Note to myseof: I reviewed the complete article [altho included only a part of it in this post] and did not find the article helpful.
Today, I review, link to and excerpt from Clinical management of cerebral small vessel disease: a call for a holistic approach [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Chin Med J (Engl). 2020 Oct 6;134(2):127-142. doi: 10.1097/CM9.0000000000001177. Una Clancy 1, Jason P Appleton 2,3, Carmen Arteaga 1, Fergus N Doubal 1, Philip M Bath 2,4, Joanna M Wardlaw 1
Editors: Xin Chen, Xiu-Yuan Hao
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Abstract
Cerebral small vessel disease (SVD) is a common global brain disease that causes cognitive impairment, ischemic or hemorrhagic stroke, problems with mobility, and neuropsychiatric symptoms. The brain damage, seen as focal white and deep grey matter lesions on brain magnetic resonance imaging (MRI) or computed tomography (CT), typically accumulates “covertly” and may reach an advanced state before being detected incidentally on brain scanning or causing symptoms. Patients have typically presented to different clinical services or been recruited into research focused on one clinical manifestation, perhaps explaining a lack of awareness, until recently, of the full range and complexity of SVD.
In this review, we discuss the varied clinical presentations, established and emerging risk factors, relationship to SVD features on MRI or CT, and the current state of knowledge on the effectiveness of a wide range of pharmacological and lifestyle interventions. The core message is that effective assessment and clinical management of patients with SVD, as well as future advances in diagnosis, care, and treatment, will require a more “joined-up”’ approach. This approach should integrate clinical expertise in stroke neurology, cognitive, and physical dysfunctions. It requires more clinical trials in order to improve pharmacological interventions, lifestyle and dietary modifications. A deeper understanding of the pathophysiology of SVD is required to steer the identification of novel interventions. An essential prerequisite to accelerating clinical trials is to improve the consistency, and standardization of clinical, cognitive and neuroimaging endpoints.
Keywords: Dementia, Magnetic resonance imaging, Mild cognitive impairment, Risk factors, Small vessel disease, Stroke, Symptoms, Treatment Introduction
Cerebral small vessel disease (SVD) is a global brain disease affecting multiple clinical domains by disrupting normal function of the perforating cerebral arterioles, capillaries, venules, and brain parenchyma, manifesting on magnetic resonance imaging (MRI) as white matter hyperintensities (WMH), small subcortical infarcts, microinfarcts, lacunes, enlarged perivascular spaces (PVS), microbleeds, superficial siderosis, intracerebral hemorrhage (ICH), and atrophy.[1,2] The core clinical manifestations include lacunar ischemic stroke, intracerebral hemorrhage and cognitive decline, including vascular cognitive impairment and amplification of pathological and cognitive Alzheimer’s disease manifestations.[3–5] There is increasing recognition that its multidomain involvement extends beyond stroke and dementia [Figure 1] to include gait and balance dysfunction, behavioral and neuropsychiatric symptoms, and subtle, non-focal neurological features [Figure 2],[6–8] resulting in presentations to diverse general and specialist services [Table 1].
The onset of sporadic SVD typically occurs during mid to late life and although the disease, its associated risk factors, and clinical features such as gait dysfunction and cognitive decline are more prevalent with advancing age, these are not just inevitable consequences of ageing. SVD often arises on a background of other complex comorbidities, and untangling SVD symptoms from those attributable to other conditions requires careful clinical judgment including neuroimaging review. Adopting a more integrated, holistic approach to identifying early and intermediate clinical brain damage markers is essential to permit prognostication, supportive management strategies, identification of patients for emerging treatment trials, and future refinement of targeted prevention and management strategies.
Here we present an evidence-based overview of the literature on clinical aspects of SVD, discussed in the context of our clinical and research experience of caring for these patients.
Methods for Searching, Identifying, Selecting, and synthesizing Data
We searched Ovid MEDLINE using the terms “Cerebral Small Vessel Diseases/” or “White matter hyperintens∗” and “Clinical” from inception to April 3, 2020. We separately searched “Lacunar state” or “Binswanger”. On risk factors for SVD and its progression, we searched Ovid MEDLINE using the terms “Cerebral small vessel disease” OR “White matter hyperintens∗” AND “vascular risk factor” OR “risk factor” AND “disease progress∗” OR “outcome” up to June 5th 2020. On therapeutic approaches to SVD, we searched Ovid MEDLINE using the terms “Cerebral small vessel disease” OR “White matter hyperintense∗” OR “lacunar” OR “vascular cognitive impairment” up to 12th May 2020. We supplemented the electronic search with the authors’ personal files and searched reference lists of identified papers. We screened 2169 papers for clinical diagnosis, 1094 for risk factors and progression, and 7695 for interventions in SVD, including the most relevant papers reporting SVD associations.
