) 12 25 (83) 165 (27) 18.7 (27.1) 6 (20) 24 (80) 18.8 (15.0)
12 73.5 (8.6) 11 7 (58) 148 (21) 50.1 (36.1) 0 (0) 11 (92) 19.8 (19.9)
.003* .000* .06 .004* .16 .65 .86
Abbreviations: GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage; MRS, modified Rankin scale; SBP, systolic blood pressure at presentation. *P < .05.
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NR 23.8 23.5 17.6 28.3 44.1 NR NR NR 70 NR 32 17.6 NR 2.3 NR NR NR 1.67 2.3 NR 2.1 7.2 2.4 NR 1.06 6.0 6.8 5.8 4.8 5.4 6.0 4.2 3.1 12.3 24.1 8.7 6.1 3.6 59.1 69.4 66 59 60 68.8 NR 79.0 64.0 68.4 65.7 60 64.2 Abbreviations: GG, ganglionic–ganglionic; LL, lobar–lobar; NR, not reported.
GG GG (60%) GG (50%) GG (85%) GG (48%) GG (41%) LL (80%) LL (100%) NR LL (44%) LL (73%) GG (55%) GG (41%) NR 3.0 NR NR NR 3.6 NR .5 5.5 7.0 3.6 4.6 3.7 Japan Japan Taiwan Taiwan South Korea Finland Sweden Scotland Netherlands Italy Canada Mexico Singapore Nakase et al15 Inagawa et al18 Yen et al19 Chen et al9 Bae et al17 Huhtakangas et al16 Zia et al14 Samarasekera et al12 Vermeer et al13 Passero et al11 Hill et al10 Gonzalez-Duarte et al6 Present study
64/1067 19/279 34/585 68/1421 53/989 58/961 20/474 4/128 30/243 27/112 15/172 22/359 68/1708
Annual recurrence rate (%/year) Crude recurrence rate (%) Mean age Predominant ICH pattern Mean follow-up (years) n (recurrent/total) Country Study
Table 4. Comparison of patterns of recurrent ICHs in previous studies based on geographical regions
Mortality rate (%) for recurrent ICH
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and medications are optimized according to target BP. In our study, recurrent ICHs developed at a lower mean SBP than that of the index ICH, suggesting that even patients who developed recurrent hypertensive ICHs had improved control of hypertension after the index ICH. With improved education level and accessibility to medical services, the population prevalence of uncontrolled hypertension seemed to have declined slightly over the past 10 years in Singapore.23 Therefore, the authors recommend that tight control of blood pressure in hypertensive patients may be a key to reduce the risk of primary and recurrent ICH. The significant risk factors associated with recurrence of ICH include a history of ischemic stroke, as well as lobar location of index ICH on multivariate analysis. This reflects the findings of Huhtakangas et al who found that previous ischemic stroke independently predicted ICH recurrence. They also reported a decrease in risk of fatal recurrent ICH with treatment of hypertension.16 Previous ischemic stroke increased the risk of recurrent ICH irrespective of the use of antiplatelet agents. It was postulated that changes in the deep arteries may occur after lacunar ischemic stroke secondary to hypertension, causing them to be more fragile, thus prone to hemorrhagic events and ICH recurrence. In our study, 15 of 20 patients who had a history of ischemic stroke had lacunar type infarcts, and 14 of these 15 patients (93.3%) were known to have hypertension as well. Our findings corroborate those of Huhtakangas et al and would suggest that hypertension is the unifying etiology and risk factor in recurrent ICH. Several Western studies have reported lobar location of index ICH to be the only significant factor for ICH recurrence10-12 This is usually due to cerebral amyloid angiopathy, which happens in small and mid-sized cortical and leptomeningeal arteries, and is thus usually found in lobar distribution. Occurrence of lobar hemorrhages classically increase with age, often beyond the age of 70, and are thought to have better functional outcomes and lower mortality rates.10,12 In our study, lobar–lobar hemorrhages occurred at a mean age of 73.5 years old, more than 10 years older than the ganglionic–ganglionic pattern of rebleed. Samarasekera et al found an association of lobar ICH with pre-ICH dementia, and postulated that the improved outcome may be due to lobar anatomy and cortical atrophy being protective against mass effect caused by ICH. In our study, index lobar ICH was associated with increased risk of recurrence in survivors beyond 14 days. The mortality of recurrent lobar ICH was low, but morbidity remains high. Because of the increased rate of recurrence and clinical morbidity, we advocate secondary prevention with optimal BP control in this group of patients as well. The overall mortality after recurrent ICH in our series was 17.6%. This is lower than most previously reported studies (Table 4). The mortality rate is also lower than that of index ICH (25.0%), in spite of larger ICH size and
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lower GCS on presentation. However, albeit the lower mortality rate, a significant proportion of patients had poor clinical outcome, with 64.9% having an MRS of 4 or 5. This was true for both ganglionic and lobar recurrences. Therefore, recurrent ICHs have comparable poor outcomes as index ICH in surviving patients.
