What this means quite simply is: If you're frail, don't have a stroke, nothing is assured about your full recovery
Stroke Literature Synopsis (Clinical)
Stroke is predominantly a disease of older people, and many people who experience stroke are also living with frailty or disability. Frailty is a clinical syndrome characterized by a decrease in physiological reserve and reduced ability to cope with stressors such as stroke. A related, but distinct construct to physical frailty is brain frailty, which refers to diminished neurocognitive reserve and vulnerability. For this synopsis, we have chosen 3 studies that discuss the complex relationship between frailty, disability, and stroke disease.
Neuroimaging can be used to assess and quantify brain frailty. Common markers of brain frailty seen on magnetic resonance imaging include atrophy, chronic infarcts, and cerebral small vessel disease. However, can measuring these brain frailty markers improve stroke care? This question was addressed in a secondary analysis of the ESCAPENA1 trial (Safety and Efficacy of Nerinetide) (Benali F, et al. Mediation of age and thrombectomy outcome by neuroimaging markers of frailty in patients with stroke. JAMA Netw Open. 2024;7:e2349628. doi: 10.1001/jamanetworkopen.2023.49628). ESCAPE-NA1 was a multicenter, double-masked trial where 1105 participants suitable for endovascular thrombectomy were randomized to receive either IV nerinetide or placebo. In this post hoc analysis, the team described how different measures of brain frailty mediated the association between age and 90-day functional outcome as determined by modified Rankin Scale.
In their analyses, increasing age was associated with poorer functional outcomes after thrombectomy. The direct effect of age on the 90-day functional outcomes was nonsignificant, but the indirect effect of age, mediated by different frailty models, showed significant associations. Brain frailty accounted for 85% of the total indirect association between age and functional outcome. For the concept of total frailty, defined as a combination of prestroke modified Rankin Scale, comorbidities, and brain frailty, this accounted for 100% of the indirect effect of age on outcome. Based on these results, the authors suggest that brain frailty should be incorporated into discussions around prognosis and treatment goals.
The association between overt stroke and cognitive decline is clear, but the neurocognitive consequences of so-called silent infarcts seen on magnetic resonance imaging brain imaging are less clear. Surgical aortic valve replacement is a procedure where acute, silent infarcts are commonly observed. In a secondary analysis of a multicenter clinical trial assessing different embolic protection devices, the association between neuroimaging features and perioperative delirium was described (Browndyke JN, et al. Infarct-related structural disconnection and delirium in surgical aortic valve replacement patients. Ann Clin Transl Neurol. 2024;11:263–277. doi: 10.1002/acn3.51949). Assessing for silent strokes, defined as lesions on diffusion-weighted imaging (DWI) magnetic resonance imaging sequences with no apparent clinical stroke features, the imaging metrics of interest included infarct volume, location, and infarct-mediated structural disconnection.
In total, 298 participants who had neuroimaging, delirium screening, and no evidence of clinical stroke were included in this post hoc analysis. The incidence of perioperative delirium was high, at 23.5%. The development of delirium was associated with significant increases in DWI lesion volume in strategic brain areas including right cerebellum and temporal lobe white matter. DWI lesion–mediated structural disconnection effects were more apparent within the right temporal lobe and frontal lobe regions in the group who developed delirium. Interestingly, no association was found between baseline white matter hyperintensity burden and incident delirium. These results do not prove a causal effect, but they strongly support the importance of infarct location and structural connectivity in the development of cognitive disturbance. These data also suggest that the term silent infarct may be a misnomer.
Frailty and disability may influence poststroke recovery through a lesser response to rehabilitation and thus may require adjustments to rehabilitation processes. However, the optimal intensity and duration of rehabilitation for this group is not clear. Boyne and colleagues (Boyne P, et al. Optimal intensity and duration of walking rehabilitation in patients with chronic stroke: a randomized clinical trial. JAMA Neurol. 2023;80:342–351. doi: 10.1001/jamaneurol.2023.0033) conducted a multicenter clinical trial involving 55 stroke survivors who had persistent walking limitations >6 months after stroke. They were randomized into 2 groups: high-intensity interval training or moderate-intensity aerobic training for 45 minutes, 3× a week for up to 12 weeks with the aim of targeting neuromotor impairment and aerobic deconditioning. The main outcome of interest was 6-minute walk test distance, which was assessed by raters masked to treatment group.
The mean age of participants was 63 years, and mean time since stroke was 2.5 years. After 4 weeks both groups showed improvements in their 6-minute walk test distance, with no significant difference between groups. At later follow ups, the high-intensity interval training group demonstrated greater improvements than the comparator. After 12 weeks, the 6-minute walk test distance gain was 71 m in the high-intensity interval training group compared with 27 m with moderate-intensity aerobic training (mean difference: 44 m [14–74]; P=0.005). High-intensity interval training also resulted in greater improvements on secondary measures including fatigue and gait speed. Limitations of this study include the small sample size and the lack of longer term follow-up to assess for sustained improvements, but the results suggest the potential for high intensity, sustained rehabilitation to offer meaningful gains in stroke survivors with chronic impairment.
Taken together, there are common learnings from these articles. While older adults may have poorer outcomes following stroke, it is not the age per se that is driving this association. Interventions need to be mindful of frailty and disability. However, there is no room for therapeutic nihilism. With bespoke interventions, and prevention of complications, improved outcomes are possible for older adults living with frailty.
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