Impact of spontaneous intracerebral hemorrhage on cognitive functioning: An update

NEUROL-1827; No. of Pages 9 revue neurologique xxx (2017) xxx–xxx

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Neuropsychology

Impact of spontaneous intracerebral hemorrhage on cognitive functioning: An update M. Planton a,b,*, N. Raposo a,b, L. Danet a,b, J.-F. Albucher a,b, P. Pe´ran b, J. Pariente a,b a

Department of Neurology, Toulouse University Hospital, place Dr-Baylac, pavillon Baudot, 31024 Toulouse cedex 3, France b Toulouse NeuroImaging Centre, universite´ de Toulouse, Inserm, UPS, 31000 Toulouse, France

info article

abstract

Article history:

Intracerebral hemorrhage (ICH) accounts for 15% of all strokes and approximately 50% of

Received 21 March 2017

stroke-related mortality and disability worldwide. Patients who have experienced ICH are at

Received in revised form

high risk of negative outcome, including stroke and cognitive disorders. Vascular cognitive

26 May 2017

impairment are frequently seen after brain hemorrhage, yet little is known about them, as

Accepted 16 June 2017

most studies have focused on neuropsychological outcome in ischemic stroke survivors,

Available online xxx

using well-documented acute and chronic cognitive scores. However, recent evidence

Keywords:

of the other. The location of the lesion also plays a significant role as regards the neuro-

Intracerebral hemorrhage

psychological profile, while the pathophysiology of ICH can indicate a specific pattern of

supports the notion that ICH and dementia are closely related and each increases the risk

Vascular cognitive impairment

dysfunction. Several cognitive domains may be affected, such as language, memory,

Cerebral amyloid angiopathy

executive function, processing speed and gnosis.

Hypertension

# 2017 Elsevier Masson SAS. All rights reserved.

Strategic hemorrhage

1.

Introduction

The low frequency (10–15% of all strokes) [1] and high mortality rate (up to 60% in the first year) [2] of intracerebral hemorrhage (ICH) may explain the lack of cognitive data for that patient population. The two main classes of ICH – traumatic and spontaneous (primitive) – are usually dissociated. Spontaneous ICH accounts for approximately 70– 80% of cases and is due to the rupture of small arteries in the brain afflicted by two main pathologies: hypertensive arteriopathy and cerebral amyloid angiopathy (CAA) [3].

The present report focuses on spontaneous ICH without vascular malformation. The question of the origin of cognitive disorders after ICH is a complex topic linked to the presence of hemorrhage itself, but also to the pathophysiological mechanisms that evolve silently and are present well before stroke happens. Furthermore, while ischemic stroke research commonly uses a specific topographical system of organization, most ICH studies are focused on the differences between lobar and non-lobar hemorrhages. This simple distinction would certainly mask the influence of an individual cause of disease.

* Corresponding author. TONIC, UMR 1214, Toulouse University Hospital, place Dr-Baylac, pavillon Baudot, 31024 Toulouse cedex 3, France. E-mail address: [email protected] (M. Planton). http://dx.doi.org/10.1016/j.neurol.2017.06.010 0035-3787/# 2017 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Planton M, et al. Impact of spontaneous intracerebral hemorrhage on cognitive functioning: An update. Revue neurologique (2018), http://dx.doi.org/10.1016/j.neurol.2017.06.010

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The present study focuses on studies performed in either an ICH or general stroke population where, in the latter, a distinction is made between ischemic and hemorrhagic stroke. The neuropsychological outcome is also described and the data compared with that of ischemic stroke survivors if available. Severity markers of small-vessel disease are also reported with descriptions of their relationship to cognitive function.

2.

Vascular cognitive disorders (VCDs)

2.1.