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4. 5.
6.
Limitations There were a few limitations to our study. Firstly, this was a single-institution study, and only patients who presented to our institution were captured. This may lead to an underestimation of recurrence if patients were admitted to another hospital with subsequent ICHs or died before reaching a hospital. However, our institution is the largest neurosurgical unit in Singapore, and local ambulance services transport patients to dedicated hospitals within each catchment area in Singapore. Due to the small geographical size of Singapore, majority of patients are able to reach hospital facilities within an hour. Therefore, the rate of missing these patients would be low. Secondly, there is a potential data miscoding in our prospectively collected database, which may underestimate the true incidence of recurrent ICH. However, previous audits have reported the rate of data miscoding to be low.
7.
8.
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10.
11.
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Conclusion The annual rate of primary ICH recurrence in Singapore is 1.1%, and is associated with previous ischemic stroke and lobar location of index ICH. Hypertension is the most common cause of recurrent ICHs. Although the mortality of recurrent ICH is lower than the index ICH, clinical morbidity is high. We recommend strict blood pressure control in the prevention of ICH recurrence. We have identified a subgroup of ICH patients in whom more intensive long-term monitoring may be beneficial. Future research is required to address measures to reduce the risk of ICH recurrence in these patients. Acknowledgment: The authors would like to thank Miss Yee Hwee Tan for her assistance with data collection.
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Incidence of Recurrent Intracerebral Hemorrhages in a Multiethnic South Asian Population Liming Qiu, MBBS, MRCS (Ed),* Trisha Upadhyaya, MBBS,† Angela An Qi See, BPsych (Hons),* Yew Poh Ng, MBBS, MRCS (Ed), MMED (Surg), FRCS (Ed),* and Nicolas Kon Kam King, MBChB, MRCS (UK), PhD-DIC, FRCS (Ed)*
Introduction: Spontaneous primary intracerebral hemorrhage (ICH) accounts for approximately 25% of all strokes in Singapore. Incidence of recurrent ICH is not well studied, and previous studies have reported inconsistent findings in the rate and risk factors associated with ICH recurrences. We aimed to study the incidence of recurrent ICHs in Singapore and to identify the associated risk factors as well as pattern of ICH recurrence. Methods: A retrospective review of all consecutive admissions for intracerebral hemorrhage at the National Neuroscience Institute between January 2006 and November 2013 was performed. Imaging and computerized clinical records were reviewed. The demographic, clinical, and radiological characteristics of index and recurrent ICH were compared. Univariate analysis was performed using chi-square and Student’s t-test, and logistic regression was used to analyze the predictors of ICH recurrence. Results: In total, 1708 patients who survived the index ICH beyond 14 days were followed up for 6398 person-years. Sixty patients developed 68 recurrences of ICH, giving rise to an annual incidence rate of ICH recurrence of 1.1%. A history of previous ischemic stroke (P = .001) and index lobar location of ICH (P = .004) were significantly associated with the occurrence of ICH recurrences on multivariate analysis. The most common pattern on ICH recurrence was ganglionic–ganglionic (44.1%), followed by lobar–lobar (17.6%). Overall mortality of recurrent ICH was 17.6%. Conclusion: The average annual incidence rate of primary ICH recurrence in Singapore is 1.1%, and is associated with previous ischemic stroke and lobar location of index ICH. Key Words: Intracerebral hemorrhage—recurrent—incidence—risk factors. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.
