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.

Profiling amyloid-ß peptides as biomarkers for cerebral amyloid angiopathy.

Brain amyloid-ß (Aß) deposits are key pathological hallmarks of both cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). Microvascular deposits in CAA mainly consist of the Aß40 peptide, whereas Aß42 is the predominant variant in parenchymal plaques in AD. The relevance in pathogenesis and diagnostic accuracy of various other Aß isoforms in CAA remain understudied. We aimed to investigate the biomarker potential of various Aß isoforms in cerebrospinal fluid (CSF) to differentiate CAA from AD pathology. We included 25 patients with probable CAA, 50 subjects with a CSF profile indicative of AD pathology (AD-like), and 23 age- and sex-matched controls. CSF levels of Aß1-34 , Aß1-37 , Aß1-38 , Aß1-39 , Aß1-40 , and Aß1-42 were quantified by liquid chromatography mass spectrometry. Lower CSF levels of all six Aß peptides were observed in CAA patients compared with controls (p = 0.0005-0.03). Except for Aß1-42 (p = 1.0), all peptides were decreased in CAA compared with AD-like subjects (p = 0.007-0.03). Besides Aß1-42 , none of the Aß peptides were decreased in AD-like subjects compared with controls. All Aß peptides combined differentiated CAA from AD-like subjects better (area under the curve [AUC] 0.84) than individual peptide levels (AUC 0.51-0.75). Without Aß1-42 in the model (since decreased Aß1-42 served as AD-like selection criterion), the AUC was 0.78 for distinguishing CAA from AD-like subjects. CAA patients and AD-like subjects showed distinct disease-specific CSF Aß profiles. Peptides shorter than Aß1-42 were decreased in CAA patients, but not AD-like subjects, which could suggest different pathological mechanisms between vascular and parenchymal Aß accumulation. This study supports the potential use of this panel of CSF Aß peptides to indicate presence of CAA pathology with high accuracy.

A Randomized Trial of Intravenous Alteplase before Endovascular Treatment for Stroke.

BACKGROUND: The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations. METHODS: We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points. RESULTS: The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P = 0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81). CONCLUSIONS: In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by the Collaboration for New Treatments of Acute Stroke consortium and others; MR CLEAN-NO IV ISRCTN number, ISRCTN80619088.).

Decreased Cerebrospinal Fluid Amyloid ß 38, 40, 42, and 43 Levels in Sporadic and Hereditary Cerebral Amyloid Angiopathy.

OBJECTIVE: Vascular amyloid ß (Aß) accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as a diagnostic biomarker of CAA. We studied the diagnostic potential of the peptides Aß38, Aß40, Aß42, and Aß43 in patients with sporadic CAA (sCAA), hereditary Dutch-type CAA (D-CAA), and Alzheimer disease (AD). METHODS: Aß peptides were quantified by immunoassays in a discovery group (26 patients with sCAA and 40 controls), a validation group (40 patients with sCAA, 40 patients with AD, and 37 controls), and a group of 22 patients with D-CAA and 54 controls. To determine the diagnostic accuracy, the area under the curve (AUC) was calculated using a receiver operating characteristic curve with 95% confidence interval (CI). RESULTS: We found decreased levels of all Aß peptides in sCAA patients and D-CAA patients compared to controls. The difference was most prominent for Aß42 (AUC of sCAA vs controls for discovery: 0.90, 95% CI = 0.82-0.99; for validation: 0.94, 95% CI = 0.89-0.99) and Aß43 (AUC of sCAA vs controls for discovery: 0.95, 95% CI = 0.88-1.00; for validation: 0.91, 95% CI = 0.83-1.0). All Aß peptides except Aß43 were also decreased in sCAA compared to AD (CSF Aß38: AUC = 0.82, 95% CI = 0.71-0.93; CSF Aß40: AUC = 0.88, 95% CI = 0.80-0.96; CSF Aß42: AUC = 0.79, 95% CI = 0.66-0.92). INTERPRETATION: A combined biomarker panel of CSF Aß38, Aß40, Aß42, and Aß43 has potential to differentiate sCAA from AD and controls, and D-CAA from controls. ANN NEUROL 2023;93:1173-1186.