Definition and criteria for VCD diagnosis

When patients present with vascular cognitive impairment (VCI) following spontaneous ICH, they then meet the International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) criteria, published by Sachdev et al. [4] in 2014. This society aimed to establish working groups to develop common minimal standards for the entire spectrum of cognitive impairment by introducing new terminology and quantitative criteria for defining the severity of vascular cognitive disorders (VCDs). VASCOG has identified seven categories of cognitive disorders: attentional and processing speed; frontal/executive function; learning and memory; language; visuoconstructional–perceptual ability; praxis–gnosis–body schema; and social recognition; it has also listed pathologies that may be responsible for cognitive decline. The term ‘dementia’ is no longer used, but has instead been replaced by major VCDs, as described in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Diagnosing major VCDs is based on objectively measured acquired declines in one or more cognitive domains in cases where a patient, relative or clinician is worried about the level of decline compared with previous levels of cognitive function [test performance of at least 2 standard deviations (SD) below the mean (or below the third percentile)] and where there is interference with daily life. When test performance are between 1 and 2 SD (between the 16th and third percentiles) with no interference on daily life, mild VCDs is diagnosed. However, the use of a cut-off of –1 SD (or 16th percentile) to consider a test performance mildly altered, as defined by the DSM-5, can lead to false positives and should therefore be discussed [5]. This issue should be borne in mind for future studies assessing the sensitivity and specificity of each criterion. In addition, VASCOG criteria have been established under the same schema as those of the US National Institute of Neurological Disorders and Stroke (NINDS) – Association internationale pour la recherche et l’enseignement en neurosciences (AIREN), where there must be a relationship between neuropsychological disorders and vascular lesions.

2.2.

Prevalence of VCDs

2.2.1.

Pre-existing VCDs

Previous cognitive changes are usually estimated via the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) [6], which is rated by a relative who estimates the degree of change over the previous 10 years. This is a powerful

tool and easy to administer, and has a short and long version (16 and 26 questions, respectively). The cut-off differs between studies, but most use a score > 3.6 to diagnose pre-existing major VCDs (such as dementia). Diagnostic accuracy of the IQCODE across cut-off points (3.3–4.1) was evaluated by a Cochrane review of 13 studies involving data from 2745 subjects (51% with dementia) [7]. Pooled analysis of all these studies showed that a cut-off of 3.3 indicated a sensitivity of 0.91 [95% confidence interval (CI): 0.86–0.94] and a specificity of 0.66 (95% CI: 0.56–0.75). Notably, no difference in accuracy was found between the short and long versions of the IQCODE. This questionnaire is widely used in clinical and research studies to overcome the lack of premorbid cognitive testing. In 2012, Pendlebury et al. [8] showed that the prevalence of prestroke dementia was 15% in cohorts of patients with multiple stroke, with comparable rates for patients presenting with ischemic stroke or ICH. Two years earlier, Cordonnier et al. [9] had found the prevalence of dementia before ICH to be 16% (IQCODE score > 4) and 14% for mild cognitive impairment (IQCODE score > 3.31 but < 3.94) in 417 ICH survivors [median age: 72 years, interquartile range (IQR): 58–79]. The authors also observed a greater prevalence within the lobar group, with a rate of pre-existing dementia of 23%, which was 12% in the deep ICH group and 9% in the fossa ICH group. More recently, Laible et al. [10], in a cohort of 89 patients (median age: 70 years, IQR: 58–78) recruited during the acute phase of ICH, found pre-ICH cognitive impairment in 16 of 89 patients (18%, IQCODE score  3.44). Of these, pre-ICH dementia was detected in 8 of 89 patients (9.0%, IQCODE score  4). These clinical data question the common comorbidity of VCI and Alzheimer’s disease (AD), especially in lobar ICH in the elderly, in which AD pathology is known to make significant contributions to cases of dementia after stroke. Indeed, autopsy studies have shown that about 50% of dementia cases can be attributed to either the association of VCI and AD or to mixed dementia [11].

2.2.2.

Post-ICH VCDs

Post-stroke dementia is highly prevalent. The risk of dementia is greatest in the immediate post-stroke period [12], and the risk of delayed dementia increases over time [13]. Despite this, there are very few studies of longitudinal cognitive outcome in ICH survivors. In 2012, Garcia et al. [14] were the first to evaluate the frequency and pattern of cognitive dysfunction in an ICH cohort (n = 48, mean age: 60.8  14.2 years) in a cross-sectional retrospective study. They classified 71% of hematomas as primitive. Dementia was observed in 23% (95% CI: 13–32%) of cases according to the DSM-IV, and cognitive impairment without dementia was observed in 77% (95% CI: 65–89%) of patients. This work supports the need to assess cognition with one major limitation: a 40-month post-ICH cognitive assessment, making the culpability of VCDs tricky. In 2016, Moulin et al. [13], in a prospective study of 218 ICH survivors (median age: 67.5, IQR: 55–76 years), described the risk factors and prevalence of dementia during a median follow-up of 6 years. Dementia diagnosis was based on the US National Institute on Aging/Alzheimer’s Association criteria for all-cause dementia. The authors showed that 14.2% of patients developed newonset dementia by 1 year of ICH, and the rate increased over

