New insights into intracerebral hemorrhage

Non-traumatic intracerebral hemorrhage (ICH) is caused by a rupture of a brain artery leading to blood penetration into brain parenchyma. The incidence of ICH is 10-22 per 100 000 persons per year worldwide. The prognosis is poor, with approximately 40% of the patients dying within one month, and a large number of the survivors remaining with major disabilities. There is no proven effective medical or surgical treatment option, treatment being mainly supportive in nature, with management in dedicated stroke units reducing mortality and morbidity. Major risk factors for ICH include hypertension and older age. Hypertension is a well-known risk factor for ICH, shown in several case-control studies. On many of the other potential risk factors, such as smoking, diabetes, and alcohol intake, the results have been conflicting. In addition to the chronic risk factors above, certain preceding triggering events may temporally predispose individuals to ICH. However, data on such triggers in ICH are virtually lacking. Factors that take part in hemostasis and coagulation affect the prognosis of ICH patients. Calcium plays an important role in coagulation, and hypocalcemia has been associated with larger ICH volumes, severity of symptoms, ICH expansion, whereas elevated calcium levels with better outcomes, regardless of similar ICH volumes between hypo-, normo- and hypercalcemic patients. However, there are some contradictions in the results between different studies. Older age, longer hospital stay, poorer motor function at discharge, severity of the neurological deficits, use of antithrombotic medication, larger and deep ICH, and intraventricular extension of ICH have all been reported to associate with worse health-related quality of life (HRQoL) after ICH. These parameters are mainly associated with the severity of the index ICH, and little is known about the effect of other components of quality of life, such as mood and anxiety. We aimed to assess factors in our population-based cohort of ICH patients that have been less studied, and gained less attention in earlier studies, taking into consideration novel factors such as feelings of depression and fatigue prior to the index ICH. We wanted to assess whether triggering factors predisposing to the event exist in ICH. We also studied the effect of hypocalcemia on ICH volume and mortality. In addition to traditional prognostic measures, we attempted to assess quality of life and depression after ICH. We further determined how occipital location, the rarest single-lobe location, affects the outcome of the patients. The prospective part of the study included patients admitted to the Helsinki University Hospital between May 2014 and December 2016. An informed written consent was needed to participate (patient/proxy). Hemorrhages related to tumor, trauma, ischemic stroke, vascular malformations, and other structural abnormalities were excluded. The patients were interviewed during hospital stay, and given structured questionnaires. HRQoL at 3 months after ICH was measured using the European Quality of Life Scale (EQ-5D-5L), and the 15D scale. The recovery was evaluated by a combination of revisiting the electronic medical records and a telephone call. Controls were matched by age and sex, and randomly selected from the participants of the FINRISK study, a large Finnish population survey on risk factors of chronic non-communicable diseases. Ages were matched in 5-year age bands. However, as the oldest FINRISK participants were 74-year-olds, controls for the age group 75-84 were selected from the age group of 70-74 years, and patients aged 85 years were excluded. The retrospective part included a registry of 1013 consecutive ICH patients admitted to the Helsinki University Hospital between January 2005 and March 2010, and the substudy on hypocalcemia included 447 of the patients that had computed tomography (CT) of the brain and serum/plasma ionized calcium taken within 72 hours of symptom onset and within 12 hours of each other. A total of 277 primary ICH patients were recruited to the prospective part of the study, of which 250 could be included in the risk factor analysis, 97 were able to provide consistent answers on the trigger questions, and 124 returned the quality of life questionnaire. In the case-control study, the cases had more often hypertension, history of heart attack, lipid-lowering medication, and reported more frequently fatigue prior to ICH. In persons aged 70 years, the factors associating with the risk of ICH were premorbid fatigue, use of lipid-lowering medication, and overweight. None of the studied possible triggers alone was more frequent during the hazard period compared to the control period. However, when all physical triggers were