Long-Term Outcomes in Patients With Spontaneous Cerebellar Hemorrhage: An International Cohort Study.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) in the cerebellum has a poor short-term prognosis, whereas data on the long-term case fatality and recurrent vascular events are sparse. Herewith, we aimed to assess the long-term case fatality and recurrence rate of vascular events after a first cerebellar ICH. METHODS: In this international cohort study, we included patients from 10 hospitals (the United States and Europe from 1997 to 2017) aged ≥18 years with a first spontaneous cerebellar ICH who were discharged alive. Data on long-term case fatality and recurrence of vascular events (recurrent ICH [supratentoria or infratentorial], ischemic stroke, myocardial infarction, or major vascular surgery) were collected for survival analysis and absolute event rate calculation. RESULTS: We included 405 patients with cerebellar ICH (mean age [SD], 72 [13] years, 49% female). The median survival time was 67 months (interquartile range, 23-100 months), with a cumulative survival rate of 34% at 10-year follow-up (median follow-up time per center ranged: 15-80 months). In the 347 patients with data on vascular events 92 events occurred in 78 patients, after initial cerebellar ICH: 31 (8.9%) patients had a recurrent ICH (absolute event rate, 1.8 per 100 patient-years [95% CI, 1.2-2.6]), 39 (11%) had an ischemic stroke (absolute event rate, 2.3 [95% CI, 1.6-3.2]), 13 (3.7%) had a myocardial infarction (absolute event rate, 0.8 [95% CI, 0.4-1.3]), and 5 (1.4%) underwent major vascular surgery (absolute event rate, 0.3 [95% CI, 0.1-0.7]). The median time to a first vascular event during follow-up was 27 months (interquartile range, 8.7-50 months), with a cumulative hazard of 47% at 10 years. CONCLUSIONS: The long-term prognosis of patients who survive a first spontaneous cerebellar ICH is poor and comparable to that of patients who survive a first supratentorial ICH. Further identification of patients at high risk of vascular events following the initial cerebellar ICH is needed. Including patients with cerebellar ICH in randomized controlled trials on secondary prevention of patients with ICH is warranted.

Cerebellar Superficial Siderosis in Cerebral Amyloid Angiopathy.

BACKGROUND AND PURPOSE: Although evidence accumulates that the cerebellum is involved in cerebral amyloid angiopathy (CAA), cerebellar superficial siderosis is not considered to be a disease marker. The objective of this study is to investigate cerebellar superficial siderosis frequency and its relation to hemorrhagic magnetic resonance imaging markers in patients with sporadic and Dutch-type hereditary CAA and patients with deep perforating arteriopathy-related intracerebral hemorrhage. METHODS: We recruited patients from 3 prospective 3 Tesla magnetic resonance imaging studies and scored siderosis and hemorrhages. Cerebellar siderosis was identified as hypointense linear signal loss (black) on susceptibility-weighted or T2*-weighted magnetic resonance imaging which follows at least one folia of the cerebellar cortex (including the vermis). RESULTS: We included 50 subjects with Dutch-type hereditary CAA, (mean age 50 years), 45 with sporadic CAA (mean age 72 years), and 43 patients with deep perforating arteriopathy-related intracerebral hemorrhage (mean age 54 years). Cerebellar superficial siderosis was present in 5 out of 50 (10% [95% CI, 2-18]) patients with Dutch-type hereditary CAA, 4/45 (9% [95% CI, 1-17]) patients with sporadic CAA, and 0 out of 43 (0% [95% CI, 0-8]) patients with deep perforating arteriopathy-related intracerebral hemorrhage. Patients with cerebellar superficial siderosis had more supratentorial lobar (median number 9 versus 2, relative risk, 2.9 [95% CI, 2.5-3.4]) and superficial cerebellar macrobleeds (median number 2 versus 0, relative risk, 20.3 [95% CI, 8.6-47.6]) compared with patients without the marker. The frequency of cortical superficial siderosis and superficial cerebellar microbleeds was comparable. CONCLUSIONS: We conclude that cerebellar superficial siderosis might be a novel marker for CAA.

Trigger Factors for Spontaneous Intracerebral Hemorrhage: A Case-Crossover Study.

