Fatal Intracerebral Hemorrhage Research Articles

Association of aspirin use with risk of intracerebral hemorrhage in patients without history of stroke or transient ischemic attack in the UK Biobank.

The association between aspirin use and the risk of intracerebral hemorrhage (ICH) among individuals without previous stroke events is inconclusive. We investigated the association between regular aspirin use and ICH risk in middle-aged and older adults without previous stroke or transient ischemic attack (TIA). This prospective population-based study included participants older than 40 years with no history of stroke or TIA from the UK Biobank. The main exposure was regular aspirin use. Cox regression analyses and propensity score matching analyses estimated the hazard ratios (HRs) for aspirin use for incident fatal and non-fatal ICH. We conducted pre-specified subgroup analyses for selecting individuals at high risk of ICH when using aspirin. Multiple sensitivity analyses were performed to test the robustness of our results. A total of 449,325 participants were included into final analyses (median (IQR) age 58 (50-63) years, 54.6% females), of whom 58,045 reported aspirin use. During a median follow-up of 12.75 (IQR: 12.03-13.47) years, 1557 (0.3%) incident ICH cases were identified, of which 399 (25.6%) were fatal. Aspirin was not associated with increased risk of overall (hazard ratio (HR): 1.11, 95% confidence interval (CI): 0.95-1.27, P = 0.188), fatal (HR: 1.03, 95% CI: 0.78-1.36, P = 0.846) and non-fatal (HR: 1.12, 95% CI: 0.95-1.33, P = 0.186) ICH. Propensity score matching analysis showed similar results. Subgroup analysis indicated that aspirin use in individuals older than 65 years or with concurrent anticoagulant use was correlated with increased risk of ICH. In this large cohort study of middle-aged and older adults without stroke or TIA events, there was no significant association between aspirin use and ICH risk in the real-world setting. However, it is possible that aspirin use in those aged over 65 years and concurrent anticoagulant treatment may increase the risk of ICH.

Danazol for the Treatment of Myelodysplastic Syndromes: A Systematic Review

Purpose To study the potential utility of danazol for treating patients with myelodysplastic syndromes, with a focus on efficacy and adverse effects (AEs). Methods MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus were searched for relevant publications from inception June 1, 1950, until June 28, 2022. The studies were screened by title and abstract, followed by full-text screening. The quality of the included studies was assessed via a prespecified set of questionnaires. Data on the efficacy measures and adverse outcomes were extracted and included in a descriptive summary. Results Nine studies consisting of 246 participants were included in our review. The overall quality of the included studies was fair. The age of the participants ranged from 61 to 78 years. In all 9 studies, more male patients had been enrolled than female patients. Overall, a proportion of patients in all the studies reported a desired major response to a danazol dose of 400 to 800 mg/day. Few studies did not observe any improvement in the platelet count. Elevated liver enzyme levels, weight gain, headache, dermatitis, and weakness were the most common AEs observed. One study reported a fatal intracerebral hemorrhage in 1 participant. Conclusions Danazol has been effective in increasing platelet count and hemoglobin level. Despite a few AEs, danazol is a safe drug for the treatment of patients with myelodysplastic syndromes.

Chronic Hepatitis B Virus Infection and Risk of Stroke Types: A Prospective Cohort Study of 500 000 Chinese Adults.

