Ocular Motor Dysfunction Due to Brainstem Disorders

The brainstem contains numerous structures including afferent and efferent fibers that are involved in generation and control of eye movements. These structures give rise to distinct patterns of abnormal eye movements when damaged. Defining these ocular motor abnormalities allows a topographic diagnosis of a lesion within the brainstem. Although diverse patterns of impaired eye movements may be observed in lesions of the brainstem, medullary lesions primarily cause various patterns of nystagmus and impaired vestibular eye movements without obvious ophthalmoplegia. By contrast, pontine ophthalmoplegia is characterized by abnormal eye movements in the horizontal plane, while midbrain lesions typically show vertical ophthalmoplegia in addition to pupillary and eyelid abnormalities. Recognition of the patterns and characteristics of abnormal eye movements observed in brainstem lesions is important in understanding the roles of each neural structure and circuit in ocular motor control as well as in localizing the offending lesion.

State-of-the-Art Review Section Editors: Valerie Biousse, MD Steven Galetta, MD Ocular Motor Dysfunction Due to Brainstem Disorders Seung-Han Lee, MD, PhD, Hyo-Jung Kim, PhD, Ji-Soo Kim, MD, PhD Background: The brainstem contains numerous structures including afferent and efferent fibers that are involved in generation and control of eye movements. Evidence Acquisition: These structures give rise to distinct patterns of abnormal eye movements when damaged. Defining these ocular motor abnormalities allows a topographic diagnosis of a lesion within the brainstem. Results: Although diverse patterns of impaired eye movements may be observed in lesions of the brainstem, medullary lesions primarily cause various patterns of nystagmus and impaired vestibular eye movements without obvious ophthalmoplegia. By contrast, pontine ophthalmoplegia is characterized by abnormal eye movements in the horizontal plane, while midbrain lesions typically show vertical ophthalmoplegia in addition to pupillary and eyelid abnormalities. Conclusions: Recognition of the patterns and characteristics of abnormal eye movements observed in brainstem lesions is important in understanding the roles of each neural structure and circuit in ocular motor control as well as in localizing the offending lesion. Journal of Neuro-Ophthalmology 2018;38:393-412 doi: 10.1097/WNO.0000000000000583 © 2017 by North American Neuro-Ophthalmology Society brainstem. Furthermore, introduction of video-based oculography has permitted more accurate characterization of abnormal eye movements. Accordingly, defining the patterns and characteristics of abnormal eye movements observed in brainstem lesions is important in understanding the roles of each neural structure and circuit in ocular motor control as well as detecting its precise location (2,3). In humans, the subclasses of eye movements include saccades, smooth pursuit, optokinetic nystagmus (OKN), the vestibulo-ocular reflex (VOR), vergence, and gazeholding (1). Comprehensive evaluation of eye movements should include examination of all these subclasses of eye movements in addition to ocular alignment, pupillary and eyelid function, and involuntary eye movements such as nystagmus and saccadic oscillations. Furthermore, these eye movements should be defined in the horizontal, vertical, and torsional planes (4). In this review, we detail abnormal eye movements that are observed in the lesions involving the brainstem from the cervicomedullary to mesodiencephalic junctions. T ABNORMAL EYE MOVEMENTS IN MEDULLARY LESIONS Department of Neurology (S-HL), Chonnam National University Medical School, Gwangju, Korea; Research Administration Team (HJK), Seoul National University Bundang Hospital, Seoul, Korea; and Department of Neurology (H-JK, J-SK), Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Korea. The medulla contains several structures that are important in the control of eye movements. These include the vestibular nuclei, perihypoglossal nuclei consisting of the nucleus prepositus hypoglossi (NPH), nucleus intercalatus, nucleus of Roller, inferior olivary nucleus (ION), inferior cerebellar