From the *Department of Neurosurgery, National Neuroscience Institute, Singapore, Singapore; and †Department of Diagnostic Radiology, Singapore General Hospital, Singapore. Received August 4, 2016; revision received October 9, 2016; accepted October 31, 2016. Address correspondence to Liming Qiu, MBBS, MRCS (Ed), Department of Neurosurgery, National Neuroscience Institute, Singapore, 11 Jalan Tan Tock Seng, Singapore 308433. E-mail: [email protected]. 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.10.044
Introduction Spontaneous primary intracerebral hemorrhage (ICH) accounts for approximately 10%-15% of all strokes globally.1 The incidence has been reported to be higher in the Asian region.2 In Singapore, stroke accounts for the fourth leading cause of death and is the top cause of long-term disability, with approximately 24.2% of all strokes due to ICH.3-5 The 2 main reported causes of ICH include hypertension and cerebral amyloid angiopathy. The incidence of recurrent ICH is not well studied, and generally thought to be low (average 3.8%).6 However, previous studies have
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shown discrepancies in the patterns of recurrent ICH and their associated risk factors. We aimed to study the incidence of recurrent ICHs in Singapore, a multiethnic South Asian population, and to identify the associated risk factors as well as pattern of ICH recurrence.
Methods This study was approved by the Centralized Institutional Review Board (CIRB). The National Neuroscience Institute is the largest center for neurosurgical practice in Singapore, and serves about 70% of the Singaporean population. A retrospective review of a prospectively collected database of all consecutive admissions for ICH at the National Neuroscience Institute, Singapore, between January 1, 2006 and November 30, 2013 was performed. Imaging studies (computed tomography, magnetic resonance imaging scans) and electronic clinical records were reviewed to verify the diagnosis of ICH. Patient demographics, including age at presentation, gender, risk factors such as coexisting hypertension, dyslipidemia, diabetes mellitus, ischemic heart disease, atrial fibrillation, use of anticoagulant or antiplatelet agents, previous strokes, smoking history, and alcohol use, were obtained on admission. The patients’ blood pressure on admission, Glasgow Coma Scale (GCS) at presentation, location and laterality of ICH, size and associated mass effects were recorded for first and subsequent ICHs. The first ICH that occurred for each patient within the study period was defined as the index ICH. Secondary ICH due to aneurysms, vascular malformations, cerebral malignancy, hemorrhagic conversion of ischemic strokes and trauma were excluded. ICHs were divided into lobar, ganglionic (thalamus, putamen, caudate), cerebellar, brainstem, and intraventricular based on anatomical location. Time to each recurrence of ICH was recorded. The primary outcome measure was recurrence of ICH or death. Secondary outcome measure was the modified Rankin scale (MRS) on discharge. Poor clinical outcome was defined by MRS of 4 or more. The follow-up period was determined by the time from first presentation to readmission for recurrent ICH, death, or censorship on November 30, 2013. The demographic, clinical, and radiological characteristics of index and recurrent ICH were compared. The overall mortality of all index ICHs was 25% (n = 545), of which 89% (n = 485) occurred within the first 14 days. Thus, for analyses of recurrence, 485 patients who did not survive beyond 14 days after the index ICH were excluded. The analysis of data was divided into 2 parts. The first part of the analysis compared the baseline characteristics and radiological features at presentation of index ICHs, between patients who subsequently developed recurrent ICHs and those who did not, to identify the clinical risk factors and radiological predictors that can help to
prognosticate the risks of rebleeding. The second part of the analysis evaluated features of recurrent ICHs as compared to index ICHs to identify patterns of rebleeding. A total of 2286 cases of ICH were identified during the study period. Twenty-five patients were excluded due to wrong coding for subarachnoid hemorrhage or intraventricular hemorrhage, or incomplete data available. The final sample consisted of 60 patients with a total of 68 recurrences of ICH, and 1648 patients with single ICH who survived beyond 14 days. Data of these patients were used to determine variables predicting ICH recurrence.
Statistical Analysis All data analyses were performed using IBM SPSS Statistics for Macintosh, Version 22.0 (IBM Corp., Armonk, NY). Differences between characteristics of patients with single and recurrent ICHs were analyzed using chisquared tests and independent samples for categorical and continuous variables, respectively. Variables with a value of P < .05 in the univariate analyses were entered into multivariate analysis using logistic regression. Odds ratios were used to examine the association of these variables with the odds of recurrence for ICH. Statistical significance was taken as P < .05.