Stroke is a leading cause of mortality and permanent disability in China, with large and unexplained geographic variations in rates of different stroke types. Chronic hepatitis B virus infection is prevalent among Chinese adults and may play a role in stroke cause. The prospective China Kadoorie Biobank included >500 000 adults aged 30 to 79 years who were recruited from 10 (5 urban and 5 rural) geographically diverse areas of China from 2004 to 2008, with determination of hepatitis B surface antigen (HBsAg) positivity at baseline. During 11 years of follow-up, a total of 59 117 incident stroke cases occurred, including 11 318 intracerebral hemorrhage (ICH), 49 971 ischemic stroke, 995 subarachnoid hemorrhage, and 3036 other/unspecified stroke. Cox regression models were used to estimate adjusted hazard ratios (HRs) for risk of stroke types associated with HBsAg positivity. In a subset of 17 833 participants, liver enzymes and lipids levels were measured and compared by HBsAg status. Overall, 3.0% of participants were positive for HBsAg. HBsAg positivity was associated with an increased risk of ICH (adjusted HR, 1.29 [95% CI, 1.16-1.44]), similarly for fatal (n=5982; adjusted HR, 1.36 [95% CI, 1.16-1.59]) and nonfatal (n=5336; adjusted HR, 1.23 [95% CI, 1.06-1.44]) ICH. There were no significant associations of HBsAg positivity with risks of ischemic stroke (adjusted HR, 0.97 [95% CI, 0.92-1.03]), subarachnoid hemorrhage (adjusted HR, 0.87 [95% CI, 0.57-1.33]), or other/unspecified stroke (adjusted HR, 1.12 [95% CI, 0.89-1.42]). Compared with HBsAg-negative counterparts, HBsAg-positive individuals had lower lipid and albumin levels and higher liver enzyme levels. After adjustment for liver enzymes and albumin, the association with ICH from HBsAg positivity attenuated to 1.15 (0.90-1.48), suggesting possible mediation by abnormal liver function. Among Chinese adults, chronic hepatitis B virus infection is associated with an increased risk of ICH but not other stroke types, which may be mediated through liver dysfunction and altered lipid metabolism.

Cerebral amyloid angiopathy: clinical presentations and management challenges in the Australian context.

Cerebral amyloid angiopathy (CAA) is a disease with several clinical manifestations. It is characterised by amyloid-beta deposition in cerebral blood vessels, making them prone to bleeding. The incidence of CAA increases with age and may be associated or co-exist with intraparenchymal neurodegenerative proteinopathies, which makes it an increasingly relevant condition for adult physicians in all areas of medical practice. The vast majority of cases of CAA are sporadic with a small minority of familial cases. CAA is asymptomatic in many older adults but increases the risk of fatal intracerebral or subarachnoid haemorrhage. We review the existing literature on CAA and summarise the key findings. We specifically explore clinical challenges relevant to CAA, particularly in diagnosis, management of intracranial haemorrhage and management of concurrent medical conditions.

Fatal thrombolysis-related intracerebral haemorrhage associated with amyloid-β-related angiitis in a middle-aged patient – case report and literature review

BackgroundAmyloid-β-related angiitis (ABRA) is a rare complication of cerebral amyloid angiopathy, characterized by amyloid-β deposition in the leptomeningeal and cortical vessels with associated angiodestructive granulomatous inflammation. The clinical presentation is variable, including subacute cognitive decline, behavioural changes, headaches, seizures and focal neurological deficits, which may mimic other conditions. Here, we present a case with fatal thrombolysis-related haemorrhage associated with ABRA in a middle-aged patient.Case presentationA 55-year-old man was admitted to hospital with sudden onset left-sided cheek, arm and hand sensory loss, blurred vision, and worsening headache, with a National Institutes of Health Stroke Scale (NIHSS) score of 3. An acute CT head scan showed no contraindications, and therefore the decision was made to give intravenous thrombolysis. Post-thrombolysis, he showed rapid deterioration with visual disturbances, headache and confusion, and a repeat CT head scan confirmed several areas of intracerebral haemorrhage. No benefit from surgical intervention was expected, and the patient died four days after the first presentation. Neuropathological examination found acute ischemic infarcts of three to five days duration in the basal ganglia, insular cortex and occipital lobe, correlating with the initial clinical symptoms. There were also extensive recent intracerebral haemorrhages most likely secondary to thrombolysis. Furthermore, the histological examination revealed severe cerebral amyloid angiopathy associated with granulomatous inflammatory reaction, consistent with ABRA.ConclusionsPresentation of ABRA in a middle-aged patient highlighted the difficulties in recognition and management of this rare condition. There is emerging evidence that patients with CAA may have increased risk of fatal intracerebral haemorrhages following thrombolysis. This may be further increased by a coexisting CAA-related inflammatory vasculopathy which is potentially treatable with steroid therapy if early diagnosis is made.