peduncles (ICPs), and cell groups of the paramedian tract (PMT) (Fig. 1). Lesions involving the vestibular nuclei produce vertigo and various patterns of central nystagmus. The medial vestibular nucleus (MVN) and NPH play an important role as the neural integrator in holding the eyes steady during eccentric horizontal gaze. Lesions involving the medulla are characterized by various patterns of nystagmus and vestibular impairments without obvious ophthalmoplegia (5). he brainstem contains numerous neurons and intricate neural circuits that are important for generation and control of eye movements (1). Thus, many disorders involving the brainstem give rise to various patterns of impaired eye movements. Recent developments in brain imaging have allowed better detection and more precise localization of disease processes in the The authors report no conflicts of interest. Address correspondence to Ji-Soo Kim, MD, PhD, Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundanggu, Seongnam-si, Gyeonggi-do 13620, Korea; E-mail: jisookim@ snu.ac.kr Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 393 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 1. Illustration of structures responsible for ocular motor control in the brainstem. HN, hypoglossal nucleus; ICP, inferior cerebellar peduncle; III, third nucleus; INC, interstitial nucleus of Cajal; IV, fourth nerve nucleus; IVN, inferior vestibular nucleus; LVN, lateral; VI, sixth nerve nucleus; VN, vestibular nuclei; MLF, medial longitudinal fasciculus; MVN, medial vestibular nucleus; ND, nucleus of Darkschewitsch; NPH, nucleus prepositus hypoglossi; riMLF, rostral interstitial nucleus of the medial longitudinal fasciculus; ON, (inferior) olivary nucleus; PC, posterior commissure; PPRF, paramedian pontine reticular formation; RN, red nucleus; SCP, superior cerebellar peduncle. Vestibular Nucleus The vestibular nuclei are located in the dorsolateral portion of the rostral medulla and caudal pons (Fig. 1). There are 4 major vestibular nuclei: the MVN, lateral (LVN), inferior (IVN), and superior (SVN). The rostral portion of MVN receives afferents from the semicircular canals (SCCs) and projects to the third, fourth, and sixth cranial nerve nuclei, thus mediating the VOR. By contrast, the caudal portion of the MVN is reciprocally connected to the cervical spinal cord, presumably mediating the vestibulo-collic reflexes, and to the cerebellum. The LVN receives afferents from the SCCs and utricle and participates in the VOR, in part through the ascending tract of Deiters to the third nerve nucleus. The LVN also projects to the spinal cord, mainly through the ipsilateral lateral vestibulospinal tract and also through the contralateral medial vestibulospinal tract. The IVN also sends efferents to the ocular motor nuclei (1). The SVN receives afferents from the vestibular apparatus and cerebellum and provides outputs to the third nerve nucleus through the medial longitudinal fasciculus (MLF) and ventral tegmental tract (VTT) and to the cerebellum. The primary vestibular afferents enter the medulla at the level of the LVN. Many afferents bifurcate, giving a descending branch to terminate in the MVN and IVN and an ascending branch to the SVN, with a final destination in the cerebellum, especially the anterior vermis and the nodulus and uvula (6). 394 The MVN and IVN are supplied by the posterior inferior cerebellar artery (PICA) in the rostral medulla, whereas all 4 vestibular nuclei are supplied by the anterior inferior cerebellar artery (AICA) in the caudal pons. The vestibular nuclei not only are the immediate recipients of the peripheral vestibular signals but also are involved in the central modulation and integration of these signals (7). The characteristic features of a lesion involving the vestibular nuclei are combined peripheral and central vestibular dysfunction (7). Findings of peripheral vestibular impairments include spontaneous horizontal-torsional nystagmus beating away from the lesion side, positive head impulse tests (HITs) for the ipsilesional semicircular canals, ipsilesional caloric paresis, ipsiversive ocular tilt reaction (OTR), tilt of the subjective visual vertical (SVV), and decreased or absent vestibular evoked