Results Incidence and Risk Factors The demographic and clinical characteristics of the patients who presented with index ICH are shown in Table 1. The total duration of follow-up for 1708 patients who survived the index ICH beyond 14 days was 6398 personyears. During this period, 60 patients had a total of 68 recurrences of ICH, giving rise to an annual incidence rate of ICH recurrence of 1.1% per year. Among 60 patients who had ICH recurrences, 4 patients had 2 recurrent ICHs and 1 patient had more than 2 recurrences. There was no significant difference in the age of patients (P = .79) or gender (P = .59) who had a single episode or recurrent ICHs. Racial distribution reflected the population racial distribution in Singapore. Hypertension was associated with both single and recurrent ICHs in 83.4% and 85.0% of patients, respectively. In univariate analysis, a premorbid history of previous ischemic stroke (P = .006), hyperlipidemia (P = .018), and the use of anticoagulation agent (P = .05) were significantly associated with the occurrence of ICH recurrences. In addition, lobar location of index ICH was associated with a higher risk of recurrence (P = .009). Presence of ischemic heart disease and atrial fibrillation, as well as the use of antiplatelet agents, were not significant risk factors for recurrence of ICH. A history of hyperlipidemia, diabetes mellitus, smoking, or alcohol drinking habits had no implication in the risk of ICH recurrence.
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Table 1. Characteristics of patients who had recurrent versus single ICH at first presentation
n Age, mean (SD), years Male, n (%) Ethnicity ratio (Chinese:Malay:Indian:Others) Comorbidities, n (%) Hypertension Hyperlipidemia Previous CVA Diabetes mellitus Cigarette smoking Antiplatelet use Ischemic heart disease Anticoagulant use Alcohol use Atrial fibrillation Location of ICH, n (%) Lobar Ganglionic Midline Multiple
Recurrent ICH
Single ICH
P value
60 61.9 (11.9) 34 (57) 48:6:4:2
1648 62.4 (14.3) 1001 (61) 1377:154:54:63
.79 .59 .55
51 (85) 40 (67) 20 (38) 17 (28) 11 (18) 11 (18) 6 (10) 5 (8) 4 (7) 3 (5)
1380 (84) 841 (51) 348 (21) 408 (25) 389 (24) 285 (17) 157 (9) 53 (3) 183 (11) 56 (3)
1.00 .018* .006* .54 .44 .86 .82 .050* .40 .47
17 (28) 32 (53) 1 (2) 1 (2)
241 (15) 1159 (70) 100 (6) 15 (1)
.009* .006* .26 .44
Abbreviations: CVA, cerebral vascular accident; ICH, intracerebral hemorrhage. *P < .05.
Multivariate analysis using logistic regression model using selected variables with P < .05 in univariate analysis showed that previous ischemic stroke and lobar location of ICH were independent predictive factors for ICH recurrence. Patients with previous ischemic stroke were 10.2 times more likely to have a recurrence of ICH (P = .001), whereas lobar location of index ICH had an adjusted odds ratio of 8.1 for recurrence of ICH (P = .004). Of 20 patients with a previous history of ischemic stroke, 15 of them were lacunar infarction and the remaining 5 were unknown due to missing data or stroke in a different institution. The use of anticoagulation agent and history of hyperlipidemia tended to increase risk of ICH recurrence, but did not reach statistical significance. The average time interval between index ICH and recurrent ICH was 20.9 (±17.4) months. Recurrent ICHs occurred at a lower mean systolic blood pressure (SBP). The median GCS on presentation of index ICH was 14, and recurrent ICH was 12 (Table 2).
