POVZETEK

Predvidevanje izida bolezni po akutni ishemični možganski kapi je zelo pomembno tako za odločitve zdravljenja kot za nadaljnje življenje bolnika in njegove družine. Predvidevanje dolgotrajnega izida po preboleli možganski kapi vsebuje funkcionalni izid, prepoznavo vnovične možganske kapi ali napredovanje bolezni in oceno tveganja. Napredovanje možganske kapi je akutni fenomen, saj se dogaja v 24 urah in poteka drugače kot vnovična možganska kap. Na napredovanje in ponovitev možganske kapi vplivajo številni dejavniki, kot so hiperglikemija, predhodno zdravljenje s statini, depresija, vnetni biološki kazalniki, ali povezava s periventrikularno levkopatijo. Če bi imeli kazalnike za izid možganske kapi resnično dobro opredeljene in dosegljive, bi bilo mogoče bolnike z možgansko kapjo v akutni fazi uspešneje zdraviti in hkrati izvajati uspešnejšo preventivo.

Ključne besede: Izid bolezni in zdravljenja; možganska kap; ponovitev ali napredovanje bolezni.

SUMMARY

Predicting outcome in patient after an acute ischemic stroke is very important both for treatment decisions and for discussion of prognosis with the patients and their family. Prediction of long-time outcome after stroke includes functional outcome, identification of stroke recurrence or progression, and risk stratification. Stroke progression is an acute phenomenon occurring most commonly in the first 24 hours and appears to be quite different process from the recurrent stroke. Many factors may influence both stroke progression and stroke recurrence such as: hyperglycemia, previous statin therapy, depression, inflammatory biomarkers, or associated periventricular white matter disease. If we had reliable predictors of stroke outcome well defined and available, it would be possible not only to treat stroke more successfully in the acute phase, but to manage prevention much more effectively as well.

Key words: Stroke; prognosis; recurrent stroke; progression.

INTRODUCTION

Not only is stroke a big medical and social, but a serious economic problem as well. Because of the aging population, the incidence of ischaemic stroke (IS) is increasing in industrialized countries with a significant burden from an individual as well as a public health perspective. One of the hardest questions asked at a stroke patient’s bedside in the acute care setting is “What is the prognosis?” or “Will I die?” and “If I don’t die, will I be disabled?” Predicting outcome in patient after an acute ischemic stroke is very important (1) both for treatment decisions and for discussion of prognosis with the patients and their family. Even though stroke progression and stroke recurrence are important for prognosticating patient outcome, in previous literature they have not often been differentiated from each other because this early outcome has not been assessed by careful neurological observation during the first 48 hours (2).

STROKE LONG-TIME OUTCOME, STROKE RECURRENCE AND BRAIN IMAGING

Prediction of long-time outcome after stroke includes functional outcome, identification of stroke recurrence or progression, and risk stratification (3). Risk stratification can contribute to individualized optimal secondary prevention in patients with cerebrovascular disease. It has been already shown that various clinical factors including age, (4) symptom severity as assessed by the baseline NIHSS (5) and the presence of diabetes mellitus (4) correlate well with shortterm outcome (6). Imaging is also a central part of the diagnosis and treatment of acute ischemic stroke. In most parts of the world computed tomography (CT) remains the most common modality used to assess hyperacute stroke patients, including those with TIA or minor stroke. Images from CT (7) and MRI (8) have been shown to correlate with short-term prognosis.

The clinical and imaging factors that predict stroke progression and recurrent stroke at 2 years are different (2). Stroke progression is an acute phenomenon occurring most commonly in the first 24 hours. Stroke progression and recurrent stroke appear to be different in mechanism as well as timing (9). As previously said progression happens extremely early and is related to the presenting event (which is why imaging early matters); however, recurrence very early is less common and is more relevant as a longer term event. The authors of a recent study (2) found that the overall rates of stroke progression and recurrent stroke were similar between the TIA/minor stroke and the moderate/severe groups, although there were differences in the predictors between the 2 groups. The presence of a DWI lesion and/or intracranial vascular occlusion predicted stroke progression in the minor stroke/TIA population. This argues for acute MR imaging of these patients in the first 24 hours. Among patients with an intracranial occlusion symptom progression may be due to failure of collaterals or less commonly to recurrent embolus. In minor stroke/TIA patients the addition of the imaging parameters mentioned above to the clinical factors, substantially increases the accuracy for predicting both stroke progression and recurrent stroke. This suggests that early MRI should be the imaging modality of choice for TIA and minor stroke. Assessing the imaging predictors of recurrent stroke the authors of the study found that carotid stenosis was most likely a reflection of the underlying risk factors for vascular disease; over 2 years, recurrence is related to risk factors for vascular disease (2). These results are consistent with the previous literature that has shown that long-term prognosis after stroke is more dependent on the underlying vascular risk factors (including stroke mechanism) than factors related to the presenting event (10). Additional advantages of having an MRI completed early, such as confirmation of ischemia, identifying the vascular territory affected and assessment of the final etiology of the stroke or TIA (11), all may alter management, suggest to us that MR should be the modality of choice of the TIA/minor stroke population.