Iatrogenic Cerebral Amyloid Angiopathy Post Neurosurgery: Frequency, Clinical Profile, Radiological Features, and Outcome.

BACKGROUND: Prion-like transmission of amyloid-ß through cadaveric dura, decades after neurosurgical procedures, has been hypothesized as an iatrogenic cause of cerebral amyloid angiopathy (CAA). We investigated new and previously described patients to assess the clinical profile, radiological features, and outcome of this presumed iatrogenic CAA-subtype (iCAA). METHODS: Patients were collected from our prospective lobar hemorrhage and CAA database (n=251) with patients presenting to our hospital between 2008 and 2022. In addition, we identified patients with iCAA from 2 other Dutch CAA-expertise hospitals and performed a systematic literature-search for previously described patients. We classified patients according to the previously proposed diagnostic criteria for iCAA, assessed clinical and radiological disease features, and calculated intracerebral hemorrhage (ICH)-recurrence rates. We evaluated the spatial colocalization of cadaveric dura placement and CAA-associated magnetic resonance imaging markers. RESULTS: We included 49 patients (74% men, mean age 43 years [range, 27-84]); 15 from our database (6% [95% CI, 3%-10%]; 45% of patients <55 years), 3 from the 2 other CAA-expertise hospitals, and 31 from the literature. We classified 43% (n=21; 1 newly identified patient) as probable and 57% (n=28) as possible iCAA. Patients presented with lobar ICH (57%), transient focal neurological episodes (12%), or seizures (8%). ICH-recurrence rate in the new patients (16/100 person-years [95% CI, 7-32], median follow-up 18 months) was lower than in the previously described patients (77/100 person-years [95% CI, 59-99], median follow-up 18 months). One patient had a 10 year interlude without ICH-recurrence. We identified no clear spatial relationship between dura placement and CAA-associated magnetic resonance imaging markers. During follow-up (median, 18 months), 20% of the patients developed transient focal neurological episodes and 20% cognitively declined. CONCLUSIONS: iCAA seems common in patients presenting with nonhereditary CAA under the age of 55. Clinical and radiological features are comparable with sCAA. After diagnosis, multiple ICH-recurrences but also long symptom-free intervals can occur. Harmonized registries are necessary to identify and understand this potentially underrecognized CAA-subtype.

The association between antiplatelet therapy and changes in intraplaque hemorrhage in patients with mild to moderate symptomatic carotid stenosis: a longitudinal MRI study.

INTRODUCTION: Carotid atherosclerotic intraplaque hemorrhage (IPH) predicts stroke. Patients with a history of stroke are treated with antiplatelet agents to prevent secondary cardiovascular events. A positive association between previous antiplatelet use and IPH was reported in a cross-sectional analysis. We investigated changes in IPH over two years in patients who recently started versus those with continued antiplatelet use. METHODS: In the Plaque at Risk (PARISK) study, symptomatic patients with <70% ipsilateral carotid stenosis underwent carotid plaque MRI at baseline and after two years to determine IPH presence and volume. Participants were categorized into new users (starting antiplatelet therapy following the index event) and continued users (previous use of antiplatelet therapy before the index event). The association between previous antiplatelet therapy and the presence of IPH at baseline MRI was investigated using multivariable logistic regression analysis. IPH volume change over a period of two years, defined as the difference in volume between follow-up and baseline, was investigated in each group with a Wilcoxon signed-rank test. The IPH volume change was categorized as progression, regression, or no change. Using multivariable logistic regression, we investigated the association between new antiplatelet use and 1) newly developed ipsilateral or contralateral IPH and 2) IPH volume progression. RESULTS: A total of 108 patients underwent carotid MRI at baseline and follow-up. At baseline, previous antiplatelet therapy was associated with any IPH (OR=5.6, 95% CI: 1.3-23.1; p=0.02). Ipsilateral IPH volume did not change significantly during the two years in patients who continued receiving antiplatelet agents (86.4 mm3 [18.2-235.9] vs. 59.3 mm3 [11.4-260.3]; p=0.6) nor in the new antiplatelet users (n=31) (61.5 mm3 [0.0-166.9] vs. 27.7 mm3 [9.5-106.4]; p=0.4). Similar results of a nonsignificant change in contralateral IPH volume during those two years were observed in both groups (p>0.05). No significant associations were found between new antiplatelet use and newly developed IPH at two years (odds ratio (OR)=1.0, 95% CI:0.1-7.4) or the progression of IPH (ipsilateral: OR=2.4, 95% CI:0.3-19.1; contralateral: OR=0.3, 95% CI:0.01-8.5). CONCLUSION: Although the baseline association between IPH and previous antiplatelet therapy was confirmed in this larger cohort, the new onset of antiplatelet therapy after TIA/stroke was not associated with newly developed IPH or progression of IPH volume over the subsequent two years.

