Central Trochlear Palsy: Report of Two Patients With Ipsilesional Palsy and Review of the Literature

The trochlear (fourth) nerve is the only cranial nerve that decussates before emerging from the posterior aspect of the brainstem. Lesions involving the trochlear nucleus or fascicles mostly give rise to contralesional superior oblique palsy (SOP).; We report 2 patients with SOP on the side of intraaxial lesions with a literature review on central trochlear palsy.; The lesions are more commonly located posterior to the cerebral aqueduct in patients with ipsilesional SOP than in those with contralesional SOP.; Intraaxial lesions may cause ipsilesional or contralesional SOP depending on the lesion location along the course of trochlear fascicle in the brainstem.

Original Contribution Central Trochlear Palsy: Report of Two Patients With Ipsilesional Palsy and Review of the Literature Seong-Hae Jeong, MD, Sung-Hee Kim, MD, Seung-Han Lee, MD, PhD, Seong-Ho Park, MD, PhD, Hyo-Jung Kim, PhD, Ji-Soo Kim, MD, PhD Background: The trochlear (fourth) nerve is the only cranial nerve that decussates before emerging from the posterior aspect of the brainstem. Lesions involving the trochlear nucleus or fascicles mostly give rise to contralesional superior oblique palsy (SOP). Methods: We report 2 patients with SOP on the side of intraaxial lesions with a literature review on central trochlear palsy. Results: The lesions are more commonly located posterior to the cerebral aqueduct in patients with ipsilesional SOP than in those with contralesional SOP. Conclusions: Intraaxial lesions may cause ipsilesional or contralesional SOP depending on the lesion location along the course of trochlear fascicle in the brainstem. Journal of Neuro-Ophthalmology 2016;36:377-382 doi: 10.1097/WNO.0000000000000432 © 2016 by North American Neuro-Ophthalmology Society lesions usually are accompanied by other neurologic signs and symptoms, but they may be isolated (3-23). The trochlear nerve originates from the contralateral nucleus. Because the trochlear fascicles run only a short course in the brainstem before decussating in the superior medullary velum and exiting the brainstem, trochlear nerve palsies due to intraaxial lesions usually result in contralesional superior oblique palsy (SOP) (24). We report on 2 patients with SOP ipsilateral to an intraaxial lesion. We also analyzed the lesions in 26 additional patients with trochlear nerve palsy from intraaxial lesions identified in a comprehensive literature review (3-23). We attempted to delineate the location of intraaxial lesions that cause ipsilateral SOP. METHODS P alsies of the trochlear (fourth) cranial nerve are one of the most common causes of acquired vertical diplopia (1). While a variety of disorders in the subarachnoid space commonly cause trochlear nerve palsy, intraaxial lesions also may affect the trochlear nerve (2). In general, intraaxial Department of Neurology (S-HJ), Chungnam National University Hospital, Daejeon, Korea; Department of Neurology (S-HK, S-HP, J-SK), Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; Department of Neurology (S-HL), Chonnam National University Medical School, Gwangju, Korea; and Department of Biomedical Laboratory Science (H-JK), Kyungdong University, Goseong-gun, South Korea. 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 full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Ji-Soo Kim, MD, PhD, Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, Korea; E-mail: [e-mail] Jeong et al: J Neuro-Ophthalmol 2016; 36: 377-382 Case Reports Case 1 An 81-year-old woman with diabetes mellitus reported vertical diplopia for 17 days. She denied diurnal variation of the diplopia, associated headache, or ocular pain. She had no history of recent head trauma. Examination revealed a right hypertropia measuring 8 prism diopters (PD) in primary gaze that increased in left gaze (10 PD) and with right head tilt (12 PD; Fig. 1A). General physical and neurologic examinations were unremarkable. Fundus photography revealed abnormal excyclotorsion of the right eye (16.3°; normal range, 0-12.6°; positive values indicate an excyclotorsion; Fig. 1B) (25). These findings were most consistent with isolated right SOP. Her hemoglobin A1C was 6.6% (normal range, 4%-6%), and the presumed diagnosis was an ischemic trochlear nerve palsy. A thinsection (1.6 mm) 3-dimensional fluid-attenuated inversion recovery volume isotopic turbo spin echo acquisition (3D FLAIR-VISTA) images