Please cite this article in press as: Planton M, et al. Impact of spontaneous intracerebral hemorrhage on cognitive functioning: An update. Revue neurologique (2018), http://dx.doi.org/10.1016/j.neurol.2017.06.010

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time: the incidence was 19.8% at 2 years; 24.5% at 3 years; and 28.3% at 4 years. They also showed that the median time between ICH and diagnosis of dementia was 12 months (IQR: 6–34 months). Moreover, they observed that the risk of dementia was twice as high in patients with lobar than with non-lobar ICH, which supports the theory that the underlying CAA in this group was a contributing factor to the development of dementia. These findings are in agreement with those of Biffi et al. [12], with 19% of patients developing early dementia within 6 months of ICH. Delayed dementia was also estimated by the authors, who found a yearly dementia incidence of 5.8% (95% CI: 5.1–7.0%) in 435 ICH survivors free of dementia at 6 months (mean age: 74.3  12.1 years), according to International Classification of Diseases, Ninth revision (ICD-9) criteria, corresponding to a dementia rate of 32% during a median follow-up of 4 years [12]. In 2000, Barba et al. [15] reported a greater incidence of dementia after 3 months in 251 unselected consecutive stroke patients. Dementia was estimated in 30.1% and 27.5% of ischemic and hemorrhagic stroke patients, respectively (mean age: 69  13 years). This high frequency was explained by the inclusion of patients with pre-existing dementia before stroke (around 10% of patients). Conversely, in 2013, Douiri et al. [16], in a cohort of 1618 patients with stroke of all etiologies combined (including 169 ICH secondary to hypertensive microangiopathy or amyloid angiopathy; mean age: 71  12.7 years), found cognitive impairment in 13.1% of ICH cases during a 3-month follow-up, as defined by a MiniMental State Examination (MMSE) score < 24 or Abbreviated Mental Test score < 8. No details were reported of the severity of the VCDs. Finally, VCDs are reported just as frequently in ICH patients as in the ischemic stroke population, and are just as dependent on the known operational definition of VCI and selection criteria.

2.3.

Risk factors of VCDs

The first studies to investigate the predictive factors of cognitive decline were in cohorts grouping stroke regardless of their ischemic or hemorrhagic origins. In fact, only recently has the medical community’s attention been focused specifically on predictors of cognitive development in spontaneous ICH patients. The main results come from three large comprehensive longitudinal studies published in 2015 and 2016 [12,13,17]. Benedictus et al. [17] aimed to determine the prognostic factors for cognitive decline in 167 consecutive ICH survivors without pre-existing dementia over a median follow-up of 4 years. The annual change in MMSE scores was used as a marker of cognitive decline. Demographic characteristics (age, gender, education level), vascular risk factors (history of hypertension, diabetes mellitus, hypercholesterolemia, current smoking, alcohol consumption), medical history [previous stroke or transient ischemic attacks (TIAs), arterial fibrillation], pre-existing cognitive and functional status (IQCODE, modified Rankin Scale score), presence of depression, ICH characteristics (volume, location, multiple hemorrhages), magnetic resonance imaging (MRI) data (presence and location of microbleeds, severity in white matter, presence of lacunes, severity of cortical atrophy) and the occurrence of

