Clinical Characteristics for Predicting Recovery of Acquired Fourth Cranial Nerve Palsy

Background: Fourth cranial nerve palsy is the most common disease diagnosed in patients with vertical diplopia. Although it is reported to present a good prognosis, there are currently no agreed on prognostic factors that anticipate the recovery of the palsy other than the etiology. The purpose of this study was to investigate the prognostic factors of acquired fourth cranial nerve palsy. Methods: The medical records of consecutive patients diagnosed with acquired unilateral fourth cranial nerve palsy from 2010 to 2020 and followed up for ≥6 months were retrospectively reviewed. The cause and degree of palsy, ocular deviation (horizontal, vertical, and cyclo), and fundus torsion were reviewed. The cause of palsy was classified as ischemic, traumatic, intracranial mass, others, or idiopathic. Patients were divided into 2 groups according to palsy recovery: complete recovery (group CR) or not CR (group NCR). The clinical characteristics of the 2 groups were compared, and the risk factors for incomplete recovery were investigated. Results: Thirty-five patients (25 men) were included in the study. The average age was 55.94 ± 16.11 years. CR was achieved in 23 patients (65.7%), and the time to recovery was 3.91 ± 4.03 months. The most common cause was traumatic (40.0%), followed by ischemia (37.1%), intracranial mass (11.4%), others (8.6%), and idiopathic (2.9%). The degree of palsy and fundus torsion was significantly higher in group NCR (P = 0.010 and P = 0.001). Severe oculomotor limitation, large fundus torsion, and intracranial mass cause rather than ischemic cause indicated a higher risk of incomplete or no recovery (P = 0.016, P = 0.009, and P = 0.043). Conclusion: Identifying whether a patient has an intracranial mass, severe oculomotor limitation, or large fundus excyclotorsion may be useful for predicting the recovery of acquired unilateral fourth cranial nerve palsy.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Clinical Characteristics for Predicting Recovery of Acquired Fourth Cranial Nerve Palsy Jae Hyun Kim, MD, Hee-Young Choi, MD, PhD, Hyeshin Jeon, MD, PhD Background: Fourth cranial nerve palsy is the most common disease diagnosed in patients with vertical diplopia. Although it is reported to present a good prognosis, there are currently no agreed on prognostic factors that anticipate the recovery of the palsy other than the etiology. The purpose of this study was to investigate the prognostic factors of acquired fourth cranial nerve palsy. Methods: The medical records of consecutive patients diagnosed with acquired unilateral fourth cranial nerve palsy from 2010 to 2020 and followed up for $6 months were retrospectively reviewed. The cause and degree of palsy, ocular deviation (horizontal, vertical, and cyclo), and fundus torsion were reviewed. The cause of palsy was classified as ischemic, traumatic, intracranial mass, others, or idiopathic. Patients were divided into 2 groups according to palsy recovery: complete recovery (group CR) or not CR (group NCR). The clinical characteristics of the 2 groups were compared, and the risk factors for incomplete recovery were investigated. Results: Thirty-five patients (25 men) were included in the study. The average age was 55.94 ± 16.11 years. CR was achieved in 23 patients (65.7%), and the time to recovery was 3.91 ± 4.03 months. The most common cause was traumatic (40.0%), followed by ischemia (37.1%), intracranial mass (11.4%), others (8.6%), and idiopathic (2.9%). The degree of palsy and fundus torsion was significantly higher in group NCR (P = 0.010 and P = 0.001). Severe oculomotor limitation, large fundus torsion, and intracranial mass cause rather than ischemic cause indicated a higher risk of incomplete or no recovery (P = 0.016, P = 0.009, and P = 0.043). Conclusion: Identifying whether a patient has an intracranial mass, severe oculomotor limitation, or large fundus excyclotorsion may be useful for predicting the recovery of acquired unilateral fourth cranial nerve palsy. Journal of Neuro-Ophthalmology 2022;42:234–238 doi: 10.1097/WNO.0000000000001426 © 2021 by North American Neuro-Ophthalmology Society A cquired ophthalmoplegia due to cranial nerve palsy accounts for 40%–60% of binocular diplopia (1). The trochlear nerve palsy is known to comprise 