HYPERGLYCEMIA AS A POSSIBLE PREDICTOR OF STROKE OUTCOME

Hyperglycemia is an important poor prognostic factor in acute stroke (12) and it remains an important area for further study. It has been shown the importance of hyperglycemia on the prediction of stroke progression, recurrent stroke and death within 2 years (2). Hyperglycemia may be the result of an acute stress response or be associated with previously undiagnosed or latent diabetes mellitus. Toward some hypothesis, the relationship with recurrent stroke at 2 years makes the latter more likely in this population. Recent preliminary trials of aggressively targeting normoglycemia have been negative or neutral, but this is an important area for further study as it is a potentially modifiable factor (13). In a study it has been established an association of elevated glucose levels with large multisectorial MCA infarcts (14). Hyperglycemia has previously been reported to predict increased stroke mortality independently of age, stroke type, and severity (15). MR perfusion and spectroscopy studies have also shown that acute hyperglycemia increased brain lactate production and facilitates conversion of hypoperfused at-risk tissue into infarction (16).

THE ROLE OF STATIN THERAPY IN PREDICTION OF INFARCT PATTERN IN PA- TIENTS WITH LARGE ARTERY ATHEROSCLEROSIS

In one study from 2009 (14), it has been found out that several factors were independently associated with distinct stroke phenotypes among patients whose index ischemic stroke was due to large artery atherosclerosis (LAA). In multivariable analysis, younger age and premorbid statin non-use were associated with large cortical pattern, whereas older age and premorbid statin use were strong independent factor for small cortical pattern. The association of older age with small cortical only pattern, accords with results from another study (17), and suggests that older patients are more vulnerable to border-zone infarctions potentially due to reduced collateral vigor. The association of statin non-use with large, multisectorial infarctions accords with several studies that found an association between premorbid statin use and better clinical stroke outcome (17). Statins have also been shown to have plaque stabilizing effects; with the occurrence of atherosclerotic plaque regression and reverse remodeling after statin therapy (18). That study indicates that statins may modify the pattern of infarct expression even within the subgroup of patients with large artery aortocervicocerebral atherosclerosis. Since only patients with LAA stroke were included in the study, it is conceivable that prestroke statin use may have stabilized symptomatic plaques to a certain extent, so that individuals on statins prior to the stroke were predisposed to smaller emboli (resulting in small cortical patterns) rather than large macroemboli (resulting in large cortical/cortical-deep patterns). Given the fact that statin-users were more likely to have advanced atherosclerosis than non-user (risk factors for atherosclerosis and previous vascular events on brain or heart were more frequently observed in statin users), it is interesting that nondisabling pattern was more prevalent in the former than the latter. Therefore, these findings support previous reports of cholesterol-independent plaque stabilizing effects in preclinical studies (19), and the use of statin regardless of LDL cholesterol levels in patients with advanced large vessel artherosclerosis (20).

Statin therapy appears not only to avert the development of atherosclerosis, but also to favorably modify the infarct expression of established large artery disease, promoting small distal rather than large proximal or distal infarcts.

Bang et al. (14) also pointed out that the probability of having large cortical infarcts increased, whereas the probability of having no cortical infarct (deep only pattern) decreased, with the increase of white blood cells (WBC) counts on admission. Several mechanisms could contribute to the association between WBC count and stroke pattern. Leukocytosis has been associated with subclinical atherosclerosis and plaque instability (21). Greater plaque instability may generate larger artery-to-artery emboli, producing large infarcts, superficial or deep, rather than small cortical infarcts (22). On the other hand, it may be possible that WBC counts increased after onset of stroke as a result of inflammatory process triggered by the presence of large ischemic lesions (23). A brain SPECT study using 99mTc-hexamethylpropyle-neamine oxime (HMPAO)-labeled leukocyte revealed that accumulation of leukocyte correlated with the severity of the brain tissue damage (24). Resuts of this study demonstrate that LAA infarcts are a complex entity, not a unitary stroke subtype. LAA patients differ in predisposing risk factors, infarct patterns, and plaque location.

