Journal of Neuro-Ophthalmology, March 2015, Volume 35, Issue 1

Risk Factors and Prognosis of Isolated Ischemic Third, Fourth, or Sixth Cranial Nerve Palsies in the Korean Population

BACKGROUND: To investigate the risk factors and prognosis for ischemic third, fourth, and sixth cranial nerve palsies in a Korean population. METHODS: A pair-matched case-control study of 54 Korean patients who were diagnosed with ischemic third, fourth, or sixth cranial nerve palsies was performed to evaluate their risk factors. Using conditional logistic regression analysis, prevalence of potential risk factors in patients and controls, included diabetes mellitus, hypertension, hyperlipidemia, ischemic heart disease, left ventricular hypertrophy (LVH), and smoking were examined retrospectively. A cohort study by Kaplan-Meier method was performed to analyze the recovery period in relation to the number of risk factors or intracranial abnormalities detected by brain computed tomography or magnetic resonance imaging. RESULTS: The mean age of onset was 64.5 years. Of the 54 patients, 16 (29.6%) developed a third nerve palsy, 19 (35.2%) a fourth nerve palsy, and 19 (35.2%) a sixth nerve palsy. The risk factors of diabetes mellitus, hypertension, and hyperlipidemia were significantly more prevalent than other risk factors of heart disease, LVH, and smoking. The mean number of risk factors was 2.3 0.6 in the third nerve palsy group, 1.7 0.9 in the fourth nerve palsy group, and 1.6 1.0 in the sixth nerve palsy group. Patients with 2 or more risk factors showed a longer recovery period (9.0 5.1 weeks) than did patients who had 1 risk factor (6.1 2.2 weeks). Patients with intracranial abnormalities on neuroimaging showed a longer recovery time (10.4 2.7 weeks) than did those without intracranial abnormalities (7.5 4.8 weeks). CONCLUSIONS: Ischemic ocular motor cranial nerve palsy is closely related to diabetes mellitus, hypertension, and hyperlipidemia in Korean patients. Compared with the fourth or sixth nerve palsy groups, the third nerve palsy group showed a tendency to have multiple risk factors. Recovery takes longer when 2 or more risk factors were present or when abnormal findings were observed on neuroimaging.

Risk Factors and Prognosis of Isolated Ischemic Third, Fourth, or Sixth Cranial Nerve Palsies in the Korean Population Ji Sung Jung, MD, Dae Hyun Kim, MD, PhD Background: To investigate the risk factors and prognosis for ischemic third, fourth, and sixth cranial nerve palsies in a Korean population. Methods: A pair-matched case-control study of 54 Korean patients who were diagnosed with ischemic third, fourth, or sixth cranial nerve palsies was performed to evaluate their risk factors. Using conditional logistic regression analysis, prevalence of potential risk factors in patients and controls, included diabetes mellitus, hypertension, hyperlipidemia, ischemic heart disease, left ventricular hypertrophy (LVH), and smoking were examined retrospectively. A cohort study by Kaplan-Meier method was performed to analyze the recovery period in relation to the number of risk factors or intracranial abnormalities detected by brain computed tomography or magnetic resonance imaging. Results: The mean age of onset was 64.5 years. Of the 54 patients, 16 (29.6%) developed a third nerve palsy, 19 (35.2%) a fourth nerve palsy, and 19 (35.2%) a sixth nerve palsy. The risk factors of diabetes mellitus, hypertension, and hyperlipidemia were significantly more prevalent than other risk factors of heart disease, LVH, and smoking. The mean number of risk factors was 2.3 ± 0.6 in the third nerve palsy group, 1.7 ± 0.9 in the fourth nerve palsy group, and 1.6 ± 1.0 in the sixth nerve palsy group. Patients with 2 or more risk factors showed a longer recovery period (9.0 ± 5.1 weeks) than did patients who had 1 risk factor (6.1 ± 2.2 weeks). Patients with intracranial abnormalities on neu-roimaging showed a longer recovery time (10.4 ± 2.7 weeks) than did those without intracranial abnormalities (7.5 ± 4.8 weeks). Conclusions: Ischemic ocular motor cranial nerve palsy is closely related to diabetes mellitus, hypertension, and hyperlipidemia in Korean patients. Compared with the fourth or sixth nerve palsy groups, the third nerve palsy group showed a tendency to have multiple risk factors. Recovery takes longer when 2 or more risk factors were present or when abnormal findings were observed on neuroimaging. Journal of Neuro-Ophthalmology 2015;35:37-40 doi: 10.1097/WNO.0000000000000214 © 2015 by North American Neuro-Ophthalmology Society Previous studies have shown that ocular motor cranial nerve palsies have a variety of causes including vascular