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new stroke or TIAs during follow-up were included in their statistical models, which showed that 37% of patients exhibited cognitive loss during the median follow-up of 4 years. Results of multivariable analyses found that preexisting cognitive impairment, severity of cortical atrophy and previous stroke or TIAs were strong prognostic factors for cognitive decline following ICH. The authors demonstrated that the risk of cognitive decline post-ICH was associated with factors already present before ICH. These results were confirmed by two longitudinal studies, by Moulin et al. [13] and Biffi et al. [12]. As already mentioned, Biffi et al. reported that the yearly incidence of new-onset dementia was 5.8% in 435 ICH patients free of pre-existent cognitive decline. Clinical (age, education level, African race, incidence of mood symptoms) and radiological [ICH volume, lobar ICH location, computed tomography (CT) of white matter] variables were collected and introduced in multivariable analyses of risk factors for early and delayed dementia after ICH. Larger hematoma size and a lobar location of ICH were associated with early post-ICH dementia, but not delayed post-ICH dementia. Education level, incident mood symptoms and white-matter disorders were associated with delayed, but not early, post-ICH dementia. A few months earlier, Moulin et al. [13] had published data from a longitudinal study in a cohort with spontaneous lobar and non-lobar ICH free of pre-existing dementia. These authors investigated the association between baseline characteristics [demographic, clinical and radiological (CT) data on admission] and the risk of new-onset dementia. Independent risk factors, as reported in a backward stepwise multivariable analysis of risk for new-onset dementia in the overall ICH population, included lobar location of hematoma [subhazard ratio (SHR): 2.22, 95% CI: 1.30–3.79], severe leukoaraiosis (SHR for score  3: 2.88, 95% CI: 1.63–5.07), history of previous stroke or TIAs (SHR: 2.57, 95% CI: 1.43–4.62), older age (SHR per 10year increase: 1.84, 95% CI: 1.43–2.38), US National Institutes of Health Stroke Scale (NIHSS) score on admission (SHR per 5point increase: 1.20, 95% CI: 1.05–1.36) and new stroke or TIAs during follow-up (SHR: 3.22, 95% CI: 1.27–8.15). This analysis was repeated in a subgroup of patients with lobar ICH, and the results showed that severe leukoaraiosis (SHR for score  3: 2.70, 95% CI: 1.35–5.38), increases in cortical atrophy score (SHR per 1-point increase: 2.33, 95% CI: 1.25–4.35), pre-existing cognitive impairment (SHR: 3.84, 95% CI: 1.79–8.20), older age (SHR per 10-year increase: 1.75, 95% CI: 1.01–1.11) and NIHSS score (SHR 1 per 5-point increase: 1.42, 95% CI: 1.16– 1.74) were risk factors for new-onset dementia. In a second multivariable risk model, the authors focused on vascular lesions visible on MRI and associated with the incidence of new-onset dementia, including white-matter hyperintensities, cortical atrophy scores, presence of old macrohemorrhages, disseminated superficial siderosis and microbleeds (MBs). They showed that, in all ICH populations, disseminated superficial siderosis (SHR: 7.45, 95% CI: 4.27–12.99), cortical atrophy score (SHR per 1-point increase: 2.61, 95% CI: 1.70– 4.01), greater number of cerebral MBs (SHR for > 5: 2.33, 95% CI: 1.38–3.94) and older age (SHR per 10-year increase: 1.34, 95% CI: 1.00–1.79) were risk factors for new-onset dementia. When this analysis was also repeated in the subgroup with lobar ICH, the results revealed that disseminated

Please cite this article in press as: Planton M, et al. Impact of spontaneous intracerebral hemorrhage on cognitive functioning: An update. Revue neurologique (2018), http://dx.doi.org/10.1016/j.neurol.2017.06.010

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superficial siderosis (SHR: 7.25, 95% CI: 3.76–13.97), cortical atrophy (SHR per 1-point increase: 6.68, 95% CI: 2.29–19.50), old macrohemorrhages (SHR: 3.6, 95% CI: 1.74–7.44) and older age (SHR per 10-year increase: 1.55, 95% CI: 1.03–2.33) were again risk factors for new-onset dementia. Thus, the authors confirmed their previous findings that the prognostic factors for cognitive decline after ICH were already present when ICH happened, suggesting a process of ongoing cognitive impairment instead of new-onset decline induced by ICH itself. The authors also suggested that the underlying CAA seemed to be a contributing factor to new-onset dementia in lobar ICH. These results are consistent with those of neuropathological studies, where evidence suggests a frequent association of CAA in older adults and especially in those with AD [18,19]. This conclusion is also in accordance with the previous findings of Cordonnier et al. [9], described above, wherein risk factors for pre-existing dementia in lobar ICH were increasing age, having < 8 years of education and increased cortical atrophy.

2.4. ICH

Neuropsychological profiles and pathophysiology of

Studies of ICH patients often use screening instruments to assess cognitive function, such as the MMSE and Montreal Cognitive Assessment (MoCA) [20,21]. In addition, while ischemic stroke research commonly uses a specific topographical organization, most ICH studies focus on differences between lobar and non-lobar hemorrhage. However, such unification of regions can mask the influence of any one particular region, a concept suggested by reviews analyzing strategic deep ICH separately from deep ICH. Whereas previously the Garcia et al. [14] study described the frequency of VCDs, the authors also looked at the neuropsychological profiles of the same 48 patients over a median follow-up of 40 months post-ICH. They found alterations in episodic memory (in 52% of cases), information-processing speed (44%), executive function (37%), language skills (35%), and visuospatial and visuoconstructive ability (19%). To our knowlegde, their cross-sectional study was the first to make a detailed report on cognitive processess and dementia data. Su et al. [22] in 2000 focused on perceptual function in a sample of stroke patients with hemorrhagic and ischemic presentations. These patients were matched by age, gender, education, disease duration and hemispheric laterality. A total of 22 ICH patients were matched to 22 ischemic stroke patients (mean age: 59.6  11 years) and compared using a battery of standard perceptual cognitive tests [Loewenstein Occupational Therapy Cognitive Assessment (LOTCA), Rivermead Perceptual Assessment Battery (RPAB) and Motor-free Visual Perception Test (MVPT)] within 3 months of stroke onset. In the ICH group, 82% had basal ganglia lesions and 18% had thalamic lesions, but with no information on the causes of hematomas. In the ischemic group, 14% had cortical lesions, 73% had subcortical lesions, and 13% had both cortical and subcortical lesions. The only difference between these two groups, observed after a median time from symptom onset of 52 ( 26) days, was noted in the perceptual domain of thinking operations (the LOTCA battery), which involves categorization and seriation

