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multiple strokes, simultaneous strokes, cause, patterns, pathogenesis, outcome
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Munakomi S and Chaulagain D. Demographical domains and clinico-radiological characteristics of study cohorts with spontaneous simultaneous multiple intracerebral hemorrhages in a tertiary neurosurgical center in Nepal: a cross-sectional study [version 2; peer review: 2 approved]. F1000Research 2022, 11:154 (https://doi.org/10.12688/f1000research.108816.2)
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Research Article
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Demographical domains and clinico-radiological characteristics of study cohorts with spontaneous simultaneous multiple intracerebral hemorrhages in a tertiary neurosurgical center in Nepal: a cross-sectional study
[version 2; peer review: 2 approved]
Previously Titled 'Demographical domains and clinico-radiological characteristics of study cohorts with simultaneous multiple intracerebral hemorrhages in a tertiary neurosurgical center in Nepal: a cross-sectional study'.
PUBLISHED 28 Nov 2022
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Abstract
Corresponding author:
Sunil Munakomi
Competing interests:
No competing interests were disclosed.
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The author(s) declared that no grants were involved in supporting this work.
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© 2022 Munakomi S and Chaulagain D.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Munakomi S and Chaulagain D. Demographical domains and clinico-radiological characteristics of study cohorts with spontaneous simultaneous multiple intracerebral hemorrhages in a tertiary neurosurgical center in Nepal: a cross-sectional study [version 2; peer review: 2 approved]. F1000Research 2022, 11:154 (https://doi.org/10.12688/f1000research.108816.2)
First published: 07 Feb 2022, 11:154 (https://doi.org/10.12688/f1000research.108816.1)
Latest published: 28 Nov 2022, 11:154 (https://doi.org/10.12688/f1000research.108816.2)
Revised Amendments from Version 1
The article has been revised as per the suggestions of the respected reviewers.
Comparisons pertaining to salient variables between cohorts of patients with spontaneous SMICHs with the cohorts of operated patients with spontaneous single ICH from our institution during the same time period have been added in the results and discussion sections.
‘Spontaneous’ was also added to the title.
To read any peer review reports and author responses for this article, follow the "read" links in the Open Peer Review table.
Introduction
Spontaneous simultaneous multiple intra-cerebral hemorrhages (SMICHs) are characterized by intracerebral hemorrhages within the two-or-more distinct and non-contiguous intracranial vascular territories visualized in the initial radiological imaging (Wu et al., 2017). Generally intracerebral hemorrhage (ICH) connotes high odds of continuum morbidity and mortality (Laiwattana et al., 2014). Among ICH patients, approximately 5% (1:20) have been identified as SMICHs (Renard et al., 2020).
Stroke ripples affect patients with continuum multi-spectral consequences (Gokce et al., 2016). Literature scarcity pertaining to spontaneous SMICHs paves the way for further research on the entity. Better knowledge and in-depth information pertaining to the incidence and patterns of spontaneous SMICHs can help formulate treatment algorithms as well as provide newer reforms in patient management system.
Hypotheses
The research focused on pattern analysis on how the patients with spontaneous SMICHs are affected by applying age and gender as demographic variable and “hypertension” as the major risk variable.
Thus, three hypotheses were formulated:
Methods
The methodology for the research was focused to spontaneous SMICHs patients from the hospital medical record section of the College of Medical Sciences, in Bharatpur, Chitwan, Nepal, presenting between January 2019 to January 2021 (time we started recording and compiling data of patients with spontaneous SMICHs). The outcomes were compiled to study the patterns through frequencies measures and analysis. The approval for the research conduction was obtained by the Institutional Review Committee (COMSTH-IRC/2021–56). Written informed consent was obtained from all the participants or their next of kin (in case their poor Glasgow coma scale did not allow taking consent from the patients themselves) at the time of their admissions.
Theoretical framework
The research mainly focused upon the spontaneous SMICHs patients as the independent variable and how it impacts the respondents under varied dependent variables like: age, gender and hypertension.
Inclusion and exclusion criteria
40 patients from the College of Medical Sciences, Chitwan, Nepal with spontaneous SMICHs were included in this study. Data was retrieved from the medical record section of the hospital pertaining to patients presenting with spontaneous SMICHs. The study size was arrived through convenience sampling.
Inclusion criteria
Exclusion criteria include:
Target and sampling
The minimal necessary sampling for research has been estimated by Fischer’s formula (Charan & Biwas, 2013) as
N=z2 x p x q/d2
Where:
z represents a value of 1.96 at the confidence-interval of 95%,
p represents SSMICH prevalence as 6%,
q as 1-p and
d represents the margin-of-error as 10%.
