Discussion
This national hospital-based study indicated that over three quarters of infarction occurred in SSSI patients without PAS. Furthermore, we found that the diagnosis of PAS could efficiently stratify the risk of recurrent stroke and composite vascular events within 3 months and 1 year of SSSI, while the parent disease was not associated with disability in both short and long terms. Our study may have important clinical implications with the large sample size of patients with SSSI included and comprehensive prognostic characteristics recorded.
In this study, we described the epidemiological characteristics of the short-term and long-term prognoses of SSSI. Our data showed that the characteristics of SSSI are heterogeneous between PAS and non-PAS groups. Compared with the non-PAS, PAS was more likely to be related to atherosclerosis indicators. Our observation was consistent with the previous studies that diabetes and coronary heart disease were more prevalent in patients with large-artery atherosclerosis than in those with small-vessel disease,12 13 while in a study on subcortical infarction in MCA territory, there were no clinical differences between infarctions caused by MCA and small vessels.6 Atherosclerosis indicators, including hypertension, diabetes and smoking, could cause not only intracranial atherosclerosis but also microatheroma and lipohyalinosis.14 15 However, it remains unknown which pathological change is dominant and symptomatic in certain high-risk populations.
The proportion of minor strokes at admission (NIHSS score <4) was 52.28% in our study. Three-month and 1-year ischaemic stroke recurrences were 5.26% and 7.79%, respectively. Nearly 90% of patients had favourable functional outcomes in both the short and long terms. Similarly, a systematic review in the UK indicated that the risk of recurrence among lacunar patients during the first month ranged from 0% to 4%, and that from 1 month to 12 months was 5%–8%.16 In a CHANCE subgroup study, stroke recurrence rates of the single acute infarction group was 8.68%.17 Our study confirmed these general findings but also indicated a differentiation by infarct aetiology.
Louis Caplan first used branch atheromatous disease to describe an occlusion or stenosis at the origin of a deep penetrating artery of the brain,18 either isolated microatheromata in the branch’s orifice or plaques seated in the wall of the parent artery, leading to a small internal capsule or pontine infarct (shown in figure 4). Thus, PAS could help to predict the prognosis of SSSI and be used as a solid standard in risk stratification. In this study, we found that the PAS predicts higher NIHSS score at admission, ischaemic stroke recurrence and composite vascular events after adjusting for age and other known predictors of poor outcome in stroke. In a subgroup study of CHANCE, severe ICAS or occlusion doubles the risk of recurrent stroke in minor stroke and TIA.9 Our study was consistent with previous studies and indicated that PAS increased short-term and long-term risk in stroke recurrence and composite vascular events in SSSI. We also examined the relationship between PAS and functional disability at 3 months and 1 year. However, it did not provide differences regarding disability in the short and long terms after considering the NIHSS score at admission and related risk factors. Therefore, PAS was a crucial aetiology of SSSI and plays a significant role in stroke recurrence, despite not being related to the severity of disability.
Figure 4Presumed mechanism of infarcts in penetrating artery territory. (A) Plaque in parent artery obstructing a branch. (B) Junctional plaque extending into the branch. (C) Microatheroma formed at the orifice of a branch. (D) Emboli from unstable microatheromatous plaque. (E) Fibrinoid degeneration or lipohyalinosis of the distal perforating artery. Y-YZ drew and created this figure with full permission. The authors confirm that this figure was not a reuse of previously published work.
In our study, dual antiplatelet use had no absolute advantage over single antiplatelet use on stroke recurrence, composite vascular events and disability. Previous research has indicated that DAPT was more efficient in treating ischaemic stroke caused by large-artery atherosclerosis.19 Despite the finding that the PAS group could be more related to intracranial atherosclerosis, DAPT was not superior to SAPT on preventing composite vascular events and improving functional outcome. The fact that patients with PAS in our study did not have significantly more indicators of atherosclerosis than non-PAS ones might be one underlying cause. In addition, antiplatelet regimes were not related to good outcomes in patients without PAS. The results confirmed the findings of previous studies that DAPT was not associated with the reduction in recurrent strokes in single small strokes. In a subgroup analysis of the CHANCE study, patients who had minor stroke with single acute infarction seem to benefit less from dual antiplatelet treatment.17 The Secondary Prevention of Small Subcortical Strokes trial indicated that dual antiplatelet treatment did not reduce the risk of ischaemic stroke.20 This finding indicates that in different types of ischaemic cerebrovascular disease, the role of platelets and the components of thrombosis are different. The reason might be that thrombosis may have a minimal role in precipitating occlusions of small penetrating cerebral arteries.2 A study indicating that procoagulant platelets are lower in lacunar stroke than non-lacunar stroke confirmed the suggestion.21
Meanwhile, in this study, DAPT did not increase haemorrhagic stroke. Our result was consistent with previous studies. In the CHANCE study and the Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation Management, and Avoidance (CHARISMA) trial, the risk of intracranial bleeding did not increase when clopidogrel was added to aspirin.8 22 While in the Platelet-Oriented Inhibition in New TIA and Minor Ischaemic Stroke trial, the increase of haemorrhagic stroke in the dual antiplatelet group might be due to the prolonged usage of clopidogrel.7
Therefore, the effective therapy for secondary prevention in SSSI needs further investigation.
Limitations
First, parent artery disease might be underdiagnosed in our study.23 24 High-resolution and ultrafield MRI has been proven capable of revealing cerebral perforating arteries25 26 and describing in much more detail intracranial vessel wall changes.27 That might enhance our understanding of the mechanism of stroke in the territory of perforating arteries.28
Second, it seems very difficult to identify the aetiologies more detailed by current clinical routine imaging examinations. Isolated atherosclerosis in the branch’s orifice or mild plaque occluding the orifice cannot be detected even by high-resolution MRI. White matter intensity and other MRI markers could be evidence for cerebral small-vessel disease. However, atherosclerotic lesions, microatheroma and fibrohyalinosis often coexist, and the aetiologies are challenging to distinguish. Thus, the distinction criteria of aetiologies we used were practical and critical in clinical practice.
Third, in this study, we were unable to evaluate early neurological deterioration, which is a characteristic clinical manifestation in acute pontine or basilar ganglia infarction and might relate to unfavourable outcomes.14 29
Fourth, we did not have detailed data about TOAST classification of recurrent ischaemic strokes in follow-up. One study suggested that cardiogenic embolism might contribute to stroke recurrence in patients who had lacunar stroke.30 This could explain the non-ideal efficacy of DAPT in our study. However, there was evidence that recurrent strokes were more likely to be lacunar if the index event was lacunar.16 Thus, the mechanism of SSSI and the recurrence needs further investigation.
