Clinical Management of Cerebral Small Vessel Disease: A Call for a Holistic Approach
Cerebral small vessel disease (SVD) is a prevalent global brain disorder that leads to cognitive impairment, ischemic or hemorrhagic stroke, mobility issues, and neuropsychiatric symptoms. The damage to the brain, visible as focal white and deep grey matter lesions on magnetic resonance imaging (MRI) or computed tomography (CT), often accumulates covertly and may reach an advanced stage before being incidentally detected or causing noticeable symptoms. Patients typically present to various clinical services or are recruited into research focused on a single clinical manifestation, which may explain the lack of awareness of the full range and complexity of SVD until recently.
This review explores the diverse clinical presentations, established and emerging risk factors, the 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 central message is that effective assessment and clinical management of patients with SVD, as well as future advances in diagnosis, care, and treatment, require a more integrated approach. This approach should combine clinical expertise in stroke neurology, cognitive, and physical dysfunctions. It necessitates more clinical trials to improve pharmacological interventions, lifestyle, and dietary modifications. A deeper understanding of the pathophysiology of SVD is essential to guide the identification of novel interventions. A critical prerequisite for accelerating clinical trials is improving the consistency and standardization of clinical, cognitive, and neuroimaging endpoints.
Introduction
Cerebral small vessel disease (SVD) is a global brain disease affecting multiple clinical domains by disrupting the normal function of the perforating cerebral arterioles, capillaries, venules, and brain parenchyma. It manifests on MRI as white matter hyperintensities (WMH), small subcortical infarcts, microinfarcts, lacunes, enlarged perivascular spaces (PVS), microbleeds, superficial siderosis, intracerebral hemorrhage (ICH), and atrophy. The core clinical manifestations include lacunar ischemic stroke, intracerebral hemorrhage, and cognitive decline, including vascular cognitive impairment and the amplification of pathological and cognitive Alzheimer’s disease manifestations.
There is increasing recognition that its multidomain involvement extends beyond stroke and dementia to include gait and balance dysfunction, behavioral and neuropsychiatric symptoms, and subtle, non-focal neurological features, resulting in presentations to diverse general and specialist services.
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 aging. 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.
Methods for Searching, Identifying, Selecting, and Synthesizing Data
The literature on clinical aspects of SVD was searched using Ovid MEDLINE with terms such as “Cerebral Small Vessel Diseases/” or “White matter hyperintens” and “Clinical” from inception to April 3, 2020. Additional searches included “Lacunar state” or “Binswanger.” For risk factors and progression, the search included terms like “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. For therapeutic approaches, the search included “Cerebral small vessel disease” OR “White matter hyperintense” OR “lacunar” OR “vascular cognitive impairment” up to May 12th, 2020. The electronic search was supplemented with the authors’ personal files and reference lists of identified papers. A total of 2169 papers were screened 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 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 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. Proposed pathophysiological mechanisms underlying SVD are outside the scope of this review but are described in detail elsewhere. We describe acute and chronic clinical and neuroimaging manifestations at various SVD stages.
Modes of Presentation
“Silent” small vessel disease 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, 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. 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.
Subtle neurological symptoms may be associated with acute infarcts on brain imaging. Almost one-quarter of transient neurological attack (TNA) patients have corresponding DWI hyperintense lesions. 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), herald a higher risk of future ischemic and hemorrhagic stroke, while TNAs also associate with chronic SVD features and dementia. Other neurological symptoms associated with SVD include dysphagia, dysarthria, pyramidal tract signs, and pseudobulbar palsy.
Neuropsychiatric symptoms are common post-stroke and in individuals with vascular dementia, but whether there is a shared neuroanatomical substrate remains unclear, and longitudinal studies are sparse. More severe WMH are associated with apathy, fatigue, and delirium but not subjective memory complaints or anxiety. 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.
Lacunar stroke clinical syndrome (LACS) is a key SVD manifestation. While specific syndromes, including pure motor/hemisensory stroke and ataxic hemiparesis, are more strongly associated with acute small subcortical infarcts, LACS classification is imprecise, and one-third of minor strokes are not accompanied by a corresponding acute infarct radiologically, even on the most sensitive diffusion MRI. Non-lacunar pathology, for example, cortical infarcts, may manifest as LACS, and conversely, small subcortical infarcts may present with other non-LACS syndromes in around 15% to 20% or develop silently.
Gait and balance dysfunction, shortened stride length, unexplained dizziness, falls, and features of vascular parkinsonism such as bradykinesia, rigidity, and gait disturbances are all associated with SVD. Urinary symptoms are also linked to SVD, with eight studies detecting urinary symptom associations with WMH, while two did not.
Vascular cognitive impairment (VCI) is a broad term encompassing mild cognitive impairment and dementia. We focus on the clinically sensitive DSM-V diagnostic criteria, which require evidence of cognitive decline from a previous performance level in one or more domains, including concern about decline from a patient, knowledgeable informant, or clinician, and 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.