The final result through sampling estimation was calculated as 21.66 and the sample-size of 40 patients was finalized for the research purpose.
Variables under focus
Spontaneous SMICHs is the presence of two-or-more ICHs that affects different vascular territories with similar tomographic density-profiles. All findings were validated with radiologists.
Data collection
All data was taken from patient medical records.
Etiologic classification for the cause of ICH was stratified as per the SMASH-U classification into hypertensive angiopathy, cerebral amyloid angiopathy, structural vascular abnormalities, medication related, other systemic causes, and undefined causes respectively (Mosconi et al., 2021). The risk factors were defined as:
1. Arterial hypertension if blood pressure was above 160/90 mm Hg for more than two readings at the time of admission, on antihypertensive drugs or previous medical history of hypertension.
2. Diabetes mellitus if fasting glucose level was >120 mg/dL at the time of admission; hypercholesterolemia, and fasting cholesterol level >220 mg/dL.
3. Vascular lesion with pertinent radiological imaging at the site of the ICH was classified as the primary cause of the hematoma.
4. Cerebral venous sinus thrombosis was diagnosed on a cerebral venogram.
5. Drug associated ICH was considered in a patient on warfarin with international normalized ratio ≥2.0, novel oral anticoagulants within three days, full-dose heparin, or on systemic thrombolysis.
6. Cerebral amyloid angiopathy was classified in patients’ ≥55 years of age with predominant lobar bleeds with microbleeds on magnetic resonance imaging (MRI) sequences sparing the basal ganglion and the thalamus.
7. Tumor associated strokes was considered among patients with proven primary lesions with a histological diagnosis following either the therapeutic hematoma evacuation or minimally invasive biopsies.
All patients were thoroughly evaluated for all possible etiological factors including cerebral angiography (including the venogram) and MRI stroke protocol (T1/T2/FLAIR/DWI/SWI/MR angiography) whenever feasible. The biopsy of the hematoma was sent for every operative case so as to aid in the definitive cause of the SMICHs.
The images of the varied etiological causes of SMICH are demonstrated in the Figure 1–Figure 3.
Figure 1. Hypertension and amyloid angiopathy as the cause of spontaneous simultaneous multiple intracerebral hemorrhages.
All images are original, deidentified, and of our patients themselves.
Figure 2. Tumor associated spontaneous simultaneous multiple intracerebral hemorrhages.
All images are original, deidentified, and of our patients themselves.
Figure 3. Miscellaneous etiological basis of spontaneous simultaneous multiple intracerebral hemorrhages.
All images are original, deidentified, and of our patients themselves.
Regression analysis and hypothesis testing
The regression through analysis of variance (ANOVA) testing was adopted for examining the hypotheses formed as part of this research. Three hypotheses were tested and are analyzed in the following sections. The pertinent study variables of all 40 patients were retrieved and there were no missing data.
Results
The patients’ demographics and clinico-radiological based outcomes are provided in Table 1.
Table 1. Analysis of our cohort presenting with spontaneous simultaneous multiple intracerebral hemorrhages.
Demographic analysis
Among the cohort of 40 patients, the most common age group with 13(32.5%) patients was the 36–45 age group followed by 12(30%) in the 56–65 age group. The male to female gender ratio was 25:15 (62.5% vs. 37.5%).
Risk, territorial and outcome analysis
The incidence of spontaneous SMICHs from our study (40 cases) within the specified duration of two years (total 250 cases) was 16%. The majority (75%) of the cohort had hypertension as the risk factor. Merely 10% of the respondents were affected by diabetes. The vast majority (97.5%) of patients lacked adherence to drug compliance. Cortical and cortical territory (60%) was the major anatomical patterns of involvement. Mortality was observed in 5 (12.5%) patients, and 14 (35%) patients left against medical advice. Surgery was required in 12% of the cohorts who presented with cortical, subcortical and cerebellar bleeds and had clinical features of cerebral herniation. Surgery was aimed to remove the clinically significant hematomas only. One mortality (20%) was observed among the individuals who underwent operative intervention. Ther overall mortality in the study was 12%.
Age and spontaneous SMICHs. Age related to spontaneous SMICHs was verified against the spontaneous SMICHs patients in the first hypothesis through the regression technique. From Table 2b, the Regression analysis (R (0.116), R2 (0.013) and Adjusted R2 (-0.012) were found; Table 2b represents that the ANOVA outcome of the age analysis is found as ‘insignificant’ (p=0.476).
