Apathy, Fatigue, Delirium Harbingers of Vascular Dementia, Stroke?

Batya Swift Yasgur, MA, LSW

February 10, 2021

Neuropsychiatric symptoms may be an early indicator of severe cerebral small-vessel disease (cSVD), a common cause of vascular dementia and stroke that until now was considered clinically silent.

Brain imaging results of a new review and meta-analysis show that severity of white matter hyperintensity (WMH) was significantly associated with apathy, fatigue, and delirium.

"We should take neuropsychiatric symptoms seriously in individuals who are at high risk for developing vascular dementia or stroke, as these symptoms may reflect accumulating damage to the brain's small blood vessels," study investigator Úna Clancy, MB BCh, BAO, chief scientist office clinical academic fellow and honorary specialist registrar in stroke and geriatric medicine, Center for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom, told Medscape Medical News.

The study was published online February 1 in The Lancet Psychiatry.

Early Warning Symptoms

"While looking after patients with vascular dementia and previous strokes, we noticed that some patients with so-called 'silent' new stroke appearing on their brain scans reported subtle symptoms that didn't technically meet diagnostic criteria for stroke or dementia," said Clancy.

"We suspected that these subtle symptoms going under the radar could actually be important early red flags for problems with the brain's small blood vessels, and we also noticed that there was a lot of overlap between neuropsychiatric symptoms experienced by patients with stroke and dementia," she added.

The investigators explored whether small-vessel disease could be the common link for these symptoms. Identifying such symptoms as early as possible, before further brain damage occurred, might be "a simple way of identifying high-risk individuals who may benefit from future prevention and treatment," Clancy said.

No published meta-analysis has assessed the association between neuropsychiatric symptoms (other than depression) and imaging features of small-vessel disease, the authors note.

The researchers searched four databases for studies published in any language up to January 24, 2020. Included studies investigated cross-sectional and longitudinal associations between a wide array of neuropsychiatric and cognitive symptoms and radiologic features (on MRI or CT scan) of small-vessel disease. Both prospective and retrospective observational studies were included.

The imaging included not only WMHs but also lacunes, lacunar infarcts, small subcortical infarcts, perivascular spaces, and microbleeds.

Frail Brains

The researchers identified 81 studies (n = 21,730 participants; mean age, 69.2 years). Of these studies, 45 (n = 8120 participants) also reported estimates of effects.

Data were pooled using random-effect meta-analyses that reported adjusted findings whenever possible. Outcomes were stratified by disease severity or the presence or absence of symptoms.

An association was found between more severe WMH and apathy (OR [95% CI], 1.41 [1.05 – 1.89]), with an adjusted standardized mean difference (SMD) of .38 (.15 – .61). More severe WMH was also associated with delirium and fatigue (adjusted OR, 2.9 [1.12 – 7.55] and 1.63 [1.20 - 2.22], respectively).

WMHs were not consistently associated with subjective memory complaints (OR, 1.34 [.61 – 2.94; unadjusted SMD, .08 [−.31 to .47]).

Because study outcomes of anxiety, dementia-related behaviors, emotional lability, and psychosis were "too sparse for meta-analysis," the researchers reviewed them narratively. They found "insufficient evidence to confirm or refute associations" between these neuropsychiatric symptoms and worse WMH severity. There was also insufficient evidence to draw conclusions about potential associations between these symptoms and other radiologic features.

Heterogeneity ranged widely across all studies, from 0% to 79%. Only five studies had a "low risk of bias across all domains," the authors report.

They note that apathy is "prevalent" in individuals with cognitive impairment and in those who have had a stroke; its prevalence increases longitudinally following stroke diagnosis as well as Alzheimer's disease.

It is unclear whether apathy "predates condition onset, develops subclinically, or occurs only in established disease states," they write.

The association of delirium with worse WMH severity implies that those with underlying SMD have brains that are "more frail, in which areas of vascular dysfunction can be more susceptible to acute impairment following systemic inflammatory insults," they write.

Insidious Progression

Commenting on the study for Medscape Medical News, Mark Etherton, MD, PhD, associate director of the acute stroke service, Massachusetts General Hospital, Boston, Massachusetts, called cSVD "an important risk factor for incident stroke, poor stroke outcomes, dementia, and death."

Because of its "insidious progression, it is often not recognized until the time of a patient's stroke or clinical evaluation for memory decline," said Etherton, who is also an instructor at Harvard Medical School. He was not involved with the study.

The study "demonstrates that the clinical sequelae of cSVD are far more pervasive, with important associations with apathy, delirium, and fatigue," and these "important findings further define the syndrome of cSVD, which is necessary for improving cSVD awareness and recognition as the first step toward cSVD treatment and prevention," Etherton stated.

"Moreover, this added knowledge of the neuropsychiatric features of cSVD will inform clinician counseling on cSVD prognosis as well as the clinical monitoring of patients with cSVD," he added.

Clancy agreed. "We need to try to integrate research and clinical management approaches to these patients to see whether these subtle symptoms could be used to screen for individuals at high risk of developing vascular dementia or stroke in the future," she said.

Clancy holds academic grants from charitable and funding agencies. The other authors' disclosures are listed in the original article. Etherton has disclosed no relevant financial relationships.

Lancet Psychiatry. Published online February 1, 2021. Abstract

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