Clinical features and long-term outcomes of symptomatic low-grade carotid stenosis

ObjectiveIn symptomatic low-grade stenosis, most of the reports did not clarify the long-term outcome. This study aims to clarify the clinical features and long-term outcomes of symptomatic low-grade stenosis cases. Materials and methodsWe included 123 symptomatic patients with low-grade (<50%) carotid stenosis. The relative plaque signal intensity (rSI) and expansive remodeling rate (ERR) were measured using carotid magnetic resonance imaging (MRI). Antiplatelet therapy and treatment for atherosclerosis risk factors were administered in all cases. Carotid endarterectomy (CEA) was performed when ischemic symptoms appeared, or the percent stenosis progressed despite medical treatment. ResultsThe mean percent stenosis, rSI, and ERR on admission were 22.3, 1.70, and 2.01, respectively. The mean volume of the hyperintense plaque on carotid MRI was 641.4± 540 mm3. Sixty percent of cases involved intraplaque hemorrhage and expansive remodeling. During a mean follow-up of 52 months, recurrence of ischemic events was confirmed in 45 cases (36.6%). Of the 67 cases performed follow-up MRI, 34 cases (50%) had an increased volume of T1-hyperintense plaque. CEA or carotid artery stenting was performed in 49 cases. During a mean follow-up of 57.8 months after CEA, two cases of death (fatal intracerebral hemorrhage and asphyxia) and one case of brain stem lacunar infarction were observed, but ipsilateral ischemic events were not. ConclusionMost of the symptomatic patients with low-grade stenosis had both intraplaque hemorrhage and expansive remodeling and presented a high risk of recurrence and stenosis progression. CEA may have preventive effects against ischemic events in low-grade stenosis.

Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM).

Cerebral Cavernous Malformation (CCM) is a cerebrovascular disease of genetic origin that predisposes to seizures, focal neurological deficits and fatal intracerebral hemorrhage. It may occur sporadically or in familial forms, segregating as an autosomal dominant condition with incomplete penetrance and highly variable expressivity. Its pathogenesis has been associated with loss-of-function mutations in three genes, namely KRIT1 (CCM1), CCM2 and PDCD10 (CCM3), which are implicated in defense mechanisms against oxidative stress and inflammation. Herein, we screened 21 Italian CCM cases using clinical exome sequencing and found six cases (~29%) with pathogenic variants in CCM genes, including a large 145–256 kb genomic deletion spanning the KRIT1 gene and flanking regions, and the KRIT1 c.1664C>T variant, which we demonstrated to activate a donor splice site in exon 16. The segregation of this cryptic splicing mutation was studied in a large Italian family (five affected and seven unaffected cases), and showed a largely heterogeneous clinical presentation, suggesting the implication of genetic modifiers. Moreover, by analyzing ad hoc gene panels, including a virtual panel of 23 cerebrovascular disease-related genes (Cerebro panel), we found two variants in NOTCH3 and PTEN genes, which could contribute to the abnormal oxidative stress and inflammatory responses to date implicated in CCM disease pathogenesis.