Defining the Natural History of Clinical Cerebral Small Vessel Disease
The earliest clinicopathological reports by Binswanger[9] in 1894, based on eight post-mortem cases, described “encephalitis subcorticalis chronica progressiva”, characterized pathologically by pronounced white matter atrophy and cortical thinning and clinically by a progressive, fluctuating course, arising predominantly in males in their 50s, characterized by chronic cognitive and emotional symptoms, and occasionally punctuated by acute hemiplegic episodes.
In 1901, Marie[10] described ‘l’état lacunaire’ or “the lacunar state”, involving one or more lacunes on neuropathology, characterized by progressive neurological decline, episodes of mild hemiparesis, and later, dysarthria, marche à petit pas (gait with little steps), imbalance, incontinence, pseudobulbar signs, and dementia.
Much remains unknown about its precise natural clinical history: the disease is elusive in its early stages unless the patient has overt symptoms that are easily recognized from the current neurological lexicon for stroke or dementia [Figure 3]. Proposed pathophysiological mechanisms underlying SVD are outside the scope of this review but are described in detail elsewhere.[2,11,12] We describe acute and chronic clinical and neuroimaging manifestations at various SVD stages.
[Fig 3 unreadable in original online manuscript]
Modes of presentation
“Silent” small vessel disease
“Silent” or “covert” SVD refers to disease incidentally detected on neuroimaging without the patient apparently having overt symptoms. While some lesions are truly clinically silent, for instance if small or located in less eloquent regions,[13] careful questioning about historical stroke or transient ischemic attack (TIA) symptoms is recommended, as a positive history may render such individuals eligible for secondary stroke prevention.[14] Furthermore, a comprehensive history and examination, including collateral history from an informant, may yield more subtle, associated features such as apathy, abrupt or insidious cognitive decline, fatigue or gait disturbances that do not necessarily meet diagnostic criteria for stroke or dementia but have been linked temporally with acute lesions on Diffusion-Weighted Imaging (DWI) MRI (n = 6/649 community sample, n = 10/30 vascular dementia population).[7,15] How patients report, and clinicians interpret, these symptoms is poorly understood and inter-individual factors influencing accurate reporting are complex. For instance, a “threshold effect” of sufficient SVD burden might accumulate before triggering symptoms[16] and this might vary between individuals and at different ages [Figure 4]. Similarly, physical reserve is likely to play a role: the fitter an individual, the more compensatory mechanisms can be employed despite accumulating deficits. Whether initially silent infarcts due to SVD are clinically “unmasked” later by increasing SVD burden and/or increasing physical frailty, revealing delayed typical or atypical symptoms, is a target for future research.
Subtle neurological symptoms
To uncover whether “non-stroke” symptoms may be associated with acute infarcts on brain imaging, some studies have focused on transient neurological attacks (TNAs). Almost one-quarter of TNA patients (n = 13/56) have corresponding DWI hyperintense lesions.[8] Moreover, both TNAs and Transient Focal Neurological Episodes, a subset of TNAs typified by spreading, recurrent, stereotyped episodes and associated with cerebral amyloid angiopathy (CAA),[17] herald a higher risk of future ischemic and hemorrhagic stroke, while TNAs also associate with chronic SVD features and dementia.[4,18,19] Other neurological symptoms associated with SVD include dysphagia,[20] dysarthria,[21] pyramidal tract signs, and pseudobulbar palsy.[22]
Neuropsychiatric symptoms
Neuropsychiatric symptoms are common post-stroke and in individuals with vascular dementia, but whether there is a shared neuroanatomical substrate remain unclear and longitudinal studies are sparse. More severe WMH are associated with apathy, fatigue, and delirium but not subjective memory complaints or anxiety (submitted). There is inadequate evidence to determine whether other symptoms including delusions or emotional lability are associated with SVD due to insufficient data and mixed approaches to symptom assessments.
Future research should target whether emotional liability, delusions, and other neuropsychiatric symptoms relate to disease severity including progression.