disease, head trauma, intracranial tumor or aneurysm, and inflammatory disorders (1-3). Systemic vascular disease, particularly diabetes mellitus and hypertension, lead to microvascular ischemia and are frequent causes of these acquired neuropathies (1-4). Other reported risk factors are advanced age, left ventricular hypertrophy (LVH), ische-mic heart disease (IHD), increased hematocrit concentra-tion, obesity, hyperlipidemia, and cigarette smoking (5-9). To the best of our knowledge, most studies analyzing these risk factors were conducted in Western populations (5-8), and only one involved an Asian population (9). In our retrospective case-control study, we assessed risk factors for isolated, acute ischemic third, fourth, or sixth cranial nerve palsies and identified the factors affecting time to recovery in a Korean patient cohort. PATIENTS AND METHODS We retrospectively reviewed the medical records of 54 patients who complained of diplopia, blepharoptosis, or ocular motility disturbance and were diagnosed with acute, ischemic, isolated third, fourth, or sixth cranial nerve palsies. All patients were evaluated in the Ophthalmology Department of Chosum University from January 2009 to December 2013. Institutional Review Board approval was obtained at the Chosum University Hospital. Inclusion criteria were (1) age greater than 50 years; (2) new onset of ocular motor cranial nerve palsy within 2 weeks of initial evaluation; (3) no history of trauma within Department of Ophthalmology, Chosun University College of Medicine, Gwangju, Korea. The authors report no conflicts of interest. Address correspondence to Dae Hyun Kim, MD, PhD, Department of Ophthalmology, Chosun University College of Medicine, No. 365 Pilmundaero, Dong-gu, Gwangju 501-717, Korea; E-mail: eyekim@ chosun.ac.kr Jung and Kim: J Neuro-Ophthalmol 2015; 35: 37-40 37 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. the preceding 3 months; and (4) no evidence of intracranial neoplasm, aneurysm, or inflammation on neuroimaging studies at the time of diagnosis or during follow-up. Patients with congenital etiologies or the presence of other neuro-logical signs and symptoms, multiple cranial neuropathies, thyroid disease, multiple sclerosis, or myasthenia gravis were excluded. In the case of third nerve palsy, patients with pupil involvement were excluded, but patients with mild anisocoria up to 1.5 mm were included if there was no evidence of aneurysm or neoplasm on brain imaging. Systemic risk factors were as follows. A diagnosis of hypertension was made if systolic pressure was $140 mm Hg or diastolic pressure was $90 mm Hg or if the patient was taking oral hypertensive medication as previously diagnosed with hypertension (10). Diabetes mellitus was defined when the patient was taking oral hypoglycemic drugs or insulin. Some individuals were newly diagnosed in the Department of Endocrinology. We assumed that individuals had hyperlipidemia if their random cholesterol level was .240 mg/dL or if the patient was taking medi-cations for cholesterol reduction (11). IHD was defined by electrocardiographic documentation of myocardial infarc-tion or a history of taking antianginal medications. LVH was defined by its presence on electrocardiography or echo-cardiography (12,13). Patients who were active cigarette smokers at the time of diagnosis or had used tobacco in the previous 5 years were regarded as smokers (14,15). Each patient had an initial neuro-ophthalmologic exam-ination by one of the authors (D.H.K.) and underwent neuroimaging with magnetic resonance imaging (MRI) or computed tomography (CT). Patients were seen at 2-week intervals until diplopia resolved and ocular motility returned to normal. We reviewed the medical records retrospectively and documented the age at onset, gender, associated risk factors, and time until recovery. We established a control group matched for age and gender selected randomly from a pool of individuals who received health examinations at the Chosun University Hospital Health Promotion Center during the same time period. The odds ratios (ORs) with 95% confidence intervals (CIs) of each risk factor were obtained by conditional logistic regression analysis to express the association of ischemic ocular motor nerve palsy and the potential risk factors. Paired t test was performed to compare the distribution of the number of vasculopathic risk factors in the patient group and the control group. The cohort study by Kaplan-Meier method was used to analyze recovery period in relation to the number of risk factors or intracranial abnormalities. Statistical analysis was performed with SPSS (version 19.0; Chicago, IL) and