combined, there was an association with the triggering event and onset of ICH (risk ratio 1.32, 95% confidence interval 1.01-1.73). Predictors for lower HRQoL by both EQ-5D-5L and 15D scales were higher NIHSS, older age, and chronic heart failure. Feeling sad/depressed for more than 2 weeks during the year prior to ICH was a predictor for lower EQ-5D-5L, and history of ICH for lower 15D utility indexes. Prior feelings of sadness/depression were associated with depression/anxiety at 3 months after ICH. In our study, we found that ICH patients had more often fatigue prior to their ICH than the controls of similar sex and age. Hypertension was associated with risk of ICH, as expected. Of the triggering factors present immediately prior to the onset of ICH, physical triggers as a group were associated with the onset time. Hypocalcemic ICH patients had larger ICH volumes than normocalcemic patients. Their higher mortality rate is likely mediated through larger ICH volumes. HRQoL after ICH was associated with the severity of the stroke, comorbidities, and age. However, in our study, feelings of depression before ICH had stronger influence on reporting depression/anxiety after ICH than stroke severity-related and outcome parameters. Few were diagnosed with depression, or had antidepressant medication. This information could be used to identify patients at risk for post-ICH depression. Compared to other ICH patients, occipital ICH patients were younger, had milder neurological deficits, smaller ICH volumes, more often structural etiology, and better outcomes. The risk for epilepsy was similar with other ICH patients. Our studies brought novel insights in lesser studied aspects of ICH.Ei-traumaattinen aivoverenvuoto aiheutuu aivovaltimon seinämän rikkoontumisesta, mikä johtaa veren purkautumiseen aivokudokseen. Noin 40 % sairastuneista menehtyy kuukauden kuluessa, ja suuri osa selviytyvistä vammautuu. Hoitokeinot ovat pääosin elintoimintoja tukevia, eikä tehokkaaksi osoitettua lääkkeellistä tai kirurgista hoitoa ole keksitty. Tässä väitöskirjassa selvitettiin vähemmän tutkittuja aivoverenvuodon riskiin, toipumiseen ja elämänlaatuun liittyviä tekijöitä, ottaen huomioon myös ennen sairastumista koetut mielialatekijät ja uupumus, sekä sairastumishetkelle mahdollisesti altistavia trigger-tekijöitä. Halusimme selvittää, miten hypokalsemia vaikuttaa aivoverenvuodon kokoon ja aivoverenvuotopotilaiden kuolleisuuteen. Tutkimme, miten aivoverenvuodon sijainti takaraivolohkossa vaikuttaa potilaiden toipumiseen. Tutkimukseen rekrytoitiin Helsingin yliopistollisessa sairaalassa aikavälillä 5/2014-12/2016 hoidettuja aivoverenvuotoon sairastuneita potilaita. Aivoverenvuodot, jotka liittyivät aivokasvaimeen, traumaan, aivoinfarktiin, vaskulaariseen malformaatioon tai muuhun rakenteelliseen poikkeavuuteen jäivät tutkimuksen ulkopuolelle. Potilaita haastateltiin sairaalassa oloaikana, ja he saivat kyselylomakkeet täytettäväkseen. Elämänlaatu kolmen kuukauden kohdalla sairastumisesta selvitettiin EQ-5D-5L- ja 15D-lomakkein. Toipumista arvioitiin sairauskertomusmerkinnöistä ja puhelinsoitolla. Kontrollihenkilöt valikoitiin sattumanvaraisesti iän ja sukupuolen perusteella FINRISKI-tutkimuksesta. Lisäksi tutkimuksessa käytettiin jo olemassa olevaa 1013 aivoverenvuotopotilaan aineistoa, johon on koottu kaikki Helsingin yliopistollisessa sairaalassa aikavälillä 1/2005-3/2010 hoidetut aivoverenvuotopotilaat. Rekrytoimme tutkimukseen 277 aivoverenvuotopotilasta. Potilaista 250 voitiin sisällyttää tapaus-verrokkitutkimukseen, 97 potilasta pystyi vastaamaan luotettavasti trigger-kysymyksiin ja 124 potilasta palautti elämänlaatukyselylomakkeet. Tutkimuksessa havaitsimme, että aivoverenvuotopotilaat kärsivät saman ikäisiä ja sukupuolisia verrokkejaan enemmän uupumuksesta jo ennen sairastumistaan. Oletetusti verenpainetauti assosioitui aivoverenvuodon riskiin ja fysikaaliset triggerit ryhmänä aivoverenvuodon tapahtumahetkeen. Hypokalseemisten potilaiden aivoverenvuodot olivat suurempia kuin normokalseemisilla. Suurempi osa hypokalseemisista potilaista menehtyi, mikä todennäköisesti johtui kookkaammista vuodoista. Aivoverenvuodon jälkeinen elämänlaatu assosioitui aivohalvausoireiston vakavuuteen, taustasairauksiin ja ikään. Merkittävimpänä tekijänä aivoverenvuodon jälkeisiin mielialaoireisiin olivat kuitenkin mielialaoireet jo ennen sairastumista. Vain harvalla oli tiedossa oleva masennusdiagnoosi tai -lääkitys. Verrattuna muihin aivoverenvuotopotilaisiin, takaraivolohkon aivoverenvuotoon sairastuneet olivat nuorempia, lievempioireisia, ja heidän aivoverenvuodot olivat pienempiä. Vuodon taustalla oli useammin rakenteellinen poikkeavuus. Riski sairastua epilepsiaan oli verrannollinen muihin potilaisiin. Tutkimuksemme toi uusia näkökulmia aivoverenvuodon vähemmän tutkittuihin puoliin

