Abstract
Background/Objective:
Infratentorial intracerebral hemorrhage (ICH) is associated with worse prognosis than supratentorial ICH; however, infratentorial ICH is often excluded or underrepresented in clinical trials of ICH. We sought to evaluate the natural history of infratentorial ICH stratified by brainstem or cerebellar location using a prospective observational study inclusive of all spontaneous ICH.
Methods:
Using a prospective, single center cohort of patients with spontaneous ICH between 2008–2019, we conducted a descriptive analysis of baseline demographics, severity of injury scores, and long-term functional outcomes of infratentorial ICH stratified by cerebellar or brainstem location.
Results:
Infratentorial ICH occurred in 82 (13%) of 632 patients in our ICH cohort. Among infratentorial ICH, cerebellar ICH occurred in 45 (55%) and brainstem ICH occurred in 37 (45%). Compared to cerebellar ICH, patients with brainstem ICH had significantly worse severity of injury scores, including lower admission Glasgow Coma Scale (median 14 [7.0 – 15.0] versus 4 [3.0 – 8.0], respectively; P < 0.001) and higher ICH Score (median 2 [1.0 – 3.0] versus 3 [2.75 – 4.0], respectively; P = 0.02). Patients with cerebellar ICH were more likely to be discharged home or to acute rehabilitation (OR 4.8, 95% CI 1.8 – 12.8) but there was no difference in in-hospital mortality (OR 0.4, 95% CI 0.1 – 1.1, P = 0.08) or cause of death (P = 0.5). Modified Rankin Scale scores at 3 months were significantly better in patients with cerebellar ICH compared to brainstem ICH (median 3.5 [1.8 – 6.0] versus median 6 [5.0 – 6.0], P = 0.03).
Conclusions:
Location of infratentorial ICH is an important determinant of admission severity and clinical outcome in unselected patients with ICH. Patients with cerebellar ICH have less severe symptoms at presentation and more favorable functional outcomes compared to patients with brainstem ICH.
Keywords: cerebral hemorrhage, intracranial hemorrhages, posterior fossa hemorrhage, brain hemorrhage
Introduction:
Spontaneous intracerebral hemorrhage (ICH) accounts for 10% of strokes in the United States annually and is associated with high morbidity and mortality[1]. Multiple severity of injury scoring systems, including the Functional Outcome in Patients With Primary Intracerebral Hemorrhage (FUNC) score; ICH Score; and ICH Grading Scale (ICH-GS), are often used to aide in risk stratification and prognostication of neurological outcome after ICH, and these scores attribute worse prognosis to infratentorial ICH[2–4]. These scoring systems are valuable; however, they consider infratentorial ICH to be a single entity and do not differentiate between brainstem and cerebellar locations.
Differences in prognosis for cerebellar and brainstem ICH subjects have been reported for a cohort of patient enrolled in INTERACT 1 and 2 trials of blood pressure control, but the clinical characteristics of those patients differ systematically from the general ICH patient population[5]. Infratentorial ICH represents 10–20% of all spontaneous ICH, but in landmark studies of ICH only 2–10% of enrolled patients have an infratentorial ICH including just 195 of 4243 (4.6%) patients in the INTERACT studies[2, 3]. Landmark clinical trials of ICH have either excluded patients with infratentorial ICH[6–10] or patients with a Glasgow Coma Scale (GCS) of 5 or less[11–14], which likely contributes to the underrepresentation of infratentorial ICH in such studies. This selection bias may limit our appreciation of clinically and prognostically relevant distinctions between brainstem and cerebellar ICH, such as greater surgical therapeutic options for cerebellar ICH[15]. We hypothesized that there are significant differences in the presentation, course, and outcomes of patients with cerebellar versus brainstem ICH in an unselected cohort.