The regression equation used in analyzing the association between spontaneous SMICHs and age in patients was calculated through:
Spontaneous SMICHs = 3.692 + (-0.846 * AGE)
This equation is made from the beta values obtained from the above Table (2a)–Table (2c) after doing regression analysis.
Table 2a. Model Summary.
Table 2b. ANOVA.
| Model | Sum of Squares | Difference in fraction (df) | Mean Square | Fischer (F) | Significance | |
|---|---|---|---|---|---|---|
| 1 | Regression | 0.698 | 1 | 0.698 | 0.519 | 0.476 |
| Residual | 51.077 | 38 | 1.344 | |||
| Total | 51.775 | 39 | ||||
Table 2c. Coefficients.
| Model | Un-standardized Coefficients | Standardized Coefficients | Significance | ||
|---|---|---|---|---|---|
| Beta | Standard Error | Beta | |||
| 1 | (Constant) | 3.692 | 1.217 | 0.004 | |
| SSMICH | -0.846 | 1.174 | -0.116 | 0.476 | |
The outcome is negative denoting that the hypothesis is invalid where age doesn’t impact the likelihood of spontaneous SMICHs.
Gender and spontaneous SMICHs. Gender was verified against the spontaneous SMICHs patients in the second hypothesis through the regression technique. From Table 3a, the R (0.207), R2 (0.043) and adjusted R2 (0.018) are shown; Table 3b suggests that the ANOVA outcome of the gender analysis is ‘insignificant’ (p=0.201).
Table 3a. Model Summary.
Table 3b. Analysis of variance.
| Model | Sum of Squares | Difference in fraction (df) | Mean Square | Fischer test | Significance | |
|---|---|---|---|---|---|---|
| 1 | Regression | 0.401 | 1 | 0.401 | 1.696 | 0.201 |
| Residual | 8.974 | 38 | 0.236 | |||
| Total | 9.375 | 39 | ||||
Table 3c represents the association between spontaneous SMICHs patients and the gender factor. Regression equation in analyzing the spontaneous SMICHs patients and gender association was calculated through:
Table 3c. Coefficients.
| Model | Un-standardized Coefficients | Standardized Coefficients | Significance | ||
|---|---|---|---|---|---|
| Beta | Standard Error | Beta | |||
| 1 | (Constant) | 0.718 | 0.510 | 0.168 | |
| Spontaneous SMICHs | 0.641 | 0.492 | 0.207 | 0.201 | |
Spontaneous SMICHs = 0.718 + (0.641 * GENDER)
This equation is made from the beta values obtained from the above Table (3a)–Table (3c) after doing regression analysis.
The outcome denotes that the hypothesis is invalid wherein gender doesn’t impact spontaneous SMICHs patients.
Hypertension and spontaneous SMICHs. Hypertension as a factor affecting spontaneous SMICHs was verified, against the spontaneous SMICHs patients in the first hypothesis through the regression technique. From Table 4a, the R (0.000), R2 (0.000) and Adjusted R2 (0.000) were found; Table 4b represents that the ANOVA outcome of the hypertension analysis is found as ‘significant’ (p=0.000).
Table 4a. Model Summary.
Table 4b. Analysis of variance.
| Model | Sum of Squares | Difference in fraction (df) | Mean Square | Fischer test | Significance | |
|---|---|---|---|---|---|---|
| 1 | Regression | 0.256 | 1 | 0.256 | 1.000 | 0.000 |
| Residual | 9.744 | 38 | 0.256 | |||
| Total | 10.000 | 39 | ||||
Table 4c represents the association between spontaneous SMICHs patients and the hypertension. Regression equation in analyzing the spontaneous SMICHs patients and hypertension association was calculated through:
Table 4c. Coefficients.
Spontaneous SMICHs = .718 + (.641 * Hypertension)
This equation is made from the beta values obtained from the above Table (4a)–Table (4c) after doing regression analysis.
The outcome denotes that the hypothesis is valid where hypertension impacts spontaneous SMICHs patients.
While comparing to the cohorts of 85 patients with single spontaneous intra-cerebral hemorrhage (ICH) that underwent operative intervention in our institution during the same interval, the male: female ratio was 1.66:1 compared to 4.3:1 for spontaneous SMICHs (Bhattarai et al., 2021). The history of hypertension and compliance to medication was observed in 83.5% and 35.5% respectively compared to 75% and 2.5% among patients with spontaneous SMICHs. The single spontaneous ICH had the predominant involvement of the basal ganglionic compared to the cortical territory at the ratio of 3:1. The cortical and cortical patterns of involvement were observed in 60% of cohorts with spontaneous SMICHs. The mortality was 3.8% in operative patients for single ICH compared to 20% among cohorts who underwent operative intervention for spontaneous SMICHs.