Outcomes of Medical Management Alone for Adult Patients with Cerebral Misery Perfusion Due to Ischemic Moyamoya Disease

ObjectivesAlthough revascularization surgery is recommended for adult patients with moyamoya disease (MMD) who present with ischemic symptoms due to hemodynamic compromise, the clinical course of such patients who are treated with medical management alone remains unclear. Here, we report outcomes of adult patients with cerebral misery perfusion due to ischemic MMD who received medical management alone. Materials and MethodsWe prospectively followed up patients who showed misery perfusion in the symptomatic cerebral hemisphere on 15O gas positron emission tomography (PET) and received strict medical management alone after refusing revascularization surgery. ResultsOf 57 patients who showed symptomatic misery perfusion on 15O gas PET, three (5%) were included into the present study. Two of these patients suffered further ischemic events at 7 and 8 months after inclusion, after which, their modified Rankin disability scale scores deteriorated. In the remaining patient, fatal intracerebral hemorrhage developed at 10 months after inclusion. ConclusionsThese findings suggest that receiving medical management alone is associated with considerably poor outcomes for adult patients with cerebral misery perfusion due to ischemic MMD.

Safety and efficacy of direct oral anticoagulants in patients with atrial fibrillation on concomitant treatment with dronedarone

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The use of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) is associated with bleedings. Interactions with dronedarone may increase this risk, but data on concomitant treatment of DOACs with dronedarone are limited. Purpose The primary endpoint was to compare the survival free from the composite endpoint of clinically relevant bleeding, thromboembolic event and all-cause death, between AF patients on treatment with dronedarone and different DOACs. The secondary endpoints were to compare the survival free from i) clinically relevant bleeding and ii) clinically relevant major bleeding. Methods A retrospective study was conducted at our Local Health Unit, from January 1st 2016 to December 31st 2020. The population included AF patients with concomitant prescriptions of DOACs and dronedarone. Patients were divided into 4 groups (rivaroxaban, apixaban, edoxaban, dabigatran). Clinically relevant major bleedings were defined as fatal bleeding or bleeding leading to transfusion of ≥2 units of blood. Clinically relevant non-major bleedings were defined as any sign of hemorrhage that does not fit the criteria for major bleeding but does lead to hospitalization or emergency room admission. Thromboembolic events were defined as ischemic stroke, transient ischemic attack (TIA), and systemic embolism. Results 165 patients were included: 46/165 (28%) on rivaroxaban, 66/165 (40%) on apixaban, 45/165 (27%) on edoxaban, and 8/165 (5%) on dabigatran (Fig.1). Over a median follow-up of 339 days, 14/165 (8%) met the primary composite endpoint: 8/165 (5%) had clinically relevant bleedings, of which 1/165 (0.6%) was a clinically relevant major bleeding (i.e., fatal spontaneous intracerebral hemorrhage), 2/165 (1%) had TIAs, and 5/165 (3%) died. We found no difference in survival free from the primary composite endpoint and from clinically relevant bleeding between groups (p=0.19 and p=0.69, respectively) (Fig. 2A-B). However, survival free from clinically relevant major bleeding was significantly lower in dabigatran users (p=0.003) (Fig. 2C). At a secondary analysis, DOACs contraindicated by 2015 EHRA guide (dabigatran, edoxaban 60 mg), and not by 2018/2021 EHRA guides (rivaroxaban, dabigatran, edoxaban 60 mg), were associated with lower survival from either clinically relevant bleeding or clinically relevant major bleeding (p=0.03 and p&amp;lt;0.001, respectively). Conclusions In our study on patients on concomitant treatment with DOACs and dronedarone, there was no difference in survival free from the primary composite endpoint and from clinically relevant bleeding between groups of coadministration. However, survival free from clinically relevant major bleeding was significantly lower in dabigatran users. DOACs contraindicated by 2015 EHRA guide (and not by the latest 2018/2021 EHRA guides) are associated with lower survival from either clinically relevant bleeding or clinically relevant major bleeding.

Nrf2 activation in the human brain after stroke due to supratentorial intracerebral haemorrhage: a case–control study

AimsPharmacological activation of the antioxidative transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) improves outcomes in experimental models of intracerebral haemorrhage (ICH). However, the Nrf2 pathway has not been...

