Maturitas Vascular cognitive impairment in dementia
Transcription
Maturitas Vascular cognitive impairment in dementia
Maturitas 79 (2014) 220–226 Contents lists available at ScienceDirect Maturitas journal homepage: www.elsevier.com/locate/maturitas Review Vascular cognitive impairment in dementia Christopher D. Etherton-Beer a,b,∗ a Western Australian Centre for Health & Ageing (M573), Centre for Medical Research, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia b Department of Geriatric Medicine, Royal Perth Hospital, 197 Wellington Street, Perth, WA 6000, Australia a r t i c l e i n f o Keywords: Dementia Vascular Cerebrovascular disorders Cerebral infarction Brain ischaemia a b s t r a c t Vascular risk factors and cerebrovascular disease are common causes of dementia. Shared risk factors for vascular dementia and Alzheimer’s disease, as well as frequent coexistence of these pathologies in cognitively impaired older people, suggests convergence of the aetiology, prevention and management of the commonest dementias affecting older people. In light of this understanding, the cognitive impairment associated with cerebrovascular disease is an increasingly important and recognised area of the medicine of older people. Although the incidence of cerebrovascular events is declining in many populations, the overall burden associated with brain vascular disease will continue to increase associated with population ageing. A spectrum of cognitive disorders related to cerebrovascular disease is now recognised. Cerebrovascular disease in older people is associated with specific clinical and imaging findings. Although prevention remains the cornerstone of management, the diagnosis of brain vascular disease is important because of the potential to improve clinical outcomes through clear diagnosis, enhanced control of risk factors, lifestyle interventions and secondary prevention. Specific pharmacological intervention may also be indicated for some patients with cognitive impairment and cerebrovascular disease. However the evidence base to guide intervention remains relatively sparse. © 2014 Elsevier Ireland Ltd. All rights reserved. Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aetiology and convergence of risk factors for the major dementias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomic and functional correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical correlates and differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of vascular cognitive impairment in dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What is the current state of the art? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ∗ Correspondence to: Western Australian Centre for Health & Ageing (M573), Centre for Medical Research, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia. Tel.: +61 8 9224 2750; fax: +61 8 9224 8009. E-mail address: [email protected] http://dx.doi.org/10.1016/j.maturitas.2014.06.004 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved. 221 221 221 221 221 222 222 223 224 224 224 225 225 225 225 225 225 225 C.D. Etherton-Beer / Maturitas 79 (2014) 220–226 221 1. Introduction Ageing populations face an increase in disease burden from chronic neurodegenerative conditions. Dementia will be a major contributor to this increased burden [1]. Cerebrovascular disease is thought to be the second most common cause of dementia and a spectrum of cognitive disorders related to cerebrovascular disease is now recognised [2]. Accordingly, the cognitive impairment associated with brain vascular disease is an increasingly important and recognised area of the medicine of older people. Despite the critical importance of dementia, there is still inconsistent definition of the major sub-types. There is increasing recognition that many, if not most, older people with dementia have mixed, or overlapping, disease due to both vascular and Alzheimer’s type changes. However the concept of “mixed dementia” remains variably recognised and operationalised. In this context, the nature, importance and management of vascular cognitive impairment are reviewed. 2. Methods This narrative review provides a brief overview of traditional teaching, and more recent research findings, relevant to clinical practitioners in the field ordered using a clinical approach. In addition, the “state of the art” was specifically considered in a search of the Medline indexed English language human studies published in the last 12 months (to April 2014) using the search terms “dementia” or “Alzheimer disease”, and “cerebrovascular disorders” or “stroke” or “cerebral infarction” or “brain ischemia”. Studies not specifically related to the relationship between cerebral vascular disease and cognitive impairment/dementia were excluded, as well as protocol papers and letters. 