Methods:
Patients presenting to a single comprehensive stroke center with spontaneous ICH from December 2008 through March 2019 were prospectively enrolled in an observational cohort study, as previously described[16]. Patients were excluded if hemorrhage was due to trauma, hemorrhagic conversion of ischemic stroke, structural lesions, or vascular malformations. All patient-level data were adjudicated prospectively by a board-certified neurologist. This study was approved by the institutional review board (IRB). Written informed consent was obtained from the patient or a legally authorized representative. The IRB approved a waiver of consent for patients who died during initial hospitalization or who were incapacitated and for whom a legal representative could not be located.
Patient variables included demographics; medical comorbidities; medications; severity of injury as measured by NIH Stroke Scale (NIHSS), Glasgow Coma Scale (GCS), and ICH score (a composite of age, radiographic characteristics including hematoma volume, presence of intraventricular hemorrhage, and location[3]). In-hospital procedures examined included percutaneous endoscopic gastrostomy (PEG), tracheostomy, craniotomy, and external ventricular drain (EVD) placement.
Primary clinical outcomes included 14-day or hospital discharge NIHSS and modified Rankin Scale (mRS, a validated outcome scale from 0, no symptoms to 6, death), 28-day mRS, and 3-month mRS. The mRS was obtained using a focused, validated interview with either patient or patient surrogate[17]. For patients without 3-month mRS data, 28-day mRS was carried forward as previously described[18]. Patients who did not have 14-day or 28-day outcome data were excluded from outcome analysis. Functional independence, defined as an mRS of 0–3, was analyzed between both groups. Discharge disposition including in-hospital all-cause mortality was summarized. Subgroup analysis of cerebellar ICH dichotomized by survival are also performed.
Statistical analyses were performed using R version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria). Descriptive statistics comparing patients by location of infratentorial hemorrhage (brainstem versus cerebellar) were analyzed by two-sided Student’s t-tests and chi-squared tests for continuous and categorical variables, respectively. Non-normally distributed data are reported using median and interquartile range. When necessary, the Fischer exact test and Wilcoxon rank sum test were used. Pearson correlation was used for analysis of admission GCS and hematoma volume. Supratentorial ICH data from our entire cohort is provided as a comparative reference.
Results:
Patient Characteristics:
We recruited 632 patients with spontaneous ICH, including 82 (13%) with infratentorial ICH. Among patients with infratentorial ICH, 45 (55%) occurred within the cerebellum and 37 (45%) within the brainstem. Patients with cerebellar ICH were significantly older than patients with brainstem ICH (P < 0.001) and a greater proportion of patients in the cerebellar group were over age 80 than in the brainstem group (P = 0.01, Table 1). Cerebellar ICH was more common among White patients (62%) than Black patients (33%) (P = 0.03). No patients with brainstem ICH had history of myocardial infarction or coronary artery disease compared to 20% of patients with cerebellar ICH (P = 0.003). There was no significant difference in the prevalence of other medical co-morbidities or aspirin, other antiplatelet agent, statin, or anticoagulant use between the two groups.
Table 1:
Descriptive Statistics of Patient Baseline Demographics and Admission Clinical Characteristics after Infratentorial Hemorrhage.