Triggering factors in non-traumatic intracerebral hemorrhage

Background: In ischemic stroke and subarachnoid hemorrhage, there are known preceding triggering events that predispose to the stroke by, for example, abruptly raising blood pressure. We explored, whether triggering events can be identified in non-traumatic intracerebral hemorrhage (ICH). Methods: We used structured questionnaires to interview consented patients with ICH treated in a tertiary teaching hospital, between 2014 and 2016. We asked of possible trigger factors, including Valsalva-inducing activity, heavy physical exertion, sexual activity, abrupt change in position, a heavy meal, a sudden change in temperature, exposure to traffic jam, and the combination of the first three (any physical trigger) during the hazard period of 0-2 h prior to ICH. The ratio of the reported trigger during the hazard period was compared to the same 2-h period the previous day (control period) to calculate the relative risks for each factor (case-crossover design). Results: Of our 216 consented ICH patients, 97 (35.0%) could be interviewed for trigger questions. Reasons for not able to provide consistent and reliable responses included lowered level of consciousness, delirium, impaired memory, and aphasia. None of the studied possible triggers alone were more frequent during the hazard period compared to the control period. However, when all physical triggers were combined, we found an association with the triggering event and onset of ICH (risk ratio 1.32, 95% confidence interval 1.01-1.73). Conclusions: Obtaining reliable information on the preceding events before ICH onset was challenging. However, we found that physical triggers as a group were associated with the onset of ICH.Peer reviewe

Quality of life and depression 3 months after intracerebral hemorrhage

Objectives: Quality of life (QoL) after intracerebral hemorrhage (ICH) is poorly known. This study investigated factors affecting QoL and depression after spontaneous ICH. Materials and Methods: This prospective study included patients admitted to Helsinki University Hospital between May 2014 and December 2016. Health-related QoL (HRQoL) at 3 months after ICH was measured using the European Quality of Life Scale (EQ-5D-5L), and the 15D scale. Logistic regression analyses were used to test factors affecting HRQoL. EQ-5D-5L anxiety/depression dimension was used to analyze factors associated with anxiety/depression. Results: Of 277 patients, 220 were alive, and sent QoL questionnaire. The questionnaire was returned by 124 patients. Nonreturners had more severe strokes with admission National Institutes of Health Stroke Scale (NIHSS) 7.8 (IQR 3.0-14.8) versus 5.0 (IQR 2.3-11.0); p = 0.018, and worse outcome assessed as modified Rankin Scale 3-5 at 3 months 59.4% versus 44.4% (p = 0.030). Predictors for lower HRQoL by both scales were higher NIHSS with OR 1.28 (95% CI 1.13-1.46) for EQ-5D-5L, and OR 1.28 (1.15-1.44) for 15D, older age (OR 1.10 [1.03-1.16], and OR 1.09 [1.03-1.15]), and chronic heart failure (OR 18.12 [1.73-189.27], and OR 12.84 [1.31126.32]), respectively. Feeling sad/depressed for more than 2 weeks during the year prior to ICH was predictor for lower EQ-5D-5L (OR 10.64 [2.39-47.28]), and history of ICH for lower 15D utility indexes (OR 11.85 [1.01-138.90]). Prior feelings of sadness/ depression were associated with depression/anxiety at 3 months after ICH with OR 3.62 (1.14-11.45). Conclusions: In this cohort of ICH patients with milder deficits, HRQoL was affected by stroke severity, comorbidities and age. Feelings of depression before ICH had stronger influence on reporting depression/anxiety after ICH than stroke severity-related and outcome parameters. Thus, simple questions on patient's premorbid feelings of sadness/depression could be used to identify patients at risk of depression after ICH for focusing follow-up and treatment.Peer reviewe

