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
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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.