myogenic potential during stimulation of the ipsilesional ear (8). However, the direction-changing gaze-evoked nystagmus (GEN), more prominent during contralesional gaze, and impaired HITs for the contralesional semicircular canals also indicate central vestibular involvements (Fig. 2, Table 1) (9). Nucleus Prepositus Hypoglossus The NPH lies near the midline in the rostral medulla and caudal pons between the hypoglossal and sixth nerve nuclei, just medial to the MVN (Fig. 1) (10). The NPH receives the vestibular signals through the afferent branches from the Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 2. A patient with an infarction restricted to the right medial vestibular nucleus (MVN, arrow, A) shows left beating horizontal-torsional nystagmus that increases without fixation (B), horizontal gazed-evoked nystagmus (C), and decreased head impulse gains of the vestibulo-ocular reflex for both horizontal and posterior semicircular canals (ipsilesional . contralesional, D). H, horizontal eye position; ICP, inferior cerebellar peduncle; IVN, inferior vestibular nucleus; LAC, left anterior canal; LHC, left horizontal canal; LPC, left posterior canal; MLF, medial longitudinal fasciculus; MVN, medial vestibular nucleus; NPH, nucleus prepositus hypoglossi; RAC, right anterior canal; RHC, right horizontal canal; RPC, right posterior canal; T, torsional eye position; V, vertical eye position. TABLE 1. Comparisons of ocular motor findings with lesions of the medulla Clinical Finding/Test Spontaneous nystagmus GEN Ocular tilt reaction Body lateropulsion SVV tilt Smooth pursuit Saccades VOR HIT Caloric Vestibular Nucleus NPH ICP Contralesional, strong Contralesional, strong Ipsiversive Ipsilesional Ipsiversive Impaired, bilateral Normal Ipsilesional, weak Strong, ipsilesional Contraversive Contralesional Contraversive Impaired, ipsilesional Normal Ipsilesional, weak None Contraversive Ipsilesional Contraversive Impaired, ipsilesional Normal Decreased gains, both HCs and PCs (Y ipsilesional . Y contralesional) Ipsilesional paresis Decrased gain, contralesional HC; increased gains, both ACs Normal Normal Normal AC, anterior canal; GEN, gaze-evoked nystagmus; HC, horizontal canal; HIT, head impulse test; ICP, inferior cerebellar peduncle; NPH, nucleus prepositus hypoglossi; PC, posterior canal; SVV, subjective visual vertical; VOR, vestibulo-ocular reflex. Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 395 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review semicircular canals, which also innervate the vestibular nuclei, and flocculus, nodulus, and uvula of the cerebellum (11). The NPH has reciprocal connections with the vestibular nucleus both directly and indirectly through the vestibulocerebellum (12). The NPH inhibit each other by GABAergic commissural projections and the IONs on both sides of the brainstem (12). The NPH also serves the neural integration for horizontal eye movements (9,12). Unilateral lesions of the NPH produce asymmetrical gain of the VOR during the rotation and impaired posture and gait in primates and cats (13). Through its connections with the inferior olive, cerebellar flocculus, and vestibular nucleus, a unilateral NPH lesion results in inhibition of the contralateral vestibular nucleus and mimic a lesion involving the contralateral vestibular nucleus (Fig. 1) (10,14). Thus, the patients with lesions involving NPH may present with vertigo and unsteadiness (9,12). Patients with a NPH lesion show an ipsilesional-beating spontaneous nystagmus, horizontal GEN more intense on looking toward the ipsilesional side, impaired pursuit more to the ipsilesional side, central patterns of head-shaking nystagmus, contralateral eye deviation (probably due to an imbalance in the horizontal VOR), decreased VOR gain during contralesionally directed head impulses, and contraversive OTR and SVV tilt (Fig. 3, Table 1) (12). Lateral Medullary Infarction (Wallenberg Syndrome) Lateral medullary infarction (LMI) is characterized by 1) ipsilateral loss of pain and temperature sensation of the face, due to involvement of the descending nucleus and tract of the trigeminal nerve; 2) contralateral loss of pain and temperature sensation in the trunk and limbs