Safety and technical efficacy of early minimally invasive endoscopy-guided surgery for intracerebral haemorrhage: the Dutch Intracerebral haemorrhage Surgery Trial pilot study.

BACKGROUND: Previous randomised controlled trials could not demonstrate that surgical evacuation of intracerebral haemorrhage (ICH) improves functional outcome. Increasing evidence suggests that minimally invasive surgery may be beneficial, in particular when performed early after symptom onset. The aim of this study was to investigate safety and technical efficacy of early minimally invasive endoscopy-guided surgery in patients with spontaneous supratentorial ICH. METHODS: The Dutch Intracerebral Haemorrhage Surgery Trial pilot study was a prospective intervention study with blinded outcome assessment in three neurosurgical centres in the Netherlands. We included adult patients with spontaneous supratentorial ICH ≥10mL and National Institute of Health Stroke Scale (NIHSS) score ≥2 for minimally invasive endoscopy-guided surgery within 8 h after symptom onset in addition to medical management. Primary safety outcome was death or increase in NIHSS ≥4 points at 24 h. Secondary safety outcomes were procedure-related serious adverse events (SAEs) within 7 days and death within 30 days. Primary technical efficacy outcome was ICH volume reduction (%) at 24 h. RESULTS: We included 40 patients (median age 61 years; IQR 51-67; 28 men). Median baseline NIHSS was 19.5 (IQR 13.3-22.0) and median ICH volume 47.7mL (IQR 29.4-72.0). Six patients had a primary safety outcome, of whom two already deteriorated before surgery and one died within 24 h. Sixteen other SAEs were reported within 7 days in 11 patients (of whom two patients that already had a primary safety outcome), none device related. In total, four (10%) patients died within 30 days. Median ICH volume reduction at 24 h was 78% (IQR 50-89) and median postoperative ICH volume 10.5mL (IQR 5.1-23.8). CONCLUSIONS: Minimally invasive endoscopy-guided surgery within 8 h after symptom onset for supratentorial ICH appears to be safe and can effectively reduce ICH volume. Randomised controlled trials are needed to determine whether this intervention also improves functional outcome. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03608423, August 1st, 2018.

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.

Elevated expression of urokinase plasminogen activator in rodent models and patients with cerebral amyloid angiopathy.