Effect of baseline hypocalcaemia on volume of intracerebral haemorrhage in patients presenting within 72 hours from symptom onset

Introduction: Calcium has a pivotal role in haemostasis. We investigated the association of baseline calcium levels with admission intracerebral haemorrhage (ICH) volume. Methods: This is a retrospective analysis of consecutive ICH patients in an academic hospital between January 2005 and March 2010. Computed tomography (CT) of the brain and serum/plasma ionized calcium had to be taken within 72 h of symptom onset and within 12 h of each other in order to fulfil the study criteria. ICH cases related to trauma or tumour as well as sole intraventricular haemorrhages were excluded. Baseline haematoma volumes were calculated using semiautomated planimetry. The hypocalcaemic (Ca-ion <1.16 mmol/L) and normocalcaemic (1.16-1.30 mmol/L) patient groups were compared in univariate analyses. Association between admission hypocalcaemia and haematoma volume was studied using multivariable regression models. Results: Out of 1013 consecutive patients, 447 fulfilled the study criteria. Hypocalcaemic patients (n = 178; 39.8%) had larger baseline hematoma volumes (median 30.2 mL, IQR 11.4-58.7 mL), compared to normocalcaemic patients (n = 255; 57.0%; median 16.8 mL, IQR 7.4-44.2 mL). The median ICH volume among hypercalcaemic patients (n = 14; 3.1% of included patients) was 6.5 mL (IQR 3.1-34.6 mL). On linear regression, admission hypocalcaemia was independently associated with larger hematoma volumes (beta = 11.77; 95% CI 4.66-18.87, P = 0.01). Patients with larger haematoma volumes had higher mortality. Conclusion: Hypocalcaemia is associated with larger admission haematoma volumes among ICH patients. Higher mortality among hypocalcaemic patients is very likely mediated through larger ICH volumes.Peer reviewe

Outcome of intracerebral hemorrhage associated with different oral anticoagulants

Objective: In an international collaborative multicenter pooled analysis, we compared mortality, functional outcome, intracerebral hemorrhage (ICH) volume, and hematoma expansion (HE) between non-vitamin K antagonist oral anticoagulation-related ICH (NOAC-ICH) and vitamin K antagonist-associated ICH (VKA-ICH). Methods: We compared all-cause mortality within 90 days for NOAC-ICH and VKA-ICH using a Cox proportional hazards model adjusted for age; sex; baseline Glasgow Coma Scale score, ICH location, and log volume; intraventricular hemorrhage volume; and intracranial surgery. We addressed heterogeneity using a shared frailty term. Good functional outcome was defined as discharge modified Rankin Scale score 33% or >6 mL from baseline within 72 hours. Results: We included 500 patients (97 NOAC-ICH and 403 VKA-ICH). Median baseline ICH volume was 14.4 mL (interquartile range [IQR] 3.6-38.4) for NOAC-ICH vs 10.6 mL (IQR 4.0-27.9) for VKA-ICH (p = 0.78). We did not find any difference between NOAC-ICH and VKA-ICH for all-cause mortality within 90 days (33% for NOAC-ICH vs 31% for VKA-ICH [p = 0.64]; adjusted Cox hazard ratio (for NOAC-ICH vs VKA-ICH) 0.93 [95% confidence interval (CI) 0.52-1.64] [p = 0.79]), the rate of HE (NOAC-ICH n = 29/48 [40%] vs VKA-ICH n = 93/140 [34%] [p = 0.45]), or functional outcome at hospital discharge (NOAC-ICH vs VKA-ICH odds ratio 0.47; 95% CI 0.18-1.19 [p = 0.11]). Conclusions: In our international collaborative multicenter pooled analysis, baseline ICH volume, hematoma expansion, 90-day mortality, and functional outcome were similar following NOAC-ICH and VKA-ICH.Peer reviewe

Neuroimaging and clinical outcomes of oral anticoagulant-associated intracerebral hemorrhage

Objective Methods 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. 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 Interpretation 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 <30cm(3) (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). 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;84:702-712Peer reviewe

