Vascular Risk Factors in Isolated Microvascular Ischemic Third Nerve Palsy: A Population-Based Study

Although presumed microvascular third nerve palsies (TNP) have been associated with vascular risk factors and/or stroke, these associations have not been explored in a population-based cohort. The purpose of this population-based case-control study was to determine whether these factors are associated with TNPs that had been classified as isolated microvascular ischemic events and determine future risk of mortality.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Vascular Risk Factors in Isolated Microvascular Ischemic Third Nerve Palsy: A Population-Based Study Bingying Zhao, MD, M. Tariq Bhatti, MD, Chengbo Fang, MD, David O. Hodge, MS, Jonathan M. Holmes, BM, BCh, Brian G. Mohney, MD, John J. Chen, MD, PhD Background: Although presumed microvascular third nerve palsies (TNP) have been associated with vascular risk factors and/or stroke, these associations have not been explored in a population-based cohort. The purpose of this population-based case–control study was to determine whether these factors are associated with TNPs that had been classified as isolated microvascular ischemic events and determine future risk of mortality. Methods: Participants were subjects .18 years old with new onset of isolated TNP attributed to presumed microvascular ischemia (n = 55) while residing in Olmsted County, Minnesota, from January 1, 1978 to December 31, 2014. Control subjects (n = 55) were randomly selected from the same population and matched for gender, age, and length of medical follow-up. We identified all cases of new-onset isolated presumed microvascular ischemic TNP using the Rochester Epidemiology Project, a record-linkage system of medical records for all patient–physician encounters in Olmsted County, Minnesota. All medical records of cases and controls were reviewed for potential risk factors, Department of Ophthalmology (BZ, MTB, CF, DOH, JMH, BGM, JJC), Mayo Clinic, Rochester, Minnesota; Department of Ophthalmology (BZ, CF), The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Department of Neurology (MTB, JJC), Mayo Clinic, Rochester, Minnesota; Department of Quantitative Health Sciences (DOH), Mayo Clinic, Jacksonville, Florida; and Department of Ophthalmology (JMH), University of Arizona, Tucson, Arizona. This study used the resources of the Rochester Epidemiology Project (REP) medical records-linkage system, which is supported by the National Institute on Aging (NIA; AG 058738), by the Mayo Clinic Research Committee, and by fees paid annually by REP users. The content of this article is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health (NIH) or the Mayo Clinic. This work was supported by the Leonard and Mary Lou Hoeft Career Development Award in Ophthalmology Research which had no role in the design or conduct of this research. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to John J. Chen, MD, PhD, Department of Ophthalmology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; E-mail: [e-mail] 248 including diabetes mellitus, diabetic retinopathy, hypertension, hyperlipidemia, smoking, and symptomatic ischemic stroke. Multivariable and univariate logistic regression analyses were used to compare the prevalence of potential risk factors between microvascular ischemic cases and controls according to the number of subjects, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Kaplan–Meier curves were used to compare mortality between cases and controls. Results: The annual incidence of microvascular ischemic TNP was 1.7 per 100,000. Univariate analysis demonstrated that hypertension (P , 0.001; OR, 4.80; 95% CI, 2.11–11.58), diabetes mellitus (P , 0.001; OR, 6.55; 95% CI, 2.72–17.32), diabetic retinopathy (P = 0.014; OR, 13.50; 95% CI, 2.48–251.55), coronary artery disease (P = 0.047; OR, 2.27; 95% CI, 1.02–5.18), and symptomatic ischemic stroke (P = 0.039; OR, 3.56; 95% CI, 1.07–11.85) all occurred more frequently in patients with microvascular ischemic TNP than controls. In multivariate analysis, only hypertension (OR of 4.14, 95% CI, 1.61–10.65, P , 0.001) and diabetes (OR of 4.12, 95% CI, 1.43–11.92, P = 0.003) remained independently statistically significant. There was numerically higher mortality in microvascular cases than in controls, but it did not reach statistical significance. Conclusions: There are multiple cardiovascular diseases that are associated with isolated microvascular ischemic TNP, including hypertension, coronary artery disease, diabetes mellitus, diabetic retinopathy, and symptomatic ischemic stroke. Given that the main drivers of this association seem to be diabetes and