disclosed a focal high signal intensity lesion involving right midbrain tegmentum, consistent 377 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Patient 1. A. The patient has a right hypertropia in primary position and limitation of depression during adduction of the right eye. B. Fundus photography shows abnormal excyclotorsion of the right eye (16.3°). C. Thin-section (1.6 mm) 3D 3-dimensional fluid-attenuated inversion recovery volume isotopic turbo spin echo acquisition (3D FLAIR-VISTA) magnetic resonance imaging reveals a high signal intensity lesion in the area of right trochlear fascicle passing posteroinferiorly around the cerebral aqueduct in the lower midbrain (arrows). with a right midbrain infarction (Fig. 1C). A pupil-sparing right oculomotor (third) nerve palsy occurred 15 months later with a resolution within 6 months. Case 2 A 48-year-old woman developed acute binocular vertical diplopia preceded one day earlier by hypesthesia on the right side of the body and tinnitus. Tinnitus was perceived as similar to the sound of a helicopter and was evident first in the right ear and then became bilateral on the day of admission to the hospital. She denied headache, ocular pain, and any medical or trauma history. Family history was unremarkable. On examination, her vital signs were normal. She had a left hypertropia (6 PD) that increased in right gaze (8 PD), down gaze (8 PD), and left head tilt (10 PD, Fig. 2A). Torsional positions of the eyes on fundus photographs and tilt of the subjective visual vertical were normal. Other findings on neurological examination were normal except right-sided hypesthesia. Pure tone audiometry and brainstem auditory evoked potentials were normal bilaterally. In view of her diplopia associated with hypesthesia and 378 tinnitus, brain MRI and MRA were performed. These disclosed small hematoma involving the midbrain tectal area and left precentral gyrus, which were suggestive of an underlying vascular anomaly, such as cavernous hemangioma (Fig. 2B). The tinnitus became a mosquito-like buzzing in both ears 2 days later and vertical diplopia resolved over the following month. Literature Review We performed a review of central trochlear palsy with a web-based search on the PubMed (http://www.ncbi.nlm. nih.gov/pubmed, up to August 2014) using various combinations of the keywords that included trochlear nerve, superior oblique, paresis, palsy, stroke, infarct, hemorrhage, midbrain, mesencephalon, and central. Initially, we identified 56 articles on central trochlear nerve palsy. We excluded 49 articles that were written in languages other than English (n = 8) or lacked descriptions of original patient data (n = 21), ocular motor signs (n = 7), or MRI findings (n = 13). We were able to retrieve 14 more articles by reviewing the references cited by the initially Jeong et al: J Neuro-Ophthalmol 2016; 36: 377-382 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Patient 2. A. Nine-gaze positions show left hypertropia and limitation of depression during adduction of the left eye. B. Axial T2 MRI reveals a hemorrhage that involves both the tegmentum and tectum of the midbrain to the left of the cerebral aqueduct. recruited articles. Thus, we could analyze the demographic features, etiologies, lesion location, prognosis, and accompanying neurologic signs in 26 additional patients from 21 articles. coincide with those of the reference templates, the lesions were reconstructed on the reference templates using anatomical landmarks. Lesion Analysis Statistical analyses were performed using x 2 and Fisher exact tests for dichotomous variables. Pearson correlation coefficient was used to evaluate the interobserver agreement. Based on the correlation coefficients, the interobserver agreement was considered poor (0.00-0.20), weak (0.21-0.39), fair to good (0.40-0.75), or excellent (.0.75) (26). The collected data were processed with SPSS (20.0; SPSS, Chicago, IL). Results were considered significant at P , 0.05. The MRI lesions in our 2 patients and the previously reported patients were classified into tegmental, tectal, or mixed (tegmental and tectal) by 2 independent neurologists (S.-H.K. and S.-H.L.) masked to the clinical information. If there was disagreement of the location of the lesion, the final determination was made by a third neurologist (J.