BACKGROUND: Whether certain activities can trigger spontaneous intracerebral hemorrhage (ICH) remains unknown. Insights into factors that trigger vessel rupture resulting in ICH improves knowledge on the pathophysiology of ICH. We assessed potential trigger factors and their risk for ICH onset. METHODS: We included consecutive patients diagnosed with ICH between July 1, 2013, and December 31, 2019. We interviewed patients on their exposure to 12 potential trigger factors (eg, Valsalva maneuvers) in the (hazard) period soon before onset of ICH and their normal exposure to these trigger factors in the year before the ICH. We used the case-crossover design to calculate relative risks (RR) for potential trigger factors. RESULTS: We interviewed 149 patients (mean age 64, 66% male) with ICH. Sixty-seven (45%) had a lobar hemorrhage, 60 (40%) had a deep hemorrhage, 19 (13%) had a cerebellar hemorrhage, and 3 (2%) had an intraventricular hemorrhage. For ICH in general, there was an increased risk within an hour after caffeine consumption (RR=2.5 [95% CI=1.8-3.6]), within an hour after coffee consumption alone (RR=4.8 [95% CI=3.3-6.9]), within an hour after lifting >25 kg (RR=6.6 [95% CI=2.2-19.9]), within an hour after minor head trauma (RR=10.1 [95% CI=1.7-60.2]), within an hour after sexual activity (RR=30.4 [95% CI=16.8-55.0]), within an hour after straining for defecation (RR=37.6 [95% CI=22.4-63.4]), and within an hour after vigorous exercise (RR=21.8 [95% CI=12.6-37.8]). Within 24 hours after flu-like disease or fever, the risk for ICH was also increased (RR=50.7 [95% CI=27.1-95.1]). Within an hour after Valsalva maneuvers, the RR for deep ICH was 3.5 (95% CI=1.7-6.9) and for lobar ICH the RR was 2.0 (95% CI=0.9-4.2). CONCLUSIONS: We identified one infection and several blood pressure related trigger factors for ICH onset, providing new insights into the pathophysiology of vessel rupture resulting in ICH.

Transcranial Doppler ultrasonography CO2 reactivity does not predict recurrent ischaemic stroke in patients with symptomatic carotid artery occlusion.

BACKGROUND: Patients with transient ischaemic attacks (TIAs) or minor disabling ischaemic stroke associated with an internal carotid artery (ICA) occlusion have a high risk of recurrent stroke in case of compromised cerebral blood flow. Recent studies showed that increased oxygen extraction fraction measured by positron emission tomography (PET) is still an independent predictor of subsequent stroke under current medical treatment, but PET facilities are not widely available. Transcranial Doppler (TCD) ultrasonography CO2 reactivity is a cheap and non-invasive alternative to measure haemodynamic compromise. The aim of our study was to investigate whether TCD CO2 reactivity is an independent predictor of recurrent ischaemic stroke in a large cohort of patients with symptomatic ICA occlusion in a time where rigorous control of vascular risk factors has been widely implemented in clinical practice. METHODS: Between July 1995 and December 2009, we included consecutive patients with TIAs or minor disabling ischaemic stroke (modified Rankin Scale ≤3) associated with ICA occlusion who were referred to the University Medical Centre Utrecht, The Netherlands. All patients were treated with antiplatelet therapy and received rigorous control of vascular risk factors, including statins, treatment for diabetes and hypertension and lifestyle advices. CO2 reactivity was measured with TCD within 3 months after presentation. We determined the predictive value of TCD CO2 reactivity for recurrent ischaemic stroke using Cox proportional hazard analysis. RESULTS: We included 201 patients with a median follow-up time of 7.1 years. Mean CO2 reactivity was 15% (±20 standard deviation). The annual rate for ipsilateral ischaemic stroke was 2.2% [95% confidence interval (CI) 1.4-3.2] and for any recurrent stroke 3.2% (95% CI 2.3-4.4). We did not find a significant relationship between CO2 reactivity and the risk of ipsilateral [hazard ratio (HR) for every increase in percentage point 1.01, 95% CI 0.99-1.02] or any recurrent ischaemic stroke (HR 1.01, 95% CI 0.998-1.02). Multivariable analysis showed a significant relationship with history of stroke (HR 4.0, 95% CI 1.8-9.0) for ipsilateral recurrent stroke, and age (HR for increase per year 1.05, 95% CI 1.01-1.09) and a history of stroke (HR 3.4, 95% CI 1.7-6.6) for any recurrent stroke. CONCLUSIONS: In patients with TIAs or non-disabling stroke associated with occlusion of the carotid artery, the long-term annual risk of stroke is generally low with careful control of vascular risk factors. Impaired CO2 reactivity measured within 3 months after presentation does not identify the subgroup of patients at high risk of recurrent ischaemic stroke.

Decreased microvascular claudin-5 levels in cerebral amyloid angiopathy associated with intracerebral haemorrhage.