Patterns of Index and Recurrent Intracerebral Hemorrhage The distribution of index and recurrent ICHs, as well as pattern of ICH recurrence, is shown in Figure 1. In this study, index and recurrent ICHs displayed similar patterns of occurrence, with the hematoma predominantly found in ganglionic regions, followed by lobar, brainstem, and cerebellar areas (Fig 1A). ICH location in midline structures such as the brainstem was associated with early mortality in the first 14 days. None of the patients who
eventually developed ICH recurrences had index ICH in midline structures, such as the brainstem. Overall, recurrent ICHs occurred at a lower blood pressure when compared to index ICH (161 mmHg versus 176 mmHg, P < .001) but were significantly larger in size mL (25.2 versus 16.3 mL, P = .001) (Table 2). A subgroup analysis showed that lobar– lobar ICH occurred at a mean SBP of 148 mmHg, compared to 165 mmHg in ganglionic–ganglionic recurrences (Table 3). Among the 68 recurrent ICHs, 30 (44.1%) occurred in the same side and 27 (39.7%) occurred in the same anatomical location as the index ICH. Forty-four percent (n = 30) of ICH recurrences occurred in the ganglionic–ganglionic in pattern. This was followed by lobar–lobar, ganglionic– lobar, or lobar–ganglionic and other patterns (Fig 1B). The mean age of patients who had lobar–lobar pattern of recurrent ICH was on average more than 10 years older than the ganglionic–ganglionic pattern of ICH recurrence (Table 3). The volume of hematoma was also significantly larger in lobar recurrences when compared to ganglionic–ganglionic recurrences (50.1 mL versus 18.7 mL, P = .004). A known history of hypertension was significantly associated with the development of ganglionic–ganglionic recurrences of ICH (83% versus 58%, P < .001). The time to ICH recurrences did not differ between ganglionic–ganglionic and lobar–lobar pattern of recurrences (P = .86).
Clinical Outcomes The mean follow-up period for all patients was 45.8 (±28.5) months. The overall mortality of all index ICHs was 25%. There were 12 mortalities (17.6%) among the
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Table 2. Clinical and radiological characteristics of recurrent compared to single ICH
n Age, mean (SD), years SBP, mean (SD), mmHg Size of ICH, mean (SD), mL Median GCS at presentation Mortality, n (%) MRS on discharge, n (%) 0 1 2 3 4 5 Median MRS Poor outcome (MRS >3), n (%) Time to recurrence, mean (SD), months Follow-up, mean (SD), months
Recurrent ICH
Single ICH
P value
68 64.1 (12.2) 161 (32) 25.2 (31.4) 12.5 12 (18)
1648 62.4 (14.3) 176 (33) 16.3 (21.6) 14 545 (25)
.32 <.001* .001* – .157
1 (1.5) 5 (7.5) 3 (4.5) 12 (17.9) 25 (37.3) 10 (14.9) 4 47 (69) 20.9 (17.4) –
69 (4.2) 178 (10.8) 111 (6.7) 131 (7.9) 785 (47.6) 311 (18.9) 4 1159 (70) – 45.8 (28.5)
–
.34
Abbreviations: GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage; MRS, modified Rankin scale; SBP, systolic blood pressure at presentation. *P < .05.
recurrent ICHs (Table 2). Subgroup analysis suggested that most of the mortalities occurred in the ganglionic– ganglionic pattern of ICH recurrences (20%), and none were from the lobar–lobar group (P = .16). Although recurrent ICHs had an overall lower mortality rate, most patients still had a poor clinical outcome, with 64.9% of patients having an MRS of 4 or 5 (Table 3). In lobar recurrences, although patients tended to survive with larger volumes of ICH, they also had high clinical disability, with all patients being incapacitated after the recurrent ICH. Overall, clinical morbidity of recurrent ICHs was comparable to index ICH, with a lower all-cause mortality rate.
Discussion There is relative paucity in the literature regarding recurrent ICH, and the incidence of recurrent ICH is generally perceived to be low.6 Previous studies have reported differences in the incidence of ICH recurrences, as well as in the pattern and factors associated with recurrences.6-9 Lobar hemorrhages, 10-12 age, 13,14 male gender, 13 hypertension,15 previous ischemic stroke,16 and use of anticoagulation agent 13 have all been implicated with recurrence of primary ICH in previous studies, but results have been inconsistent across studies. Most Asian population had a predominance of ganglionic pattern of ICHs9,17-19 whereas Western studies showed more heterogenous patterns of ICH recurrences, with higher rates of lobar–lobar hemorrhages11,20,21 (Table 4).
