POVZETEK

Levkoraioza (LR) je pogosta najdba pri možganski kapi (predvsem ishemični) in je močno povezana s tveganjem za možgansko kap in demenco. Za LR so značilni podobni dejavniki tveganja in patofiziološki mehanizmi kot za ishemično možgansko kap in možgansko krvavitev. LR je lahko tudi neodvisen napovednik izida možganske kapi. V splošni populaciji sta lakunarna kap in LR povezani z velikim tveganjem za ponavljajoče se dogodke, možgansko kap in kognitivni upada. Po akutni ishemični možganski kapi je LR povezana s povečanim tveganjem za smrt ali odvisnost, vnovično kap, znotrajmožgansko krvavitev pri protikoagulacijski terapiji, miokardni infarkt in vaskularno demenco. Na osnovi slikovnih preiskav v nevrologiji je vse več dokazov v prid konceptu, da v nekaterih primerih možganske kapi pride do ishemičnih okvar v beli možganski snovi, ki so lahko še posebej poudarjene pri bolnikih z boleznimi malih žil. Relativno podobna porazdelitev LR, ne glede na distribucijo žilne patologije, nakazuje nagnjenost k okvari bele snovi tudi pri različnih drugih žilnih boleznih. Potrebno je več raziskav s področja patofiziologije levkoarajoze, da bi zmanjšali stroške invalidnosti, ki so povezani z opisanimi stanji.

ABSTRACT

Leukoaraiosis (LA) is a common finding in stroke (particularly ischemic) and has been strongly associated with risk of incident stroke and dementia. LA shares similar risk factors and pathophysiologic mechanisms with both ischemic and hemorrhagic stroke. LA may also be an independent predictor of stroke outcomes. In general populations, both lacunar strokes and LA are associated with a high risk of recurrent stroke events and cognitive decline. After an acute ischemic stroke LA is associated with increased risk of death or dependency, recurrent stroke, intracerebral hemorrhage under anticoagulation, myocardial infarction, and poststroke dementia. There is increasing evidence from neuroimaging studies to support the concept that some cases of LA are caused by white matter infarcts, which may be particularly frequent in patients with widespread small vessel disease. The relatively similar distribution of LA regardless of the distribution of vascular pathology suggests a conserved vulnerability to white matter injury across various vascular diseases, possibly related to resting patterns of blood flow. More insights into the pathophysiology of leukoaraiosis are needed to reduce the burden of disability associated with this common condition.

INTRODUCTION

White matter hyperintensity (WMH), also known as leukoaraiosis (LA), is frequently detected in the aging brain. This term refers to lesions of altered signal intensity on computed tomography (CT) and magnetic resonance imaging (MRI) in the periventricular and subcortical cerebral white matter (Figure 1). Its presence and severity have important clinical impact through associations with cognitive deterioration, dementia, gait disturbances and increased risk of stroke (both ischemic and hemorrhagic) (1). It also constitutes the core pathology of Binswanger’s disease, a type of vascular dementia. Furthermore, LA has an important role in the brain’s response to acute ischemia, as increasing severity of LA predicts infarct progression and a poor clinical outcome after acute ischemic stroke (1). Risk factors associated with LA are: hypertension, hypotension, diabetes, obesity, increasing age, cigarette smoking, elevated homocysteine levels, hyperlipidemia, coronary artery disease and chronic kidney disease (1-3).

ASSOCIATION BETWEEN LA AND STROKE

LA is frequently observed in patients with acute stroke, ishemic as well as hemorrhagic. (1-3) Previous studies indicated that LA was strongly associated with lacunar strokes rather than non-lacunar, territorial strokes (1-3). LA is caused by several pathological changes (demyelination, gliosis, cavitated and noncavitated small deep infarcts) and various etiologies (hypoperfusion, vessel lipohyalinosis, blood-brain barrier structural and functional changes). Stroke and LA are likely two related diseases. In many aspects, LA is an ischemic disease, as is ischemic stroke. Also, intracerebral hemorrhage (ICH) and LA share a common cause, that of arterial hypertension. If LA shares with stroke (ischemic and hemorrhagic) common mechanisms, and the appearance of LA on imaging predicts stroke, then, according to current terminology, LA can be regarded as an intermediate surrogate of stroke (4).