-S.K.). The tegmentum of the midbrain was defined by the area from the ventral aspect of the substantia nigra to an imaginary line drawn just dorsal to the cerebral aqueduct, which separates the tectum from the tegmentum. The lesions were then inspected to select the most appropriate templates from a neuro-anatomy atlas (24) and were traced onto a template by another coauthor (H.-J.K.) who also was masked to the clinical findings. When the slice angles of the MRI did not Jeong et al: J Neuro-Ophthalmol 2016; 36: 377-382 Statistical Analysis RESULTS Clinical Features Including our 2 patients, we were able to analyze the clinical features of 28 patients with SOP from central lesions. The 379 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution patients included 17 men with age ranging from 10 to 81 years (median age, 44.0 years; mean age ± standard deviation, 43.0 ± 18.4 years). The SOP mostly occurred in association with lesions located on the contralateral side (22 of 28; 78.6%). In contrast, only 6 patients (6 of 28; 21.4%) showed ipsilesional SOP and 2 (3 of 28; 10.7%) had bilateral SOP. Underlying etiologies included hemorrhage in 14 patients, infarction in 8, tumor in 2, and demyelination and trauma in 1 each. In the remaining 2 patients, the etiology of the cranial nerve palsy was not identified on MRI. The SOP was isolated in 6 patients (8 of 28; 28.6%), but usually accompanied other symptoms and signs that included sensory disturbance (n = 5), tinnitus (n = 4), Horner syndrome (n = 3), ataxia (n = 3), motor weakness (n = 2), internuclear ophthalmoplegia (n = 2), pupillary light-near dissociation (n = 1), hearing loss (n = 1), amnesia (n = 1), loss of consciousness (n = 1), and relative afferent pupillary defect (n = 1) (see Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A209). Lesion Analysis The independent assessors showed a high consensus in classifying the lesion location (kappa = 0.93). All 6 patients with ipsilesional SOP had MRI lesions involving the tectal portion, but the lesions also extended into the tegmental area in 4 of them. In contrast, all 16 patients with contralesional SOP demonstrated MRI lesions involving the tegmental area, and only 3 showed an extension of the lesions into the tectal portion. Bilateral trochlear nerve paresis occurred in association with the lesions involving both the tegmental and tectal portions in 2 patients (Fig. 3). The tectal involvement was much more common in ipsilateral SOP (6 of 6; 100%) than in contralesional SOP (6 of 22; 27.3%; P = 0.002) (Fig. 3); while the tegmental involvement was more frequently observed in contralateral SOP than in ipsilesional SOP (4 of 6; 66.7% vs 22 of 22; 100%; P = 0.040). Therefore, the key structure for ipsilesional SOP in the brainstem appears to be located posterior to the cerebral aqueduct. DISCUSSION Our patients showed ipsilesional SOP as an isolated or predominant sign of intraaxial lesions involving the trochlear nerve fascicle after decussation in the brainstem. Ipsilesional SOP due to intraaxial lesions is extremely rare, previously described in 4 patients with brainstem astrocytoma and traumatic hemorrhage (3,17,18,27). When the trochlear nucleus is affected or the trochlear fascicles are involved before decussation in the brainstem, contralateral SOP ensues (3-5). In contrast, damage to the fascicles after decussation or to the nerve in the subarachnoid space causes ipsilateral SOP, as occurred in our 2 patients (see Supplemental Digital Content, Table E1, 380 FIG. 3. Topographic distributions of the lesions in our patients and the previously reported patients with ipsilateral (A), contralateral (B), and bilateral (C) trochlear nerve palsies from intraaxial lesions. http://links.lww.com/WNO/A209) (6-16). Lesion locations in our patients with ipsilesional SOP were different from those in patients with contralesional SOP from intraaxial lesions. While the former were located posterior to the cerebral aqueduct, the latter were in the periaqueductal area, especially anterior or lateral to the aqueduct without involving the retroaqueductal portion (Fig. 3). These findings are consistent with the intraaxial route of the trochlear nerve; after leaving the nucleus, the trochlear fascicles decussate in the anterior medullary velum at the roof of the cerebral aqueduct and then exit the brainstem dorsally. The trochlear fascicle is divided into 2 portions-tegmental (ventral and dorsolateral to the periaqueductal gray matter) and tectal (dorsomedial to the periaqueductal gray matter) Jeong et al: J Neuro-Ophthalmol 2016; 36: 377-382 