hypertension, patients with microvascular ischemic TNP should be evaluated for these conditions. Journal of Neuro-Ophthalmology 2023;43:248–253 doi: 10.1097/WNO.0000000000001755 © 2022 by North American Neuro-Ophthalmology Society T he most common cause of third nerve palsy (TNP) is presumed microvascular ischemia (1). Microvascular ischemic TNP has been reported to be associated with vascular risk factors such as hypertension (2,3), hyperlipidemia (3), diabetes mellitus (2,4), and smoking (5), but this has not been explored in a population-based study. DeterminZhao et al: J Neuro-Ophthalmol 2023; 43: 248-253 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution ing the true association of these potential vascular risk factors is important because they are potentially modifiable, and could be related to increased risk of stroke or mortality. Therefore, the purpose of this study is to conduct a population-based study to determine whether microvascular ischemic TNP are associated with vascular risk factors, stroke, and/or mortality. METHODS The resources of the Rochester Epidemiology Project (REP) were used to identify the records of cases and controls, which is a medical record-linkage system of all patients and health care providers’ encounters among residents of Olmsted County, Minnesota. These institutions include Mayo Clinic, Olmsted Medical Center, their affiliated hospitals, and the few private practitioners in the area (3,6–8). Institutional review board of Mayo Clinic and Olmsted County approved this retrospective chart review study. We identified all cases .18 years old with new-onset TNP diagnosed from January 1, 1978 to December 31, 2014 in a previous study (1). An isolated presumed microvascular ischemic TNP was diagnosed in patients who demonstrated spontaneous recovery or significant improvement within 4 months without signs of aberrant regeneration, had no other neurologic symptoms or signs, and had other causes were excluded (4). Potential systemic risk factors were reviewed for all patients, including diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease, symptomatic ischemic stroke, and smoking, as defined here: Diabetes mellitus: subjects taking oral hypoglycemic agents, or insulin, or had elevated plasma glucose as defined as a fasting plasma glucose $126 mg/dL or $200 mg/dL on an oral glucose tolerance test (9); Hypertension: subjects taking antihypertensive medications or had an elevated blood pressure as defined by a systolic blood pressure $140 mm Hg or diastolic blood pressure $90 mm Hg (10); Diabetic retinopathy: retinopathy noted on dilated eye examination at or around the time of the diagnosis of the TNP; Hyperlipidemia: subjects taking a cholesterol medication or had LDL $160 mg/dL or total cholesterol $240 mg/dL (11); Coronary artery disease: subjects having a history of electrocardiographic documentation of ischemia or myocardial infarction, previous coronary revascularization intervention, or coronary occlusion $50% on coronary angiography; Stroke: subjects who suffered a symptomatic ischemic stroke before or after the diagnosis of the TNP (asymptomatic stroke, transient ischemic attacks, and hemorrhagic strokes were excluded); Smoking: patients smoking at the time of diagnosis of the TNP or were former smokers with a 20 pack-year smoking history. For all variables other than stroke, subjects were considered to have the disease if they had the diagnosis before or around the time of onset of TNP. A control group was established from the REP by randomly selecting from a pool of individuals who received Zhao et al: J Neuro-Ophthalmol 2023; 43: 248-253 health care in Mayo Clinic, Olmsted Medical Center, their affiliated hospitals, or local private practitioners. Each control subject was matched to each microvascular ischemic TNP subject for gender and age. The controls were assigned for a matching “index year,” which was the date of onset of the case’s microvascular third nerve palsy. The same potential systemic risk factors were also reviewed for all control subjects through the REP, including diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease, symptomatic ischemic stroke, and smoking. In using the REP, there was no missing data for the variables, including ophthalmic examination and smoking status. All diabetic patients and controls had ophthalmic examinations documented in the charts. The prevalence of potential systemic risk factors among microvascular ischemic TNP subjects and controls was compared by univariate logistic regression analysis. The odds ratios (ORs) with 95% confidence intervals (CIs) of each risk factor were calculated. We then conducted multivariate analysis of