Etiology of isolated pontine infarctions: a study based on high-resolution MRI and brain small vessel disease scores

Isolated pontine infarctions are usually classified into two types: paramedian pontine infarcts (PPIs) and lacunar pontine infarcts (LPIs), i.e., small deep pontine infarcts (SDPIs), according to the lesion shapes and locations [1, 2]. In PPI, the infarct abuts on the basal surface of the pons. In SDPI, the infarct does not reach to the surface of the pons [2].

So far, asymptomatic lacunar infarcts, white matter lesions (WMLs), deep and infratentorial cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVS) in the basal ganglia have all been identified as silent magnetic resonance imaging (MRI) markers of arteriolosclerotic cerebral small vessel disease (SVD), a pathological process involving the small arteries and arterioles of the brain [3‐8]. Recently, a total SVD scoring system was developed, which involves summing the scores (0 or 1) for each of the various MRI features. It has been proved that this scoring system provides a simple and pragmatic overall score (range: 0–4), providing a more complete view of the impact of SVD on the brain than the individual MRI features [9‐11].

In recent years, high-resolution MRI (HR-MRI) has been gradually used in more clinical studies. The advantage of HR-MRI is its high spatial resolution in displaying vessel walls, thus improving the power of MRI for helping to understand the pathogenesis of cerebral vascular disease. HR-MRI can be helpful to diagnose intracranial atherosclerosis [12], artery dissection [13, 14], Moyamoya disease [15], vasculitis [16], reversible cerebral vasoconstriction syndrome [17, 18], and radiation-induced intracranial vasculopathy [19].

The main pathogenesis of each of the two types of isolated pontine infarction has been investigated by several authors. Fisher and Caplan carried out individual case studies and suggested that the pathogenic mechanism of SDPI involved perforating small arterial disease caused by lipohyalinosis, whereas PPI was caused by atheromatous branch occlusion of the paramedian or circumferential basilar branch [20‐22]. However, other in vivo studies concluded that SVD and BA plaques were both significant causes of PPIs [2, 23]. Possible reasons for the different conclusions include the limited sample sizes and defects in methodology. Thus, the underlying mechanisms warrant further investigations involving larger sample sizes and newly developed methods.

Based on the abovementioned issues, this study was designed to investigate the main causes of isolated pontine infarctions based on the total “SVD score” combined with HR-MRI findings.

Of the 157 enrolled patients, there were 117 with PPI and 40 with SDPI. All the patients underwent MRI, MRA, DWI, and SWI scans, which amounted to 122 patients receiving HR-MRI scans. Regarding the observations of BA plaques, three patients were excluded due to poor-quality HR-MRI T1 and T2 images, so eventually 119 patients were retrospectively analyzed for BA plaques.The clinical characteristics are summarized in Table 1. The prevalence of diabetes mellitus in the PPI group (43.6%) was much higher than that in the SDPI group (17.5%). The median NIHSS score in the PPI group was also higher than that in the SDPI group. The laboratory test data between the two groups were similar, as summarized in Table 2.

The results showed that BA atherosclerosis may be the major cause of PPI, while SVD may be the main mechanism underlying SDPI. To the best of our knowledge, this study is the largest retrospective study of an Asian population to explore the main mechanisms of the two types of isolated pontine infarction. For the first time, the total SVD score combined with HR-MRI was used in the investigation. There is no doubt that this will be helpful to understand the etiology of isolated pontine infarctions.

Previous studies have investigated the main causes of PPI and SDPI [1, 2, 20‐23], but their conclusions were conflicting. We argue that there are two main limitations associated with these previous studies. Firstly, the sample size in some of them was small, so it is difficult to make an exact judgement about the major etiology of PPI and SDPI; secondly, the various studies also had methodological limitations. Although pathology is the gold standard for judging etiology, isolated pontine infarctions are rarely fatal, so it is difficult to explore the major causes from individual pathologic case studies. In one of the previous studies [23], although HR-MRI was used to detect BA plaques, only WMLs and lacunae were used as imaging markers of cerebral small vessel disease. Thus, in the present study, the total SVD score combined with HR-MRI was used to investigate the etiology of isolated pontine infarctions in a larger sample.

The results showed that the mean total SVD score was significantly higher in the SDPI group than in the PPI group, indicating that SVD is the main pathogenesis of SDPI. The prevalence of BA plaques relevant to the infarcts was much higher in the PPI group than in the SDPI group, while the frequency of irrelevant BA plaques was similar between the two groups, which indicates that BA atherosclerosis is significantly associated with PPI. These results imply that the main cause of PPI is probably large artery atherosclerosis, while SDPI may be attributable to SVD, which is in accordance with the findings of previous pathology-related research [21].

BA plaques were detected in 87.8% of the patients with PPI, which is higher than that in a previous report [26]. This might be due to application of the 3.0-T MR scanner (which is more sensitive for detecting plaques than a 1.5-T MR scanner), and also the high prevalence of intracranial atherosclerosis in Asian populations. The degree of BA stenosis in the PPI group was slightly higher than that in the SDPI group, and diabetes mellitus was more prevalent in the PPI group, which further supports the proposal that the main etiology of PPI is probably large artery atherosclerosis. In addition, the prevalence of asymptomatic lacunar infarcts in the pons was higher in the SDPI group, which also supports the role of SVD as the main mechanism underlying SDPI.

In clinical practice, the identification of the etiopathogenesis of stroke might be crucial for guiding appropriate use of early therapies and secondary prevention strategies. For example, if the etiology is large artery atherosclerosis, enhanced antiplatelet and statin treatment is reasonable in the acute phase of stroke, while routine antiplatelet and statins should be given if the etiology involves SVD.

In the present study, we found no significant difference in the prevalence of hypertension between patients with PPI and SDPI, and no increase in the prevalence of hypertension in patients with high total SVD scores. One possible reason for this is that ambulatory blood pressure levels were not evaluated, despite the fact that ambulatory blood pressure is now considered to be an important and modifiable risk factor for SVD [5, 27]. According to the NIHSS scores, neurological deficits in the PPI group were more severe than those in the SDPI group, which is in accordance with the larger maximum diameter of infarcts in the PPI group. This may explain the sample size difference between the PPI and SDPI groups, i.e., due to more severe neurological deficits, more PPI patients were hospitalized in the same period of time than SDPI patients.

Our study suffered from several limitations. 1. There is likely to have been sample selection bias due to the retrospective single-center nature of the investigation. For example, the mean NIHSS score in the sample was low, so patients with severe deficits were not adequately represented in the study. 2. Although the study is the largest retrospective study of an Asian population, the sample was still too small to allow stratification, or to analyze the relationships between isolated pontine infarction, diabetes mellitus, and BA plaques. 3. Embolisms from more proximal arteries, e.g., vertebral arteries and the aortic arc, could not be completely excluded. 4. The definition of BA plaques relevant to the infarcts was based on the normal direction of blood flow in the vessels. Sometimes, especially when there is severe stenosis in the BA, the direction of blood flow can be reversed. In these cases, plaques located in distal segments could be responsible plaques. 5. Contrast-enhanced MRA, which would have mildly affected the precision of the degree of BA stenosis, was not used in the study.

This study suggests that BA atherosclerosis is probably the major cause of PPI, and SVD may be main mechanism underlying SDPI. This information is likely to be crucial for making appropriate early therapy decisions and implementing appropriate secondary prevention strategies. HR-MRI combined with the total SVD score could play an important role in determining the main pathogenesis in the two types of isolated pontine infarctions, especially in cases with low-grade BA stenosis.