3. Clinical definitions Traditional teaching described vascular (or “multi-infarct”) dementia as the second leading type of dementia, usually with relatively abrupt onset and stepwise decline, related to multiple large volume or lacunar brain infarcts. Also included were people who may have had fewer strokes, but the strategic position of the lesions(s) and temporal relationship to the onset of cognitive impairment suggested aetiological relevance. Increasingly a broader spectrum of cognitive disorders associated with brain cerebrovascular disease has been recognised. It is now accepted that diffuse white matter disease (as distinct from circumscribed infarction) is a common cause of vascular cognitive impairment [3]. This spectrum includes people who may not be aware of ever having had a “stroke” or brain vascular disease, but who nonetheless have sub-cortical (white matter) disease [4] sufficient to cause clinically relevant cognitive and physical signs. Reflecting this progression in the understanding of brain vascular diseases, DSM now refers to major and mild vascular neurocognitive disorder, and continues to provide specific criteria for an assumed vascular basis of the cognitive impairment [5]. “Vascular cognitive impairment” is the descriptor now in general use encompassing this spectrum of vascular brain disorders [6]. In addition to the DSM criteria, several other clinical criteria and scoring systems have been utilised. Early scoring systems [7] distinguished presumed vascular ischaemic aetiology based on the history of abrupt onset, stroke, or hypertension, the presence of hypertension or focal neurological symptoms or signs, a stepwise deterioration, somatic complaints and emotional lability. Subsequent criteria also included imaging evidence of cerebrovascular disease and additional clinical features such as the early presence of a gait disturbance or falls, incontinence, pseudobulbar palsy, and additional neuropsychiatric signs (personality change, Fig. 1. Periventricular hypodensity, and atrophy, on CT. abulia, depression, psycho-motor retardation and impaired executive function) [8,9]. 4. Aetiology and convergence of risk factors for the major dementias Age and the major traditional vascular risk factors (hypertension, smoking, diabetes and hypercholesterolemia) account for the majority of a person’s lifetime risk of cardiovascular events [10]. The presence of vascular risk factors such as hypertension and diabetes in midlife is negatively associated with subsequent cognitive function in older age [11,12]. In addition to predicting atherosclerotic disease, these “vascular” risk factors also predict, and appear to promote development of, Alzheimer’s disease [13,14]. Data regarding the progression over time of established Alzheimer’s dementia are not conclusive, but suggest association of vascular risk factors with progression of cognitive decline in some groups of patients [15]. Other shared risk factors for both vascular and Alzheimer’s disease include hyperhomocysteinaemia [16,17], inflammation [14,18], and genetic variants [19]. Depression is a possible further shared risk factor for both vascular and Alzheimer’s dementia [20], although residual confounding (for example, by subcortical brain vascular disease) cannot be excluded. Traditional teaching has emphasised the presumed atherosclerotic aetiology of white matter disease. However white matter changes may relate both to arteriolar disease and venulopathy, as well as other processes such as ependymal leakage, oedema due to blood brain barrier disruption and endothelial activation [35]. Venular disease may be particularly important in the typical periventricular white matter changes seen around the anterior and posterior horns (Fig. 1) [35]. 5. Epidemiology Given that dementia and vascular disease are strongly age related, population ageing will be associated with absolute increases in the overall burden of dementia and stroke. Stroke and dementia frequently co-exist; around one in ten patients have dementia prior to their first stroke, increasing to one in five within 222 C.D. Etherton-Beer / Maturitas 79 (2014) 220–226 the first year after first stroke, and over one in three within the first year after recurrent stroke [21]. Relatively, chronic neurodegenerative conditions (of which dementia is foremost) are anticipated to be an increasingly important cause of death and disability [1]. Age standardised death rates from Alzhemier’s dementia are increasing [22]. This increase in the relative importance of mortality from dementia is in the context of substantial decreases in incidence of, and mortality associated with, cardiovascular and cerebrovascular disease [23]. These improvements are thought to be related to more effective control of traditional vascular risk factors, as well as enhanced medical interventions and care (such as coronary care units). 