potential risk factors found significant with univariate analysis (P , 0.1). To account for potential correlations between factors, we repeated multivariate analysis retaining only 2 factors at a time to investigate the relationships and see what influence the correlated variables had on each other. Kaplan–Meier method was conducted to look at mortality. A log-rank test was used to compare mortality between microvascular cases and controls and hazards ratio (HR) with 95% CI was calculated. RESULTS During the 36-year study period, a total of 55 cases of microvascular ischemic TNP were identified among residents of Olmsted County, Minnesota, yielding an annual incidence of 1.7 per 100,000. Among the microvascular third nerve palsy patients, 30 (55%) were male and the mean age at onset of microvascular third nerve palsy was 68.0 years (SD: 13.3). A control group of 55 age and gender matched controls were chosen from the REP that were 55% male and had a mean age of 68.0 (SD 13.2), (P = 0.994). The distribution of potential risk factors observed in microvascular ischemic TNP and controls are shown in Figure 1 and Table 1. All but 2 patients with microvascular ischemic TNPs had at least one potential risk factor (96%) with a median of 3 risk factors (range 0–6). With univariate analysis, hypertension occurred more commonly in patients with microvascular ischemic TNP (n = 44, 80.0%) than in controls (n = 25, 45.5%; P , 0.001), with an OR of 4.80 (95% CI, 2.11–11.58). Diabetes mellitus occurred more frequently in microvascular ischemic TNP (n = 29, 52.7%) than in controls (n = 8, 14.5%; P , 0.001), giving an OR of 6.55 (95% CI, 2.72–17.32). Moreover, diabetic retinopathy occurred more commonly in microvascular ischemic TNP (n = 11, 20.0%) than in controls (n = 1, 249 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Distribution and univariate logistic regression analysis of potential risk factors in patients with microvascular ischemic third nerve palsies compared with controls. 1.8%; P = 0.014), with an OR of 13.50 (95% CI, 2.48– 251.55). Coronary artery disease was more common in microvascular ischemic TNP (n = 24, 43.6%) than in controls (n = 14, 25.5%; P = 0.047), giving an OR of 2.27 (95% CI, 1.02–5.18). Finally, symptomatic ischemic stroke was also more common in microvascular ischemic TNP (n = 12, 21.8%) than in controls (n = 4, 7.3%; P = 0.039), yielding an OR of 3.56 (95% CI, 1.07–11.84). Entering these significant variables into a multivariate regression model, hypertension (OR of 4.14, 95% CI, 1.61–10.65, P , 0.001) and diabetes (OR of 4.12, 95% CI, 1.43– 11.92, P = 0.003) were the only vascular risk factors that were independently associated with microvascular ischemic TNP (Table 2). To account for correlation between diabetic retinopathy and diabetes, we explored alternative pairwise models (See Supplemental Digital Content, Table S1, http://links.lww.com/WNO/A646) and in models that did not include diabetes, but did include diabetic retinopathy, we found diabetic retinopathy was strongly associated with TNP. Based on these findings, it is difficult to distinguish between the effect of diabetes vs diabetic retinopathy. We therefore conducted an alternative analysis where we excluded all cases of diabetic retinopathy, and we found diabetes remained significantly associated with ischemic TNP (OR = 4.64, 95% CI 1.72–12.58) and we conclude that diabetes seems to be the primary driver of that association. When hypertension was not included in pairwise models (e.g., diabetes with coronary artery disease, and diabetes with ischemic stroke, See Supplemental Digital Content, Table S1, http://links.lww.com/WNO/A646), the second factor (coronary artery disease or ischemic stroke) was not associated with TNP; the associated factor was diabetes alone. These findings suggest that in the “all factor” model, the strong relationship with hypertension (and potential correlation to coronary artery disease or ischemic stroke) was not masking a relationship with coronary artery disease or ischemic stroke. Under univariate analysis, hyperlipidemia was not found to be significantly different between patients with microvascular ischemic TNP (n = 26, 47.3%) and controls (n = 18, 32.7%; P = 0.121), with an OR of 1.84 (95% CI, 0.86–4.04). Smoking was also not found to be significantly different between patients with ischemic TNP (n = 17, 30.9%) and controls (n = 18, 32.7%; P = 0.841), with an OR of 0.92 (95% CI, 0.41–2.06). There was numerically higher mortality in microvascular cases (49%) than in controls (30%) at 10 years, but it did TABLE 1. Univariate logistic regression analysis between patients with microvascular ischemic third nerve palsy and