18%– 25% of the ocular motor palsy (2–5). The trochlear nerve has the longest course from the central nervous system to the target muscle (6), making it more prone to trauma compared with the third and sixth cranial nerves and thus presents a distinct etiology (7,8). The recovery of ocular motor palsy is known to be related to the cause of the palsy; ischemic palsy is likely to show a better outcome (3). Clinical features have also shown to be associated with the prognosis of paralysis. A smaller angle of deviation is reported to be related to better recovery in patients with third, fourth, and sixth cranial nerve palsies (5,9). In a recent study that included only patients with fourth cranial nerve palsy, patients who had not fully recovered had a larger vertical angle of deviation and more frequent fundus torsion and head tilt (10). However, the study included the late decompensation of congenital palsy, and currently, the literature has not studied the prognostic factors of acquired fourth cranial nerve palsy alone. Fourth cranial nerve palsy is the most common cause of vertical strabismus in adults and causes severe discomfort due to vertical diplopia (11). Although high recovery rates and good prognosis have been reported, there is insufficient evidence to predict recovery (1,4,5), and further studies on this subject are indispensable. We aimed to investigate the clinical implications of ophthalmic characteristics concerning the recovery of acquired fourth cranial nerve palsy. METHODS Department of Ophthalmology (JHK, HYC, HJ), School of medicine, Pusan National University, Busan, South Korea; and Biomedical Research Institute (HYC, HJ), Pusan National University Hospital, Busan, South Korea. The authors report no conflicts of interest. Address correspondence to Hyeshin Jeon, MD, PhD, Department of Ophthalmology, Pusan National University Hospital, 179 Gudeok-Ro Seo-Gu, Busan 602-739, South Korea; E-mail: [e-mail] 234 Patient Recruitment The study was approved by the Institutional Review Board of Pusan National University Hospital (2105-034-103). Medical records of consecutive patients who were diagnosed with acquired unilateral fourth cranial nerve palsy from 2010 to 2020 and followed up for more than 6 months in Pusan Kim et al: J Neuro-Ophthalmol 2022; 42: 234-238 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution National University Hospital were retrospectively reviewed. Patients who were followed up for less than 6 months with complete recovery (CR) were also included. The fourth cranial nerve palsy was diagnosed based on the clinical presentation that included hypertropia in the primary position, which worsened at contralateral gaze and ipsilateral tilt, underaction of the superior oblique muscle, overaction of the inferior oblique muscle, and/or excyclotorsion of the fundus in patients presenting with acute vertical diplopia. Patients were excluded if they had a history of previous orbital, strabismus surgery, or systemic diseases that might influence ocular deviation, such as thyroid disease, myasthenia gravis, and multiple sclerosis. Patients with congenital or decompensated long-standing fourth nerve palsy were also excluded. The etiology of palsy was classified into 5 categories: ischemic, traumatic, intracranial mass, others, and idiopathic. Patients were assigned to the ischemic group if they had predisposing vascular risk factors, including hypertension, diabetes mellitus, and dyslipidemia, without any other suspicious cause of palsy. If there was microangiopathy or other vascular abnormalities on brain imaging, it was also assigned to the ischemic group. Those with an apparent trauma history before symptom onset were classified into the traumatic group. If there was an aneurysm or neoplasm on imaging, it was classified into the intracranial mass group. If there was presumed to be a causative lesion and differed from the above 3 causes, it was classified as others. If any of the etiologic criteria mentioned above were met, it was considered idiopathic. Ophthalmic Assessment All the patients underwent a complete ophthalmic examination. The angle of ocular deviation was measured by a prism and alternative cover test at primary, secondary, and tilting positions, fixing both 6 m and 1/3 m. Ductions were evaluated concordantly. Superior and inferior oblique muscle dysfunction