6. Anatomic and functional correlates Traditional teaching emphasised the distinct pathological processes of vascular disease and neurodegeneration secondary to Alzheimer’s pathology. These distinctions now appear to be less relevant clinically, given that people surviving to old age frequently have co-existent changes of both Alzheimer’s type pathology and vascular disease [24]. Healthy adults have substantial cerebral reserve and thus many older people have sub-clinical disease. For example, it is not uncommon for an older person with no memory complaints to have imaging evidence of vascular brain disease. The commonest imaging findings, mild periventricular changes, may have limited clinical impact on the patient’s cognitive function or gait [25]. It may be intuitive to assume that large volume brain changes are more likely to be associated with clinically obvious cognitive impairment. However, cognitive impairment appears to be common after both lacunar (small volume) and non-lacunar stroke [3], perhaps in part because of the common association of lacunes with small vessel disease. Brain changes of established ischaemic vascular disease appear hypodense (dark) on CT, hypointense (dark) on T1 weighted MRI and hyperintense (bright) on T2 weighted MRI sequences [26]. Whilst specific stroke lesions are usually circumscribed they are heterogeneous, ranging from small, deep lacunar infarcts to large volume hemispheric infarcts, and from single to multiple (Fig. 2) synchronous acute lesions. Subcortical white matter (in distinction from cortical “grey matter”) changes may be punctate, or when advanced, more confluent. Periventricular changes are usually most pronounced around the anterior and posterior horns of the lateral ventricles. Deep white matter changes are sub-cortical changes that are not immediately periventricular. Subcortical changes are commonly described as “small vessel disease” (in distinction to stroke due to large artery embolism). Other historical terms (such as the eponymous “Binswanger’s disease”) are descriptions of advanced subcortical disease, and the associated clinical syndrome. These terminologies can be used imprecisely, leading some authors to propose new nomenclature [27]. In addition to ischaemia, white matter disease is associated with micro-haemorrhage. Increasing use of (more sensitive) MRI has revealed that micro-bleeds are more common than previously appreciated [28]. Like large volume bleeds, the distribution of micro-bleeds is thought to vary according to aetiology, with lobar micro-bleeds being suggestive of amyloid angiopathy and involvement of deep structures such as the basal ganglia and thalamus more suggestive of a hypertensive aetiology [28]. Atrophy is another common structural brain change identified on imaging. Although it is usually assumed that substantial atrophy is clinically relevant, maximal brain volume may confound observed associations between atrophy and cognitive deficit [29]. Semi-quantitative rating of brain images is both reliable and valid [30]. Sulcal widening (SW) and ventricular enlargement (VE) can be rated by comparison to a standard reference image that shows moderate brain changes. Periventricular white matter changes (PVWMC) and deep white matter changes (DWMC) can be rated using the method originally described by Fazekas et al. [31] (Fig. 3). For PVWMC, a rating of ‘0’ indicates no changes, ‘1’ indicates ‘caps’ or pencil-thin periventricular bands, ‘2’ indicates a smooth ‘halo’ and 3 indicates irregular periventricular changes extending into deep white matter. For DWMC ‘0’ indicates no changes, ‘1’ indicates punctate foci, ‘2’ beginning confluence of foci and ‘3’ large confluent areas. Stroke is a risk factor for cognitive impairment and vice versa [21], suggesting an interplay between the pathophysiologic processes underlying both clinical conditions. Specifically, there are several potential mechanisms for interaction between brain vascular disease and Alzhemier’s disease, both at the biological and clinical levels. At the biological level shared pathophysiology (including increased oxidative stress, impaired vascular function [32], and arterial stiffness [33]), and direct interactions between the two pathological processes (such as ischaemia promoting Alzheimer’s pathology, and vice versa) may be relevant [13]. At the clinical level, vascular disease could contribute to, or unmask, cognitive impairment also contributed to by Alzheimer’s type changes, and vice versa [14]. 7. Clinical correlates and differential diagnosis Fig. 2. Multiple acute infarcts (hyperintensity) demonstrated on diffusion weighted MRI. Structural vascular brain disease is thought to cause cognitive impairment through strategic cortical infarcts, infarction of the basal ganglia or thalamus, or disruption of white matter tracts by lacunar infarcts or small vessel disease. Strategic infarcts will cause a pattern of cognitive deficits according to the infarct location [34]. Subcortical vascular cognitive impairment is characterised by relative preservation of memory with impaired cognitive speed, attention and executive function (including impaired initiation, planning and sequencing). Important additional behavioural or psychiatric features can include depression, apathy, and psychosis [6,26]. Early findings (such as a modest degree of cognitive slowing) are often compensated, and in the absence of functional impairment a high index of clinical suspicion is required. In addition, executive dysfunction may not be detected by screening tools in common use (such as the Mini Mental State Examination). Because