| Patient Demographics | Supratentorial | Cerebellar | Brainstem | P-value (Cerebellar vs. Brainstem) |
|---|---|---|---|---|
| Number of patients | 550 | 45 | 37 | |
| Mean Age ± SD | 65.8 ± 14.3 | 66.9 ± 15.2 | 54.8 ± 12.4 | <0.001 |
| Female sex | 263 (48%) | 26 (58%) | 20 (54%) | 0.9 |
| Race | 0.006 | |||
| Black or African American | 218 (40%) | 15 (33%) | 21 (57%) | |
| White | 298 (54%) | 28 (62%) | 13 (35%) | |
| Other | 31 (6%) | 2 (4%) | 3 (8%) | |
| Hispanic or Latino Ethnicity | 50 (9%) | 6 (13%) | 1 (3%) | 0.1 |
| History of Ischemic Stroke | 76 (14%) | 4 (9%) | 2 (5%) | 0.7 |
| History of Coronary Artery | 91 (17%) | 9 (20%) | 0 (0%) | 0.003 |
| Disease or Myocardial Infarction | ||||
| Atrial Fibrillation | 53 (10%) | 8 (18%) | 2 (5%) | 0.1 |
| Hypertension | 412 (75%) | 31 (69%) | 28 (76%) | 0.6 |
| Diabetes | 113 (21%) | 9 (20%) | 7 (19%) | 1 |
| Aspirin Use | 178 (32%) | 16 (36%) | 9 (24%) | 0.4 |
| Other Antiplatelet Use | 43 (8%) | 4 (9%) | 0 (0%) | 0.1 |
| Warfarin Use | 54 (10%) | 8 (18%) | 3 (8%) | 0.3 |
| Direct Oral Anticoagulant Use | 10 (2%) | 0 (0%) | 0 (0%) | 1.0 |
| Low-Molecular Weight Heparin | 8 (1%) | 1 (2%) | 2 (5%) | 0.6 |
| Statin Use | 124 (23%) | 10 (22%) | 5 (14%) | 0.4 |
| Admit ICH Score (IQR) | 1 (0.0 – 2.0) | 2 (1.0 – 3.0) | 3 (2.75 – 4.0) | 0.02 |
| Admit GCS (IQR) | 13 (8.0 – 15.0) | 14 (7.0 – 15.0) | 4 (3.0 – 8.0) | <0.001 |
| ICH Score – GCS | <0.001 | |||
| ICH Score GCS 13 – 15 | 323 (59%) | 25 (56%) | 6 (16%) | |
| ICH Score GCS 5 – 12 | 176 (32%) | 12 (27%) | 9 (24%) | |
| ICH Score GCS 3–4 | 51 (9%) | 8 (18%) | 22 (59%) | |
| Hematoma Volume > 30 mL | 178 (32%) | 9 (20%) | 2 (5%) | 0.1 |
| Intraventricular Hemorrhage | 257 (47%) | 22 (49%) | 21 (57%) | 0.6 |
| Age > 80 years | 101 (18%) | 11 (24%) | 1 (3%) | 0.01 |
| Admit NIHSS (IQR) | 10 (4.0 −20.0) | 4 (2.0 – 24.0) | 26 (19.0 – 26.0) | 0.001 |
| Hematoma Volume (mL) | 27.2 ± 35.6 | 16.2 ± 12.6 | 8.9 ± 8.7 | 0.004 |
Baseline Clinical Severity Scores
Admission ICH Score was significantly worse in patients with brainstem ICH compared to patients with cerebellar ICH (median 3 [2.75 – 4.0] versus 2 [1.0 – 3.0], P = 0.02, Table 1). When compared to supratentorial ICH, patients with cerebellar ICH and brainstem ICH have worse ICH scores on admission (P < 0.001). Similarly, admission NIHSS was significantly worse in patients with brainstem ICH compared to patients with cerebellar ICH (median 26 [19.0 – 26.0] versus 4 [2.0 – 24.0], P = 0.001). Admission GCS was similar between patients who had supratentorial ICH and cerebellar ICH (P = 0.9), whereas patients with brainstem ICH had worse admission GCS when compared to both patients with supratentorial ICH (P<0.001) and cerebellar ICH (P < 0.001) There was no difference in the frequency of intraventricular hemorrhage (P = 0.6) (Table 1).
Hematoma Volume:
Brainstem hematoma volume was significantly smaller compared to cerebellar hematoma volume (8.9 ± 8.7 mL versus 16.2 ± 12.6 mL, P = 0.004). Compared to supratentorial ICH, hematoma volumes are significantly smaller in both cerebellar (P <0.001) and brainstem (P < 0.001) ICH. Hematoma volume was correlated with worse admission GCS for both cerebellar ICH (correlation coefficient −0.6, p < 0.002) and brainstem ICH (correlation coefficient −0.5, P = 0.002).