AIMS: The aim of this work is to study the association of urokinase plasminogen activator (uPA) with development and progression of cerebral amyloid angiopathy (CAA). MATERIALS AND METHODS: We studied the expression of uPA mRNA by quantitative polymerase chain reaction (qPCR) and co-localisation of uPA with amyloid-ß (Aß) using immunohistochemistry in the cerebral vasculature of rTg-DI rats compared with wild-type (WT) rats and in a sporadic CAA (sCAA) patient and control subject using immunohistochemistry. Cerebrospinal fluid (CSF) uPA levels were measured in rTg-DI and WT rats and in two separate cohorts of sCAA and Dutch-type hereditary CAA (D-CAA) patients and controls, using enzyme-linked immunosorbent assays (ELISA). RESULTS: The presence of uPA was clearly detected in the cerebral vasculature of rTg-DI rats and an sCAA patient but not in WT rats or a non-CAA human control. uPA expression was highly co-localised with microvascular Aß deposits. In rTg-DI rats, uPA mRNA expression was highly elevated at 3 months of age (coinciding with the emergence of microvascular Aß deposition) and sustained up to 12 months of age (with severe microvascular CAA deposition) compared with WT rats. CSF uPA levels were elevated in rTg-DI rats compared with WT rats (p = 0.03), and in sCAA patients compared with controls (after adjustment for age of subjects, p = 0.05 and p = 0.03). No differences in CSF uPA levels were found between asymptomatic and symptomatic D-CAA patients and their respective controls (after age-adjustment, p = 0.09 and p = 0.44). Increased cerebrovascular expression of uPA in CAA correlates with increased quantities of CSF uPA in rTg-DI rats and human CAA patients, suggesting that uPA could serve as a biomarker for CAA.

Prevalence of cerebral amyloid angiopathy: A systematic review and meta-analysis.

Reported prevalence estimates of sporadic cerebral amyloid angiopathy (CAA) vary widely. CAA is associated with cognitive dysfunction and intracerebral hemorrhage, and linked to immunotherapy-related side-effects in Alzheimer's disease (AD). Given ongoing efforts to develop AD immunotherapy, accurate estimates of CAA prevalence are important. CAA can be diagnosed neuropathologically or during life using MRI markers including strictly lobar microbleeds. In this meta-analysis of 170 studies including over 73,000 subjects, we show that in patients with AD, CAA prevalence based on pathology (48%) is twice that based on presence of strictly lobar cerebral microbleeds (22%); in the general population this difference is three-fold (23% vs 7%). Both methods yield similar estimated prevalences of CAA in cognitively normal elderly (5% to 7%), in patients with intracerebral hemorrhage (19% to 24%), and in patients with lobar intracerebral hemorrhage (50% to 57%). However, we observed large heterogeneity among neuropathology and MRI protocols, which calls for standardized assessment and reporting of CAA.

Normal cerebrospinal fluid concentrations of PDGFRß in patients with cerebral amyloid angiopathy and Alzheimer's disease.

BACKGROUND: Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-ß (PDGFRß) has been proposed as a biomarker of blood-brain barrier (BBB) breakdown. We studied PDGFRß levels as a biomarker for cerebral amyloid angiopathy (CAA), amnestic mild cognitive impairment (aMCI), or Alzheimer's disease (AD). METHODS: CSF PDGFRß levels were quantified by enzyme-linked immunosorbent assay in patients with CAA, patients with aMCI/AD, and in matched controls. In aMCI/AD we evaluated CSF PDGFRß both by clinical phenotype and by using the AT(N) biomarker classification system defined by CSF amyloid (A), tau (T), and neurodegeneration (N) biomarkers. RESULTS: PDGFRß levels were similar in CAA patients and controls (P = .78) and in aMCI/AD clinical phenotype and controls (P = .91). aMCI/AD patients with an AD+ biomarker profile (A+T+[N+]) had increased PDGFRß levels compared to (A-T-[N-]) controls (P = .006). CONCLUSION: Our findings indicate that PDGFRß levels are associated with an AD+ biomarker profile but are not a suitable biomarker for CAA or aMCI/AD clinical syndrome.

Computed Tomography Angiography Spot Sign, Hematoma Expansion, and Functional Outcome in Spontaneous Cerebellar Intracerebral Hemorrhage.