C.D. Etherton-Beer / Maturitas 79 (2014) 220–226 223 Fig. 3. Fazekas scale grading of white matter hyperintensities reproduced with permission, see acknowledgements. of the cognitive slowing and psychomotor retardation that can be associated with brain vascular disease, depression is an important differential diagnosis. Larger volume (anterior and posterior circulation) and lacunar infarcts are associated with characteristic clinical syndromes [35]. In addition to the cognitive changes, it has long been appreciated that substantial ischaemic brain disease is commonly associated with clinical features including bilateral upper motor neurone signs (such as brisk reflexes), gait disorder and urinary incontinence [36]. The characteristic parkinsonian gait disorder (“vascular parkinsonism”, “marche a petits pas”, “magnetic”, “apraxic–ataxic”) may be associated with a history of unsteadiness and frequent, unprovoked falls. Vascular disease is thought to cause at least 5% of cases of parkinsonism in older people [37]. The physical signs are sometimes characterised as “lower half parkinsonism” because of the parkinsonian gait disorder, but absence of prominent upper body signs of idiopathic Parkinson’s disease, such as tremor. The signs are also often bilateral, whereas idiopathic Parkinson’s disease tends to cause prominent asymmetric signs such as tremor and rigidity. Clinical findings are important to clarify the relevance of structural changes noted on brain imaging. For example, if a patient is free from physical signs, modest white matter changes on imaging may be of uncertain clinical significance. However, imaging findings of substantial vascular brain disease are likely to be clinically relevant in a patient with upper motor neurone signs, gait disorder and a pattern of subcortical cognitive impairment. 8. Prevention Given the challenge of reversing established brain vascular disease, prevention is a cornerstone of management. Lifestyle interventions, including physical and cognitive activity are often recommended to maintain wellbeing in middle and later life. There is evidence that physical activity has beneficial effects on endothelial function [32] and may prevent cognitive impairment [38]. Improved control of vascular risk factors in mid-life is assumed to be a key strategy to reduce the burden of vascular cognitive impairment in ageing populations. Controlled (but non-randomised) data support the notion that an active prevention programme (targeting treatment of vascular risk factors in middle aged people) can reduce the need for long term care, by about 10% [39]. However, uncertainties persist regarding the benefits of specific pharmacotherapies in prevention of cognitive impairment. Despite epidemiologic evidence suggesting that statins reduce the risk of Alzheimer’s disease, 224 C.D. Etherton-Beer / Maturitas 79 (2014) 220–226 Table 1 State of the Art: brief summary. Study Participants Main finding Associations between serum cholesterol levels and cerebral amyloidosis (Reed 2014 [49]) 74 older people recruited from clinics or the community, most with normal cognition (n = 33) or mild cognitive impairment (n = 38) 177 older adults free from stroke or cognitive impairment Higher low density lipoprotein cholesterol and lower high density lipoprotein cholesterol levels, but not statin use, were independently associated with a greater burden of cerebral amyloid Pulse pressure was independently associated with cerebrospinal fluid biomarkers of Alzheimer’s disease 203 patients with amnestic mild cognitive impairment In people converting to AD (n = 74) WMHs were associated with decreased frontal, but not temporoparietal, metabolism. In contrast, low cerebrospinal fluid -amyloid (a biomarker of Alzheimer’s disease) was associated with temporoparietal, but not frontal, hypometabolism Cerebral atherosclerosis was positively associated with vascular disease but not Alzheimer’s type disease pathology. Cerebral amyloid angiopathy was inversely associated with lacunar infarcts and positively associated with Alzheimer’s type changes Impaired executive function predicted stroke and Alzheimer’s disease. Low total brain volume and white matter hyperintensity volume were associated with stroke, but not Alzheimer’s disease. In contrast, low hippocampal volume predicted Alzheimer’s disease Association of pulse pressure with biomarkers of Alzheimer’s disease in cognitively normal older adults (Nation 2013 [50]) Association of Alzheimer’s disease markers and white matter hyperintensities (WMH) with brain metabolism (Haight 2013 [51]) Association of cerebral atherosclerosis with vascular, but not Alzheimer’s type, pathologic changes (Zheng 2013 [52]) Autopsy sub-study (n = 163) of participants from a longitudinal study of subcortical ischaemic vascular disease, Alzheimer’s disease, and normal ageing Brain imaging and cognitive predictors of stroke and Alzheimer’s disease in the Framingham Heart Study (Weinstein 2013 [53]) 1679 Framingham offspring (age >55 years; mean, 65.7 ± 7.0) free from dementia and stroke intervention trials to date have failed to demonstrate that statin therapy can prevent the development of cognitive problems [40]. Similarly, despite the epidemiologic evidence identifying hypertension as a risk factor for cognitive impairment, the overall randomised data do not conclusively demonstrate that antihypertensive therapy can prevent cognitive impairment [41]. 