was graded on a scale from 24 to +4. Cyclotorsion was quantified by fundus photography. The angle between a horizontal line that passes the center of the optic disc and another line connecting the fovea and the optic disc center was measured. The presence of subjective cyclodeviation was also recorded using the Lancaster red–green test. Statistical Analysis Patients were divided into 2 groups according to the recovery status at 6 months from initial visit: CR (group CR) or not CR (group NCR). CR was defined as the absence of hypertropia and subjective diplopia. The time to recovery was assessed if the patient achieved a CR. The clinical characteristics of the 2 groups were compared using the Mann–Whitney U test, and risk factors for incomplete recovery were investigated by binary logistic regression analysis. Statistical analysis was performed using SPSS (version 19.0, Chicago, IL), and statistical significance was set at P , 0.05. RESULTS A total of 35 patients (25 men) were included in the study. The mean age was 55.94 ± 16.11 years. The etiologic distribution was as follows: traumatic (14 patients, 40.0%), ischemic (13 patients, 37.1%), intracranial mass (4 patients, 11.4%), others (3 patients, 8.6%), and idiopathic (1 patient, 2.9%). The mean follow-up period was 9.08 ± 9.95 months. Twenty-three patients (65.7%) achieved CR and were allocated to group CR, and the mean recovery time was 3.91 ± 4.03 months (Table 1). The initial clinical characteristics of patients in the 2 groups were compared. Patients in group CR were older than group NCR (59.39 ± 14.98 vs. 49.33 ± 16.76 years, P = 0.021). The most common cause was ischemia in group CR, whereas it was trauma in group NCR. The angles of vertical deviation and horizontal deviation were not significantly different between the 2 groups. Superior oblique underaction was more severe in group NCR (P = 0.010), whereas the grade of inferior oblique overaction was not significantly different (P = 0.593). A larger amount of fundus excyclotorsion was observed in group NCR (P = 0.001). Subjective cyclotorsion was observed in 24 patients (68.5%). Ten of 11 patients (90.9%) without subjective cyclotorsion fully recovered from the palsy, whereas only 13 of 24 patients (54.1%) with subjective cyclotorsion achieved full recovery. Twenty-six patients (74.2%) showed more prominent excyclotorsion in the paretic eye, whereas 9 patients in the contralateral eye (25.7%) (Table 2). TABLE 1. Demographic of patients according to etiologies Etiology Total Ischemic Traumatic No of patients (%) 35(100) 13(37.1) 14(40.0) Gender (male:female) 25:10 11:2 8:6 Age (years) 55.94 ± 16.11 64.23 ± 8.57 51.36 ± 16.78 No. of patients with 23(65.7) 11(84.6) 7(50.0) complete recovery (%) Recovery time (months) 3.91 ± 4.03 2.24 ± 1.74 6.99 ± 5.87 Kim et al: J Neuro-Ophthalmol 2022; 42: 234-238 Intracranial Mass Others Idiopathic 4(11.4) 2:2 49.50 ± 27.16 1(25.0) 3(8.6) 3:0 51.00 ± 17.77 3(100) 1(2.9) 1:0 53.00 1(100) 0.78 3.97 ± 2.64 3.7 235 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution In the binary logistic regression analysis, larger oculomotor limitations of the superior oblique muscle and larger torsion angle of the fundus were significant risk factors for incomplete recovery (P = 0.016 and P = 0.009). Intracranial mass was a significant risk factor for incomplete recovery compared with ischemic cause (P = 0.043) (Table3). DISCUSSION In summary, the degree of palsy and fundus torsion of the acquired unilateral fourth cranial nerve palsy was significantly more prominent in the incomplete recovery group. Severe oculomotor limitation, larger fundus torsion, and intracranial mass rather than ischemic cause indicated the risk of incomplete or no recovery of the palsy. The fourth cranial nerve is more prone to traumatic injury than the third and sixth cranial nerve palsy because of its long course and slender anatomy, contributing to different etiologic distribution (6). Previous studies showed that although the ischemic cause was the predominant cause of the third and sixth palsies, the traumatic cause shared a similar proportion with the ischemic cause in the fourth cranial nerve palsy. Rucker (2) reported that head trauma and vascular disease were the leading causes of fourth cranial nerve palsy (35% and 35%, respectively). Richards et al (3) reported that among 657 patients with