Decreased microvascular levels of claudin-5 in the occipital and temporal lobe of patients with cerebral amyloid angiopathy are associated with intracerebral haemorrhage.

Histopathology of Cerebral Microinfarcts and Microbleeds in Spontaneous Intracerebral Hemorrhage.

In patients with spontaneous intracerebral hemorrhage caused by different vasculopathies, cerebral microinfarcts have the same aspect on MRI and the same applies to cerebral microbleeds. It is unclear what pathological changes underlie these cerebral microinfarcts and cerebral microbleeds. In the current study, we explored the histopathological substrate of these lesions by investigating the brain tissue of 20 patients (median age at death 77 years) who died from ICH (9 lobar, 11 non-lobar) with a combination of post-mortem 7-T MRI and histopathological analysis. We identified 132 CMIs and 204 CMBs in 15 patients on MRI, with higher numbers of CMIs in lobar ICH patients and similar numbers of CMBs. On histopathology, CMIs and CMBs were in lobar ICH more often located in the superficial than in the deep layers of the cortex, and in non-lobar ICH more often in the deeper layers. We found a tendency towards more severe CAA scores in lobar ICH patients. Other histopathological characteristics were comparable between lobar and non-lobar ICH patients. Although CMIs and CMBs were found in different segments of the cortex in lobar ICH compared to non-lobar ICH patients, otherwise similar histopathological features of cortical CMIs and CMBs distant from the ICH suggest shared pathophysiological mechanisms in lobar and non-lobar ICH caused by different vasculopathies.

The association between blood pressure variability and perihematomal edema after spontaneous intracerebral hemorrhage.

Background: Perihematomal edema (PHE) after spontaneous intracerebral hemorrhage (sICH) is associated with clinical deterioration, but the etiology of PHE development is only partly understood. Aims: We aimed to investigate the association between systemic blood pressure (BP) variability (BPV) and formation of PHE. Methods: From a multicenter prospective observational study, we selected patients with sICH who underwent 3T brain MRI within 21 days after sICH, and had at least 5 BP measurements available in the first week after sICH. Primary outcome was the association between coefficient of variation (CV) of systolic BP (SBP) and edema extension distance (EED) using multivariable linear regression, adjusting for age, sex, ICH volume and timing of the MRI. In addition, we investigated the associations of mean SBP, mean arterial pressure (MAP), their CVs with EED and absolute and relative PHE volume. Results: We included 92 patients (mean age 64 years; 74% men; median ICH volume 16.8 mL (IQR 6.6-36.0), median PHE volume 22.5 mL (IQR 10.2-41.4). Median time between symptom onset and MRI was 6 days (IQR 4-11), median number of BP measurements was 25 (IQR 18-30). Log-transformed CV of SBP was not associated with EED (B = 0.050, 95%-CI -0.186 to 0.286, p = 0.673). Furthermore, we found no association between mean SBP, mean and CV of MAP and EED, nor between mean SBP, mean MAP or their CVs and absolute or relative PHE. Discussion: Our results do not support a contributing role for BPV on PHE, suggesting mechanisms other than hydrostatic pressure such as inflammatory processes, may play a more important role.

Cerebral small vessel disease and perihematomal edema formation in spontaneous intracerebral hemorrhage.

Objective: Blood-brain barrier (BBB) dysfunction is implicated in the pathophysiology of cerebral small vessel disease (cSVD)-related intracerebral hemorrhage (ICH). The formation of perihematomal edema (PHE) is presumed to reflect acute BBB permeability following ICH. We aimed to assess the association between cSVD burden and PHE formation in patients with spontaneous ICH. Methods: We selected patients with spontaneous ICH who underwent 3T MRI imaging within 21 days after symptom onset from a prospective observational multicenter cohort study. We rated markers of cSVD (white matter hyperintensities, enlarged perivascular spaces, lacunes and cerebral microbleeds) and calculated the composite score as a measure of the total cSVD burden. Perihematomal edema formation was measured using the edema extension distance (EED). We assessed the association between the cSVD burden and the EED using a multivariable linear regression model adjusting for age, (log-transformed) ICH volume, ICH location (lobar vs. non-lobar), and interval between symptom onset and MRI. Results: We included 85 patients (mean age 63.5 years, 75.3% male). Median interval between symptom onset and MRI imaging was 6 days (IQR 1-19). Median ICH volume was 17.0 mL (IQR 1.4-88.6), and mean EED was 0.54 cm (SD 0.17). We found no association between the total cSVD burden and EED (B = -0.003, 95% CI -0.003-0.03, p = 0.83), nor for any of the individual radiological cSVD markers. Conclusion: We found no association between the cSVD burden and PHE formation. This implies that mechanisms other than BBB dysfunction are involved in the pathophysiology of PHE.