In-Hospital Events
Seven (16%) patients with cerebellar ICH underwent craniotomy compared to no patients with brainstem ICH (P = 0.01). There was no significant difference in the rate of EVD placement between the two groups (29% in cerebellar group versus 32% in brainstem group, P = 0.8, Table 2). Patients with cerebellar hematoma were less likely to undergo tracheostomy (OR 0.2, 95%CI 0.03 – 0.7, P=0.007) or gastrostomy (OR 0.3, 95%CI 0.1 – 0.9, P=0.03).
Table 2:
In-Hospital Events, Disposition and Mortality Among Patients with Intracerebral Hemorrhage by Location
| Patient ICH Location | Supratentorial | Cerebellar | Brainstem | P-value (Cerebellar vs Brainstem) |
|---|---|---|---|---|
| In-Hospital Procedures | ||||
| Craniotomy | 54 (10%) | 7 (16%) | 0 (0%) | 0.01 |
| Venticulostomy | 119 (22%) | 13 (29%) | 12 (32%) | 0.8 |
| Gastrostomy | 91 (17%) | 6 (13%) | 12 (32%) | 0.03 |
| Tracheostomy | 75 (14%) | 3 (7%) | 11 (30%) | 0.007 |
| Hospital Disposition | N = 531 | N = 41 | N = 35 | 0.009 |
| Home | 116 (22%) | 15 (37%) | 3 (9%) | |
| Acute Inpatient Rehabilitation | 186 (35%) | 12 (29%) | 7 (20%) | |
| Long-term Acute Care Hospital | 51 (10%) | 1 (2%) | 4 (11%) | |
| Skilled Nursing Facility | 63 (12%) | 2 (5%) | 4 (11%) | |
| Dead | 115 (22%) | 11 (27%) | 17 (49%) | |
| Cause of Death (Within 3 months) | N = 150 | N = 13 | N = 20 | 0.5 |
| Brain Death | 23 (15%) | 6 (46%) | 5 (25%) | |
| Cardiac Arrest | 43 (29%) | 1 (8%) | 5 (25%) | |
| Withdrawal of Life Support | 66 (44%) | 6 (46%) | 9 (45%) | |
| Other Medical Causes | 18 (12%) | 0 (0%) | 1 (5%) |
Hospital disposition was different between the two groups (P = 0.009, Table 2). Patients with cerebellar ICH were more likely to discharge home or to acute rehab than patients with brainstem ICH (OR 4.8, 95% CI 1.8 – 12.8, P = 0.001). In-hospital mortality was not statistically different between the two groups (OR 0.4, 95% CI 0.1 – 1.1, P = 0.08). There was no difference in the cause of death within the first 3 months, including withdrawal of life support, between both groups (P = 0.5, Table 2).
Clinical Outcomes
We obtained 28-day outcomes in 60 of 82 patients with infratentorial ICH. Three month outcome data was carried forward from 28-day mRS in 10 patients with infratentorial ICH (3 with brainstem ICH and 7 with cerebellar ICH). Outcome analysis excluded 8 patients with brainstem ICH and 20 with cerebellar ICH, due to no 14-day and 28-day mRS being available.
There was a significant difference in 14-day or discharge NIHSS between patients with cerebellar ICH and patients with brainstem ICH (median 3.5 [2.0 – 42.0] versus median 34.5 [15.0 – 42.0], P = 0.002). Patients with cerebellar ICH also had more favorable functional outcomes compared to patients with brainstem ICH based on 14 day or discharge mRS (median 4 [3.0 – 6.0] versus 5 [5.0 – 6.0], P = 0.003, Figure 1A). This difference continued at 28 days (median mRS 4 [2.0 – 6.0] versus 6 [5.0 – 6.0], P = 0.009, Figure 1B) and at 3 months (median 3.5 [1.8 – 6.0] versus 6 [5.0 – 6.0], P = 0.03, Figure 1C). Patients with cerebellar ICH were also more likely to have functional independence compared to patients with brainstem ICH at 28-days (OR = 7.7, 95% CI 2.3 – 43.7) and at 3 months (OR 5.3, 95% CI 1.9 – 21.2).