9. Treatment of vascular cognitive impairment in dementia Although traditional teaching was that nervous system lesions were essentially irreversible, the potential for plasticity of the nervous system is increasingly recognised. Neuroplasticity persists in ageing brains, and facilitates recovery from acute stroke lesions [42]. The potential for plastic remodelling in the face of neurodegeneration or chronic small vessel disease is less well understood. Systematic review of the randomised studies of cognitive rehabilitation or cognitive training in people with dementia suggests limited efficacy, although the current evidence base is, overall, limited and not of high quality [43]. Despite this uncertainty consensus indicates that modifiable lifestyle factors (including diet, and physical and cognitive activity) are addressed when this is clinically appropriate. Generally these aspects of a choosing a healthier lifestyle are indicated for improved wellbeing for many older people. Other simple non-pharmacologic interventions, such as withdrawing medicines with adverse cognitive effects, and ensuring good sleep hygiene are helpful to optimise cognitive function. Although many studies have evaluated agents that could potentially promote neuroplasticity or be used as treatments for nervous system injury, particularly in patients with stroke [42], pharmacotherapy largely focuses on secondary prevention and symptomatic interventions. There are also some positive clinical data regarding the use of aspirin and nimodipine [44,45] in patients with vascular cognitive impairment. Cholinesterase inhibitors and memantine have modest effects in treatment of patients with Alzheimer’s disease, and there are data suggesting that these agents also have some efficacy in treatment of subjects with vascular or mixed dementia. Overall the efficacy of these agent appears to be very modest [46], and may thus not be clinically important for many patients. Efficacy of rivastigmine for treatment of vascular cognitive impairment has been systematically reviewed most recently [47]. Three trials (n = 800) were included, but most data were from one trial (n = 710). In this trial randomisation to rivastigmine therapy (mean dose 9.4 mg) was associated with a statistically significant difference of 0.6 points on the mini-mental state examination, as well as an increase in gastrointestinal adverse events and a doubling in odds of withdrawal from therapy. If a parkinsonian gait is present, a trial of dopaminergic therapy is sometimes indicated to determine whether the patient is dopamine responsive. Parkinsonism due to vascular disease is generally considered to be poorly or non-responsive to L-dopa therapy, in contrast to idiopathic Parkinson’s disease, which is characteristically dopamine sensitive, at least in the early stages of the disease. However, some small studies emphasise that a response to L-dopa is observed in at least some patients with vascular parkinsonism [48]. Holistic assessment of other falls risk factors, and multifactorial intervention, is usually indicated when an older person has vascular gait disorder associated with history, or high risk, of falls. 10. What is the current state of the art? The search produced 29 clinical trials of which 22 were excluded because of limited relevance. Additionally, one letter and one protocol paper were excluded (see supplementary material). Included studies are summarised in Table 1. The included studies are all observational [49–53]. They highlight that, despite twenty years of literature regarding the relationship between cerebrovascular and Alzheimer’s disease, current work continues to try to unravel the associations between vascular risk factors and amyloid deposition. 11. Conclusion In the context of increasing longevity, clinicians can expect to care for increased numbers of older people living with cognitive impairment. Given the intertwined risk factors for the major causes of cognitive impairment, prevention by control of vascular risk factors, and addressing lifestyle factors is important. A spectrum of cognitive disorders related to brain vascular disease is recognised and careful clinical assessment is required to understand the significance of the various contributing factors, and the importance of imaging findings, for an individual patient. Treatment interventions, such as recommendations to maintain cognitive and physical activity, are often based on consensus and clinical judgement. Although the convergence of risk factors for C.D. Etherton-Beer / Maturitas 79 (2014) 220–226 vascular and Alzheimer’s disease has received broad attention for two decades, work continues to try and clarify the pathogenetic mechanisms underlying these common causes of cognitive impairment. In addition to these gaps in knowledge, treatments with substantial efficacy that are well tolerated remain elusive. Contributors C.E.B. designed the review, extracted the references, drafted and critically revised the manuscript. Competing interests None. Funding The author has received no funding for this article. Provenance and peer review Commissioned and externally peer reviewed. Acknowledgements Swithin Song’s assistance providing Figs. 1 and 2 is gratefully acknowledged. Frederik Barkhof’s permission to reproduce Fig. 3 (originally published at http://www.radiologyassistant. nl/en/p43dbf6d16f98d/dementia-role-of-mri.html) is gratefully acknowledged. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.maturitas. 2014.06.004. References [1] Australia’s Health. Australian Institute of Health and Welfare 2010. Australia’s health series no. 12. Cat. no. AUS 122. Canberra: AIHW; 2010. [2] Ballard C, McKeith I, O’Brien J, et al. Neuropathological substrates of dementia and depression in vascular dementia, with a particular focus on cases with small infarct volumes. Dement Geriatr Cogn Disord 2000;11:59–65. [3] Makin SD, Turpin S, Dennis MS, Wardlaw JM. Cognitive impairment after lacunar stroke: systematic review and meta-analysis of incidence, prevalence and comparison with other stroke subtypes. J Neurol Neurosurg Psychiatry 2013;84:893–900. 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Arbre décisionnel Notion de maladie d'Alzheimer ou maladie apparentée CONTEXTE À RISQUE - - Personnel Pathologie connue État général altéré Dépendance Facteurs de stress ET/ OU Environnement - Changement - Faible soutien - Contraintes Changements de comportement - Difficultés relationnelles - Attitudes inhabituelles ou jugées inadaptées - Difficultés d’adaptation Diagnostic positif Caractérisation symptômes (définition, fréquence, sévérité) Recherche autres signes (définition, fréquence, sévérité) Degré d’urgence et de dangerosité Anamnèse : ancienneté, contexte et période de survenue Facteurs prédisposants/déclenchants Confusion Affection intercurrente, iatrogénie Traitement confusion, affection somatique, iatrogénie Recherche pathologie psychiatrique décompensée Traitement cause psychiatrique Symptômes psychologiques et comportementaux de la démence Prise en charge spécifique Réévaluation régulière, par plusieurs sources Neurologie Mise au point Octobre 2011 SY NT HÈ SE D’ AVI S DE L A CO MMI SSI O N DE L A T RANS PARE NCE ARICEPT (donépézil), EXELON (rivastigmine), REMINYL (galantamine), EBIXA (mémantine), médicaments du traitement symptomatique de la maladie d’Alzheimer Un intérêt thérapeutique faible L’essentiel Quatre médicaments ont une autorisation de mise sur le marché (AMM) dans le traitement symptomatique de la maladie d’Alzheimer : – trois inhibiteurs de l’acétylcholinestérase (IAChE) : ARICEPT (donépézil), REMINYL / REMINYL LP (galantamine) et EXELON (rivastigmine) ont une AMM dans les formes « légères à modérément sévères », – un antagoniste des récepteurs NMDA : EBIXA (mémantine) a une AMM dans les formes « modérées à sévères ». Leur efficacité est au mieux modeste et de pertinence clinique discutable. Elle a été démontrée essentiellement sur la cognition et les activités de la vie quotidienne. Aucun impact n’a été démontré sur le délai d’entrée en institution, la qualité de vie ou la morbi-mortalité. Ils peuvent entrainer des effets indésirables digestifs, cardiovasculaires et neuropsychiatriques pouvant nécessiter leur arrêt. Il existe aussi un risque d’interactions médicamenteuses, notamment avec les psychotropes, souvent co-prescrits. L’intérêt thérapeutique des médicaments de la maladie d’Alzheimer doit être considéré comme faible. Néanmoins, dans le souci de ne pas priver les patients répondeurs (impossibles à identifier a priori) d’un éventuel bénéfice clinique à court terme, il reste suffisant pour leur prise en charge par la solidarité nationale. En l’absence de donnée clinique à long terme, l’utilisation de ces médicaments doit faire l’objet d’une réévaluation attentive à un an, au cas par cas. La pertinence de la poursuite du traitement au delà d’un an ne sera décidée qu’après une réunion de concertation pluridisciplinaire. Stratégie thérapeutique En l’absence de donnée clinique solide sur l’effet à long terme de ces médicaments et en raison de l’incertitude sur la pertinence des effets cliniques et du risque d’effets indésirables graves, leur prescription ne repose que sur des considérations de très faible niveau de preuve. – Au stade léger de la maladie, on peut utiliser un inhibiteur de l’acétylcholinestérase (IAChE) : donépézil, galantamine ou rivastigmine. – Aux stades modéré et modérément sévère, on peut utiliser un IAChE (sans privilégier l’un plutôt qu’un autre). Dans ces formes, les IAChE représentent une alternative à la prescription de la mémantine. L’intérêt d’administrer la rivastigmine sous forme de dispositif transdermique par rapport à la voie orale est discutable, en raison d’un risque de mésusage dont les conséquences peuvent être graves. – Au stade sévère, seule la mémantine a l’AMM, mais son bénéfice clinique