Discussion
The incidence of spontaneous SMICHs from our study (40 cases) within the specified duration of two years (total 250 cases) in our institution was 16%. In a study by Yen et al. (2005), the mean age of the patients presenting with SSMICH was 60.6 ±7.9 years with a male:female ratio of 1.5:1. The mean age of similar cohorts in another study was 68.5 ± 12.8 years (Yamaguchi et al., 2017). Comparatively, our study saw much younger patients with 32.5% of patients in the age groups of 36–45 years. The male to female ratio in our study was 1.66:1.
Contrary to single ICH, spontaneous SMICHs significantly showed lobar territorial preponderance (Wu et al., 2017) (Renard et al., 2020). Our study had cortical-cortical patterns of involvement in 60% of the patients and basal ganglion and thalamic involvement in 12.5% of cases. Putamen and thalamus patterns of involvement were the most common anatomical patterns of involvement in a study by Yamaguchi et al. (2017) whereas bilateral thalamic hemorrhages variants were the most common in a study by Yen et al. (2005).
The indication of surgery among patients with spontaneous SMICHs depends upon variables such as presenting GCS, location and size of the hematomas (Yi et al., 2013). Surgery has been advocated among patients with lobar or cerebellar hematomas (Yen et al., 2005). In a study by Yamaguchi et al. (2017), 35.3% of patients underwent craniotomy. Surgery was performed in only 12% of our cohort.
There are variables connoting clinical outcome among patients with spontaneous SMICHs. One study found low Glasgow Coma Scale (GCS) results, large hematoma and concurrent ventricular extension to be prognostic markers determining 90-day mortality (Wu et al., 2017). Unilateral supratentorial hematomas showed the most favorable outcomes (Zaorsky et al., 2019), while deep seated spontaneous SMICHs had the highest mortality (Renard et al., 2020). The spontaneous SMICHs mortality described in the literature is high, ranging from 37% to 50% (Wu et al., 2017) (Yen et al., 2005). The mortality in our study was comparatively low at 12%. 15% of the patients in our study were referred to appropriate oncology center while 35% of them left despite medical advice.
Hypertensive angiopathy and cerebral amyloid angiopathy accounted for more than 50% of cases in spontaneous SMICHs (Wu TY et al.) (Renard et al., 2020) (Stemer et al., 2010). They accounted for only 42.5% of the spontaneous SMICHs in our study. In total, 75% of our patients presenting with spontaneous SMICHs had a history of hypertension and were hypertensive on presentation. Paradoxically, 97.5% of diagnosed cases of hypertension lacked compliance to their medications.
The pathophysiology of spontaneous SMICHs was proposed to be due to degenerative alterations in the intraparenchymal arterioles caused by long-term, uncontrolled hypertension and the simultaneous rupture of bilateral charcot-bouchard microaneurysms (Yen et al., 2005). As per the “biphasic hypothetical mechanism," an initial ictal hematoma causes an adrenaline spike that disrupts the cerebral autoregulation thereby harbingering the rupture of already weakened arterioles (Yen et al., 2005). Primary spontaneous SMICHs characteristically showed high microhemorrhages burden of varying age in MRI studies. This also highlights the probable role of auto-regulatory dysfunction following the ictal bleed as the prime pathological genesis behind the spontaneous SMICHs (Stemer et al., 2010).
While reviewing the study conducted in our institution, cohorts with spontaneous SMICHs had higher male preponderance, poor compliance to antihypertensive therapy, predominant cortical involvement and increased operative mortality when compared to cohorts undergoing operative intervention for single spontaneous ICH (Bhattarai et al., 2021).
This real-world incidence, patterns and outcome of spontaneous SMICHs can only be validated following a nation-wide multicenter database study. Due to the location and specificity of our results they may not be generalizable to patients from other ethnic and geographic backgrounds. The recall bias (about the risk factors and the medical compliance by the patients when the information was provided by their kin) can be another limiting issue in this observational study.
Conclusions
This is one of the first observational studies pertaining to spontaneous SMICHs to be carried out within our subcontinent. This study proves the need for a national stroke data bank pertaining to spontaneous SMICHs. This will help foster effective patient education during preoperative counseling; as well as formatting a management algorithm combating them.