Background and Purpose: The computed tomography angiography spot sign is associated with hematoma expansion, case fatality, and poor functional outcome in spontaneous supratentorial intracerebral hemorrhage (ICH). However, no data are available on the spot sign in spontaneous cerebellar ICH. Methods: We investigated consecutive patients with spontaneous cerebellar ICH at 3 academic hospitals between 2002 and 2017. We determined patient characteristics, hematoma expansion (>33% or 6 mL), rate of expansion, discharge and 90-day case fatality, and functional outcome. Poor functional outcome was defined as a modified Rankin Scale score of 4 to 6. Associations were tested using univariable and multivariable logistic regression. Results: Three hundred fifty-eight patients presented with cerebellar ICH, of whom 181 (51%) underwent a computed tomography angiography. Of these 181 patients, 121 (67%) were treated conservatively of which 15 (12%) had a spot sign. Patients with a spot sign treated conservatively presented with larger hematoma volumes (median [interquartile range]: 26 [7­41] versus 6 [2­13], P=0.001) and higher speed of expansion (median [interquartile range]: 15 [24­3] mL/h versus 1 [5­0] mL/h, P=0.034). In multivariable analysis, presence of the spot sign was independently associated with death at 90 days (odds ratio, 7.6 [95% CI, 1.6­88], P=0.037). With respect to surgically treated patients (n=60, [33%]), 14 (23%) patients who underwent hematoma evacuation had a spot sign. In these 60 patients, patients with a spot sign were older (73.5 [9.2] versus 66.6 [15.4], P=0.047) and more likely to be female (71% versus 37%, P=0.033). In a multivariable analysis, the spot sign was independently associated with death at 90 days (odds ratio, 2.1 [95% CI, 1.1­4.3], P=0.033). Conclusions: In patients with spontaneous cerebellar ICH treated conservatively, the spot sign is associated with speed of hematoma expansion, case fatality, and poor functional outcome. In surgically treated patients, the spot sign is associated with 90-day case fatality.

Neurosurgical Intervention for Supratentorial Intracerebral Hemorrhage.

OBJECTIVE: The effect of surgical treatment for supratentorial spontaneous intracerebral hemorrhage (ICH) and whether it is modified by key baseline characteristics and timing remains uncertain. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials of surgical treatment of supratentorial spontaneous ICH aimed at clot removal. We searched MEDLINE, Embase, and Cochrane databases up to February 21, 2019. Primary outcome was good functional outcome at follow-up; secondary outcomes were death and serious adverse events. We analyzed all types of surgery combined and minimally invasive approaches separately. We pooled risk ratios with 95% confidence intervals and assessed the modifying effect of age, Glasgow Coma Scale, hematoma volume, and timing of surgery with meta-regression analysis. RESULTS: We included 21 studies with 4,145 patients; 4 (19%) were of the highest quality. Risk ratio of good functional outcome after any type of surgery was 1.40 (95% confidence interval [CI] = 1.22-1.60, I2 = 46%, 20 studies), and after minimally invasive surgery it was 1.47 (95% CI = 1.26-1.72, I2 = 47%, 12 studies). For death, the risk ratio for any type of surgery was 0.77 (95% CI = 0.68-0.85, I2 = 23%, 21 studies), and for minimally invasive surgery it was 0.68 (95% CI = 0.56-0.83, I2 = 14%, 13 studies). Serious adverse events were reported infrequently. Surgery seemed more effective when performed sooner after symptom onset (p = 0.04, 12 studies). Age, Glasgow Coma Scale, and hematoma volume did not modify the effect of surgery. INTERPRETATION: Surgical treatment of supratentorial spontaneous ICH may be beneficial, in particular with minimally invasive procedures and when performed soon after symptom onset. Further well-designed randomized trials are needed to demonstrate whether (minimally invasive) surgery improves functional outcome after ICH and to determine the optimal time window of the treatment after symptom onset. ANN NEUROL 2020;88:239-250.

Secondary Hematoma Evacuation and Outcome After Initial Conservative Approach for Patients with Cerebellar Hematoma Larger than 3 cm.