Leukoaraiosis shares similar risk factors and pathophysiologic mechanisms with both ischemic and hemorrhagic stroke. In general populations, both lacunar strokes and LA are associated with a high risk of recurrent stroke events and cognitive decline.

After an acute ischemic stroke LA is associated with increased risk of death or dependency, recurrent stroke, intracerebral hemorrhage under anticoagulation, myocardial infarction, and poststroke dementia (5).

Silent brain infarcts and LA in young adults

Regarding younger adults, data on silent brain infarcts (SBIs) and LA are limited. Two studies have documented the prevalence of SBIs in detail in healthy middle-aged subjects: the prevalence among younger participants was 0% in those aged 20–39 years and 1.7% in those aged 40–49 years in a South Korean study (6) and 8% among those aged 30–49 years in the Framingham Offspring Study (7). In a study of Putaala et al. it was observed that approximately 13% of 1,008 consecutive young adults aged 15–49 years with first-ever ischemic stroke had one or more SBIs and more than 5% presented with LA on CT or MRI (8). Young adults have a different risk factor profile and stroke etiology compared with the elderly. Small-vessel disease and large-artery atherosclerosis are much less frequent, whereas cervical artery dissection and cardioembolism are common. However, the spectrum of underlying stroke mechanisms is extremely wide (8).

In another study, Putaala et al. hypothesized that risk factors, neuroimaging characteristics, and associations with the overt clinical stroke may be different in young patients with ischemic stroke with or without SBIs and LA.

Of the 669 patients included, 86 (13%) had SBIs, 50 (7%) had LA, 17 (3%) had both, and 550 had no SBIs or LA and served as controls. The majority (54%) had a single SBI, 20% had two SBIs, and 27% had three or more SBIs. Most SBIs were located in basal ganglia (39%) or subcortical regions (21%), but cerebellar SBIs also were rather frequent (15%). LA was mainly mild to moderate. Silent cardioembolism may in part explain the frequency of cerebellar SBIs in younger patients. As observed, younger stroke patients tend to have more frequently overt posterior territory ischemia and cerebellar infarcts. This observation, jointly with the frequency of cerebellar SBIs, might reflect the same, yet unclear, pathophysiologic mechanisms.

Independent risk factors for SBIs in younger adults were type 1 diabetes, obesity, smoking, and increasing age. Risk factors for LA were type 1 diabetes, obesity, female sex, and increasing age. Small-vessel disease was the predominant cause of stroke in both those with SBIs (31%) and LA (44%) (9).

Silent brain infarcts and LA in elderly

WMHs are often found on MRI in elderly people and they are attributed to degenerative changes of long penetrating arteries (10).
Reported prevalence ranges from 5% to 90%, depending on study design, study population, and rating scales (10, 11). There is evidence that periventricular WMHs are especially related to cognitive decline, whereas subcortical WMHs may be related to late onset depression. WMHs can be divided into the subcortical and periventricular region. Only a few studies considered lesions in these regions separately, but some based their analysis on a summary score of subcortical and periventricular white matter lesions, as in other studies (10, 11). Although it is well established that the prevalence of LA increases with age, little is known about site specific frequency, including possible differences between the subcortical and periventricular region and the lobar location of the lesions. This distinction may be of potential interest as the subcortical and periventricular white matter lesions might have a different pathogenesis and may result in different cognitive or motor consequences. Some studies reported a higher prevalence of white matter lesions among women then men. The differences were, however, not statistically significant, and were only reported for total white matter lesions burden.