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (24). When we classified the lesion location according to this division in our patients and the previously reported patients with trochlear nerve palsy from intraaxial lesions (kappa = 0.93), ipsilesional SOP was more commonly caused by lesions involving the tectal portion of the trochlear fascicles, while contralesional SOP was mostly found in lesions affecting the tegmental or periaqueductal portion. It appears that ipsilesional SOP occurs with lesions posterior to the cerebral aqueduct. Bilateral trochlear nerve paresis also occurred in lesions involving the tectal portion posterior to the cerebral aqueduct (4). The clinical-radiologic correlations have limitations in defining the lesion extent and delineating the responsible structures in this small area. Furthermore, limited availability of the source images from the previous reports added difficulty in deciding the extent of the lesion and could not completely exclude the effect of surrounding edema, especially in hemorrhagic lesions. Indeed, in any 1 patient, a similar MRI lesion caused an ipsilateral or contralateral SOP (Fig. 3: I1, C1). Additionally, the patients with ipsilesional SOP often had MRI lesions large enough to involve the ipsilesional trochlear nucleus, which caused bilateral SOP (Fig. 3: I1, I2, I3, and I6). Furthermore, at least 2 of the contralateral cases (Fig. 3: C1 and C8) had lesions posterior enough to expect an ipsilateral trochlear palsy. Despite these findings, it appears that all the ipsilateral cases and only some of the contralateral cases had a tectal involvement. The trochlear nucleus and fascicles are located in the midbrain periaqueductal gray matter just below the oculomotor (third nerve) nucleus. Nuclear or fascicular trochlear palsy may be accompanied by various neurologic deficits, including Horner syndrome (6), internuclear ophthalmoplegia (7), upbeat nystagmus (12), or ataxia (4,6), due to coinvolvement of neighboring structures including the descending sympathetic tract, medial longitudinal fasciculus, brachium conjunctivum, and ascending trigeminothalamic/ spinothalamic tracts. Our second patient reported tinnitus and sensory changes, which indicated additional involvements of the inferior colliculus (4,14) and ascending trigeminothalamic/ spinothalamic tracts (4,6,8,11). Tinnitus was once described in association with trochlear nerve palsy in a patient with acute midbrain infarction (14). In that patient, the preexisting intermittent mild tinnitus as "chirrups of a cicada" for several years became louder than "airplane sounds" and persistent with the onset of trochlear palsy (14). The tinnitus in central trochlear palsy may be due to damage to the central auditory pathway, especially to the inferior colliculus that provides inhibitory GABAergic synapses for central auditory processing (28). In view of the bilateral tinnitus, and normal hearing and intact brainstem auditory evoked potentials, the nonclassical auditory pathway appears to have been involved in the current and previously reported patients (14,28). Our case highlights Jeong et al: J Neuro-Ophthalmol 2016; 36: 377-382 the importance of a detailed history of auditory symptoms in patients with SOP (14). The differentiation of SOP from skew deviation is also challenging in patients with vertical diplopia and internuclear ophthalmoplegia from midbrain lesions, especially when the hypertropic eye does not show excyclotorsion. However, the 2 patients with internuclear ophthalmoplegia in our literature review showed hypertropia in the eye contralateral to the lesion and internuclear ophthalmoplegia, which is inconsistent with skew deviation from midbrain lesions (29). STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S.-H. Jeong, S.-H. Kim, S.-H. Lee, S.-H. Park, H.-J. Kim, J.-S. Kim; b. Acquisition of data: S.-H. Jeong, S.-H. Kim, S.-H. Lee, S.-H. Park, H.-J. Kim, J.-S. Kim; c. Analysis and interpretation of data: S.-H. Jeong, S.-H. Kim, S.-H. Lee, S.-H. Park, H.-J. Kim, J.-S. Kim. Category 2: a. Drafting the manuscript: S.-H. Jeong, S.-H. Kim, S.-H. Lee, S.-H. Park, H.-J. Kim, J.-S. Kim; b. Revising it for intellectual content: S.-H. Jeong, S.-H. Kim, S-H. Lee, S-H. Park, H-J. Kim, J-S. Kim. Category 3: a. Final approval of the completed manuscript: S-H. Jeong, S.-H. Kim, S.-H. Lee, S.-H. Park, H.-J. Kim, J.-S. Kim. REFERENCES 1. Leigh RJ, Zee DS. The Neurology of Eye Movements. New York, NY: Oxford University Press, 2006. 