Diffusion-Weighted Lesions After Intracerebral Hemorrhage: Associated MRI Findings.

The current study aimed to investigate whether diffusion-weighted imaging-positive (DWI+) lesions after acute intracerebral hemorrhage (ICH) are associated with underlying small vessel disease (SVD) or linked to the acute ICH. We included patients ≥18 years with spontaneous ICH confirmed on neuroimaging and performed 3T MRIs after a median of 11 days (interquartile range [IQR] 6-43). DWI+ lesions were assessed in relation to the hematoma (perihematomal vs. distant and ipsilateral vs. contralateral). Differences in clinical characteristics, ICH characteristics, and MRI markers of SVD between participants with or without DWI+ lesions were investigated using non-parametric tests. We observed 54 DWI+ lesions in 30 (22%) of the 138 patients (median age [IQR] 65 [55-73] years; 71% men, 59 lobar ICH) with available DWI images. We found DWI+ lesions ipsilateral (54%) and contralateral (46%) to the ICH, and 5 (9%) DWI+ lesions were located in the immediate perihematomal region. DWI+ lesion presence was associated with probable CAA diagnosis (38 vs. 15%, p = 0.01) and larger ICH volumes (37 [8-47] vs. 12 [6-24] ml, p = 0.01), but not with imaging features of SVD. Our findings suggest that DWI+ lesions after ICH are a feature of both the underlying SVD and ICH-related mechanisms.

Location-specific risk factors for intracerebral hemorrhage: Systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of studies reporting on risk factors according to location of the intracerebral hemorrhage. METHODS: We searched PubMed and Embase for cohort and case-control studies reporting ≥100 patients with spontaneous intracerebral hemorrhage that specified the location of the hematoma and reported associations with risk factors published until June 27, 2019. Two authors independently extracted data on risk factors. Estimates were pooled with the generic variance-based random-effects method. RESULTS: After screening 10,013 articles, we included 42 studies totaling 26,174 patients with intracerebral hemorrhage (9,141 lobar and 17,033 nonlobar). Risk factors for nonlobar intracerebral hemorrhage were hypertension (risk ratio [RR] 4.25, 95% confidence interval [CI] 3.05-5.91, I 2 = 92%), diabetes mellitus (RR 1.35, 95% CI 1.11-1.64, I 2 = 37%), male sex (RR 1.63, 95% CI 1.25-2.14, I 2 = 61%), alcohol overuse (RR 1.48, 95% CI 1.21-1.81, I 2 = 19%), underweight (RR 2.12, 95% CI 1.12-4.01, I 2 = 31%), and being a Black (RR 2.83, 95% CI 1.02-7.84, I 2 = 96%) or Hispanic (RR 2.95, 95% CI 1.69-5.14, I 2 = 71%) participant compared with being a White participant. Hypertension, but not any of the other risk factors, was also a risk factor for lobar intracerebral hemorrhage (RR 1.83, 95% CI 1.39-2.42, I 2 = 76%). Smoking, hypercholesterolemia, and obesity were associated with neither nonlobar nor lobar intracerebral hemorrhage. CONCLUSIONS: Hypertension is a risk factor for both nonlobar and lobar intracerebral hemorrhage, although with double the effect for nonlobar intracerebral hemorrhage. Diabetes mellitus, male sex, alcohol overuse, underweight, and being a Black or Hispanic person are risk factors for nonlobar intracerebral hemorrhage only. Hence, the term hypertensive intracerebral hemorrhage for nonlobar intracerebral hemorrhage is not appropriate.

Disturbed balance in the expression of MMP9 and TIMP3 in cerebral amyloid angiopathy-related intracerebral haemorrhage.

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of the amyloid ß (Aß) protein in the cerebral vasculature and poses a major risk factor for the development of intracerebral haemorrhages (ICH). However, only a minority of patients with CAA develops ICH (CAA-ICH), and to date it is unclear which mechanisms determine why some patients with CAA are more susceptible to haemorrhage than others. We hypothesized that an imbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) contributes to vessel wall weakening. MMP9 plays a role in the degradation of various components of the extracellular matrix as well as of Aß and increased MMP9 expression has been previously associated with CAA. TIMP3 is an inhibitor of MMP9 and increased TIMP3 expression in cerebral vessels has also been associated with CAA. In this study, we investigated the expression of MMP9 and TIMP3 in occipital brain tissue of CAA-ICH cases (n = 11) by immunohistochemistry and compared this to the expression in brain tissue of CAA cases without ICH (CAA-non-haemorrhagic, CAA-NH, n = 18). We showed that MMP9 expression is increased in CAA-ICH cases compared to CAA-NH cases. Furthermore, we showed that TIMP3 expression is increased in CAA cases compared to controls without CAA, and that TIMP3 expression is reduced in a subset of CAA-ICH cases compared to CAA-NH cases. In conclusion, in patients with CAA, a disbalance in cerebrovascular MMP9 and TIMP3 expression is associated with CAA-related ICH.