BACKGROUND: In patients with spontaneous cerebellar intracerebral hemorrhage (ICH) guidelines advocate evacuation when the hematoma diameter is > 3 cm. We studied outcome in patients with cerebellar ICH > 3 cm who did not undergo immediate hematoma evacuation. METHODS: We included consecutive patients with cerebellar ICH > 3 cm at two academic hospitals between 2008 and 2017. Patients who died < 24 h (h) were excluded because of probable confounding by indication. We determined patient characteristics, hematoma volumes, EVD placement, secondary hematoma evacuation, in-hospital and 3-month case-fatality, and functional outcome. RESULTS: Of 130 patients with cerebellar ICH, 98 (77%) had a hematoma > 3 cm of whom 22 (23%) died < 24 h and 28 (29%) underwent hematoma evacuation < 24 h. Thus, 48 patients were initially treated conservatively (mean age 70 ± 13, 24 (50%) female). Of these 48 patients, 7 (15%) underwent secondary hematoma evacuation > 24 h, of whom 1 (14%) had received an EVD < 24 h. Five others also received an EVD < 24 h without subsequent hematoma evacuation. Of the 41 patients without secondary hematoma evacuation, 11 (28%) died and 20 (51%) had a favorable outcome (mRS of 0-3) at 3 months. The 7 patients who underwent secondary hematoma evacuation had a decrease in GCS score of at least two points prior to surgery; two (29%) had deceased at 3 months; and 5 (71%) had a good functional outcome (mRS 0-3). CONCLUSIONS: While cerebellar ICH > 3 cm is often considered an indication for immediate hematoma evacuation, there may be a subgroup of patients in whom surgery can be safely deferred. Further data are needed to assess the optimal timing and indications of surgical treatment in these patients.

Contribution of acute infarcts to cerebral small vessel disease progression.

OBJECTIVE: To determine the contribution of acute infarcts, evidenced by diffusion-weighted imaging positive (DWI+) lesions, to progression of white matter hyperintensities (WMH) and other cerebral small vessel disease (SVD) markers. METHODS: We performed monthly 3T magnetic resonance imaging (MRI) for 10 consecutive months in 54 elderly individuals with SVD. MRI included high-resolution multishell DWI, and 3-dimensional fluid-attenuated inversion recovery, T1, and susceptibility-weighted imaging. We determined DWI+ lesion evolution, WMH progression rate (ml/mo), and number of incident lacunes and microbleeds, and calculated for each marker the proportion of progression explained by DWI+ lesions. RESULTS: We identified 39 DWI+ lesions on 21 of 472 DWI scans in 9 of 54 subjects. Of the 36 DWI+ lesions with follow-up MRI, 2 evolved into WMH, 4 evolved into a lacune (3 with cavity <3mm), 3 evolved into a microbleed, and 27 were not detectable on follow-up. WMH volume increased at a median rate of 0.027 ml/mo (interquartile range = 0.005-0.073), but was not significantly higher in subjects with DWI+ lesions compared to those without (p = 0.195). Of the 2 DWI+ lesions evolving into WMH on follow-up, one explained 23% of the total WMH volume increase in one subject, whereas the WMH regressed in the other subject. DWI+ lesions preceded 4 of 5 incident lacunes and 3 of 10 incident microbleeds. INTERPRETATION: DWI+ lesions explain only a small proportion of the total WMH progression. Hence, WMH progression seems to be mostly driven by factors other than acute infarcts. DWI+ lesions explain the majority of incident lacunes and small cavities, and almost one-third of incident microbleeds, confirming that WMH, lacunes, and microbleeds, although heterogeneous on MRI, can have a common initial appearance on MRI. ANN NEUROL 2019;86:582-592.

Neuroimaging and clinical outcomes of oral anticoagulant-associated intracerebral hemorrhage.