processes representative of executive functions, with lower scores in the ICH group. These findings were also consistent with those of some earlier work [23,24].

2.4.1.

Cerebral amyloid angiopathy

Spontaneous lobar ICH in the elderly is usually due to CAA, and spontaneous CAA is a common age-related cerebral small-vessel disease characterized by deposition of amyloidbeta (Ab) in the walls of cortical and leptomeningeal vessels, leading to loss of smooth muscle cells [25]. CAA-related ICH is associated with a high risk of recurrence. Risk factors for lobar ICH recurrence include high blood pressure, greater number of cerebral MBs, presence of APOE e2 and/or e4 alleles, and use of antithrombotic agents. Recently, cortical superficial siderosis (cSS) was identified as a strong neuroimaging marker of CAA and was thus included in the modified Boston criteria for CAA diagnosis [26]. A definite CAA diagnosis requires a full postmortem neuropathological examination. It has also recently been confirmed that CAA could result in mild and major VCDs, independent of AD dementia. Epidemiological and neuropathological data indicate considerable overlap between CAA and AD. A mild degree of CAA is present in around 80% of AD patients [18], while around 50% of patients who die of CAA-related ICH meet criteria for AD [19]. This suggests additive or synergistic effects between the two pathologies to promote more severe cognitive decline. In addition, three studies have established correlations between neuropathological findings and cognitive scores suggesting an independent effect of CAA, even after controlling for AD [27– 29]. One of these studies described the cognitive profiles of elderly subjects, belonging to the Catholic order, who had moderate to very severe CAA pathological abnormalities at autopsy, and lower levels of perceptual speed and episodic memory compared with very few or no CAA patients [27]. More recently, Xiong et al. [30] detailed the neuropsychological outcome of a probable-CAA population (n = 58) with a history of ICH (mean age: 70.3  7.8 years): patients showed significantly poorer cognitive performance in all cognitive domains compared with 138 healthy controls. The most altered functions were processing speed (mean z-score: –1.92  1.56 SD vs. controls) followed by executive (–0.93  1.01), episodic memory (–0.87  1.29), semantic fluency (–0.73  1.06) and attentional (–0.42  0.98). The authors also found correlations between total brain volume and processing speed and executive functions. These findings also confirm those of a recent study in a similar cohort using diffusion tensor imaging (DTI). Reijmer et al. [31] observed significantly reduced efficiency of the brain structural network in 38 non-dementia probable-CAA patients (17 with symptomatic ICH, mean age of all CAA patients: 71.3  7.1 years), which was related to poorer performance in processing speed and executive functions, confirming impairment predominantly in the executive domain. Moreover, those authors recently showed that brain network impairment in the hemisphere free of ICH in CAA patients progresses from posterior to frontal connections with increasing disease severity [32], while global thinking efficiency is related to the total amount of lesional changes in the brain. That same year, Case et al. [33] analyzed cognitive data from 34 probable-CAA patients and compared their scores to those of 16 AD patients, 69 patients with mild cognitive