controls Potential Risk Factors Microvascular Ischemic Third Nerve Palsy, n (%) Controls, n (%) Odds Ratio, (95% Confidence Interval) P Hypertension Diabetes Diabetic retinopathy Coronary artery disease Ischemic stroke Hyperlipidemia Smoking 44 (80.0%) 29 (52.7%) 11 (20.0%) 24 (43.6%) 12 (21.8%) 26 (47.3%) 17 (30.9%) 25 (45.5%) 8 (14.5%) 1 (1.8%) 14 (25.5%) 4 (7.3%) 18 (32.7%) 18 (32.7%) 4.8 (2.11–11.58) 6.55 (2.72–17.32) 13.50 (2.48–251.55) 2.27 (1.02–5.18) 3.56 (1.07–11.84) 1.84 (0.86–4.04) 0.92 (0.41–2.06) ,0.001 ,0.001 0.014 0.047 0.039 0.12 0.84 250 Zhao et al: J Neuro-Ophthalmol 2023; 43: 248-253 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Multivariate logistic model to predict microvascular ischemic third nerve palsy vs controls Potential Risk Factors Odds Ratio, (95% Confidence Interval) P Hypertension Diabetes Diabetic retinopathy Coronary artery disease Ischemic stroke 4.14 (1.61–10.65) 4.12 (1.43–11.92) 3.66 (0.34–38.90) 1.07 (0.40–2.83) 2.58 (0.64–10.42) ,0.001 0.003 0.283 0.900 0.185 not reach statistical significance (HR = 1.51 [95% CI 0.90– 2.53], P = 0.12) (Fig. 2). DISCUSSION In this population-based cohort, microvascular ischemic TNP was associated with hypertension, diabetes, diabetic retinopathy, coronary artery disease, and symptomatic ischemic stroke, but not hyperlipidemia or smoking. After multivariate analysis, only hypertension and diabetes were associated when all variables were taken into account. Although other studies have reported on vascular risk factors in microvascular palsies, our study has the benefit of using the REP, which better represents the spectrum of disease at a population level, because it draws from a population-based cohort that does not suffer from referral bias that can occur in studies from tertiary centers and is able to be compared against age-matched controls from the same population (12). Diabetes mellitus has been identified to be a risk factor of microvascular ischemic ocular motor cranial nerve palsies in previous non–population-based studies (3,4,13,14). We were able to establish this association by finding a 6-fold increase in the OR when we compared the prevalence of diabetes mellitus between microvascular ischemic TNP subjects and controls. This remained statistically significant under multivariate analysis. Furthermore, the OR was increased to 13-fold when we compared patients who had diabetic retinopathy between microvascular ischemic TNP subjects and controls, although this did not remain statistically significant under multivariate analysis that included the presence of diabetes. Although diabetes without diabetic retinopathy was associated with microvascular TNP, it remains unclear whether diabetic retinopathy is associated with microvascular TNP independently from diabetes alone given the low number of patients and large confidence intervals. Galvez-Ruiz et al (15) performed a retrospective study without controls assessing for diabetic retinopathy in diabetic patients with microvascular ocular motor cranial nerve palsies and found that 61.1% of patients had diabetic retinopathy. However, Trigler et al (16) and Acaroglu et al (17) found that diabetic retinopathy was less common in patients with TNP when compared with patients with diabetes mellitus of equal duration of disease. These conflicting studies highlight the need for future larger studies to examine the relationship between diabetic retinopathy and microvascular ocular motor cranial nerve palsies. We found a 5-fold increase in the OR of hypertension in microvascular ischemic TNP compared with controls, which remained significantly significant after multivariate analysis. This is consistent with the findings from the study performed in Korea by Jung et al (3). Contrary to our study, Jacobson et al (4) found no relationship between hypertension alone and ocular motor nerve FIG. 2. The Kaplan–Meier curves for 10-year mortality of microvascular ischemic third nerve palsy cases and controls. Zhao et al: J Neuro-Ophthalmol 2023; 43: 248-253 251 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution cranial nerve palsies, but they did note that left ventricular hypertrophy was independently associated with ischemic ocular motor nerve palsy, which represents end organ damage caused by hypertension. Interestingly, when potential vascular risk factors were evaluated in patients with isolated sixth nerve palsy using the REP, hypertension was also not independently associated with microvascular ischemic sixth nerve palsies, but the OR was highest in patients with diabetes mellitus and hypertension (2). In this cohort, there was a 2-fold increase in the OR of having coronary artery in microvascular ischemic