Whether depression contributes to, or results from, SVD is unclear. Further pathological, clinical, and imaging relationships need investigation, focusing on interactions with shared vascular risk factors, medications, treatment resistance, neurotransmitter alterations, and associations with cognitive impairment.[23]
Lacunar stroke presentations
Lacunar stroke clinical syndrome (LACS) is a key SVD manifestation.[3] While specific syndromes including pure motor/hemisensory stroke and ataxic hemiparesis are more strongly associated with acute small subcortical infarcts,[24] LACS classification is imprecise[24,25] and one-third of minor strokes are not accompanied by a corresponding acute infarct radiologically, even on the most sensitive diffusion MRI (n = 264).[26] Non-lacunar pathology, for example, cortical infarcts, may manifest as LACS and conversely, small subcortical infarcts may present with other non-LACS syndromes[25,27] in around 15% to 20% (n = 137), or develop silently.[13] While some LACS may masquerade as cortical stroke syndromes when the responsible brain lesion is close to the cortex,[27] or in specific locations such as the thalamus. Other cases where LACS and partial anterior circulation stroke (PACS) are confused may simply reflect disappearance of, or failure to recognize, cortical symptoms, mistaking dysarthria for dysphasia, or overlooking visual field defects.[25] Furthermore, other comorbidities may alter or obscure stroke presentations [Figure 4], for example, a patient with arthritis and peripheral neuropathy may not notice an ataxic hemiparesis.
Associated short-term with infarct growth (n = 61)[28] and poor functional outcomes (n = 4011)[29] in stroke, SVD effects outlast the acute phase, contributing increased risk long-term of recurrent ischaemic stroke, disability, dementia, and death (n = 71,298).[30]
Mobility and movement
Gait and balance dysfunction, shortened stride length (n = 431),[6] unexplained dizziness (n = 122),[31] falls (n = 187),[32] and features of vascular parkinsonism such as bradykinesia, rigidity, and gait disturbances (n = 503 community-dwelling)[33] are all associated with SVD.
Urinary symptoms
Eight studies, mostly in older community dwelling-subjects, detected urinary symptom associations with WMH (total n = 1944),[34–41] while two did not (n = 648).[42,43] These findings need to be reproduced in large prospective blinded studies, adjusting for mobility, frailty and co-morbidities.
Vascular cognitive impairment: clinical features
Vascular cognitive impairment (VCI) is a broad term, encompassing mild cognitive impairment and dementia. We focus on the clinically sensitive DSM-V diagnostic criteria,[44] which require evidence of cognitive decline from a previous performance level in one or more domains including: (a) concern about decline from a patient, knowledgeable informant or clinician, and (b) objective impairment or decline on testing. To establish a vascular etiology, either a temporal association with stroke/s or prominent decline in complex attention/processing speed and frontal-executive functions is required, although it is increasingly apparent that SVD is not confined to specific domains,[45] in contrast to previous thinking that focused on domain-specific impairments. Further discrimination between mild cognitive impairment and dementia is based on whether cognition is sufficiently impaired to result in loss of functional independence.[44] This may be described by either patient or informant, e.g. non-specific reports of “not managing at home” or deficits in instrumental activities of daily living, e.g. inability to independently manage one’s finances. Clinicians frequently rely on the informant account, which is invaluable, as many individuals with cognitive impairment lack insight or minimise their symptoms.
Distinguishing the subcortical subtype of vascular cognitive impairment
The small vessel contribution to dementia exceeds that of large vessel disease, with incident lacunes thought to herald the highest dementia risk at least in community-dwelling subjects.[46] Cognitive features include slow thought processing, poor memory retrieval, and executive dysfunction.[47] The subcortical vascular cognitive impairment (VCI) subtype is supported by symptoms such as impaired problem-solving, personality changes including apathy, mood disorders, pseudobulbar palsy, dysarthria, subtle sensory and motor deficits, urinary symptoms, and gait deterioration including postural instability.[47,48] Although these clinical symptoms are frequently cited as subcortical VCI features, many of these correlations are based on older, small, clinicopathological and CT-based studies. There is a scarcity of MRI studies confirming these associations in VCI populations, with recent studies’ main clinical focus on cognitive tests and vascular risks. Abrupt cognitive impairment due to single strategic small subcortical infarcts has been described rarely,[47] is understudied, and requires further characterization.