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impairment (MCI) and 27 ischemic stroke patients. CAA patients were assessed 90 days after symptomatic ICH together with presentation of ICH or a CAA-related syndrome (mean age: 73  7.6 years). In the CAA group, they found low executive function scores, but relatively preserved memory scores in comparison to AD patients. CAA patients also had memory and executive scores similar to those of MCI patients, but slower processing-speed performance. Compared with the ischemic stroke group, CAA patients had lower executive and processing-speed scores. Thus, executive function seems to be preferentially altered in CAA patients, suggesting a specific and different neuropsychological profile from those with AD. Nevertheless, all of the above studies used composite cognitive scores with few variables for each domain, which may have disguised cognitive processes and made it more difficult to determine the source of the poor performance. In the same field of research, our present team conducted a study to determine the prevalence and patterns of VCDs in 20 patients with CAA-related ICH, and compared these data with those of 20 patients with MCI due to AD, 20 hypertensionrelated deep ICH patients and 17 healthy controls [34]. Each participant underwent comprehensive neuropsychological assessment (at a mean of 4 months in the ICH groups) and brain MRI. The ICH patients with pre-existing cognitive decline (IQCODE scores  3.4) were excluded from the analysis. The prevalence of cognitive disorders was estimated using VASCOG criteria. The average age across the four groups was 70 ( 7.2) years. The first results revealed that VCDs were very frequent 4 months after ICH in deep and CAA-related ICH, while major and mild VCDs were observed in 2.5% and 87.5% of all ICH patients, respectively. No significant difference was observed in cognitive function between CAA and deep ICH patients, a finding that was explained by the presence of extensive and multidomain cognitive impairment in both groups. In deep ICH, neuropsychological outcome were essentially explained by the strategic location of the ICH (72.5% of strategic lesions). Compared with the control group, the most impaired process in the CAA group was naming, with a mean ( SD) z-score of –5.2  5.5, followed by processing speed (–4.1  3.3), executive functions (–2.6  2.5), memory (– 2.4  3.5) and attention (–0.9  1.3). CAA patients were statistically different from MCI–AD patients in gestural praxis and, not surprisingly, memory processes. These findings highlight the high frequency and severity of VCDs in ICH groups, with a pattern of cognitive dysfunction that differs from the effects of AD pathology. The mechanisms underlying cognitive decline in CAA remain undetermined, but appear to be dependent on cumulative structural and functional changes. A research team recently emphasized the need to develop new markers of CAA and has suggested that one might be cognitive decline [35]. The recent development of brain amyloid imaging in ICH populations could also help to make a CAA diagnosis in vivo; its potential diagnostic value is currently being studied.

2.4.2.

Hypertensive vascular changes

High blood pressure (HBP) is an important modifiable risk factor for cerebrovascular disease and both ischemic and hemorrhagic stroke [36]. HBP is the initial cause of sponta-

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neous ICH, and its presence is twice as frequent in patients with deep ICH than with spontaneous lobar ICH. In fact, the diagnosis of hypertension-related ICH is made on the basis of ICH location in the deep or infratentorial regions and a history of hypertension [37]. Some longitudinal studies have highlighted an association between HBP in midlife and dementia in later life [38,39]. The literature on cognition following deep ICH is not extensive. Most studies only describe the neuropsychological impact of strategic lesions as either caudate or thalamic. The first study, in 1959, was by Fisher et al. [40] and described aphasia after thalamic hemorrhage. Strategic lesions in the thalamus, caudate nucleus and putamen, and internal capsule, frequently produce complex cognitive and behavioral symptoms and can lead to major VCDs, especially after massive destruction of frontal–subcortical pathways or in the event of bilateral lesions. As already mentioned, cognitive deficits reported after strategic hemorrhages include aphasia/fluency, as well as memory, visuospatial ability and executive function disorders [41–43]. Neglect and anosognosia are also frequently reported after thalamic hemorrhages [44]. Two well-conducted studies focused on putaminal hemorrhages with a comprehensive neuropsychological assessment in ICH survivors. In 2007, Su et al. [45] assessed attention, memory, visuospatial ability, language and executive function through numerous specific cognitive tests in spontaneous first-ever basal ganglia ICH patients within the first 6 months of stroke (97  40 days post-ICH) in 30 patients, with a mean age of 53.8 ( 8.3) years, compared with 37 healthy controls. A criterion of –2 SD vs. healthy controls was selected to define altered performance. Hematoma was restricted to the putamen in 83% of patients and was in the right hemisphere in 70% of cases. Neuropsychological scores for ICH patients were lower in all cognitive domains, with 97% of deep ICH patients showing altered performance on at least three such tests. One explanation proposed by the authors for this high rate of VCDs was that these patients were less educated and, in particular, had been assessed soon (within 1–6 months) after their stroke. Cognitive disorders were more restricted in the Kokubo et al. [46] study of 15 patients with first-ever putaminal ICH (mean age: 53  10.2 years), assessed 2 months after onset and compared with 15 healthy matched controls. Their data indicated that isolated putaminal hemorrhage led to executive dysfunctions, with poorer performance on letter– number sequence tests in the Wechsler Adult Intelligence Scale (WAIS III), lexical fluency, motor series subtest of the Frontal Assessment Battery and the Wisconsin Card Sorting Test, whereas general cognitive efficiency and memory performance were not affected. None of the patients showed signs of aphasia, apraxia or spatial neglect. In the same way, behavioral and psychiatric symptoms, including apathy and personality changes, were unexpectedly not observed in any patient’s neuropsychiatric inventory. The absence of mood disorders, usually frequent in this population of patients, was explained by the authors by the fact that most other studies involved more extensive lesions, including not only the caudate nucleus, but also neighbouring structures such as the anterior putamen and internal capsule [47,48].