In the study of de Leeuw et al. a total of 1077 subjects aged between 60–90 years were randomly sampled from the general population. All subjects underwent 1.5T MRI scanning; white matter lesions were rated separately for the subcortical region and the periventricular region. Of all subjects 8% were completely free of subcortical white matter lesions, 20% had no periventricular white matter lesions, and 5% had no white matter lesions in either of these locations. The proportion with white matter lesions increased with age, similarly for men and women. Women tended to have more subcortical white matter lesions than men, mainly caused by marked differences in the frontal white matter lesion volume (0.89 ml vs. 0.70 ml). Periventricular white matter lesions were also more frequent among women than men (12). Also, severe degrees of subcortical white matter lesions were more common in women than in men (12). This study confirmed the significant association between severity of WMHs and age. In addition, it was found that women tended to more often have white matter lesions of both types, especially in the frontal region (12). The postmenopausal estrogen reduction might make an explanation, why the female brain is more vulnerable, by reduction of cerebral blood flow (ischemia) and impairment of neuronal repair mechanisms.

LA and risk of TIA and/or stroke

The long-term clinical significance of LA in patients after stroke or TIA, regarding the risk of death, recurrent stroke, and functional outcome remains incompletely defined. (13) It has been reported that LA has no influence on outcome, length of hospital stay, or mortality. Conversely, other researchers have found that LA increases the risk of death or dependency 3 months after an ischemic stroke, the risk of stroke recurrence, and is associated with a poorer prognosis regarding mortality and activities of daily living in patients with lacunar infarcts (13-16).
In a study of Koton et al. moderate/severe LA was diagnosed in 177 of 1024 patients (17.3%) and mild LA in 362 patients (35.3%). After 1 year, adjusted ORs for moderate/severe LA compared with no LA were 2.0 (95%CI 1.1–4.0) for Barthel Index; 1.9 (95%CI 0.9–4.0) for help needed in ADL; 2.5 (95%CI 1.0–6.3) for not feeling totally recovered; 2.0 (95%CI 1.1–4.1) for low QoL; 1.9 (95%CI 1.0–3.5) for psychological distress, and 1.6 (95%CI 0.9–2.9) for reduced community integration. (13) Median LA volume in individuals with TIA was significantly lower (3.7 cm3) compared to 6.9cm3 in acute ischemic stroke. In multivariable analysis, the odds of completed infarct were higher in subjects with larger volumes of LA (13). These data from a nested case-control study drawn from a prospective, hospital-based cohort of patients presenting for evaluation of acute ischemic stroke suggest that preexisting injury to the brain as measured by MRI-detectable LA burden may be associated with a diminished capacity of the cerebral tissue to withstand acute ischemia. The burden of LA was greater in patients who went on to have an acute cerebral infarct as compared to those patients whose cerebrovascular ischemia was transient (13, 14). Furthermore, greater volumes of LA independently predicted the probability of the cerebrovascular event being a stroke as opposed to TIA. These findings suggest that the brain’s intrinsic capacity to withstand cerebrovascular ischemia could be related to the extent of preexisting, chronic cerebrovascular injury marked by LA and measured on MRI (13-16). Severity of LA has been shown to affect infarct growth in patients with acute ischemic stroke and inversely correlate with functional outcome (13-16). A greater susceptibility of “tissue-at-risk” for progression to infarction could arise from impaired mechanisms of cerebral perfusion in those patients with the greatest burden of LA, or alternatively could be the result of chronic mechanisms of injury to the cerebral vasculature. Whether the injury reflected by LA affects the reactivity of vessels or their collective structural integrity is unknown; however, it ultimately leads to infarction of cerebral tissue that was initially only ischemic (16).