Risk Factors for Lobar and Non-Lobar Intracerebral Hemorrhage in Patients with Vascular Disease.

INTRODUCTION: Lobar and non-lobar non-traumatic intracerebral hemorrhage (ICH) are presumably caused by different types of small vessel diseases. The aim of this study was to assess risk factors for ICH according to location. METHODS: In two large prospective studies, SMART (n = 9088) and ESPRIT (n = 2625), including patients with manifest cardiovascular, cerebrovascular or peripheral artery disease or with vascular risk factors, we investigated potential risk factors for ICH during follow-up according to lobar or non-lobar location by Cox proportional hazards analyses. RESULTS: During 65,156 patient years of follow up 19 patients had lobar ICH (incidence rate 29, 95% CI 19-42 per 100,000 person-years) and 24 non-lobar ICH (incidence rate 37, 95% CI 26-51 per 100,000 person-years). Age significantly increased the risk of lobar ICH (HR per 10 years increase 1.90; 95% CI 1.17-3.10) in the multivariable analysis, but not of non-lobar hemorrhage. Anticoagulant medication (HR 3.49; 95% CI 1.20-10.2) and male sex (HR 3.79; 95% CI 1.13-12.8) increased the risk of non-lobar but not lobar ICH. CONCLUSION: This study shows an elevated risk of future ICH in patients with manifestations of, or risk factors for, cardiovascular, cerebrovascular or peripheral artery disease. Our data suggest that risk factors for ICH vary according to location, supporting the hypothesis of a differential pathophysiology of lobar and non-lobar ICH.

Time trends in incidence, case fatality, and mortality of intracerebral hemorrhage.

OBJECTIVE: To assess age- and sex-specific trends in incidence and 30-day and 1-year case fatality of intracerebral hemorrhage (ICH) in the Netherlands. METHODS: Patients hospitalized for first ICH were identified through linkage of the national hospital discharge register and population register using ICD-9 code 431. We identified out-of-hospital deaths in the national cause of death register. Incidence, 30-day and 1-year case fatality, and total mortality rate were calculated by age and sex. We identified time trends by joinpoint regression analysis and Mann-Kendall tests. RESULTS: We identified 41,068 cases of ICH (51% men) between 1998 and 2010, of which 6% were out-of-hospital deaths. ICH incidence declined in men and women younger than 75 years (p ≤ 0.01, not significantly in men 35-54 years) but remained stable in patients 75 years and older. Thirty-day and 1-year case fatality declined in patients younger than 75 years (not significantly in women 35-54 years). In patients aged 35 to 54 years, ICH mortality remained stable until 2003 and then declined slightly (annual percentage change [APC] men: -7.09%; 95% confidence interval [CI] -11.39 to -2.59; women: -8.67%; 95% CI -15.18 to -1.66). In patients 55 to 74 years, mortality declined in men between 1995 and 2010 (APC -4.55%; 95% CI -5.49 to -3.59) and in women between 1992 and 2010 (APC -3.51%; 95% CI -4.16 to -2.85). Mortality did not decline in patients aged 75 years and older. CONCLUSION: In the Netherlands, ICH incidence, case fatality, and mortality rates have declined significantly in men and women younger than 75 years but remained stable in patients 75 years and older. The observed time trends may be explained by better prevention and treatment during the previous 2 decades of which the elderly do not seem to benefit.

Cortical microinfarcts on 7T MRI in patients with spontaneous intracerebral hemorrhage.

In patients with spontaneous intracerebral hemorrhage (ICH) coexisting abnormalities on brain imaging can provide clues on the etiology of the underlying small vessel disease. We examined cortical cerebral microinfarcts as a novel marker of coexistent vascular damage in ICH. Twelve patients with spontaneous ICH and 15 controls underwent 7Tesla magnetic resonance imaging (MRI). Microinfarcts were present in 9 of 12 patients with spontaneous ICH, and in 5 of 15 controls. This explorative study shows, for the first time, that microinfarcts appear to be a very common vascular comorbidity in spontaneous ICH. Future larger studies should further assess the etiological significance of these lesions.