Worsening neurological deficits, also known as early neurological deterioration (END), occur in up to one-third of patients with acute ischemic stroke and have been shown to be associated with increased mortality and subsequent functional disabilities (1, 2). Pontine infarctions account for ~7% of all ischemic strokes, and isolated pontine infarctions are the most common type related to the posterior circulation, accounting for ~15% of cases (3). Extensive studies regarding END prediction in isolated pontine infarction have been performed to enable physicians to better predict END occurrence (4–6). With the popularity of magnetic resonance imaging (MRI) in clinical practice, the correlation between neurological impairment and topographic location has been deeply studied (7, 8). There are also some studies concerning the treatment and prognosis of ischemic stroke (9, 10). However, there are few studies on hematological indexes in the study of the aggravation of nervous system function. Recently, the monocyte to high-density lipoprotein ratio (MHR) has been considered to be a novel inflammatory marker of atherosclerotic cardiovascular disease, especially coronary artery disease (11). It has been reported to be related to the prediction of ischemic stroke from the general population (12) and carotid artery intima-media thickness in patients with type 2 diabetes (13). In stroke-related studies, MHR has been reported to be a good predictive value of stroke-associated pneumonia (14) and mortality in patients with ischemic stroke (15). However, there are no studies exploring the value of MHR in predicting END in patients with acute isolated pontine infarction. Therefore, the aim of our study is to elucidate the association between MHR with END after acute isolated pontine infarction.

Among 2,789 consecutive patients with ischemic stroke, 218 (7.82%) were diagnosed with an isolated pontine infarction, 6 of whom experienced aggravation due to extracerebral illness. A total of 212 patients with acute isolated pontine infarctions were included in the final analysis. The mean age of patients was 68.27 ± 11.57 years, and 127 (59.9%) were male. The mean NIHSS score was 3.59 ± 2.25. A total of 41 (19.3%) patients had basilar artery stenosis. END was diagnosed in 58 (27.36%) patients. END occurred within the first 48 h after admission in 38 patients (65.52%). The mean MHR level was 0.44 ± 0.22. Detailed demographic data are summarized in Table 1. As expected, the presence of basilar artery stenosis (P = 0.028), hypertension (P = 0.028), and END (P = 0.001) was significantly different between groups.

Patient baseline clinical characteristics in the END and non-END groups are shown in Table 2. Basilar artery stenosis (P = 0.002), NIHSS at admission (P < 0.001), previous stroke (P = 0.049), and PPI (P = 0.001) were significantly higher in the END group than in the non-END group. Prevalence of hypertension, diabetes, coronary heart disease, hyperlipidemia, atrial fibrillation, and current smoking showed no significant difference between the two groups.

Patient laboratory test and imaging results are shown in Table 3. Patients in the END group had larger infarct size (P = 0.004), higher HR (P < 0.001), higher blood glucose level on admission (P < 0.001), and higher monocyte count (P < 0.001) than those patients in the non-END group. At the same time, compared with that in the non-END group, the HDL level in the END group was lower (P = 0.024).

As presented in Table 4, multivariate logistic regression analysis showed that NIHSS at admission [P = 0.018, odds ratio (OR) = 1.228, 95% confidence interval (CI) = 1.036–1.456], basilar artery stenosis (P = 0.021, OR = 2.843, 95% CI = 1.205–6.727), and fasting blood glucose (P = 0.046, OR = 1.296, 95% CI = 1.004–1.672) were independently associated with END. The odds ratio for END increased with increasing quartile of MHR with the lowest quartile used as the reference value. A high (≥0.43) MHR was independently associated with END (third quartile OR, 4.847; 95% CI, 1.532–15.336; fourth quartile OR, 5.824; 95% CI, 1.845–18.385) in multivariate analysis. The third and fourth highest quartiles of MHR levels were identified to be independently associated with END. Receiver-operating characteristic curve analysis suggested the sensitivity, specificity, and area under the curve for MHR to discriminate END from non-END were 65.5, 76.6, and 71.5% (95% CI, 64–79%; P < 0.001), respectively. Youden's index was 0.421. The cutoff was 0.51 (Figure 3).

