In this retrospective nationwide population-based cohort study, the incidence of ocular motor CNP among Koreans significantly increased according to the glycemic status (nondiabetes, IFG, newly detected, duration < 5 years, and duration ≥ 5 years groups). In particular, the results showed that the risk of ocular motor CNP was significantly increased even in subjects with IFG compared to non-diabetes subjects. The term “prediabetes” was adopted to identify the condition in which blood glucose levels are above normal but below that of DM [25, 26]. It is reported that up to 70% of individuals with prediabetes develop type 2 DM [27]. In addition, prediabetes itself is related to other conditions including obesity and hypertension [28]. The possibility of involvement of small unmyelinated nerve fibers in prediabetes was also previously reported, which was expressed as a dysfunction of cardiac autonomic activity and impairment of nerve fibers associated with pain and temperature [29]. Also, in the Diabetes Prevention Program (DPP) study, which was a cross-sectional study on diabetic patients, 8% of patients with prediabetes had vasculopathy such as retinopathy and coronary heart disease [29, 30]. Our study suggested that prediabetic status is also related to increased risk of ocular motor CNP. Intensive lifestyle interventions are reported to have a beneficial effect for slowing the rate of progression to diabetes in prediabetic patients in previous studies [30, 31]. Currently, it is debatable whether or not drug treatment should be initiated in prediabetes [21, 29, 30, 32]. Despite controversies over the guidelines relating to the criteria for prediabetes [21] and pharmacotherapy [32], studies suggested the importance of preventive action in prediabetic status to lessen the possibility of progression of diabetes (5–10%) and its complications [21, 30, 32]. Our study is the first to report on the association between prediabetes and ocular motor CNP, which suggests that prediabetes can cause peripheral neuropathies relating to ocular movement and early treatment in prediabetic patients can potentially reduce the risk of this type of complication. Further prospective studies are needed to clarify the effect of the treatment in this group of patients.
In this study, the risk of ocular motor CNP was higher with longer diabetes duration. These results were consistent after adjusting for various potential confounders. We found that individuals with prediabetes group (IFG) had a 1.10 times higher risk of developing CNP compared with nondiabetic subjects, while the newly detected group had a 1.79 times higher, within 5 years of diabetes group had a 1.96 times higher, and 5 years or more group had a 2.60 times higher risk of developing ocular motor CNP. It is well known that longer diabetes duration is a major risk factor for diabetic complications such as macrovascular and microvascular events [15, 19, 20]. Since the majority of acquired ocular motor CNP is also a microvascular ischemic disorder [6, 12, 20], it can be assumed that the duration of diabetes also increases the risk of this type of neuropathy. Stephenson et al. analyzed the risk factor of diabetic peripheral neuropathy and revealed that in the case of long duration of DM, the risk of peripheral neuropathy was significantly increased [33]. Specifically, people diagnosed with diabetes at a younger age are expected to have a longer lifetime risk of these cranial neuropathies, suggesting the need for intensive glycemic management and optimization of other risk factors.
Although the exact pathophysiology of diabetic neuropathy is not fully understood, numerous hypotheses have been proposed [34–36]. In hyperglycemic status, nerve perfusion is reduced [37, 38]. Hyalinization of the basal lamina and increased wall thickness of the blood vessels supplying the peripheral nerve induce nerve ischemia [36–38]. In addition, various mechanisms such as polyol pathway hyperactivity, microglial activation, sodium and calcium channel expression change, and oxidative stress have been found to induce metabolic disorders in the nerve itself [34, 36]. Based on this, we hypothesized that those mechanisms may also cause cranial nerve disorder.
In our study, we found that diabetic patients with young age, male gender, smoking, and hypertension showed a higher risk of ocular motor CNP compared to those without them. According to Eman et al., who analyzed clinical data from The Saudi National Diabetes Registry (SNDR), the most significant risk factors for CNP in diabetic patients were age ≥ 45 years, diabetes duration ≥ 10 years, and male gender, while smoking and hypertension were not significant [19]. In the same contexts with Saudi, in the Caucasian diabetic patients, male gender was an independent risk factor for CNP [37]. Another study also reported that males developed neuropathic complications at 63 years, approximately 4 years earlier than did females (at 67 years) [38]. While DM and HTN are known risk factors of CNP, several studies revealed that HTN did not increase the risk of CNP significantly. Patel et al. reported that patients with DM were six times more likely to have 6th CNP, while there was no significant association between HTN and 6th CNP [39]. Jacobson et al. suggested that left ventricular hypertrophy, one of the peripheral organ injuries, was considered to be an independent risk factor for CNP, rather than HTN itself [11]. Further research on the exact pathomechanisms underlying the association between various risk factors and the development of CNP is required.
This study has several limitations. First, as this study has a retrospective design, the causal relationship between the diseases cannot be confirmed. Second, due to the nature of the data, patients who did not use health care services, and patients whose physicians registered incorrect diagnostic codes could not be counted. However, the acute nature of the symptom and its significant impact on the visual function caused by ocular motor CNP might lead the majority of patients to use healthcare services.
In conclusion, this population-based study showed that the incidence of ocular motor CNP increased according to glycemic status (non-diabetes, IFG, new-onset, within 5 years and over 5 years groups) and the longer duration of diabetes increases the likelihood of this complication. Also, prediabetic people, who are below the diagnostic threshold for diabetes were at more risk of cranial neuropathy, compared with normal glycemic status. Relatively younger age, male gender, and smoking patients could have a higher risk of developing ocular motor CNP related to diabetes or prediabetes.