from involvement of the spinothalamic tract; 3) ipsilateral Homer FIG. 3. A patient with an infarction involving the right nucleus prepositus hypoglossi (NPH, A) shows right beating horizontaltorsional nystagmus with an upbeating component (B), horizontal gaze-evoked nystagmus greater to the side of the lesion (C), and decreased head impulse gain of the vestibulo-ocular reflex for the contralesional left horizontal canal (D). By contrast, the gains for both anterior canals are increased. H, horizontal eye position; ICP, inferior cerebellar peduncle; IVN, inferior vestibular nucleus; LAC, left anterior canal; LHC, left horizontal canal; LPC, left posterior canal; MLF, medial longitudinal fasciculus; MVN, medial vestibular nucleus; NPH, nucleus prepositus hypoglossi; RAC, right anterior canal; RHC, right horizontal canal; RPC, right posterior canal; T, torsional eye position; V, vertical eye position. 396 Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review syndrome from interruption of descending sympathetic fibers; 4) dysarthria and dysphagia from weakness of the palate, pharynx, and larynx secondary to involvement of the nucleus ambiguus; 5) ataxia of the ipsilateral limbs because of involvement of the ICP and cerebellar hemisphere; and 6) vertigo and nystagmus from involvement of the IVN and MVN and their afferent and efferent pathways (15,16). The spontaneous nystagmus in Wallenberg syndrome is usually horizontal or mixed horizontal-torsional with a small vertical component (17,18). While viewing straight ahead, the slow phase is usually directed toward the side of the lesion, although it may reverse direction in eccentric positions, suggesting coexistent involvement of the gazeholding mechanism. Head-shaking nystagmus, when present, almost always beats toward the side of the lesion even when the spontaneous nystagmus in primary position may beat oppositely (17). Lid nystagmus, synkinetic lid twitches with horizontal nystagmus also can occur (19). Patients with LMI describe a sensation of being pulled toward the side of the lesion as if an external force is acting on their body. The eyes may also be pulled to the side of the lesion (15,20). Ocular lateropulsion, a compelling deviation of the eyes to 1 side without limitations of ocular motor range, is a common finding in LMI. In LMI, the ocular lateropulsion is typically toward the lesion (ipsipulsion) (15). If a patient is asked to fixate straight ahead and then gently close the lids, both eyes deviate toward the lesion. This deviation becomes evident by corrective saccades that the patients must make after opening the eyes to fixate on a target. Saccadic asymmetry also is a manifestation of ocular lateropulsion. Horizontal saccades directed toward the lesion usually overshoot the target (hypermetria), whereas contralesional saccades undershoot the target (hypometria). Vertical saccades also are directed obliquely toward the lesion (21). The ocular ipsipulsion in LMI has been ascribed to damage to the climbing fibers from the ION to the contralateral cerebellar Purkinje cell in the dorsolateral medulla after decussation (Fig. 4) (15). Ipsiversive OTR is an invariable finding during the acute phase of LMI because of interruption of the pathways from ipsilateral utricle or vertical SCCs at the level of the vestibular nucleus (21,22). Medial Medullary Infarction Medial medullary infarction (MMI) is characterized by a triad of contralesional hemiparesis, decreased position and vibration sensation in the contralateral side of the body, and ipsilesional tongue paralysis (23). MMI generates distinct patterns of ocular motor abnormalities in contrast to those observed in LMI. The horizontal nystagmus beats toward the lesion (24). GEN is more intense on looking ipsilesionally (24). The mechanisms of spontaneous nystagmus and GEN in MMI can be explained by damage to the NPH (12,24,25). Upbeat nystagmus in MMI has been ascribed to lesions involving the perihypoglossal nuclei (24). However, Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 FIG. 4. Schematic representation of the involved pathways in ocular lateropulsion. The Purkinje cells (PC) of the dorsal ocular motor vermis inhibit the ipsilateral caudal fastigial