Intracerebral haemorrhage due to vaccine-induced immune thrombocytopenia and thrombosis

Introduction: Vaccine-induced Immune thrombocytopenia and thrombosis (VITT) is a rare complication following vaccination with the ChAdOx1 nCov-19 [recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)]. VITT has been reported in several countries and there are no published reports of this entity from Sri Lanka. We report a case of VITT causing fatal intracerebral haemorrhage (ICH) following ChAdOx1 nCov-19 vaccination.

Abstract 11121: Outcomes in Left Ventricular Thrombi Treated with Direct Oral Anticoagulants at a Safety Net Hospital

Introduction: Direct oral anticoagulants (DoACs) are increasingly used off-label for the treatment of left ventricular (LV) thrombus due to ease of use. Current efficacy and safety data are mixed. DoACs offer advantages in low resource populations and have not been studied in this context. This study aimed to assess the efficacy of DOACs for the treatment of LV thrombus in a medically underserved population. Methods: A retrospective chart review was performed of patients treated with DoACs for LV thrombus from January 2017 to February 2020 in a medically underserved, multi-ethnic population receiving care at a large county hospital. Baseline demographic, clinical, and echocardiographic data were collected. Adverse events were obtained via chart review. AE were categorized into fatal bleeding, intracerebral hemorrhage and non-hemorrhagic stroke documented on CT or MRI, bleeding event requiring transfusion, myocardial infarction, and death. Results: Forty patients were identified. Average age was 52 ± 11 years, 19 (48%) were African American and 12 (30%) were women. At thrombus diagnosis, 19 (48%) initiated rivaroxaban. 21 started warfarin then transitioned to rivaroxaban (17, 43%) or apixaban (4, 10%). Average LV ejection fraction at diagnosis was 23 ± 13 % and average treatment length was 16 ± 10 months. Twenty-two (76%) of 29 follow up echoes showed thrombus resolution. Four patients were lost to follow up. Adverse events included 2 non-hemorrhagic strokes and 3 deaths. Conclusion: This is the largest single center retrospective study of LV thrombi at a publicly funded, county hospital caring for a diverse, medically underserved patient population. For this patient population treated with DoACs, successful resolution of LV thrombi occurred in most patients with few adverse events. These results underscore the need for randomized trials to understand the efficacy and safety of DOACs for the treatment of LV thrombus, particularly in underserved communities.

Fatal cerebral hemorrhage in a patient with thrombotic thrombocytopenic purpura with a normal platelet count during treatment with caplacizumab

Acquired thrombotic thrombocytopenic purpura (aTTP) is a thrombotic microangiopathy with a severe mortality and morbidity. Caplacizumab has recently been approved in the Netherlands as a new therapeutic option in patients with life-threatening organ failure due to aTTP. We describe the case of a 50 year old patient with aTTP who was referred to our hospital for treatment with caplacizumab. After undergoing treatment with plasmapheresis, prednisolone, rituximab and caplacizumab, her platelet count recovered and she was ready to be discharged. Unfortunately, before discharge she developed a fatal intra-cerebral hemorrhage. Fatal hemorrhage as an adverse event of caplacizumab has not been described before. Up to now there is no evidence-based treatment for caplacizumab induced heavy bleeding.

Intracerebral haemorrhage in patients with brain metastases receiving therapeutic anticoagulation

BackgroundVenous thromboembolism is common in patients with solid malignancies and brain metastases. Whether to anticoagulate such patients is controversial given the possibility of intracerebral haemorrhage (ICH). We evaluated the added...

Fatal hemorrhage complicated with methamphetamine poisoning and its post-mortem CT features.