attendu est très limité. – L’intérêt d’associer deux IAChE ou un IAChE à la mémantine n’est pas démontré. Au delà de 6 mois de traitement, si le patient a atteint les objectifs fixés (stabilisation ou ralentissement du déclin cognitif par exemple) et en l’absence d’effet indésirable grave et/ou altérant la qualité de vie, le traitement pourra être poursuivi jusqu’à six mois supplémentaires. Si l’efficacité à 1 an a été maintenue, la poursuite du traitement peut être décidée, en concertation avec l’aidant et, si possible, avec le patient, à la suite d’une réunion pluridisciplinaire associant médecin traitant, gériatre et neurologue ou psychiatre, en relation avec le réseau de soins prenant en charge le patient. La prise en charge nécessite une coordination avec les acteurs sociaux, en particulier avec les aidants familiaux, dont le rôle est essentiel. Elle exige des compétences spécifiques de la part des soignants, notamment pour réagir face aux troubles du comportement. La prescription de psychotropes peut parfois être justifiée, pour une période aussi courte que possible. Des traitements non médicamenteux (activité physique, stimulation, entrainement cognitif) sont aussi à envisager. Données cliniques Les données cliniques ne permettent pas de considérer qu’il existe une différence d’effet entre les IAChE et la mémantine, ni entre les différents IAChE, dans les indications de l’AMM. Elles montrent une supériorité de ces médicaments par rapport au placebo, principalement documentée sur les troubles cognitifs et les activités de la vie quotidienne, au bout de 6 mois de traitement. La taille d’effet est au mieux modeste et de pertinence clinique discutable. L’efficacité reste insuffisamment documentée au-delà de 6 mois et n’est pas établie sur les critères cliniques majeurs (notamment le retard à l’entrée en institution). Le risque de troubles digestifs (vomissements, diarrhée, hémorragies) parfois graves est établi. Des études pharmacoépidémiologiques ont montré un risque accru de bradycardie, de syncopes, de troubles neuropsychiatriques (léthargie, hallucinations, dépression, etc.) et d’interactions, en particulier avec les antipsychotiques, souvent co-prescrits. Conditions particulières de prescription Médicament soumis à prescription annuelle réservée aux médecins spécialistes en neurologie et en psychiatrie, aux médecins spécialistes titulaires du diplôme d’études spécialisées complémentaires de gériatrie et aux médecins spécialistes ou qualifiés en médecine générale titulaires de la capacité de gérontologie. Médicament nécessitant une surveillance particulière pendant le traitement. Intérêt du médicament Le service médical rendu* par ces quatre médicaments est faible. Ils n’apportent pas d’amélioration du service médical rendu** (ASMR V) dans le traitement symptomatique de la maladie d'Alzheimer. * Le service médical rendu par un médicament (SMR) correspond à son intérêt en fonction notamment de ses performances cliniques et de la gravité de la maladie traitée. La Commission de la transparence de la HAS évalue le SMR, qui peut être important, modéré, faible, ou insuffisant pour que le médicament soit pris en charge par la solidarité nationale. Ce document a été élaboré sur la base des avis de la Commission de la transparence du 19 octobre 2011 (CT-10649, 10676, 10677, 10755), disponibles sur www.has-sante.fr © Haute Autorité de Santé 2011 ** L’amélioration du service médical rendu (ASMR) correspond au progrès thérapeutique apporté par un médicament par rapport aux traitements existants. La Commission de la transparence de la HAS évalue le niveau d’ASMR, cotée de I, majeure, à IV, mineure. Une ASMR de niveau V (équivalent de « pas d’ASMR ») signifie « absence de progrès thérapeutique ». SYNTHESE DES RECOMMANDATIONS DE BONNE PRATIQUE Maladie d’Alzheimer et maladies apparentées : prise en charge des troubles du comportement perturbateurs Mai 2009 Ces recommandations portent sur la prise en charge des troubles du comportement jugés par l’entourage comme dérangeants, perturbateurs, dangereux, que ce soit pour le patient ou pour son entourage. Sont concernés les comportements perturbateurs suivants : idées délirantes, hallucinations, opposition, agitation, agressivité, comportements moteurs aberrants, désinhibition, cris, troubles du rythme veille-sommeil. Les données de la littérature identifiée dans le cadre de ce travail n’ont pas permis de fonder les recommandations sur des preuves. En conséquence, toutes les recommandations reposent sur un accord professionnel au sein du groupe de travail, après avis du groupe de lecture. MESSAGES CLÉS • Les troubles du comportement perturbateurs (TCP) ont une origine multifactorielle. Ils peuvent être déterminés par : des facteurs écologiques, liés à l’environnement et l’entourage, aux aidants et aux professionnels ; des facteurs propres à la personne ou à la maladie. L’enquête doit rechercher en priorité les causes somatiques et psychiatriques, les facteurs déclenchants et les facteurs prédisposants. • Il est recommandé d’utiliser en première intention des techniques de soins non médicamenteuses appropriées