Spearman's correlation was used to determine the relationship between MHR level and NIHSS at 7 days. The results showed that there was a correlation between MHR level and NIHSS at 7 days r_s = 0.573, P < 0.001.

There are limited reports describing the predictive value of MHR level for early deterioration during the acute phase of an isolated pontine infarction. This study found that elevated MHR levels are associated with END and that the risk of END tended to increase with increasing MHR. It has been unequivocally shown that progressive neurological deficit after ischemic stroke may lead to increased mortality and morbidity (1). Progression of neurologic deficit, however, does not have an authoritative definition, as it could be considered to be either a neuropathological or a clinical event. Early neurological deterioration in patients with isolated pontine infarction is relatively common.

This study showed that 27.36% of the patients with isolated pontine infarction had END, which is consistent with previous studies that reported a prevalence of 20–58% in patients with acute stroke (17, 18). The incidence of END differs between studies according to its definition and the timing and duration of observation (3, 19–21). Although the majority of the relevant studies were based on an increase in NIHSS scores, the exact increase in NIHSS score used to define END has varied drastically. For example, some studies used an NIHSS score increase of 1–2 points combined with motor function impairment to define END, whereas others defined END as an NIHSS increase of 4 points. In terms of the timeframe, END has been defined to occur within 3 days, 5 days, or 1 week after symptom onset in different studies. In our study, END was defined as an elevation in the total NIHSS score ≥2 or an increase in NIHSS score ≥1 in motor power within the first week after symptom onset, which is congruent with most previous studies (7, 22).

Acute inflammation has been observed in brain injury caused by cerebral ischemic diseases, such as the production of inflammatory cells, release of proinflammatory mediators, and tissue infiltration (7, 22). In fact, there is growing evidence that inflammation exerts a prominent effect in the pathogenesis and progression of ischemic stroke (23, 24). A few hours after stroke onset, the number of circulating polymorphonuclear neutrophils increase in a stroke severity-dependent manner (25). Monocytes from the bloodstream reach the damaged site most abundantly 3–7 days after ischemia onset (26). In the early stages after brain injury, the number of total monocytes in the blood circulation shows an increasing trend (27). In addition, previous studies have reported an influx of different immune cells and cytokines produced in the brain, which play an immunomodulatory role in postischemic inflammation (27). Wang et al. suggested that high monocyte counts have the value in predicting the prognosis in various cardiovascular diseases (28). Monocytes play a pivotal role in the initiation and progression of the atherosclerotic process (29). Monocytes in the blood are involved in the start of the process of atherosclerosis by migrating to the intima and differentiating into macrophages under the action of cytokines (30). The increase in the number of macrophages and monocytes around vulnerable plaques can also lead to an increase in the monocyte count in the peripheral blood (31). This inflammatory response takes place during all subtypes of stroke. It could, at least in part, explain the more critical neurological symptomatology and worse outcomes (32). In contrast, HDL-C can control the activation of monocytes while inhibiting the migration of macrophages, protecting endothelial cells from inflammation and oxidative stress (33). Previous studies showed that impaired HDL-mediated cholesterol efflux and low HDL levels caused monocytosis proliferation, leading to a progression of the atherosclerotic plaque (34).

Intracranial atherosclerosis is the main feature of ischemic cerebrovascular disease (35, 36). Branch atherosclerosis, arterial embolism, and hypoperfusion after intracranial atherosclerosis are likely to lead to ischemic stroke (37, 38). Recent studies showed that the occurrence of END was also associated with the severity of basilar artery stenosis (7). By performing autopsies, Caplan identified the basis of pontine infarctions, such as plaque blocking the branch orifice within the parent artery, atherosclerotic plaques originating in the trunk and extending to the branches, and microatheroma originating in the orifice of branches (39). Atherosclerotic stenosis of the basilar trunk was observed in 50% of patients with isolated pontine infarction extending to the basal surface (40). Meanwhile, early neurological deterioration is one of the most concerning clinical problems in patients with branch atherosclerotic diseases. Progressive deficit has been associated with basilar artery branch disease and poor functional outcomes (41). Therefore, the progression of vascular stenosis or thrombosis caused by intracranial atherosclerosis is related to END.