Distinguishing the subcortical subtype of vascular cognitive impairment 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. 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.
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 such as advancing age and hypertension are major contributors to SVD. In community-based samples, WMH prevalence was low before 55 years of age but increased sharply with age thereafter. Cerebral microbleeds (CMB), CAA, PVS, and lacunes also increase with age. The most important modifiable vascular risk factor for SVD is arterial hypertension, defined as blood pressure greater than 140/90 mmHg. 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. Abnormal circadian BP variations during sleep, specifically non-dipping and reverse-dipping patterns, are associated with WMH. Hypertension is also associated with CMBs in adults with and without established cerebrovascular disease.
Diabetes mellitus types 1 and 2 are associated with lacunar infarction and other biomarkers of SVD on MRI, including atrophy and CMBs. The duration of diabetes is important in determining ischemic stroke risk, with early onset of type 1 diabetes conferring a cumulatively higher lacunar stroke risk. Fasting glucose level and high insulin resistance scores are also associated with increased incident lacunes. Metabolic syndrome is associated with silent brain infarction and incident lacunes. The potential impact of dyslipidemia remains uncertain, with high triglycerides increasing the risk of incident lacunes, while elevated high-density lipoproteins (HDL) reduced the risk.
Lifestyle risk factors such as regular exercise, a healthy diet (Mediterranean diet, folic acid, and vitamin B12), and avoiding adverse lifestyle factors such as smoking, excess alcohol, or high dietary sodium are all associated with having fewer SVD features in observational studies. Alcohol intake is associated with worse WMH in patients with minor stroke. High dietary sodium increases stroke risk (crucially lacunar stroke) and worsens WMH and total SVD burden. Sleep dysfunction is an important and largely overlooked risk factor for adverse brain health, with abnormal sleep patterns associated with brain atrophy and increased daytime sleep associated with increased PVS on MRI.
Environmental, lifetime, and cultural risk factors are likely related to SVD burden and its associated outcomes such as cognitive impairment. Data are currently unclear on male-female differences, and apparent differences may reflect age or recruitment bias rather than a true difference in SVD burden. Some hospital-based studies suggest that males have a higher burden of both sporadic and monogenic SVDs, but further research is needed to differentiate any true male-female difference in incidence or severity and the reasons behind any difference observed.
Brain and cognitive reserves in later life are influenced by lifetime experiences, including those early in life. Early life exposures could explain some of the variation between SVD and cognitive function and include childhood cognitive ability, with lower cognitive ability in childhood being associated with increased total WMH scores in later life. Adverse childhood socioeconomic status (SES) increases the risk of worse deep and periventricular WMH, and lower educational attainment is associated with more WMH in later life.
Use of brain imaging appearances to predict risk of SVD progression involves lesions seen on MRI adopted as biomarkers of SVD, including recent small subcortical (or lacunar) infarct (RSSI), WMH, lacune, CMB, visible PVS, and cerebral atrophy. All of these lesions have been associated with dysfunction of the cerebral small vessels when measured in patients using MRI, including blood-brain barrier leakage, impaired cerebral vasoreactivity, and increased vascular pulsatility, reflecting impaired endothelial function and related effects on the glia and neurons. These lesions are individually and collectively associated with increased risk of stroke, cognitive decline and dementia, and poor functional outcomes after stroke, and are highly heritable.
The single strongest risk factor for SVD lesion progression identified so far is having a severe SVD lesion burden at presentation. Potential advances in neuroimaging of SVD based on MRI, such as diffusion tensor imaging (DTI) metrics like fractional anisotropy (FA) and mean diffusivity (MD), show promise in research for detecting early white matter damage and may in future become widely used clinical applications.
Therapeutic Approaches
Given the chronic nature and insidious progression of SVD, potential treatments will likely be required over the longer term, as is done for the secondary prevention of vascular diseases. Due to the worldwide prevalence of SVD and association with increasing age, potential therapeutic agents will need to be affordable, easy to administer, safe, simple, and have limited drug-drug interactions. Currently, there is considerable variability in selection and definitions of endpoints for SVD trials, including imaging endpoints and clinically relevant magnitudes of change, cognitive and functional outcomes, recurrent stroke, bleeding, and death.
Lifestyle interventions such as aerobic exercise and resistance training have been assessed in trials, with mixed results on WMH volume but improved cognitive scores at 6 months in those randomized to aerobic exercise compared with those receiving usual care. Smoking is strongly associated with an increased burden of SVD and cortical loss in observational studies, and therefore, smoking cessation should be strongly encouraged. High dietary sodium was associated with increased stroke, particularly lacunar events, WMH, and SVD burden in patients with stroke, and with risk of stroke in population studies. Trials assessing the effect of dietary sodium in SVD are lacking, as they are for other vascular disease, but reduction in dietary salt is good general health advice.