The purpose of this study was to assess the incidence of fatal hemorrhage complicated with methamphetamine (MA) poisoning and to examine the postmortem computed tomography (PMCT) features of fatal intracerebral hemorrhage (ICH) with and without MA poisoning. The study also attempted to determine the differences in PMCT between those two groups. Consecutive medicolegal autopsy data from November 2011 to February 2018 were searched for 3044 cases. First, the incidence and distribution of all cases of nontraumatic fatal hemorrhage with various causes were examined. Second, cases of ICH on the basal ganglia and brain stem were extracted. The PMCT findings were compared with respect to nine parameters: volume of hematoma, ventricular perforation, midline shift distance, aortic calcification, calcification of aortic valve, calcification of coronary artery, cardiothoracic ratio, circumference of ascending aorta, and volume of bladder contents. Of the 3044 cases, 97 were nontraumatic fatal hemorrhage; of these 97 cases, 20 were classified as MA poisoning with 9 ICH cases, and 60 cases were classified as non-MA poisoning with 14 ICH cases. A statistically significant difference in ages was observed between the two groups. On PMCT comparison of ICH, statistically significant differences were evident in the midline shift distance and calcification of the aortic valve. Forensic radiologists should be aware of the possibility of ICH with MA poisoning if fatal hemorrhage is detected on PMCT. Younger age, less calcification of the aortic valve, and a remarkable midline shift may be the keys to recognition.

Premature vascular disease in young adult stroke: a pathology-based case series.

The prevalence of modifiable vascular risk factors is increasing in young adults and may contribute to the growing frequency of stroke in this population. The neuropathology and end-organ damage profile of young adult stroke patients with clinically advanced atherosclerosis or arteriosclerosis has not been studied. This retrospective study included patients aged 18-60years admitted to our hospital from 1995 to 2017 with recurrent ischemic or hemorrhagic strokes, fatal stroke, or stroke associated with advanced small vessel disease (SVD) on brain MRI, who had no evidence for structural, genetic, inflammatory, or infectious etiology for stroke, and had adequate pathological materials available for analysis. The presence of atherosclerosis, arteriolosclerosis, left ventricular hypertrophy, and nephrosclerosis was evaluated. Twelve patients (mean age 47 ± 9years, range 31-57years, 67% male) met inclusion criteria. Four had fatal intracerebral hemorrhage (ICH), three had recurrent non-fatal ICH, one had ICH with advanced SVD on MRI, and four had recurrent ischemic strokes including two with transient ischemic attacks. Pathological studies showed moderate/severe atherosclerosis in 64% and moderate/severe arteriolosclerosis in 42% of patients. Pathological data to evaluate end-organ damage were available for nine patients; eight showed left ventricular hypertrophy and all showed nephrosclerosis. Young adult stroke patients with recurrent stroke, fatal stroke, or SVD on imaging have advanced atherosclerosis and arteriolosclerosis-related pathological changes in multiple organ systems. Aggressive control of atherosclerosis risk factors is warranted even in young individuals.

ECMO without anticoagulation in patients with disease-related severe thrombocytopenia: Feasible but futile?

Severe thrombocytopenia poses a high risk for bleeding thus representing a relative contraindication for anticoagulation and therefore extracorporeal membrane oxygenation (ECMO). We herein report on a series of immunocompromised patients with severe thrombocytopenia undergoing long-term ECMO without systemic anticoagulation. We retrospectively identified seven adult patients with anticoagulation withdrawal for ≥3 days (range 5-317) during venovenous ECMO therapy due to thrombocytopenia < 50 G/L treated in a university-affiliated hospital from January 2013 to April 2017. All ECMO systems used were heparin coated. Overall, 530 ECMO days were observed, 404 (76%) of them without systemic anticoagulation. Platelet count during ECMO treatment was 24 G/L (median, range 1-138), ECMO duration was 35 days (5-317), and ECMO was run without any anticoagulation for 20 days (5-317). Altogether, five clotting events were seen leading to oxygenator exchanges. Bleeding was common including one fatal intracerebral hemorrhage. Altogether, 29 platelet concentrates per patient (7-207) were administered, which correspond to 0.8 per day (0.6-1.3). One patient survived ICU and hospital. In patients with thrombocytopenia, ECMO can be run without anticoagulation even for considerably long periods of time. Bleeding remains common, while clotting events seem to be rare. However, prognosis of this patient population undergoing ECMO support seems grim.