aux TCP. • • Les psychotropes n’ont pas d’effet préventif sur la survenue des TCP. Un traitement par psychotrope ne doit pas être prescrit sans évaluation préalable en cas d’opposition, de cris, de déambulations. Les TCP sont des symptômes différents dans leur nature, mais qui ont des caractéristiques communes : • ils sont fréquents au cours de ces maladies ; • ils signalent souvent une rupture par rapport au fonctionnement antérieur du patient ; • ils sont souvent fluctuants en intensité ou épisodiques ; • ils sont interdépendants, souvent associés, et interagissant entre eux. I. Étiologie et démarche diagnostique La conduite à tenir recommandée est la suivante : • apprécier le degré d’urgence, de dangerosité ou de risque fonctionnel à court terme pour le patient ou pour autrui ; • interroger et examiner le patient et interroger l’entourage (ancienneté et caractéristiques du trouble, circonstances de survenue) ; • rechercher une cause écologique, une cause somatique (rétention d’urine, infection, douleur aiguë, fécalome, etc.) ou psychiatrique (crise d’angoisse sévère) à traiter en priorité, ainsi que des facteurs iatrogènes ; • • approfondir l’évaluation clinique des troubles avec leur intensité et leur retentissement ; répéter cette recherche étiologique à différents moments de la prise en charge si le trouble persiste. Il est recommandé d’observer le comportement du patient quand il est seul et en interaction avec les autres personnes, et à différents moments de la prise en charge. En cas de troubles persistant depuis plusieurs jours, il est recommandé de les objectiver à l’aide d’un outil tel que l’inventaire neuropsychiatrique (NPI ou INP). Le NPI est un inventaire de 12 symptômes parmi les plus fréquents au cours de la maladie d’Alzheimer et des maladies apparentées, qui évalue leur fréquence et leur sévérité, ainsi que le retentissement sur l’aidant ou le professionnel. Il existe aussi une version courte de passation plus rapide : le NPI-Réduit, et une version destinée aux équipes soignantes en établissement : le NPI-ES. Malgré un temps de passation assez long et la nécessité de former les aidants à cet inventaire, l’usage du NPI est recommandé. Il n’y a pas de consensus sur l’utilisation systématique de cet outil, notamment en ville. Selon le lieu de vie, les versions suivantes du NPI peuvent être utilisées : • à domicile : NPI ou NPI-Réduit, renseigné par l’aidant ou un professionnel ; • en établissement : NPI-ES, renseigné par les soignants. Il est recommandé d’appliquer les trois principes suivants, quel que soit le lieu de vie : • un recueil écrit des informations qui doivent être rassemblées dans des fiches ou un dossier pour faciliter leur traçabilité et leur transmission ; • il est utile qu’un interlocuteur désigné, éventuellement une personne référente, rassemble ces informations afin de faciliter leur transmission ; • les différents professionnels en charge du patient doivent échanger et/ou se rencontrer pour discuter de ces informations et participer ensemble à l’adaptation de la prise en charge. II. Prise en charge thérapeutique Il est recommandé d’utiliser en première intention des techniques de soins non médicamenteuses appropriées aux TCP. Elles peuvent permettre d’éviter le recours à des traitements médicamenteux. Les interventions non médicamenteuses sur la qualité de vie, le langage, la cognition, la stimulation sensorielle, l’activité motrice et les activités occupationnelles n’ont pas apporté la preuve de leur efficacité. Toutefois, elles peuvent être, tant en ambulatoire qu’en institution, un élément de la prise en charge thérapeutique globale. Elles peuvent être proposées à titre individuel ou collectif et doivent être pratiquées par un personnel formé. Les psychotropes peuvent être utilisés lorsque les techniques de soins sont d’efficacité insuffisante, notamment quand la sévérité des troubles met en danger le patient, altère son comportement, ou est une menace ou une source importante de souffrance pour son entourage. Il est recommandé de les utiliser en synergie avec les techniques de soins. Ils n’ont pas d’effet préventif sur les TCP. Il n’est pas recommandé de les prescrire en première intention et sans évaluation préalable en cas d’opposition, de cris, de déambulations. III. Suivi et prévention des TCP La prévention des TCP doit reposer sur une stratégie développée et adaptée à chaque patient. Les actions générales de prévention concernent : • l’information et le soutien aux aidants naturels ; • la formation des professionnels ; • l’environnement du patient, qui doit être le plus adapté possible à son état. Ce document présente les points essentiels des recommandations de bonne pratique : « Maladie d’Alzheimer et maladies apparentées : prise en charge des troubles du comportement perturbateurs » Recommandations pour la pratique clinique – Mai 2009 Ces recommandations et l’argumentaire scientifique sont consultables dans leur intégralité sur www.has-sante.fr © Haute Autorité de Santé – 2009 Un traitement par psychotrope ne doit pas être instauré si les symptômes sont d’origine somatique ou iatrogène.