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2.5. Impact of ‘silent lesions’ on neuropsychological outcome Patients with ICH demonstrate a higher prevalence of neuroimaging markers of underlying cerebral small-vessel disease compared with the general elderly population [12,49]. Accumulation of intracerebral vascular lesions has an additive or perhaps synergistic effect on VCD severity and is strongly linked to dementia [12,13]. In the absence of cognitive data with enlarged perivascular spaces and lacunar infarcts in ICH patients, only the consequences of white-mater hyperintensities, brain MBs and cSS can be discussed.

2.5.1.

White-matter hyperintensities

These are a reflection of demyelination and axonal loss secondary to chronic ischemia in white matter. There is consensus concerning their involvement in VCDs. While the initial research was uncertain, numerous studies since 2005 have found an association of vascular leukoencephalopathy with decreases in processing speed and poorer performance of executive functions [50,51], and sometimes of memory [52], in population-based patients and cohorts with ischemic and with hemorrhagic stroke [53,54].

2.5.2.

Brain microbleeds (MBs)

These are defined as small foci of chronic blood products, which are most likely caused by structural abnormalities of small vessels of the brain. Their distribution may reflect underlying pathological changes, with lobar MBs presumably related to CAA, whereas MBs in the deep and infratentorial regions are mostly associated with hypertensive microangiopathy [55,56]. Histopathological studies have shown that the presence of MBs indicates widespread damage in arterioles due to hypertension or amyloid deposition, as well as surrounding gliosis, or even frank necrosis or infarction, resulting in microstructural damage to the surrounding white matter [57,58]. Thus, MBs appear to interfere with the whitematter tracts underlying cognitive functions. The influence of the location and presence of MBs on other small-vessel markers of cognitive functions has been recognized in the general population [59,60], in elderly patients with small-vessel disease [61,62] and in stroke populations [12,13,63]. In the study by Moulin et al. [13], the presence of five or more MBs was identified as an independent risk factor for new-onset dementia in ICH patients. The presence of MBs is also frequently associated with global cognitive scores, and sometimes with executive and attentional disorders. However, most studies using comprehensive neuropsychological assessments were inconclusive due to the small number of subjects with MBs. In 2015, Gregg et al. [64] evaluated the association of incidental MBs with restingstate cerebral blood flow (CBF), using MRI arterial spinlabeling sequences, and cognition in 55 normal elderly subjects (mean age: 86.8  2.7 years). They also investigated the relationship between MBs and fibrillary Ab. Subjects with cortical MBs had a 25% reduction in resting-state CBF compared with those with other MBs (subcortical, cerebellar, brainstem), with the largest reductions in the frontal, parietal and precuneus cortices. No difference was found in CBF between subjects with all types of MBs and no MBs.

Analyses of cognition between patients with or without cortical MBs showed a trend towards cognitive impairment, with 45% vs. 19%, respectively, having a non-zero global Clinical Dementia Rating scale score. Also, no difference was reported in cortical amyloid uptake between those with and without MBs.

2.5.3.

Cortical superficial siderosis (cSS)