fourth nerve palsy, 28% had an undetermined etiology, 25% had head trauma, and 15% had vascular disease. More recent research by Park et al (5) reviewed 46 cases of fourth cranial nerve palsy, which consisted of 37% of vascular causes and 30% of traumatic causes. In this study, there were 40.0% of traumatic causes and 37.1% of ischemic causes, consistent with previous studies. The recovery rates of fourth cranial nerve palsy are reported as 50%–53.3% (1,4,5). The CR rate in our study was 65.7%, comparable with previous studies. The cause of cranial nerve palsy may influence the recovery rate; ischemic cause has better recovery prognosis than others. Oh and Oh (10) reported the CR rate of fourth cranial nerve palsy according to the etiology. Patients with ischemic cranial nerve palsy achieved the highest CR rate of 91.6% and a traumatic cause of 64.7%. In our study, 84.6% of the ischemic fourth cranial nerve palsy recovered completely, whereas 50.0% of the traumatic palsy recovered completely. A larger initial angle of deviation is reportedly a risk factor for incomplete recovery. Park et al (5) reported that a larger angle of deviation in ocular motor palsy is TABLE 2. Comparison of clinical characteristics and ophthalmic manifestations according to the recovery status Recovery Status Complete Recovery Partial Recovery or Persistence No. of patients Age (years, mean ± SD) Gender (male:female) Etiology (no. of patients [%]) Ischemic Traumatic Intracranial mass Others Idiopathic Angle of vertical deviation (PD, mean ± SD) Primary position at distance fixation Primary position at near fixation Contralateral gaze Ipsilateral tilt Up gaze Down gaze Angle of horizontal deviation (PD, mean ± SD) Primary position at distance fixation Primary position at near fixation Superior oblique underaction (mean ± SD) Inferior oblique overaction (mean ± SD) Excyclotorsion in fundus photography (degree, mean ± SD) Cyclotorsion in Lancaster red–green test (no. of patients [%)] Absent Present Excyclotorsion prominence laterality (no. of patients [%]) Paretic eye Contralateral eye 23 59.39 ± 14.98 18:5 12 49.33 ± 16.76 7:5 11(47.8) 7(30.4) 1(4.3) 3(13.0) 1(4.3) 2(16.7) 7(58.3) 3(25.0) 0(0) 0(0) P 0.021 0.258 4.36 2.00 4.77 6.90 3.71 5.24 ± ± ± ± ± ± 3.03 1.79 3.62 4.07 2.57 4.13 4.17 ± 2.95 1.83 ± 2.44 5.45 ± 2.70 8.83 ± ± 5.17 3.42 ± 2.07 6.50 ± 4.98 0.852 0.543 0.162 0.137 0.738 0.813 0.90 3.50 0.55 0.10 7.96 ± ± ± ± ± 1.65 3.99 0.74 0.09 3.23 4.82 ± 7.33 5.27 ± 5.46 1.67 ± 1.30 0.25 ± 0.18 12.99 ± 3.97 0.109 0.308 0.010 0.593 0.001 0.055 10(28.5) 13(37.1) 1(2.8) 11(31.4) 15(42.8) 7(20.0) 11(31.4) 1(2.8) 0.210 P-value in bold means significant at a level of P = 0.05. PD, prism diopters. 236 Kim et al: J Neuro-Ophthalmol 2022; 42: 234-238 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Factors associated with the prognosis of the fourth cranial nerve palsy investigated by univariate binary logistic regression analysis 95% Confidence Interval P Age Gender Etiology Ischemic Traumatic Intracranial mass Others Idiopathic Angle of vertical deviation Primary position at distance fixation Primary position at near fixation Contralateral gaze Ipsilateral tilt Up gaze Down gaze Angle of horizontal deviation Primary position at distance fixation Primary position at near fixation Superior oblique underaction Inferior oblique overaction Excyclotorsion in fundus photography Cyclotorsion in Lancaster red–green test Excyclotorsion prominence laterality Odds Ratio Lower Upper 0.095 0.222 0.960 2.571 0.916 0.565 1.007 11.712 0.276 0.069 0.043 0.999 1.000 (ref) 5.500 16.5 0 0 0.878 1.088 0 0 34.461 250.176 0.851 0.817 0.577 0.245 0.725 0.492 0.977 0.958 1.064 1.100 0.946 1.068 0.766 0.667 0.856 0.936 0.694 0.908 1.246 1.376 1.322 1.293 1.289 1.255 0.060 0.219 0.016 0.412 0.009 0.093 0.151 1.336 1.107 3.216 1.806 1.536 6.769 0.195 0.988 0.941 1.249 0.440 1.112 0.729 0.021 1.806 1.302 8.283 7.406 2.122 62.861 1.821 PD, prism diopters. related to a worse prognosis. However, the study analyzed the fourth cranial nerve palsy and the third and sixth cranial nerve palsies. Because fourth nerve palsy usually presents a smaller angle of deviation than the third and sixth cranial nerve palsies, the analysis may not accurately reflect the characteristics of the fourth nerve palsy. Oh and Oh (10) analyzed only patients with fourth cranial nerve palsy