Figure 1.
Patient Outcomes following Infratentorial Intracerebral Hemorrhage by Location. 14-day or discharge (DC) (panel A), 28-day (panel B), and 3-month (panel C) Modified Rankin Scale (mRS) are more favorable in patients with cerebellar ICH compared to patients with brainstem ICH.
Cerebellar ICH Subgroup Analysis
Given observed dichotomy of patients with cerebellar ICH who survived versus those who died within 3 months, a further subgroup analysis was performed to determine differences between the two subgroups (see Table 3). In our cohort, 17 patients with cerebellar ICH survived compared to 13 patients who died within 3 months. There was no difference between age, race, or sex between the two groups. Patients who survived at 3 months had a lower ICH score (median 1 [1.0 – 2.0] versus 4 [3.0 – 4.0], P < 0.001) and higher admission GCS (median 15 [15.0 – 15.0] versus 4 [4.0 – 8.0], P <0.001).
Table 3:
Subgroup Analysis of Patients with Cerebellar Intracerebral Hemorrhage
| Survival at 3 months | Alive (N = 17) | Dead (N = 13) | P- value |
|---|---|---|---|
| Age | 64.9 ± 17.7 | 73.3 ± 11.9 | 0.13 |
| Female sex | 9 | 8 | 1.0 |
| Race | 0.8 | ||
| Black | 4 | 5 | |
| White | 12 | 9 | |
| Other | 1 | 0 | |
| Admit ICH Score (median) (IQR) | 1 (1.0 – 2.0) | 4 (3.0 – 5.0) | <0.001 |
| Admit Glasgow Coma Scale | <0.001 | ||
| (median, IQR) | 15 (15.0 – 15.0) | 4 (3.0 – 8.0) | |
| Hematoma Volume > 30 mL | 1 | 7 | 0.01 |
| Intraventricular Hemorrhage | 5 | 12 | 0.003 |
| Age > 80 years | 4 | 6 | 0.5 |
| Hematoma Volume (mL) | 9.6 ±10.4 | 27.4 ± 9.8 | < 0.001 |
| Admit NIHSS (median) | 2.0 (2.0 – 3.0) | 28 (24.0 – 32.0) | < 0.001 |
| In-Hospital Procedures | |||
| Craniotomy | 1 | 2 | 0.6 |
| Ventriculostomy | 5 | 6 | 0.5 |
| Gastrostomy | 1 | 0 | 1.0 |
| Tracheostomy | 0 | 0 | 1.0 |
Hematoma volume was larger in patients with cerebellar ICH who died (mean 27.4 ± 9.8 mL versus 9.6 ± 10.4 mL) (P < 0.001). Ninety-two percent of patients with cerebellar ICH who died had intraventricular hemorrhage (IVH) compared to a 29% incidence of IVH amongst cerebellar ICH patients who survived (P = 0.003). There was no difference in craniotomy, EVD placement, tracheostomy, or gastrostomy rates between the two groups. The most common causes of death were brain death (n = 6) or withdrawal of life support (n = 6).
Discussion:
In an unselected cohort of patients with ICH, we found that patients with cerebellar ICH had less severe clinical presentations, were less likely to need tracheostomy or gastrostomy tube placement, were more likely to be discharged to acute inpatient rehabilitation or home, and had better functional outcomes than patients with brainstem ICH. Although infratentorial ICH has been associated with worse prognosis overall[3, 19, 20], these data demonstrate that there is considerable heterogeneity among this group. Few patients with cerebellar ICH who survive hospitalization die in the subsequent 3 months and most regain functional independence, while the majority of brainstem ICH patients remain functionally dependent or have fatal outcomes.