P-values ,0.05 were considered significant. RESULTS Among the 54 patients in this study, 16 showed third cranial nerve palsies (29.6%), 19 showed fourth cranial nerve palsies (35.2%), and 19 showed sixth cranial nerve palsies (35.2%). Thirty-one of the patients (57.4%) were male, and 23 (42.6%) were female. The mean age was 64.5 ± 10.2 years, and 33 of the patients (61.1%) were #60 years. The mean time from symptom onset to first examination was 9.8 ± 9.8 days, and the mean follow-up period was 37.6 ± 21.7 weeks. The distribution of potential risk factors in the subject and control groups is shown in Table 1. In the patient group, 34 of the 54 patients (63.0%) had hypertension, 29 (53.7%) had diabetes mellitus, 13 (24.1%) had hyper-lipidemia, 4 (7.4%) had IHD, 7 (13.0%) had LVH, and 12 (22.2%) were smokers. Diabetes mellitus was significantly more prevalent in the patient group than in the control group (OR of 9.57; 95% CI, 3.23-28.35). Hyperlipidemia (OR of 3.92; 95% CI, 1.09-14.12) and hypertension (OR of 2.73; 95% CI, 1.02-7.29) were also significantly more frequent in the patient group. IHD, LVH, and smoking also were more common in the patient group, but the differences were not statistically different. The average number of accompanying risk factors was 1.8 ± 0.9 in the patient group. This result was significantly higher than the 0.9 ± 1.0 in the control group (P , 0.001). The percentage of those with 2 or more risk factors was significantly greater in the patient group (n = 34, 63.0%) than in the control group (n = 13, 24.1%) (P , 0.001). The most frequent combination of risk factors was hyper-tension and diabetes (9 patients, 26.5%), followed by hypertension, diabetes, and LVH (4 patients), diabetes TABLE 1. Distribution of risk factors for ischemic ocular motor nerve palsy group and control group Risk Factor Cases, N = 54 (%) Controls, N = 54 (%) OR 95% CI Hypertension 34 (63.0) 20 (37.0) 2.731 1.023-7.287 Diabetes mellitus 29 (53.7) 6 (11.1) 9.573 3.233-28.350 Hyperlipidemia 13 (24.1) 5 (9.3) 3.917 1.087-14.121 IHD 4 (7.4) 3 (5.6) 1.360 0.290-6.388 LVH 7 (13.0) 4 (7.4) 1.862 0.172-3.795 Smoking 12 (22.2) 8 (14.8) 1.643 0.612-4.411 CI, confidence intervals; IHD, ischemic heart disease; LVH, left ventricular hypertrophy; OR, odds ratio. 38 Jung and Kim: J Neuro-Ophthalmol 2015; 35: 37-40 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. and smoking (4 patients), and then by coexisting hyperten-sion, diabetes, and hyperlipidemia (3 patients). Analyzing the average number of accompanying risk factors based on the affected nerve in the patient group, the third cranial nerve palsy group had 2.3 ± 0.5 risk factors compared with 1.7 ± 0.9 in the fourth nerve palsy and 1.6 ± 1.0 in the sixth nerve groups (P = 0.047) (Table 2). In our study, 48 of the 54 patients (88.9%) underwent brain imaging studies, MRI in 44, and CT in 4. Eleven patients (22.9%) had incidental intracranial abnormalities in which the lesion was not directly related to the cause of the neuropathy, including 5 multiple lacunar infarctions, 2 old cerebellar infarctions, 2 old cerebral infarctions, and 2 stenosis of the internal carotid artery. The mean duration to recovery of all 54 patients was 7.9 ± 4.4 weeks; 9.0 ± 6.6 weeks in the third nerve palsy group, 7.3 ± 2.9 weeks in the fourth nerve group, and 7.6 ± 3.4 weeks in the sixth nerve group (Table 3). Patients who had 2 or more risk factors showed a significantly longer recovery period (9.0 ± 5.1 weeks) than did patients who had 1 risk factor (6.1 ± 2.2 weeks) (P = 0.025). In addition, we observed that patients who showed abnormal brain imaging findings had a longer recovery period of 10.4 ± 2.7 weeks compared with patients who had no intracranial abnormalities at 7.5 ± 4.8 weeks (P = 0.008). DISCUSSION In this study involving Korean patients, the risk of developing an ocular motor cranial nerve palsy was 10 times higher in patients with diabetes than in non-diabetic control group. This is consistent with previous studies (3,5,6,16-18), which have shown the frequency of dia-betes mellitus in patients with ischemic ocular motor neuropathies ranges from 36% to 48% (5,6,9). This is less than the 53.7% frequency found in our study. The differ-ence in results may depend on the diagnostic criteria. For example, in our patients, we did not include blood glucose intolerance in establishing the diagnosis of diabetes. In most studies, hypertension is significantly more common in patients with ischemic ocular motor cranial nerve palsy and identified as an important risk factor (1-3,5,19). However, after controlling for the other risk factors in the control group, Jacobson et al (6) determined that hypertension was not an independent risk factor. In a report of Japanese individuals, Kobashi et al (9) found that hypertension was not present at an increased frequency when patients were compared with a control group. In this study of Korean subjects, hypertension was found to be present in 63% of the patient group, 3 times the frequency found in the control group, and was statistically significant. Jacobson et al (6) identified that LVH was an independent risk factor, but this was not the case in our patient cohort. Increased cholesterol was a significant risk factor in our Korean patients, observed in 11 of the 54 subjects in the patient group (24%). Our findings are similar to the study performed in Japan (9), where 13 of the 46 patients (28%) had increased cholesterol, but lower than those found in the study by Jacobson et al (6), where 30 of 65 patients (46%) had increased blood cholesterol and not found to be an independent risk factor. Murchison et al (20) reported that 61 of 93 patients (65%) who had ischemic ocular motor cranial nerve palsy also had increased cholesterol level, but did not compare this with a control group. Smoking increases vasoconstriction, platelet aggregation, and red and white blood cell counts and is known to increase the risk of stroke and IHD among patients with diabetes mellitus and hypertension. It also decreases high-density TABLE 2. Distribution of patients with ischemic ocular motor cranial nerve palsy group by the summation of risk factors 3rd Nerve (n = 16) 4th Nerve (n = 19) 6th Nerve (n = 19) Total (n = 54) P value 1 risk factor 1 (6.3%) 9 (47.4%) 10 (52.6%) 20 (37.0%) 2-3 risk factors 15 (93.8%) 10 (52.6%) 9 (47.4%) 34 (63.0%) Average number of accompanying risk factors 2.3 ± 0.6 1.7 ± 0.9 1.6 ± 1.0 1.8 ± 0.9 0.047* *Kruskal-Wallis test among the each cranial palsy group by summation of risk factor. TABLE 3. Recovery period of patients with ischemic ocular motor cranial nerve palsy 3rd Nerve (n = 16) 4th Nerve (n = 19) 6th Nerve (n = 19) Total (n = 54) P value Recovery period, wk 9.0 ± 6.6 7.3 ± 2.9 7.6 ± 3.4 7.9 ± 4.4 1 risk factor 4.9 ± 0.0 5.9 ± 2.2 6.5 ± 2.4 6.1 ± 2.2 0.025* 2-3 risk factors 9.3 ± 6.8 8.7 ± 3.0 9.0 ± 3.9 9.0 ± 5.1 Intracranial abnormalities (+) 9.6 ± 1.1 12.1 ± 1.0 10.2 ± 4.9 10.4 ± 2.7 0.008* Intracranial abnormalities (2) 9.0 ± 8.1 6.3 ± 2.4 7.4 ± 2.8 7.5 ± 4.8 *Kaplan-Meier method between the number of risk factors or intracranial abnormalities. Jung and Kim: J Neuro-Ophthalmol 2015; 35: 37-40 39 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. lipoprotein levels (21). The frequency of smoking in our study was 12 of 54 patients (22.2%), which was not an independent risk factor, similar to other reports (6,9). We found that patients with ischemic third nerve palsy had vascular risk factors more frequently than patients with fourth or sixth nerve palsy. The reason for this finding is unclear. We analyzed the factors that influence time to recovery in patients with ischemic ocular motor cranial nerve palsy. As in the study of Japanese patients (9), our results showed that recovery takes longer when more than 2 risk factors are present. Patients who demonstrated intracranial abnormalities on neuroimaging had a longer recovery period. However, patients who showed abnormal findings on brain imaging had more than 2 risk factors, and it was difficult to identify whether these risk factors independently influenced the time to recovery. Of 54 patients, 48 underwent brain imaging and abnormal findings were detected in 11 (22.9%). The most frequent finding was multiple lacunar infarctions, observed in 5 patients. 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J Korean Ophthalmol Soc. 2002;43:131-135. 19. Green WR, Hackett ER, Schlezinger NS. Neuro-ophthalmologic evaluation of oculomotor nerve paralysis. Arch Ophthalmol. 1964;72:154-167. 20. Murchison AP, Gilbert ME, Savino PJ. Neuroimaging and acute ocular motor mononeuropathies. Arch Ophthalmol. 2011;129:301-305. 21. Johnson LN, Stetson SW, Krohel GB, Cipollo CL, Madsen RW. Aspirin use and the prevention of acute ischemic cranial nerve palsy. Am J Ophthalmol. 2000;129:367-371. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. S. Jung, D. H. Kim; b. Acquisition of data: J. S. Jung, D. H. Kim; c. Analysis and inter-pretation of data: J. S. Jung, D. H. Kim. Category 2: a. Drafting the manuscript: J. S. Jung, D. H. Kim; b. Revising it for intellectual content: J. S. Jung, D. H. Kim. Category 3: a. Final approval of the completed manuscript: J. S. Jung, D. H. Kim. 40 Jung and Kim: J Neuro-Ophthalmol 2015; 35: 37-40 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.