In one of our studies, we examined the association of carotid atherosclerosis, defined by intima-media thickness (IMT) and prevalence of carotid plaques, with LA in ischemic stroke patients. One hundred and seventy patients with a documented event of acute ischemic stroke (classified according to the TOAST classification) or TIA were included in the study. Seventy two patients (42.4%) were found to have WMHs, of whom 28.8% had advanced LA on CT scans. Mean IMT was significantly higher in patients with LA and with advanced LA (p=0.002, p=0.003, respectively). In addition, LA and LA severity were associated with existence of carotid plaque (p=0.007, p=0.004, respectively). Stroke patients with LA differed significantly from stroke patients without LA in their age (71.4 vs. 62.6 years, p<0.001) and the prevalence of hypertension (74.6% vs. 54.1%, p=0.006) and diabetes mellitus (36.1% vs. 22.4%, p=0.051). In multivariate logistic regression analysis, including all vascular risk factors, LA was found to be associated with age and IMT. (17) This study demonstrated a significant relation between carotid atherosclerosis, reflected as IMT and existence of carotid plaques, and LA in a cohort of acute ischemic stroke and TIA patients. We found that age and IMT are superior contributors to LA than other classic cardiovascular risk factors, provided further evidence that the relation between carotid atherosclerosis and WMHs is independent of classic vascular risk factors and history of stroke. Moreover, strengthening for those findings received by the multivariate analysis, where the only significant and independent predictors of advanced LA were age and increased IMT. We concluded that a chronic atherosclerotic disease is probably the basic pathophysiology of LA and its progression (17).

PROGNOSIS AND TREATMENT

In several prospective studies, LA has been associated with an increased risk of cerebral large artery arteriosclerosis and territorial ischemic stroke (Figure 2), cerebral hemorrhage (Figure 3), vascular death and all-cause mortality (18).

Increased mortality occurs not just through stroke and vascular death but also via an increased risk of pneumonia and falls. In acute stroke or TIA, there is no evidence to suggest that a different approach to treatment should be taken in the presence of LA. Recently, the implications of finding LA in patients eligible for thrombolysis have been evaluated in the Canadian Alteplase for Stroke Effectiveness Study (CASES). Although the risk of rt-PA related haemorrhage was higher the chances of a good outcome were not reduced (19). Patients with LA also benefit from carotid endarterectomy, despite higher perioperative risks (20). In general, based on current evidence, the same therapeutical approach should be taken except, perhaps, if anticoagulants are to be used.

LA and anticoagulants in ischemic stroke

The association of LA with treatment-associated hemorrhage is especially important as it may be partly preventable by carefully weighed treatment decisions.
In the SPIRIT trial of oral anticoagulation following non-disabling cerebral ischemia, patients in sinus rhythm received either anticoagulation with a target INR of 3–4.5, or aspirin. The trial was stopped early because of an unacceptable increase in cerebral hemorrhage, and LA was found to be a strong independent risk factor for this complication (21). Furthermore, in patients with a previous ischemic stroke, LA is a strong risk factor for subsequent symptomatic hemorrhage, (22) either of lobar or deep subcortical type.

It is not yet clear whether the risk of bleeding can be predicted by the pattern or severity of LA, or any associated imaging features. Severity is probably important. In SPIRIT, patients with ‘‘severe’’ LA had a hemorrhage risk 2.5 times that of ‘‘moderate’’ LA and a dose-response relation was also seen in the case-control study of ICH. However, all of the studies of bleeding risk are based on collapsing LA severity into only 1 or 2 grades (corresponding to the van Swieten scale) on CT assessment. The potential role of more detailed severity rating, based on MRI, or of additional MRI techniques such as the detection of microbleeds is unclear. There is at least one further source of uncertainty; the relation between LA and bleeding risk seems to vary in different clinical contexts. For example, there was a striking difference between ICH risk in patients with ‘‘ischemia of presumed arterial origin’’ (SPIRIT), and stroke in the context of atrial fibrillation. This almost certainly reflects pathological heterogeneity (21). Given these major uncertainties, these therapeutical recommendations can be made (21):

CONCLUSION

There is strong evidence that LA is associated with stroke, independent of other stroke risk factors. Even though the most common stroke type predicted by LA is lacunar infarct. In patients with LA the risk of cortical infarct is also increased, as is that of vascular death. The presence of extensive LA predisposes to ICH, especially in patients treated with anticoagulants for secondary prevention after an ischemic stroke. Both specialists and family physicians should be educated to recognize the importance of LA as an intermediate surrogate of stroke; surveillance and accurate management of conventional risk factors are suggested, even in subjects without prior events. LA should be taken into account as a potential confounder of stroke in any trial that seeks to investigate stroke prevention and should be considered a potential cofactor of hemorrhage in trials investigating antithrombotic agents.

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