Risk Factors of Intracerebral Hemorrhage : A Case-Control Study

Background: Hypertension is a well-known risk factor for intracerebral hemorrhage (ICH). On many of the other potential risk factors, such as smoking, diabetes, and alcohol intake, results are conflicting. We assessed risk factors of ICH, taking also into account prior depression and fatigue. Methods: This is a population-based case-control study of 250 primary ICH patients, conducted in Helsinki University Hospital, Finland. The controls (n = 750) were participants of the FINRISK study, a large Finnish population survey on risk factors of chronic noncommunicable diseases, matched with cases by sex and age. Ages were matched in 5-year age bands. However, as the oldest FINRISK participants were 74-year-olds, controls for the age group 75-84 were selected from the age group of 70-74 years. Patients aged greater than or equal to 85 years were excluded. Patients and controls were compared in univariate analyses. The age categories less than 70, and greater than or equal to 70 years were also analyzed separately. Binary logistic regression analysis was performed for variables with P less than .1 in univariate analysis. Results: Analyzing all cases and controls, the cases had more hypertension, history of heart attack, lipid-lowering medication, and reported more frequently fatigue prior to ICH. In persons aged less than 70 years, hypertension and fatigue were more common among cases. In persons aged greater than or equal to 70 years, factors associated with risk of ICH were fatigue prior to ICH, use of lipid-lowering medication, and overweight. Conclusions: Hypertension was associated with risk of ICH among all patients and in the group of patients under 70 years. Fatigue prior to ICH was more common among all ICH cases.Peer reviewe

Occipital intracerebral hemorrhage-clinical characteristics, outcome, and post-ICH epilepsy

Objectives Posterior location affects the clinical presentation and outcome of ischemic stroke, but little is known about occipital intracerebral hemorrhage (ICH). We studied non-traumatic occipital ICH phenotype, outcome, and post-ICH epilepsy. Materials and Methods Occipital ICH patients were retrospectively identified from the Helsinki ICH Study registry of 1013 consecutive ICH patients treated in our tertiary center in 2005-2010. They were compared to non-occipital ICH patients to evaluate the effect of location on functional outcome at discharge (dichotomized modified Rankin Scale, mRS), 3- and 12-month mortality, and incidence of epilepsy. Results We found 19 occipital ICH patients (5.3% of lobar and 1.9% of all ICH). Compared to non-occipital lobar ICHs, they were younger (median age 63 vs 71 years,P= .007) and had lower National Institutes of Health Stroke Scale on admission (1 vs 8,P<.001), smaller hematoma volume (6.3 vs 17.7 ML,P= .008), and more frequently structural etiology underlying the ICH (26% vs 7%,P= .01). Mortality at both 3 and 12 months was 6%, whereas 84% reached favorable outcome (mRS 0-2) at discharge. Occipital location was associated with favorable outcome at discharge in lobar ICH (OR 11.02, 95% CI 1.55-78.20). Incidence of post-ICH epilepsy (median follow-up 2.7 years) was 18%, equaling to that of non-occipital lobar ICH. Conclusions Occipital ICH patients are younger, have less severe clinical presentation, smaller hematoma volume, more often structural etiology, and better outcome than other ICH patients. They exhibit a similar risk of epilepsy as non-occipital ICHs.Peer reviewe

Impact of white matter hypodensities on outcome after intracerebral hemorrhage

Objectives: White matter hypodensities (WMH), a surrogate of small vessel disease, associate with cognitive decline and stroke risk. The impact of WMH on functional outcome after intracerebral hemorrhage (ICH) has differed between studies. We aimed to examine factors associated with the severity of WMH in ICH, and whether there is an independent association between the extent of WMH and outcome. Materials and methods: This was a prospective study of consented patients with non-traumatic primary ICH, admitted to the Helsinki University Hospital between May 2014 and December 2018. To evaluate the extent of the WMH, modified van Swieten score of the side contralateral to the ICH was obtained. Patients were grouped into 3 categories of the scores. We performed univariate and multivariable analyses to find out factors associated with the severity of WMH, and whether WMH associate with functional outcome and mortality up to 12 months, adjusted for the known major outcome predictors. Results: In our cohort of 417 ICH patients, WMH severity associated with older age, female sex, admission National Institutes of Health Stroke Scale (NIHSS) points, and signs of previous ischemic stroke on CT. We found an independent association between WMH severity and poor functional outcome at 3 months (OR 1.72, 95% CI 1.27-2.33), and 1 year (OR 2.16, 95% CI 1.57-2.95), and mortality at 1 year (OR 1.91, 95% CI 1.29-2.85). Conclusions: In our ICH patients, vascular comorbidities and older age associated with the presence of WMH, which, in turn, strongly associated with poor functional outcome. (c) 2022 Elsevier Inc. All rights reserved.Peer reviewe