The present study is the first series of patients with recurrent ICHs in Singapore. The annual incidence of ICH recurrence in our series is 1.1%, which is lower in comparison to previous studies (1.7%-12%, average 4.1%). In Asia, previously reported recurrence rate was between 1.8% and 11%.19 The most common pattern of ICH recurrence in this study was ganglionic–ganglionic, reflecting the results of previous studies done in Asia, namely Japan,15,18 South Korea,17,22 and Taiwan.7,9,19 Lobar–lobar pattern of ICH recurrence happened in 17.6% of all ICH recurrences in our study, significantly lower than reported rates in the Western population10,14 (Table 4). Congruent to previous studies, hypertension and amyloid angiopathy likely account for the 2 primary causes of primacy ICH in Singapore. This is reflected in the high proportion of hypertensive patients in both primary and recurrent ICHs. The distribution of ICH also reflects the predilection of hypertensive ICH to deep ganglionic regions. Epidemiological studies of strokes showed a higher incidence of primary hypertensive ICH in Asian countries, suggesting a more important role of hypertension in ICH in the Asian population. The differences found between ganglionic–ganglionic and lobar–lobar ICH patterns in our study support the notion that the lobar–lobar ICH recurrences were more likely due to amyloid angiopathy. These ICHs with lobar predilection tended to occur in those of older age and have lower mean blood pressure, higher volume of ICH, and lower mortality rates. The annual incidence rate of recurrent ICHs in our study is lower than previous reports, when compared to Asian
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Figure 1. (A) Intracerebral hemorrhage (ICH) distribution in index and recurrent ICHs by laterality and anatomical location. (B) Pattern of ICH recurrence.
countries where ganglionic–ganglionic patterns of ICH recurrences predominate. This may be the result of strict monitoring and control of blood pressure in these patients. In Singapore, 23.5% of the general adult population
have hypertension, with 67.4% having good blood pressure control.23 Patients who develop complications of hypertension such as ICH are regularly followed up every 3 months in the community clinics or general practitioners,
Table 3. Characteristics of ganglionic–ganglionic and lobar–lobar ICH recurrences
n Age, mean (SD), years Median GCS at presentation Known hypertension, n (%) SBP, mean (SD), mmHg Size of ICH, mean (SD), mL Mortality, n (%) Poor outcome (MRS 4-5), n (%) Time to recurrence, mean (SD), months
Ganglionic–ganglionic
Lobar–lobar
P value
30 61.9 (11.6) 12 25 (83) 165 (27) 18.7 (27.1) 6 (20) 24 (80) 18.8 (15.0)
12 73.5 (8.6) 11 7 (58) 148 (21) 50.1 (36.1) 0 (0) 11 (92) 19.8 (19.9)
.003* .000* .06 .004* .16 .65 .86
Abbreviations: GCS, Glasgow Coma Scale; ICH, intracerebral hemorrhage; MRS, modified Rankin scale; SBP, systolic blood pressure at presentation. *P < .05.
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NR 23.8 23.5 17.6 28.3 44.1 NR NR NR 70 NR 32 17.6 NR 2.3 NR NR NR 1.67 2.3 NR 2.1 7.2 2.4 NR 1.06 6.0 6.8 5.8 4.8 5.4 6.0 4.2 3.1 12.3 24.1 8.7 6.1 3.6 59.1 69.4 66 59 60 68.8 NR 79.0 64.0 68.4 65.7 60 64.2 Abbreviations: GG, ganglionic–ganglionic; LL, lobar–lobar; NR, not reported.