nucleus, which generates contralateral saccades when stimulated. The fibers from the caudal fastigial nucleus (FN) cross the midline, exit the cerebellum in the uncinate fasciculus, and project to the contralateral paramedian pontine reticular formation (PPRF). Ocular ipsipulsion commonly occurs in Wallenberg syndrome because of damage to the olivocerebellar fibers after decussation (1), while ocular contrapulsion occurs in the superior cerebellar infarction (2) or in the medial medullary lesions (3) by damaging the fibers from the FN to the PPRF or the olivocerebellar fibers before decussation. III, third nerve nucleus; VI, sixth nerve nucleus; CF, climbing fibers; DN, dentate nucleus; HN, hypoglossal nucleus; ICP, inferior cerebellar peduncle; ION, inferior olivary nucleus; MLF, medial longitudinal fasciculus; NPH, nucleus prepositus hypoglossi; RN, red nucleus; UF, uncinate fasciculus; VN, vestibular nucleus. NPH lesions do not generate upbeat nystagmus in monkeys (25). Instead, evolution of upbeat into hemiseesaw nystagmus with resolution of a unilateral lesion, as previously observed in a patient with bilateral MMI, suggests an involvement of the VOR pathways from both anterior SCCs as a mechanism of upbeat nystagmus (26). Because the MLF is a midline structure that carries signals from the vestibular to the ocular motor nuclei, upbeat nystagmus in unilateral lesions may be explained by concurrent damage to decussating fibers from both anterior SCCs at the rostral medulla. The cell groups of the PMT, which are involved in processing of vertical eye position through their projections to the cerebellar flocculus, may be another neural substrate for upbeat nystagmus in MMI (27). Ocular contrapulsion also has been described in MMI and is explained by damage 397 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 5. A patient with an infarction in the area of right inferior cerebellar peduncle (A) shows contraversive ocular torsion (B) and fine right beating nystagmus without fixation (C). LH, horizontal movements of the left eye; RH, horizontal movements of the right eye. to the climbing fiber before decussation around the hilus of upper part of the ION in the rostral medulla (23). Patients with MMI may also show contraversive OTR and SVV tilt (24,26). Inferior Cerebellar Peduncle The ICP is located in the posterior portion of caudal pons and rostral medulla between the lower part of the fourth ventricle and the roots of the glossopharyngeal and vagus nerves (28). It is a thick rope-like neural bundle that contains the afferent and efferent fibers to and from the vestibulocerebellum involved in the integration of the proprioceptive and vestibular function (29). The ICP consists of the restiform and juxtarestiform bodies (30). The juxtarestiform body carries fibers in both directions between the vestibular nuclei and the cerebellum and lies on the lateral wall of the fourth ventricle, just medial to the restiform body at the caudal pontine level (30). Thus, a lesion involving the ICP may present isolated vestibular syndrome (9,30,31). The distinct features of isolated ICP lesions include ipsilesional spontaneous nystagmus, negative HITs, and directional dissociation between the contraversive OTR/SVV tilt and ipsiversive falling (Table 1) (30). Ipsilesional spontaneous nystagmus and contralesional OTR/SVV tilt in a unilateral ICP lesion can be explained by loss of cerebellar inhibition over the ipsilesional vestibular nuclear complex (Fig. 5) (30). 398 Inferior Olivary Nucleus The ION is a nuclear complex lying in the ventral medulla, dorsal to the pyramids and lateral to the medial lemniscus. It plays an important role in adaptive control of movements through error signals carried by its climbing fibers, which cross the midline and ascend in the ICP to densely contact the Purkinje cells (1). The axon collaterals also contact the deep cerebellar nuclei (32). The inferior olivary neurons have dendritic gap junctions (connexin 36) that may synchronize the discharges of adjacent groups of neurons (electronic coupling) when denervated (33). Oculopalatal tremor (OPT), palatal tremor in association with pendular nystagmus, occurs as a delayed complication of damage to the