Association between incidence of fatal intracerebral hemorrhagic stroke and fine particulate air pollution

ObjectiveFew studies investigating associations between fine particulate air pollution and hemorrhagic stroke have considered subtypes. Additionally, less is known about the modification of such association by factors measured at the individual level. We aimed to investigate the risk of fatal intracerebral hemorrhage (ICH) incidence in case of PM2.5 (particles ≤ 2.5 μm in aerodynamic diameter) exposure.MethodsData on incidence of fatal ICH from 1 June 2012 to 31 May 2014 were extracted from the acute stroke mortality database in Shanghai Municipal Center for Disease Control and Prevention (SCDC). We used the time-stratified case-crossover approach to assess the association between daily concentrations of PM2.5 and fatal ICH incidence in Shanghai, China.ResultsA total of 5286 fatal ICH cases occurred during our study period. The averaged concentration of PM2.5 was 77.45 μg/m3. The incidence of fatal ICH was significantly associated with PM2.5 concentration. Substantial differences were observed among subjects with diabetes compared with those without; following the increase of PM2.5 in lag2, the OR (95% CI) for subjects with diabetes was 1.26 (1.09–1.46) versus 1.05 (0.98–1.12) for those without. We did not find evidence of effect modification by hypertension and cigarette smoking.ConclusionsFatal ICH incidence was associated with PM2.5 exposure. Our results also suggested that diabetes may increase the risk for ICH incidence in relation to PM2.5.

Immunotherapy with ponezumab for probable cerebral amyloid angiopathy.

ObjectiveCerebral amyloid angiopathy (CAA) is caused by cerebrovascular deposition of β‐amyloid fragments leading to cerebrovascular dysfunction and other brain injuries. This phase 2, randomized, double–blind trial in patients with probable CAA assessed the efficacy and safety of ponezumab, a novel monoclonal antibody against Aβ 1–40.MethodsThirty‐six participants aged 55–80 years with probable CAA received intravenous placebo (n = 12) or ponezumab (n = 24). The change from baseline to Days 2 and 90 in cerebrovascular reactivity (CVR) was measured in the visual cortex as the natural log of the rising slope of the BOLD fMRI response to a visual stimulus. Safety and tolerability were also assessed.ResultsThe mean change from baseline to Day 90 was 0.817 (ponezumab) and 0.958 (placebo): a mean ratio of 0.852 (90% CI 0.735–0.989) representing a trend towards reduced CVR in the ponezumab group. This trend was not present at Day 2. There was one asymptomatic occurrence of amyloid–related imaging abnormality–edema in the ponezumab group. The total number of new cerebral microbleeds from baseline to day 90 did not differ between groups. The ponezumab group had a participant with nonfatal new cerebral hemorrhage with aphasia and a participant with subdural hemorrhage that site investigators deemed to be nondrug related. In the placebo group one participant had a fatal intracerebral hemorrhage and one participant had migraine with aura.InterpretationPonezumab was safe and well‐tolerated. The ponezumab group showed a trend towards treatment effect at Day 90 that was opposite to the hypothesized direction. The prespecified efficacy criteria were thus not met.

Fatal bilateral intracerebral hemorrhage following treatment with alemtuzumab for multiple sclerosis

Alemtuzumab is approved for treating multiple sclerosis. It can, however, cause intracerebral hemorrhage (ICH) mediated by an immune thrombocytopenia. So far, only one fatal case of ICH following alemtuzumab treatment in a patient with a normal platelet count has been reported. A connection to alemtuzumab could, however, not be verified because no autopsy was performed on the deceased. The main objective of this article is to report the case of a patient with normal platelet count, who suffered a fatal bilateral ICH shortly after treatment with alemtuzumab was initiated. Histological signs of increased vascular permeability were found. Under consideration of the clinical cause and the neuropathological findings, it is suggested that a causal connection exists between the alemtuzumab treatment and the ICH, which was possibly mediated by vascular damage.