The MHR has recently been used to predict a variety of cardiovascular abnormalities as a developed measure of inflammation and oxidative stress, which reflects the anti-inflammatory and antioxidative effects of HDL, as well as the balance of inflammation and oxidative stress caused by the proinflammatory effects of monocytes. At the same time, MHR has been used as a prognostic indicator in a series of studies. Compared to the control group, patients with acute ischemic stroke had higher MHR, and high values of MHR were found to be a significant independent variable predictive of 30-day mortality in patients with acute ischemic stroke (42). A higher MHR was found to be associated with an increased risk of disability or death at discharge and 3 months after intracerebral hemorrhage, whereas an increase in monocytes was only associated with an increased risk of disability or death after 3 months (43). There are few studies on the association between MHR and acute cerebrovascular disease, especially in the acute phase. We analyzed the correlation between MHR and END in the acute stage of pontine infarction. To our knowledge, this is the first time that inflammatory factors and infarct size have been considered together to study the factors related to END in ischemic cerebrovascular disease. Our study indicated that MHR was an effective and convenient measure in predicting neurological deficit aggravation following pontine infarction. The MHR is a simple and convenient measure that can be effectively applied in clinical practice and provides clinical utility in risk stratification in subjects presenting with isolated pontine stroke. These findings have implications for strategies aimed at lowering the MHR to prevent early neurological progression in patients with ischemic stroke.

Earlier studies have identified the presence of comorbidities (such as diabetes and hypertension), female sex, infarct size, and neurological severity at onset to be associated with progressive deficit in patients with isolated pontine infarctions. However, some studies have reported inconsistent findings (41). In addition, the infarct area extending to the basal surface was 2.5 times greater than deep infarctions without extension to the basal surface (41). Compared to LPI, PPI was related to END in the univariate analysis in our study. In the present study, infarct size had a very high value in the crosstab analysis, which was consistent with many previous studies on infarct size and progression (18); however, in the multiple logistic regression analysis, there was no significant difference in infarct size between the two groups.

In the current study, hyperglycemia correlated with END in patients with isolated pontine infarction after adjusting for other confounding factors in the multivariate analysis. Poststroke hyperglycemia is a common finding among diabetic and nondiabetic patients as a stress response, which is also commonly known as stress hyperglycemia (44). Approximately one-third of stroke patients had hyperglycemia on admission, which was associated with a poor prognosis in patients treated with thrombolytic drugs after ischemic stroke. A recent study reported that stress hyperglycemia increases the risk of severe neurological dysfunction in patients with acute ischemic stroke and is associated with mortality within 1 year (45). Although the exact mechanism underlying the relationship between hyperglycemia and END remains unknown, studies have illuminated the involvement of endothelial injury, tissue acidosis, blood–brain barrier destruction, and production of excessive active oxygen species (46, 47). Therefore, additional studies are necessary to determine whether optimizing blood glucose control could improve the clinical outcomes of patients with pontine infarction.

END following ischemic stroke was a serious event associated with long-term functional outcomes, as reported previously. It was also related to composite event outcomes after discharge during the first year after stroke (48). As inflammatory and immune-mediated mechanisms of neuronal injury have received greater attention, anti-inflammatory treatments have been developed or tested in the preclinical studies and clinical trials, such as IL1-Ra (49, 50), statins (51), and edaravone (52). Despite clinical developments, no beneficial long-term interventions targeting inflammation are currently available.

In conclusion, patients with acute isolated pontine infarction and elevated MHR levels are at increased risk for END. MHR could be a convenient and effective measure related to END following pontine infarction. In the future, prospective multicenter studies will be needed to conclusively determine the predictive value of MHR for END in acute isolated pontine infarctions.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the ethics committees of Beijing Shijitan Hospital, Capital Medical University (No. sjtky11-1x-202091). The participants provided written informed consent to participate in this study. If the participant was unable to provide written informed consent due to illness, the informed consent was signed by the client instead.

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.