In a study of Weimar et al. (25) the authors prospectively investigated the prediction of the Essen Stroke Risk Score (ESRS) and a pathological Ankle Brachial Index (ABI) in consecutive patients hospitalised with acute ischaemic stroke or transient ischaemic attack (TIA) in 85 neurological stroke units throughout Germany. It has been shown that the ESRS is convenient to use, targets a distinctly important clinical outcome and is reasonably accurate for clinical stratification of high risk patients. Both the ESRS and ABI seem suitable for routine application to increase awareness of recurrent stroke risk in cerebrovascular patients. This prospective follow-up study showed a significantly higher rate of recurrent stroke or cardiovascular death and a clear trend for a higher rate of recurrent stroke in patients with acute cerebrovascular events classified as high risk by an ESRS >3 or a pathological ABI.

There is growing evidence that inflammation plays an important role in atherogenesis. Previous studies showed that C-reactive protein (CRP), an inflammatory marker, was associated with stroke outcomes and future vascular events. It is not clear whether this is due a direct dose-response effect or rather an epiphenomenon. The group of Norvegian researchers (26) studied the effect of CRP measured within 24 hours after stroke onset on functional outcome, mortality and future vascular events. Their results showed that admission CRP was associated with stroke severity and long-term mortality when measured at least 24 hours after onset. There is a crude association between high CRP and short term functional outcome which is likely secondary to stroke severity. CRP is an independent predictor of long-term mortality after ischemic stroke.

DEPRESSION AS POSSIBLE PREDICTOR OF STROKE OUTCOME

Depression is highly prevalent after stroke, and may influence recovery. A research group from USA (27) recently found that depressed mood after stroke was associated with disability but not mortality after stroke. Their conclusion is that early screening and intervention for mood disorders after stroke may improve outcomes and requires further research. More detailed they found that stroke patients who had depressed mood within the week following their stroke were more likely to be severely disabled up to 24 months after stroke. This disability started at the earliest time of follow up of 6 months. Our findings were independent of stroke severity, socio-demographic factors, and medical co-morbidities, but stroke severity was the strongest mediator, highlighting the importance of the initial deficit on ultimate outcome. Surprisingly, the authors did not find an effect on mortality, or on moderate disability.

INFLAMMATORY BIOMARKERS AS RISK PREDICTORS AFTER LACUNAR STROKE (LEVELS OF INFLAMMATORY MARKERS IN THE TREATMENT OF STROKE LIMITS STUDY)

Inflammation is increasingly recognized as playing a central role in atherosclerosis, and peripheral blood markers of inflammation have been associated with incident and recurrent cardiac events. The relationship of these potentially modifiable risk markers to prognosis after ischemic stroke is less clear. Little is known about the role of anti-platelet therapy in reducing inflammatory markers among stroke patients or the relative efficacy of antiplatelet therapy among those with, and without elevated levels of inflammation.
Lacunes, or small subcortical strokes comprise about 25 % of brain infarcts, are especially frequent, and are the most common cause of vascular dementia (28) (29). Though infrequently fatal, lacunes are associated with a high risk of recurrence and cognitive impairment. Inflammatory mechanisms have been associated with lacunes and their prognosis in some studies. A polymorphism of the interleukin-6 gene associated with increased inflammation was an independent risk factor for lacunar stroke in one study. (30) This same polymorphism was found to be associated with carotid artery intima-media thickness, as well, providing evidence that polymorphisms related to inflammation may relate to both large and small vessel disease (31). Others also reported that lacunar stroke patients with elevated tumor necrosis factor (TNF)-α and intercellular adhesion molecule 1 (ICAM-1) levels were more likely to experience early neurological deterioration and poor outcome at 3 months (32). An association between leukocyte count and outcomes after stroke has also been found in those with lacunar stroke, as well as other stroke subtypes. In conclusion, LIMITS (33) provides the opportunity for identification of novel risk factors for prognosis after stroke that will help the medical community plan better prevention and treatment strategies. High risk patients may be identified and target areas may be revealed if specific risk factors are found or if they are found to be more important in specific ethnic groups.