This reflects linear residues of blood in either the subarachnoid space or superficial layers of the cerebral cortex, and appears to be a strong new marker for CAA; it is now included in the modified Boston criteria [65,66]. In clinical practice, there are two ways to observe cSS as brain MBs. First, it may be discovered in memory clinics when structural brain MRI is performed for etiological assessment of cognitive impairment. In this context, there have been four US studies of the interaction between cSS and cognition to evaluate its prevalence in subjects followed by consultations [67–70]. Second, neuropsychological data may become available when patients are enrolled in stroke units as a result of ICH secondary to CAA or subarachnoid hemorrhage. Only the work of Moulin et al. [13] on post-ICH cognitive decline dealt with this question, albeit in a roundabout way. The accumulation of iron in neurons in the cerebral cortex has toxic effects beyond the cognitive alterations associated with the underlying disease. This is all the more so as a number of particular clinical phenomena, such as transient focal neurological episodes (TFNE), also called ‘amyloid spells’, seem to be associated with cSS, thereby advocating its specific clinical expression [71]. In parallel, cSS may reflect a subtype of CAA with possibly a specific neuropsychological profile. In 2014, Wollenweber et al. [69] investigated the frequency of cSS in 212 patients (mean age: 74  7.5 years) with cognitive impairment recruited at a memory clinic: cSS was observed in 6.1%, was more frequent in men, and was significantly correlated with lower scores on the MMSE, and with more white-matter hyperintensities and MBs. As already mentioned, however, it is difficult to draw any conclusions as to the possible impact of cSS on cognition, as other confounding factors of microangiopathy were significantly less important in the control group. Also, this cSS rate was higher than those of two other studies conducted in memory clinic populations (3%, 2.7% and 2.1%, respectively) [67,68,70] and significantly higher than in the general population (0.7%) [72]. These findings question the comorbidity, more frequent with age, between AD pathology and CAA, and are suggestive of a mixed distribution of Ab protein in the central nervous system. Such a distribution, which is both vascular and parenchymal, could be partly mediated by genetic factors. Charidimou et al. [73] reported that the e2 allele of the apolipoprotein E (APOE) gene was associated with both ICH and disseminated cSS in CAA patients, whereas CAA patients without ICH were more likely to be carriers of the APOE e4 allele. Among cohorts of spontaneous ICH patients, Moulin et al. [13] showed that disseminated cSS is an independent prognostic factor of postICH cognitive decline (SHR: 7.45, 95% CI: 4.27–12.99), and has also been identified as an independent imaging marker of increased risk for early recurrent ICH, as was acute convexity subarachnoid hemorrhage (cSAH) [74]. In addition, Le Scanff

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et al. [75] have reported on two patients who presented with progressive cognitive impairment, with dementia as the primary manifestation of cSS. Surprisingly, these two patients experienced rapid cognitive decline, which generally arises later in cSS and is usually not severe. A correlation between cognitive profiles, especially executive and visuoconstructive dysfunctions, and cSS in the frontoparietal lobes, was observed. No vascular lesion was documented in the first case, and no details were provided in the second case.

2.6.

Mood disorders in ICH survivors

ICH located in critical circuits of mood control, such as the basal ganglia and prefrontal lobe, may lead to complex behavioral symptoms in addition to reactions to the neurological condition. Most of the evidence for vascular mood disorders comes from studies of white-matter changes or indirectly from studies of ischemic post-stroke depression. In ICH populations, only four publications were identified as dealing with this topic: the first three were cohort studies [14,20,34], and the third was a case report [76]. In the Garcia et al. [14] study detailed above, the reported rate of depression was 23% in ICH patients, whereas anxiety without depression was observed in four out of 48 cases (8%). Koivunen et al. [20] described mood disorders in 336 young ICH patients (median age: 42 years, IQR: 34–47) after a median follow-up of 9.7 years (7.0–12.0) from the onset of symptoms. Structured questionnaires for depression [Beck Depression Inventory (BDI)-II], anxiety [Hospital Anxiety and Depression Scale (HADS)] and pain symptoms [Pain Anxiety Symptoms Scale (PASS) and Brief Pain Inventory (BPI)] were also used, while fatigue was estimated by three fatigue-related questions in the BDI-II. Depression was estimated to be present in 23.3% of cases and anxiety in 40%, while pain-related anxiety was found in 19.2% of patients. Fatigue was observed in 53.8% of patients and 3.8% reported difficulty carrying out their daily activities of life. In Planton et al. [34] study, depression was reported in 27,5% of all ICH patients. Thus, behavioral and mood disorders are frequent, but underdiagnosed.

3.

Conclusion

Vascular-related cognitive and behavioral disorders frequently arise after ICH; yet remain underdiagnosed. This suggests the need for ICH outcome research to include longitudinal and extensive cognitive examinations, and separation of the effects on cognitive outcome of acute bleeding events vs. any potential underlying disease processes. In addition, future studies should emphasize behavioral, mood and quality-of-life data in ICH, as these are currently lacking. The percentages and profiles of VCDs, irrespective of the diagnosis of dementia, should also be used to elucidate the recovery curve of cognitive functions.

Disclosure of interest The authors declare that they have no competing interest.

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