dentatorubro-olivary pathway (the Guillain-Mollaret triangle) and subsequent pseudohypertrophic olivary degeneration (34,35). Damage to the dento-rubral circuit is associated with hypertrophy of the contralateral ION, whereas involvement of the central tegmental tract between the red nucleus and the medulla is associated with hypertrophy of the ipsilateral ION (35). The pendular nystagmus is usually vertical-torsional, but frequently dissociated between the eyes (35). Palatal tremor is more active on the contralesional side. OPT is explained by rhythmic hypersynchronous oscillation of the inferior olivary neurons and cerebellar maladaptation (34). Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review Nuclei of Roller and Intercalatus and the Cell Groups of the Paramedian Tracts The nuclei of Roller and intercalatus, which are the caudal components of the perihypoglossal nuclei, have been proposed as anatomic substrates for upbeat nystagmus observed in caudal medullary lesions (36). The nucleus of Roller receives a projection from the SVN and projects to the flocculus through a tract that could be inhibitory (37). Accordingly, damage to the nucleus of Roller itself or to its afferent and efferent fibers may induce upbeat nystagmus by inhibiting the upward VOR pathway from disinhibition of the inhibitory flocculovestibular neurons. The cell groups of the PMT, which are involved in the processing of vertical eye position through their projections to the cerebellar flocculus, may be another neural substrate for upbeat or downbeat nystagmus in medial medullary lesions (27,38). ABNORMAL EYE MOVEMENTS IN PONTINE LESIONS The pontine tegmentum harbors important structures for conjugate horizontal gaze, which include the paramedian pontine reticular formation (PPRF), sixth nerve nucleus, nucleus raphe interpositus, and MLF (Fig. 1) (1). Thus, horizontal gaze palsy is characteristic of disorders involving the pontine tegmentum (39,40). However, various patterns of vertical eye movement abnormalities, including vertical GEN and impaired vertical smooth pursuit and the VOR, may occur in pontine lesions because the pontine ocular motor centers are connected through the MLF to the midbrain and midbrain-diencephalic junctional area that are mainly concerned with vertical gaze (41). Localization of the lesions causing horizontal gaze palsy usually relies on concurrent neurological findings such as hemiparesis, sensory loss, and cranial nerve palsies. However, isolated conjugate horizontal gaze palsy may occur in lesions selectively involving the pontine gaze centers, such as the PPRF or sixth nerve nucleus. Sixth Nerve Nucleus and Fascicle The sixth nerve nucleus lies on the floor of the fourth ventricle adjacent to the fascicles of the facial nerve that arc poterolaterally forming the facial colliculi. The sixth nerve nucleus contains 2 main groups of neurons: the motoneurons that innervate the ipsilateral lateral rectus muscle and the interneurons that cross the midline and ascend in the MLF to innervate the contralateral medial rectus FIG. 6. A patient has a left horizontal gaze palsy (A) and left facial palsy of the peripheral type (B) from a small infarction of the left facial colliculus (arrows) (C). Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 399 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review TABLE 2. Comparison of clinical characteristics between the lesions of the sixth nerve nucleus and paramedian pontine reticular formation (PPRF) Sixth Nerve Nucleus Horizontal gaze Primary position GEN Other characteristic PPRF Loss of all conjugate movements toward the lesion In the intact hemifield of gaze, ipsilaterally directed saccades may be relatively preserved Contralateral gaze deviation during the acute phase Horizontal GEN on looking contralaterally Ipsilateral facial palsy often associated Selective horizontal saccadic palsy toward the lesion Contralateral gaze deviation during the acute phase Horizontal GEN on looking contralaterally Bilateral lesions cause slowing of vertical saccades GEN, gaze-evoked nystagmus. motoneurons (42). Thus, lesions involving the sixth nerve nucleus cause an ipsilateral palsy of horizontal conjugate gaze for saccades, smooth