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how to cite this article
Munakomi S and Chaulagain D. Demographical domains and clinico-radiological characteristics of study cohorts with spontaneous simultaneous multiple intracerebral hemorrhages in a tertiary neurosurgical center in Nepal: a cross-sectional study [version 2; peer review: 2 approved]. F1000Research 2022, 11:154 (https://doi.org/10.12688/f1000research.108816.2)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 2
VERSION 2
PUBLISHED 28 Nov 2022
Revised
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How to cite this report:
Thapa A. Reviewer Report For: Demographical domains and clinico-radiological characteristics of study cohorts with spontaneous simultaneous multiple intracerebral hemorrhages in a tertiary neurosurgical center in Nepal: a cross-sectional study [version 2; peer review: 2 approved]. F1000Research 2022, 11:154 (https://doi.org/10.5256/f1000research.141319.r156807)
The direct URL for this report is:
https://f1000research.com/articles/11-154/v2#referee-response-156807
https://f1000research.com/articles/11-154/v2#referee-response-156807
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 01 Dec 2022
Approved
VIEWS 5
The authors have revised the article suitably. The 16% incidence rate of SMICH is considerable. SMICH has been found increasingly in younger age males over cortical areas with non-compliance on anti hypertensive drugs and required more surgical intervention than isolated
... Continue reading
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HOW TO CITE THIS REPORT
Thapa A. Reviewer Report For: Demographical domains and clinico-radiological characteristics of study cohorts with spontaneous simultaneous multiple intracerebral hemorrhages in a tertiary neurosurgical center in Nepal: a cross-sectional study [version 2; peer review: 2 approved]. F1000Research 2022, 11:154 (https://doi.org/10.5256/f1000research.141319.r156807)
The direct URL for this report is:
https://f1000research.com/articles/11-154/v2#referee-response-156807
https://f1000research.com/articles/11-154/v2#referee-response-156807
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Version 1
VERSION 1
PUBLISHED 07 Feb 2022
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How to cite this report:
Thapa A. Reviewer Report For: Demographical domains and clinico-radiological characteristics of study cohorts with spontaneous simultaneous multiple intracerebral hemorrhages in a tertiary neurosurgical center in Nepal: a cross-sectional study [version 2; peer review: 2 approved]. F1000Research 2022, 11:154 (https://doi.org/10.5256/f1000research.120245.r153191)
The direct URL for this report is:
https://f1000research.com/articles/11-154/v1#referee-response-153191
https://f1000research.com/articles/11-154/v1#referee-response-153191
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 14 Nov 2022
Approved with Reservations
VIEWS 11
Authors have studied 40 patients over a period of two years with spontaneous simultaneous multiple intra-cerebral hemorrhages (SMICHs). Being not so common, this entity demands more elaborate study.
The present study evaluates the association of age, gender and presence ... Continue reading
The present study evaluates the association of age, gender and presence ... Continue reading
CITE
HOW TO CITE THIS REPORT
Thapa A. Reviewer Report For: Demographical domains and clinico-radiological characteristics of study cohorts with spontaneous simultaneous multiple intracerebral hemorrhages in a tertiary neurosurgical center in Nepal: a cross-sectional study [version 2; peer review: 2 approved]. F1000Research 2022, 11:154 (https://doi.org/10.5256/f1000research.120245.r153191)
The direct URL for this report is:
https://f1000research.com/articles/11-154/v1#referee-response-153191
https://f1000research.com/articles/11-154/v1#referee-response-153191
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Gao GY. Reviewer Report For: Demographical domains and clinico-radiological characteristics of study cohorts with spontaneous simultaneous multiple intracerebral hemorrhages in a tertiary neurosurgical center in Nepal: a cross-sectional study [version 2; peer review: 2 approved]. F1000Research 2022, 11:154 (https://doi.org/10.5256/f1000research.120245.r122721)
The direct URL for this report is:
https://f1000research.com/articles/11-154/v1#referee-response-122721
https://f1000research.com/articles/11-154/v1#referee-response-122721
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 07 Mar 2022
Guo-Yi Gao,
Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Approved
VIEWS 14
This study described the clinical features of simultaneous multiple intracerebral hemorrhages in a neurosurgical center in Nepal. The study was well designed and the data acquisition and analysis are both reasonable. The limitation, such as the sample size may influence
... Continue reading
CITE
HOW TO CITE THIS REPORT
Gao GY. Reviewer Report For: Demographical domains and clinico-radiological characteristics of study cohorts with spontaneous simultaneous multiple intracerebral hemorrhages in a tertiary neurosurgical center in Nepal: a cross-sectional study [version 2; peer review: 2 approved]. F1000Research 2022, 11:154 (https://doi.org/10.5256/f1000research.120245.r122721)
The direct URL for this report is:
https://f1000research.com/articles/11-154/v1#referee-response-122721
https://f1000research.com/articles/11-154/v1#referee-response-122721
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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