The neurological examination provides clues to subtyping VCI: subtle abnormalities including dysarthria, dysphagia, and parkinsonian, rather than hemiplegic gait, are all more prevalent in subcortical vascular dementia (n = 706).[22] Subcortical may also be differentiated from cortical VCI and Alzheimer’s disease by the absence of aphasia, apraxia, agnosia, amnesia, and hemianopia[48] although cortical and subcortical lesions, with or without Alzheimer’s disease, frequently coexist so the specificity of these symptoms will be limited. Supportive findings on neuroimaging raise diagnostic certainty from possible to probable when there is no clear temporal relationship to stroke events,[44] although the extent of radiological SVD considered sufficient to contribute to a VCI diagnosis is debated.[49] Neuroimaging is particularly important for distinguishing SVD-related VCI, where stepwise cognitive decline is often absent, instead characterized by insidious, fluctuating cognitive decline, punctuated by neurological deficits [Figure 3].[48]
Function
SVD substantially limits independence, contributing to functional impairment,[29] stroke recurrence, dementia, and mortality after stroke,[30] as well as functional decline and mortality in non-disabled adults.[50] SVD is associated with longer hospital lengths of stay in cognitively impaired,[51] and earlier institutionalization in stroke patients.[52]
Recommended approaches to patients presenting with the SVD syndrome
Many clinical features described in this review are non-specific when considered in isolation. However, clinical presentations are frequently multifactorial, particularly in older people in whom SVD is highly prevalent [Table 1]. When faced with these features in combination, supported by previous neuroimaging, and especially in individuals with a history of lacunar stroke or cognitive impairment, one should consider SVD presence and/or progression as a contributor.
Risk Factors for SVD and its Progression
Risk factors for progression in SVD include “traditional vascular risk factors” such as age and hypertension, and MRI biomarkers, which not only represent the cornerstone for SVD diagnosis but also identify risk of progression, provide a feasible strategy for monitoring patients, and a therapeutic target.
Vascular risk factors
Several vascular risk factors are associated with SVD, but the two major ones are advancing age and hypertension.[50,53] Specifically, In community-based samples, WMH prevalence was low before 55 years of age but increased sharply with age thereafter, from 11% to 21% in the subjects 64 years of age on average to 94% in individuals 82 years of age on average.[14] Cerebral microbleeds (CMB), CAA, PVS and lacunes also increase with age.[17,50,54–56]
The most important modifiable vascular risk factor for SVD is arterial hypertension (defined as blood pressure greater than 140/90 mmHg).[57] Ambulatory blood pressure (BP) provides more accurate data on BP status than office-based BP measurements and may help BP control in patients with extensive SVD.[58] In addition, abnormal circadian BP variations during sleep, specifically non-dipping (<10% fall in nocturnal BP) and reverse-dipping patterns (rise in nocturnal BP) are associated with WMH.[59] Hypertension is also associated with CMBs in adults with and without established cerebrovascular disease.[60] SVD lesions can occur in individuals without hypertension,[61] plus recent data from large consortia genetic analyses indicate that some patients with more severe SVD may be particularly sensitive to any BP elevation (in press). Since it is currently difficult to identify individuals whose small vessels may be particularly sensitive to even minor BP elevations, it remains uncertain how intensively blood pressure should be lowered.[50]
Diabetes mellitus types 1 (relative ratio [RR] 7.2, 95% confidential interval [CI] 3.2–16.1) and 2 (RR 2.8, 95% CI 2.3–3.5) are associated with lacunar infarction[62] and other biomarkers of SVD on MRI, including atrophy[63] and CMBs.[60] Because the duration of diabetes is important in determining ischemic stroke risk, early onset of type 1 diabetes confers a cumulatively higher lacunar stroke risk in such patients. Furthermore, fasting glucose level (odds ratio [OR] 1.27, 95% CI 1.10–1.46) and high insulin resistance scores (OR 1.33, 95% CI 1.05–1.68) are also associated with increased incident lacunes.[54] People with type 2 diabetes have a 1.5 times increased risk of dementia, and high HbA1c, concentration and glucose variability are negatively associated with cognitive function.[63] Interestingly, type 2 diabetes is associated with a greater increase in depressive symptoms, which SVD may contribute to.[23,64]
Additionally, metabolic syndrome is associated with silent brain infarction and incident lacunes.[53,54] The potential impact of dyslipidemia remains uncertain. In the atherosclerosis risk in communities (ARIC) study, high triglycerides increased the risk of incident lacunes (OR 1.24, 95% CI 1.04–1.47), while elevated high-density lipoproteins (HDL) reduced the risk (OR 0.77, 95% CI 0.59–0.99).[65] Moreover, the use of lipid-lowering medications was associated with fewer incident lacunes (OR 0.15, 95% CI 0.04–0.61) in an observational study,[55] but higher total (OR 1.67, 95% CI 1.20–2.31) and lobar (OR 1.52, 95% CI 1.02–2.27) CMB presence in a separate community-based study.[66] In contrast, lower HDL may predict WMH volume increase in people aged between 73 and 76 years[67] so the relationship between HDL and SVD needs further research.