GG GG (60%) GG (50%) GG (85%) GG (48%) GG (41%) LL (80%) LL (100%) NR LL (44%) LL (73%) GG (55%) GG (41%) NR 3.0 NR NR NR 3.6 NR .5 5.5 7.0 3.6 4.6 3.7 Japan Japan Taiwan Taiwan South Korea Finland Sweden Scotland Netherlands Italy Canada Mexico Singapore Nakase et al15 Inagawa et al18 Yen et al19 Chen et al9 Bae et al17 Huhtakangas et al16 Zia et al14 Samarasekera et al12 Vermeer et al13 Passero et al11 Hill et al10 Gonzalez-Duarte et al6 Present study
64/1067 19/279 34/585 68/1421 53/989 58/961 20/474 4/128 30/243 27/112 15/172 22/359 68/1708
Annual recurrence rate (%/year) Crude recurrence rate (%) Mean age Predominant ICH pattern Mean follow-up (years) n (recurrent/total) Country Study
Table 4. Comparison of patterns of recurrent ICHs in previous studies based on geographical regions
Mortality rate (%) for recurrent ICH
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and medications are optimized according to target BP. In our study, recurrent ICHs developed at a lower mean SBP than that of the index ICH, suggesting that even patients who developed recurrent hypertensive ICHs had improved control of hypertension after the index ICH. With improved education level and accessibility to medical services, the population prevalence of uncontrolled hypertension seemed to have declined slightly over the past 10 years in Singapore.23 Therefore, the authors recommend that tight control of blood pressure in hypertensive patients may be a key to reduce the risk of primary and recurrent ICH. The significant risk factors associated with recurrence of ICH include a history of ischemic stroke, as well as lobar location of index ICH on multivariate analysis. This reflects the findings of Huhtakangas et al who found that previous ischemic stroke independently predicted ICH recurrence. They also reported a decrease in risk of fatal recurrent ICH with treatment of hypertension.16 Previous ischemic stroke increased the risk of recurrent ICH irrespective of the use of antiplatelet agents. It was postulated that changes in the deep arteries may occur after lacunar ischemic stroke secondary to hypertension, causing them to be more fragile, thus prone to hemorrhagic events and ICH recurrence. In our study, 15 of 20 patients who had a history of ischemic stroke had lacunar type infarcts, and 14 of these 15 patients (93.3%) were known to have hypertension as well. Our findings corroborate those of Huhtakangas et al and would suggest that hypertension is the unifying etiology and risk factor in recurrent ICH. Several Western studies have reported lobar location of index ICH to be the only significant factor for ICH recurrence10-12 This is usually due to cerebral amyloid angiopathy, which happens in small and mid-sized cortical and leptomeningeal arteries, and is thus usually found in lobar distribution. Occurrence of lobar hemorrhages classically increase with age, often beyond the age of 70, and are thought to have better functional outcomes and lower mortality rates.10,12 In our study, lobar–lobar hemorrhages occurred at a mean age of 73.5 years old, more than 10 years older than the ganglionic–ganglionic pattern of rebleed. Samarasekera et al found an association of lobar ICH with pre-ICH dementia, and postulated that the improved outcome may be due to lobar anatomy and cortical atrophy being protective against mass effect caused by ICH. In our study, index lobar ICH was associated with increased risk of recurrence in survivors beyond 14 days. The mortality of recurrent lobar ICH was low, but morbidity remains high. Because of the increased rate of recurrence and clinical morbidity, we advocate secondary prevention with optimal BP control in this group of patients as well. The overall mortality after recurrent ICH in our series was 17.6%. This is lower than most previously reported studies (Table 4). The mortality rate is also lower than that of index ICH (25.0%), in spite of larger ICH size and
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lower GCS on presentation. However, albeit the lower mortality rate, a significant proportion of patients had poor clinical outcome, with 64.9% having an MRS of 4 or 5. This was true for both ganglionic and lobar recurrences. Therefore, recurrent ICHs have comparable poor outcomes as index ICH in surviving patients.
7
4. 5.
6.
Limitations There were a few limitations to our study. Firstly, this was a single-institution study, and only patients who presented to our institution were captured. This may lead to an underestimation of recurrence if patients were admitted to another hospital with subsequent ICHs or died before reaching a hospital. However, our institution is the largest neurosurgical unit in Singapore, and local ambulance services transport patients to dedicated hospitals within each catchment area in Singapore. Due to the small geographical size of Singapore, majority of patients are able to reach hospital facilities within an hour. Therefore, the rate of missing these patients would be low. Secondly, there is a potential data miscoding in our prospectively collected database, which may underestimate the true incidence of recurrent ICH. However, previous audits have reported the rate of data miscoding to be low.
7.
8.
9.
10.
11.
12.
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Conclusion The annual rate of primary ICH recurrence in Singapore is 1.1%, and is associated with previous ischemic stroke and lobar location of index ICH. Hypertension is the most common cause of recurrent ICHs. Although the mortality of recurrent ICH is lower than the index ICH, clinical morbidity is high. We recommend strict blood pressure control in the prevention of ICH recurrence. We have identified a subgroup of ICH patients in whom more intensive long-term monitoring may be beneficial. Future research is required to address measures to reduce the risk of ICH recurrence in these patients. Acknowledgment: The authors would like to thank Miss Yee Hwee Tan for her assistance with data collection.
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