THE IMPORTANCE OF PERIVENTRICULAR WHITE MATTER DISEASE AND RACE IN CLINICAL PREDICTION OF FUNCTIONAL OUTCOME AFTER ISCHEMIC STROKE

Kissela et al (34) with the results of their study suggest several unique findings. Their short-term model for functional outcomes reveals that severe periventricular white matter disease (PVWMD) was associated with poor outcome. Furthermore, nonwhite race significantly predicts four-year mortality. This research group is currently in the process of finalizing data collection on a similar cohort of patients to which they are going to apply their original models to assess not only the feasibility of this practical way of thinking but also the validity of the models themselves. As shown, severity of stroke is one incontrovertible determinant of outcome. However, it is conceivable that recovery is limited for those patients with severe PVWMD due to structural damage to the white matter tracts, limiting the physiologic process of neuroplasticity. Notably, PVWMD grade was independent of stroke severity. It is not surprising in this study that outcomes at three months are highly significant predictors of outcomes at four years, although this approach is not commonly considered. It is surprising, however, that non-white race significantly predicts four-year mortality (34).

OTHER POSSIBLE PREDICTORS OF STROKE OUTCOME

The results of the present investigation demonstrate that nitrate (NO2) content in the CSF appears to reflect the severity of the oxidative stress reaction that develops in the ischemic neurovascular unit in the first hours of stroke and can predict functional outcome (25). CSF IL-6 content seems to be the most reliable prognostic indicator in the acute phase of ischemic stroke, with regard to the probability of infarct size, the clinical course of disease and the functional outcome of stroke at one month (25).

Large vessel intracranial occlusion accounted for nearly half of acute ischemic strokes in unselected patients presenting to academic medical centers. In addition to age and baseline stroke severity, occlusion of either the basilar or internal carotid terminus segment is an independent predictor of outcome at 6 months (35).

Multiple lines of evidence suggest that genetic factors contribute to stroke recovery. The matrix metalloproteinases -2 (MMP-2) and -9 (MMP-9) are modulators of extracellular matrix components, with important regulatory functions in the Central Nervous System (CNS). Shortly after stroke, MMP-2 and MMP-9 have mainly damaging effects for brain tissue. However, MMPs also have a beneficial activity in angiogenesis and neurovascular remodelling during the delayed neuroinflammatory response phase, thus possibly contributing to stroke functional recovery (36). Six SNPs in the MMP-2 gene were significantly associated with stroke outcome. The results presented strongly indicate that MMP-2 genetic variants are an important mediator of functional outcome after stroke (36).

It is imperative to address many of the aspects in stroke presentation, treatment, and care that may differ in men and women. Attention to these differences will ensure equivalent levels of prevention, acute treatment, and diagnostic testing in men and women. Women are more likely to be disabled after stroke than men. The current literature indicates that this disparity may result from the older age and poorer pre-stroke functional status of women than men at the time of stroke onset; however, even in age-matched cohorts, overall functional status is worse in women than men (37). Differences in hormone exposure, social networks, and comorbid function may contribute to these sex differences in functional recovery.

Korean authors (38) estimated the long-term prognosis of stroke patients with isolated symptomatic (middle cerebral artery, MCAD) under current medical management in Korea. Diabetes mellitus was found to be a significant predictor for stroke recurrence and mortality.

Because fibrinogen is an acute phase reactant, elevated fibrinogen levels may be associated with severity of the ischemic event. Higher fibrinogen levels appeared to be related to poorer functional outcome in two studies (39). Moreover, in one of them (39), a baseline fibrinogen level ≥450 mg/dL was significantly associated with poor functional outcome at 90 days even taking into account the covariates of age and pretreatment stroke severity. Our results suggesting an association between the initial fibrinogen level and functional outcome from acute ischemic stroke. This emerging association between high initial fibrinogen levels and poor outcome from stroke suggests that defibrinogenation might be a useful therapeutic modality and that fibrinolytics like rt-PA might be more effective if the dose were modestly increased in patients with high admission fibrinogen levels. These therapeutic implications emphasize the importance of determining whether the relationship of fibrinogen to outcome can be confirmed in other databases of acute ischemic stroke and in new prospective studies.

INSTEAD OF CONCLUSION

Establishing the predictors of stroke long-term outcome together with factors that may predict the recurrent stroke, represent an extremely important task. If we had such predictors well defined and available, it would be possible not only to treat stroke more successfully in the acute phase, but to manage prevention much more effectively as well. Final result would be both a significant reduction of severe functional disability and prolonged life after having a such disaster as stroke is.

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