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