and reported that the vertical angle of deviation was significantly different between the complete and incomplete recovery groups, contrary to our study. This contradictory result is believed to be due to the inclusion of decompensated long-standing palsy. Decompensated fourth cranial nerve palsy is known to have an abnormally large vertical angle of deviation (12,13). In the study by Oh and Oh (10), all cases with decompensated causes were classified into the incomplete recovery group, and this may have influenced the higher vertical angle of deviation of the incomplete recovery group. These cases were not included in our study because decompensated palsy showed different clinical features and prognosis than those acquired palsies (13–15). The higher degree of ocular limitation indicated a higher risk of incomplete recovery in our study, which was contrary to the previous study of Park et al (5). They analyzed the relationship of the degree of ocular motor restriction of the third, fourth, and sixth cranial nerve palsy with the recovery of the Kim et al: J Neuro-Ophthalmol 2022; 42: 234-238 palsy. In their study, the degree of ocular motor restriction was not different between the CR group and partial recovery and persistence group. By contrast, superior oblique underaction in our study was more severe in the NCR group, which was a risk factor of incomplete recovery. Fundus extorsion was reported to be more frequent in the patients with poorer outcome (10). In our study, fundus torsion was quantified by analyzing the fundus image and yielded the result that larger fundus excyclotorsion is a risk factor of poor prognosis. We also analyzed subjective torsion using the Lancaster red–green test. Although the frequency of subjective torsion in each recovery group was not significantly different, 10 of 11 patients who showed no subjective cyclotorsion fully recovered. Considering this, subjective torsion may also be a predictor of prognosis and worthwhile for further research. Previous studies reported the proportion of the correspondence of the excyclotorted eye with the paretic eye. Lee et al (16) studied both congenital and acquired fourth nerve palsy and reported that 64.2% had the correspondence, whereas 35.8% showed excyclotorsion in the contralateral eye. In our study, 74.2% of the patients showed excyclotorsion in the paretic eye, whereas 25.7% showed larger excyclotorsion in the nonparetic eye. Although it was not statistically significant, 7 of 8 patients (87.5%) with excyclotorsion in the contralateral eye achieved full recovery, 237 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution whereas 15 of 26 patients (57.6%) with excyclotorsion prominence in the paretic eye. Our study has some limitations. First, the patients were recruited from a single tertiary medical center, resulting in selection bias. Because our medical center has a major trauma center, it may affect the etiology of the patients. Second, because of the small sample size, the clinical features of each etiology were not analyzed. This study included only patients with acquired fourth cranial nerve palsy, excluding decompensated congenital palsy, and attempted to clarify the clinical features that affect the prognosis. Ocular deviation in both the horizontal and vertical directions did not affect prognosis. Conversely, fundus torsion remained a valuable factor related to palsy prognosis in both objective and subjective ways. In addition to previous reports, it would help manage patients with acquired fourth cranial nerve palsy. In conclusion, intracranial cause, severe oculomotor limitation, and large fundus excyclotorsion may be related to poor acquired fourth cranial nerve palsy outcomes. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. H. Kim, H.-Y. Choi, and H. Jeon, b. Acquisition of data: J. H. Kim and H. Jeon, c. Analysis and interpretation of data: J. H. Kim, H.-Y. Choi, and H. Jeon. Category 2: a. Drafting the manuscript: J. H. Kim and H. Jeon, b. Revising it for intellectual content: J. H. Kim, H.-Y. Choi, and H. Jeon. Category 3: a. Final approval of the completed manuscript: J. H. Kim, H.-Y. Choi, and H. Jeon. REFERENCES 1. Tiffin P, MacEwen C, Craig E, Clayton G. Acquired palsy of the oculomotor, trochlear and abducens nerves. Eye. 1996;10:377–384. 238 2. 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