2. Tamhankar MA, Biousse V, Ying GS, Prasad S, Subramanian PS, Lee MS, Eggenberger E, Moss HE, Pineles S, Bennett J, Osborne B, Volpe NJ, Liu GT, Bruce BB, Newman NJ, Galetta SL, Balcer LJ. Isolated third, fourth, and sixth cranial nerve palsies from presumed microvascular versus other causes: a prospective study. Ophthalmology. 2013;120:2264- 2269. 3. Taguchi H, Kashii S, Kikuchi M, Yasuyoshi H, Honda Y. Superior oblique paresis with contralateral relative afferent pupillary defect. Graefes Arch Clin Exp Ophthalmol. 2000;238:927-929. 4. Gold DR, Shin RK, Galetta S. Pearls and oy-sters: central fourth nerve palsies. Neurology. 2012;79:e193-196. 5. Adachi K, Hironaka K, Suzuki H, Oharazawa H. Isolated trochlear nerve palsy with perimesencephalic subarachnoid haemorrhage. BMJ Case Rep. 2012:2012. doi: 10.1136/bcr. 2012.006175. 6. Guy J, Day AL, Mickle JP, Schatz NJ. Contralateral trochlear nerve paresis and ipsilateral Horner's syndrome. Am J Ophthalmol. 1989;107:73-76. 7. Vanooteghem P, Dehaene I, Van Zandycke M, Casselman J. Combined trochlear nerve palsy and internuclear ophthalmoplegia. Arch Neurol. 1992;49:108-109. 8. Kim JS, Kang JK, Lee SA, Lee MC. Isolated or predominant ocular motor nerve palsy as a manifestation of brain stem stroke. Stroke. 1993;24:581-586. 9. Galetta SL, Balcer LJ. Isolated fourth nerve palsy from midbrain hemorrhage: case report. J Neuroophthalmol. 1998;18:204- 205. 10. Thomke F, Ringel K. Isolated superior oblique palsies with brainstem lesions. Neurology. 1999;53:1126-1127. 11. Keane JR. Tectal fourth nerve palsy due to infarction. Arch Neurol. 2004;61:280. 12. Makki AA, Newman NJ. A trochlear stroke. Neurology. 2005;65:1989. 13. Lee SH, Park SW, Kim BC, Kim MK, Cho KH, Kim JS. Isolated trochlear palsy due to midbrain stroke. Clin Neurol Neurosurg. 2010;112:68-71. 381 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 14. Choi SY, Song JJ, Hwang JM, Kim JS. Tinnitus in fourth nerve palsy: an indicator for an intra-axial lesion. J Neuroophthalmol. 2010;30:325-327. 15. Walsh RA, Murphy RP, Moore DP, McCabe DJ. Isolated trochlear infarction: an uncommon cause of acquired diplopia. Arch Neurol. 2010;67:892-893. 16. Bazan R, Braga GP, Gomes DL, Yamashita S, Betting LE, Resende LA. Trochlear nerve palsy associated with claude bernard-horner syndrome after brainstem stroke. Case Rep Neurol. 2011;3:248-251. 17. Lavin PJ, Troost BT. Traumatic fourth nerve palsy. Clinicoanatomic correlations with computed tomographic scan. Arch Neurol. 1984;41:679-680. 18. Abarbanel JM, Hertzanu Y, Herishanu Y. Traumatic trochlearnerve palsy due to haematoma. Dev Med Child Neurol. 1986;28:509-511. 19. Prosst RL, Majetschak M. Traumatic unilateral trochlear nerve palsy. J Trauma. 2007;62:E1-E3. 20. Thurtell MJ, Tomsak RL, Leigh RJ. Upbeat-torsional nystagmus and contralateral fourth nerve palsy due to unilateral dorsal ponto mesencephalic lesion. Ann N Y Acad Sci. 2009;1164:476-478. 21. Sudhakar P, Bapuraj JR. CT demonstration of dorsal midbrain hemorrhage in traumatic fourth cranial nerve palsy. J Neuroophthalmol. 2010;30:59-63. 382 22. Raghavendra S, Vasudha K, Shankar SR. Isolated trochlear nerve palsy with midbrain hemorrhage. Indian J Ophthalmol. 2010;58:66-67. 23. Bhola R, Olson RJ. Dorsal midbrain syndrome with bilateral superior oblique palsy following brainstem hemorrhage. Arch Ophthalmol. 2006;124:1786-1788. 24. Naidich TP, Duvernoy HM. Duvernoy's Atlas of the Human Brain Stem and Cerebellum: High-field MRI: Surface Anatomy, Internal Structure, Vascularization and 3D Sectional Anatomy. New York, NY: Springer Wien, 2009. 25. Choi KD, Oh SY, Kim HJ, Koo JW, Cho BM, Kim JS. Recovery of vestibular imbalances after vestibular neuritis. Laryngoscope. 2007;117:1307-1312. 26. Fleiss JL. The Design and Analysis of Clinical Experiments. Wiley classics library ed. New York, NY: Wiley, 1999. 27. Hara N, Kan S, Simizu K. Localization of post-traumatic trochlear nerve palsy associated with hemorrhage at the subarachnoid space by magnetic resonance imaging. Am J Ophthalmol. 2001;132:443-445. 28. Bartels H, Staal MJ, Albers FW. Tinnitus and neural plasticity of the brain. Otol Neurotol. 2007;28:178-184. 29. Zwergal A, Cnyrim C, Arbusow V, Glaser M, Fesl G, Brandt T, Strupp M. Unilateral INO is associated with ocular tilt reaction in pontomesencephalic lesions: INO plus. Neurology. 2008; 71:590-595. Jeong et al: J Neuro-Ophthalmol 2016; 36: 377-382 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.