There is limited information regarding the natural history and outcomes specific to patients with infratentorial ICH patients that can guide the clinician in prognostication and family discussions. A recent analysis of infratentorial ICH from the INTERACT trials suggested patients with brainstem ICH had higher mortality than patients with cerebellar ICH, but that there was no difference in functional outcome[5]. However, the INTERACT trials excluded patients presenting with GCS ≤5 and only included patients who met criteria for a clinical trial, and therefore, may not generalize to unselected patients. Based on GCS criteria alone, 24 of 37 patients (65%) with brainstem ICH in our cohort would have been excluded from the INTERACT trials while only 10 of 45 (22%) patients with cerebellar ICH would have been excluded, suggestive of a selection bias against patients with brainstem ICH. Our study has the benefit that all spontaneous ICH patients were eligible for consent and inclusion, and therefore, is less likely to exhibit this selection bias.
Our results have implications for the management of patients with infratentorial ICH. Prognostication scores may unfairly bias patients with infratentorial ICH towards poor prognosis, influencing physician treatment recommendations, leading to early withdrawal of life support, and generating a self-fulfilling prophecy[21, 22]. Previous literature suggests that avoidance of early Do-Not-Resuscitate orders in patients with intracerebral hemorrhage could lead to improved mortality[23]. Our results suggest that uncorrected application of prognostication scores to guide family discussions may mislead clinicians on the natural history for some patients with infratentorial ICH. Our data may be useful for refining the natural history and long-term functional outcome expectations for infratentorial patients with ICH, which could be beneficial for goals of care discussions.
In our cohort, we found an association between race and infratentorial hematoma location, with Black patients having a higher rate of brainstem hemorrhage and White patients having a higher rate of cerebellar hemorrhage. This may be attributable to the higher prevalence of uncontrolled hypertension amongst Blacks leading to small vessel hemorrhagic events[24]. We have previously identified racial disparities in the treatment of supratentorial ICH, with Blacks more likely to have deep hematomas, and a correspondingly lower likelihood of receiving prophylactic seizure medications[25]. A higher rate of brainstem hemorrhages may contribute to known racial disparities in severity[26] and worse outcomes[27] after ICH. While racial ethnic disparities in gastrostomy and tracheostomy have been described[28], these data suggest they may be attributable to hematoma location, at least in part.
There are limitations to these data. This study was performed at a single center that is an urban tertiary referral center and our patient demographics may differ from other institutions. Notably, our cohort has a relatively low rate of anticoagulant-related ICH. Thirty-four percent of patients in our cohort did not have follow-up information, and loss to follow-up is a concern. There was a higher proportion of patients with cerebellar ICH (44%) who were excluded from analysis compared to 22% of patients with brainstem ICH who were excluded. If patients who were excluded had worse neurological outcome, our results could be biased with more favorable outcome in patients with cerebellar ICH. We prospectively identified hematoma location, however, this is not feasible for large data sets. Obtaining phenotypic data on subtypes of ICH from large data sets may require new methodologies, such as natural language processing, in order to accurately identify radiographic hemorrhage characteristics[29].
Conclusions
In summary, these data suggest that grouping cerebellar and brainstem hematomas into a single category may reduce the accuracy of severity of injury scores. Patients with cerebellar hematomas have less severe clinical presentations and have more favorable outcomes in comparison to patients with brainstem hematomas. Accounting for hematoma location may improve the accuracy of prognosis with implications for patient management and goals of care discussions.
Declaration of Interest:
Funding Sources: This work was supported in part by K18 HS023437 and R01 NS110779 to Dr. Naidech, and by K23 NS092975 to Dr. Maas. For Dr. Liotta, research reported in this publication was supported, in part, by the National Institutes of Health’s National Center for Advancing Translational Sciences, Grant Number UL1TR001422 and Grant Number KL2 TR001424. Dr. Garcia served as the StrokeNet research fellow under grant U24 NS107233-01 and Fogarty Global Health Trainee under award D43 TW010543. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Drs. Patel and Swor have no disclosures to report.
Footnotes
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