Traditional stroke prevention treatments include antiplatelet medication, BP lowering, and lipid lowering. Single antiplatelet therapy reduced recurrent stroke compared with no antiplatelet agent in a meta-analysis of 17 trials totaling 42,234 patients with previous lacunar ischemic stroke. Intensive lowering of BP in a subgroup of the large Systolic blood PRessure INtervention Trial (SPRINT) with WMH was associated with reduced WMH progression and decreased risk of mild cognitive impairment but no difference in brain volume or risk of dementia over a 4-year period compared with standard BP management. The effect of statins on other outcomes specific to SVD has had mixed results to date, with simvastatin not influencing cognitive outcome in the Heart Protection Study, nor WMH progression in the ROCAS study, whilst pravastatin did not impact cognitive function or WMH progression in the PROSPER study.
Pharmacological agents under investigation include cilostazol, nitric oxide donors, vitamins, xanthine oxidase inhibitors, and remote ischemic conditioning. Cilostazol, a phosphodiesterase 3’ inhibitor, is commonly used for stroke prevention in the Asia-Pacific region and may be beneficial in preventing SVD accumulation through endothelial stabilization, myelin repair, neuroprotective, and anti-inflammatory mechanisms. Nitric oxide (NO) and its donors, such as organic nitrates, have multiple effects that might be beneficial in patients with SVD. Vitamins of interest in SVD include vitamins B6, B12, and folate, with low levels of B12 associated with more severe WMH. Allopurinol, a xanthine oxidase inhibitor, has multiple effects that may be beneficial in SVD, with a trial demonstrating reduced BP, augmentation index, and carotid intima-media thickness progression following one year of receiving allopurinol. Remote ischemic conditioning (RIC) has been shown to be neuroprotective in pre-clinical models, with a small study of 30 patients with SVD showing improved visuospatial and executive function and reduced WMH compared with sham.
Discussion and Conclusions
We recommend a holistic, multidisciplinary assessment of individual needs in patients with suspected SVD. This includes rigorous management of modifiable risk factors, including smoking cessation, dietary improvements, and appropriate evidence-based medications while balancing risks of side effects. In advancing disease, onwards referral to relevant services should be considered to maximize independence, including cognitive clinics, physiotherapists, occupational therapists, and social care. We suggest highlighting awareness of practical issues, including driving, accessible home environments, appointing power of attorney, and advance care planning. We support close liaison with patients, family members, and general practitioners to monitor for clinical deterioration. We note wide variability in choice and definitions of endpoints used in trials in SVD that would benefit from some standardization. Finally, we advocate for more clinical trials to identify effective lifestyle and pharmaceutical interventions.
Future targets for clinical practice and research include better recognition of symptoms that best predict disease progression in longitudinal clinical-imaging-pathological studies across healthy, cognitively impaired, and stroke populations, establishing the natural history of SVD. Serial imaging studies assessing neuropsychiatric symptoms are especially lacking. Further work on interactions between SVD, depression, and their confounders will help to clarify the vascular depression hypothesis. Urinary symptom relationships with SVD require appropriate adjustment for confounders. Research should give greater prominence to informants, paralleling clinical practice.
We need to determine whether widely-accepted clinical features of subcortical VCI described in early pathological and CT studies still hold true on longitudinal MRI studies in VCI populations. How lesion volume, location, background SVD burden, and rate of lesion change interact with symptoms, cognition, function, and physical and cognitive reserves needs to be determined. The natural history of VCI, including subcortical subtypes, needs to be better defined, for example, prevalence of stepwise vs. progressive cognitive decline.
Further work is needed to understand the pathophysiology of SVD, using advanced preclinical, neuroimaging, and pathological research methods. We need more trials of medications and simple lifestyle modifications, or combinations thereof. Further, detailed, observational research on modifiable and non-modifiable factors is required, integrating these into clinical trial design, determining whether using different treatment strategies for individuals with non-modifiable risk factors produces any additional benefit.
Integrating approaches to research and clinical care of patients with SVD involves empowering patients and informants to self-monitor symptoms, signs, vascular risk factors, and cognitive test performance, e.g., using mobile phone applications, virtual clinics, and evolving smart technology that recognizes alterations in gait or speech patterns. We should use healthcare encounters to opportunistically seek features of SVD progression, for example, screening during vascular risk factor reviews. We should devise electronic record-based alerts based on notification of relevant healthcare referrals, combined with existing imaging data. We should devise composite prediction scores of SVD progression for use as screening tools in everyday clinical settings, incorporating available symptom, risk factor, cognitive, demographic, and imaging reports, similar to those used for estimating cardiovascular or fracture risks.
Efforts to refine an SVD phenotype, including but extending beyond stroke and cognitive impairment, are necessary. Apart from initial identification, we need to recognize those at the highest risk of SVD progression, tracking which clinical and imaging features herald progression. This will allow us to research targeted interventions earlier in the SVD course, preventing progression before its most disabling manifestations develop.
doi.org/10.1097/CM9.0000000000001177
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