TNP subjects over controls, but this did not remain statistically significant under multivariate analysis. Kobashi et al (13) found that coronary artery disease correlated closely with ischemic ocular motor nerve palsy, with a 13-fold increase in OR of having coronary artery disease in cases over controls, which was conducted in an Asian population. Unexpectedly, we did not find hyperlipidemia significantly more common in microvascular ischemic TNP than in controls, whereas Jung et al (3) found 11 of 54 (24%) of their subjects with microvascular palsies had increased levels of cholesterol compared with 9.3% in their controls. We observed hyperlipidemia in 26 of 55 subjects in cases (47.3%), compared with 18 of 55 subjects in controls (32.7%), which were both higher than reported by Jung et al (3), but the difference between cases and controls was not statistically significant in our study, which may be because of our sample size or differences in demographics. Interestingly, the study by Jung et al was conducted in Asians, whose dietary patterns are different from Whites, including a lower intake of fat (18). Accordingly, the study by Jacobson et al conducted in the United States had similar findings to ours, which showed 30 of 65 patients (46%) had hypercholesterolemia, but was not significantly different when compared with controls (4). Although smoking affects vascular diseases such as peripheral artery disease, carotid artery disease, and abdominal artery aneurysms, it was not found to be a risk factor for microvascular ischemic TNP in this cohort, similar to other investigations (3,4,13). Interestingly, patients with microvascular ischemic TNP had a higher risk of symptomatic ischemic stroke and had numerically higher mortality rate when compared with agematched controls, but not statistically significant. We looked strictly at symptomatic ischemic stroke because patients with TNP often undergo neuroimaging that could increase the odds of finding incidental old strokes. The higher risk of stroke may be because of vascular risk factors observed in patients with microvascular ischemic TNP because the difference was no longer statistically significant after multivariate analysis and accounting for hypertension, diabetes, and coronary artery disease, but does highlight that the presence of a microvascular third nerve palsy has likely broader implications for vascular wellbeing. Although microvascular ischemic ocular motor cranial nerve palsies 252 are not embolic in origin, modification of stroke risk factors should be undertaken in patients with a microvascular third nerve palsy. There are several limitations to the findings of this study. Olmsted County is a predominantly White population and therefore the results cannot be readily extrapolated to non-White populations (7). When we did the logistic regression analysis for mortality and stroke, the controls were matched for potential follow-up time, but not lead in time, which may have potentially affected diagnosis of studied conditions. Another limitation is the relatively small sample size (110) compared with tertiary center studies or studies that use big data. Although there were some small cell sizes for individual variables, the overall number was still sufficient to fit the univariate and multivariate models. However, the advantage of using the REP is that our cases and controls were selected from a population-based cohort, which minimizes bias that can occur at tertiary centers. In addition, because each medical record was individually reviewed, we were able to confirm these diagnoses, which cannot be conducted with most big data studies that rely on diagnosis codes that can have inaccuracies (19). In this population-based case–control study, microvascular ischemic TNP was associated with diabetes mellitus, diabetic retinopathy, hypertension, symptomatic ischemic stroke, and coronary artery disease, whereas smoking and hyperlipidemia were not. Because the main drivers of this association were diabetes and hypertension, vascular risk factors should be investigated and optimized when a diagnosis of microvascular TNP is made. STATEMENT OF AUTHORSHIP Conception and design: J. Chen; Acquisition of data: B. Zhao, C. Fang, J. Chen; Analysis and interpretation of data: D. O. Hodge. Drafting the manuscript: B. Zhao, J. Chen; Revising the manuscript for intellectual content: M. T. Bhatti, J. M. Holmes, B. G. Mohney, J. Chen. Final approval of the completed manuscript: B. Zhao, M. T. Bhatti, C. Fang, D. O. Hodge, J. M. Holmes, B. G. Mohney, J. Chen. REFERENCES 1. Fang C, Leavitt JA, Hodge DO, Holmes JM, Mohney BG, Chen JJ. 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