OBJECTIVE: Whether intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOAC-ICH) has a better outcome compared to ICH associated with vitamin K antagonists (VKA-ICH) is uncertain. METHODS: We performed a systematic review and individual patient data meta-analysis of cohort studies comparing clinical and radiological outcomes between NOAC-ICH and VKA-ICH patients. The primary outcome measure was 30-day all-cause mortality. All outcomes were assessed in multivariate regression analyses adjusted for age, sex, ICH location, and intraventricular hemorrhage extension. RESULTS: We included 7 eligible studies comprising 219 NOAC-ICH and 831 VKA-ICH patients (mean age = 77 years, 52.5% females). The 30-day mortality was similar between NOAC-ICH and VKA-ICH (24.3% vs 26.5%; hazard ratio = 0.94, 95% confidence interval [CI] = 0.67-1.31). However, in multivariate analyses adjusting for potential confounders, NOAC-ICH was associated with lower admission National Institutes of Health Stroke Scale (NIHSS) score (linear regression coefficient = -2.83, 95% CI = -5.28 to -0.38), lower likelihood of severe stroke (NIHSS > 10 points) on admission (odds ratio [OR] = 0.50, 95% CI = 0.30-0.84), and smaller baseline hematoma volume (linear regression coefficient = -0.24, 95% CI = -0.47 to -0.16). The two groups did not differ in the likelihood of baseline hematoma volume < 30cm3 (OR = 1.14, 95% CI = 0.81-1.62), hematoma expansion (OR = 0.97, 95% CI = 0.63-1.48), in-hospital mortality (OR = 0.73, 95% CI = 0.49-1.11), functional status at discharge (common OR = 0.78, 95% CI = 0.57-1.07), or functional status at 3 months (common OR = 1.03, 95% CI = 0.75-1.43). INTERPRETATION: Although functional outcome at discharge, 1 month, or 3 months was comparable after NOAC-ICH and VKA-ICH, patients with NOAC-ICH had smaller baseline hematoma volumes and less severe acute stroke syndromes. Ann Neurol 2018;84:702-712.

Microvasculature and intraplaque hemorrhage in atherosclerotic carotid lesions: a cardiovascular magnetic resonance imaging study.

BACKGROUND: The presence of intraplaque haemorrhage (IPH) has been related to plaque rupture, is associated with plaque progression, and predicts cerebrovascular events. However, the mechanisms leading to IPH are not fully understood. The dominant view is that IPH is caused by leakage of erythrocytes from immature microvessels. The aim of the present study was to investigate whether there is an association between atherosclerotic plaque microvasculature and presence of IPH in a relatively large prospective cohort study of patients with symptomatic carotid plaque. METHODS: One hundred and thirty-two symptomatic patients with ≥2 mm carotid plaque underwent cardiovascular magnetic resonance (CMR) of the symptomatic carotid plaque for detection of IPH and dynamic contrast-enhanced (DCE)-CMR for assessment of plaque microvasculature. Ktrans, an indicator of microvascular flow, density and leakiness, was estimated using pharmacokinetic modelling in the vessel wall and adventitia. Statistical analysis was performed using an independent samples T-test and binary logistic regression, correcting for clinical risk factors. RESULTS: A decreased vessel wall Ktrans was found for IPH positive patients (0.051 ± 0.011 min- 1 versus 0.058 ± 0.017 min- 1, p = 0.001). No significant difference in adventitial Ktrans was found in patients with and without IPH (0.057 ± 0.012 min- 1 and 0.057 ± 0.018 min- 1, respectively). Histological analysis in a subgroup of patients that underwent carotid endarterectomy demonstrated no significant difference in relative microvessel density between plaques without IPH (n = 8) and plaques with IPH (n = 15) (0.000333 ± 0.0000707 vs. and 0.000289 ± 0.0000439, p = 0.585). CONCLUSIONS: A reduced vessel wall Ktrans is found in the presence of IPH. Thus, we did not find a positive association between plaque microvasculature and IPH several weeks after a cerebrovascular event. Not only leaky plaque microvessels, but additional factors may contribute to IPH development. TRIAL REGISTRATION: NCT01208025 . Registration date September 23, 2010. Retrospectively registered (first inclusion September 21, 2010). NCT01709045 , date of registration October 17, 2012. Retrospectively registered (first inclusion August 23, 2011).