Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
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Subcortical vascular cognitive impairment, characterized by subcortical and executive cognitive dysfunction, is now recognized to be the most common form of vascular cognitive impairment. It arises on the basis of small vessel cerebrovascular disease, in turn, causing lacunar infarcts and ischemic damage to the deep subcortical white matter. Most importantly, the underlying etiologies are those of well-recognized vascular risk factors such as age, hypertension, and diabetes. This is, therefore, a form of cognitive impairment that is amenable to prevention, as well as to some element of symptomatic relief.
• Subcortical vascular cognitive impairment is the most common form of vascular cognitive impairment. It includes patients with mild cognitive impairment or dementia who have signs of small vessel disease (lacunar infarcts, subcortical white matter hyperintensities, enlarged perivascular spaces).
• The most severe cognitive deficits in subcortical vascular cognitive impairment are impaired executive function, reduced phonemic word generation and reduced processing speed.
• Seventy percent of the risk in subcortical vascular cognitive impairment is inherited. Hypertension, diabetes, and blood pressure fluctuation are other important risk factors.
• Cerebral amyloid angiopathy is a subtype of subcortical vascular cognitive impairment that is associated with executive dysfunction and mild cognitive impairment.
• Data from the SPRINT-MIND study showed that intensive blood pressure control in hypertensive individuals 50 years of age and older can significantly reduce the risk of mild cognitive impairment but not the risk of dementia.
Subcortical vascular cognitive impairment is now recognized as the most common form of vascular cognitive impairment (43). It includes patients with mild cognitive impairment or dementia who have signs on imaging of small vessel disease (subcortical lacunes, multiple microinfarcts, and/or extensive subcortical white matter changes). Its clinical pattern, risk factors, and imaging features are sufficiently consistent for it to be considered a single entity for the purposes of diagnosis, clinical trials, and management. Research criteria for subcortical vascular cognitive impairment initially included 2 subtypes: Binswanger disease and the lacunar state (26). The initial name for Binswanger disease was “subcortical arteriosclerotic encephalopathy” (02). At autopsy in patients with Binswanger disease, lipohyalinosis and sclerotic changes were found in the long, penetrating medullary arteries, especially those in the frontal lobes.
Leukoaraiosis. Significant small vessel disease was rarely reported before the arrival of CT scanning and MRI. Throughout the last 2 decades of the twentieth century, there were numerous reports of "Binswanger disease" diagnosed solely by the appearance of extensive white matter changes on neuroimaging but without clinical correlates. This is now recognized to be inappropriate. “Leukoaraiosis” was the term used to describe extensive subcortical white matter rarefaction on CT, and this term became erroneously synonymous with Binswanger disease (36). When MRI scans were developed, subcortical white matter hyperintensities (WMH) replaced the term leukoaraiosis as a sign of cerebral small vessel disease (arteriosclerosis, microinfarcts, gliosis and myelin loss) (43; 32; 47).
Small vessel disease. Subcortical white matter hyperintensities can be associated with neurologic signs and psychological deficits, particularly the attention and speed components of executive function. Initial work suggested that only CT-demonstrated leukoaraiosis had clinical correlates, the interpretation being that MRI, a more sensitive tool, was detecting numerous asymptomatic lesions. That a majority of elderly individuals had some degree of white matter hyperintensities without necessarily being demented was taken to support this. The most consistent finding among vascular dementia patients in 1 early MRI study was ventricular atrophy and not white matter hyperintensities (39). However, detailed neuropsychological assessment has subsequently shown that subtle, predominantly subcortical deficits like poor executive function and slowed processing speeds are associated with white matter hyperintensities in the absence of dementia and in apparently normal-aged subjects (22; 42). Longitudinal studies have also demonstrated a correlation between increasing white matter hyperintensities and declining cognition (05). These changes are closely associated with hypertension and other vascular risk factors. These findings, along with the close association between lacunar infarcts and hypertension, have led to the realization that subcortical vascular cognitive impairment begins with mild white matter hyperintensities and may progress to advanced subcortical vascular dementia with an underlying pathology comprising not only white matter hyperintensities but also incomplete infarcts, microinfarcts, and lacunar infarcts in the deep white matter (43; 101). Recent studies have shown that enlarged perivascular spaces are also features of small vessel disease that are associated with cognitive decline and dementia, independent of other markers of small vessel disease (70; 65; 06).
Cerebral amyloid angiopathy. There are many ways that cerebral amyloid angiopathy manifests itself. One common way is with intracerebral hemorrhage but it can also be seen in association with cerebral microbleeds, superficial siderosis, white matter hyperintensities, and microinfarction (10; 74). Mild cognitive impairment is commonly associated with cerebral amyloid angiopathy, and the cognitive profile (poor executive function and slow processing speed) is more similar to that seen in vascular cognitive impairment than it is with Alzheimer disease (09). In 1 autopsy study, participants with cerebral amyloid angiopathy had worse cognitive performance in the domains of perceptual speed, episodic memory, and semantic memory at the last clinical examination before the patients’ demise (07).
Cognitive tests. Early work confused the cognitive impairment of small-vessel cerebrovascular disease with Alzheimer disease, but this is now well recognized to be inappropriate. Consequently, case identification should be based on predominant frontal and executive cognitive impairment, rather than memory. Following from this, the use of the mini mental state examination (MMSE) is inappropriate, as the MMSE is insensitive for frontal and executive deficits. It should not be used in rating or diagnosing subcortical vascular cognitive impairment. Tests including elements directed at frontal and executive functions are more appropriate, including CLOX, trail making, and digit symbol substitution. Some validation data now exist for the 30-item Montreal Cognitive Assessment (MoCA) (68; 105; 67; 113) and the Addenbrooke’s Cognitive Examination (revised edition) (69).
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