pursuit, OKN, and the VOR (Fig. 6, Table 2) (1,42). However, saccades toward the lesion may be relatively preserved in the contralateral hemifield (1). For example, in a lesion involving left sixth nerve nucleus, saccades from right gaze to the center are relatively preserved because those are achieved mostly by relaxation of the antagonist muscles (right lateral rectus and left medial rectus), which is mediated by the inhibitory burst neurons in the left medullary reticular formation. In addition, vertical and vergence eye movements are spared (1). Ipsilateral facial palsy of the peripheral type usually is accompanied by sixth nerve nuclear lesions because of concurrent damage to the adjacent facial nerve fascicle (Fig. 6) (43). Lesions restricted to the sixth nerve nucleus are rare (44), and such lesions more commonly involve the adjacent tegmental structures, especially the MLF and PPRF. Complete horizontal gaze palsy may occur with bilateral pontine lesions such as infarction, demyelination, and infection. Vergence and vertical eye movements are preserved. The sixth nerve nucleus is susceptible to maldevelopment or injury during embryogenesis or early life. Duane retraction syndrome is characterized by narrowing of the palpebral fissure on adduction secondary to retraction of the eye. This syndrome has been classified into 3 forms (45,46). In the most common type 1, the abduction is limited, but the adduction is preserved. Type 2 is characterized by normal abduction but incomplete adduction. Patients with type 3 show limitation of both abduction and adduction. There may be abnormal "upshoot" or "downshoot" of the eye on attempted horizontal gaze (47). Esotropia is uncommon (48). Duane syndrome is bilateral in less than 20% (45) and may be associated with developmental delay (49) or other congenital abnormalities (50). Duane syndrome is more common in the left eye and in females. It is generally sporadic, but approximately 10% of cases may be familial, including autosomal dominant inheritance (51). Neuropathological examination has shown absent sixth nerve motoneurons and nerve, and aberrant innervation of the lateral rectus by a branch of the third nerve (52). Absence of the sixth nerve nerve has been observed on MRI in both type 1 and type 3 Duane syndrome (53). Thus, failure of abduction is due to lack of innervation of the lateral rectus by the sixth nerve nerve. Retraction during attempted horizontal gaze may be ascribed to co-contraction of the medial and lateral recti that are supplied by the third nerve nerve (54). Möbius syndrome is characterized by bilateral facial palsies in association with bilateral horizontal gaze palsies or TABLE 3. Syndromes of nuclear or fascicular sixth nerve palsy Syndrome Associated Signs Raymond Ipsilateral ataxia Contralateral hemiparesis Contralateral hemihypesthesia Facial nucleus Trigeminal neurons Ciliospinal tract Corticospinal tract Facial nucleus Corticospinal tract Foville Millard Gubler 400 Lesion Cerebellar peduncles Corticospinal tract Medial lemniscus Ipsilateral facial palsy Abnormal ipsilateral facial sense Horner syndrome Contralateral hemiparesis Ipsilateral facial palsy Contralateral hemiparesis Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review impaired abduction of both eyes (55). Frequently, there are other systemic congenital abnormalities in patients with Möbius syndrome. The cause of Möbius syndrome is unknown, but may be hereditary in some cases. MRI and pathology studies have documented the absence of the sixth nerve and facial nuclei and nerves (56,57). Some patients show features of both Duane and Möbius syndromes, suggesting that they both belong to a spectrum of congenital cranial dysinnervation disorders (58,59). Congenital paralysis of horizontal gaze may be associated with progressive scoliosis (60). This syndrome of horizontal gaze palsy with progressive scoliosis is caused by mutations in the ROBO3 gene on chromosome11q24, which is important for hindbrain midline axon crossing (61). MRI may show brainstem hypoplasia with the absence of the facial colliculi, presence of a deep midline FIG. 7. A patient with left internuclear ophthalmoplegia (A) from a small medial tegmental pontine infarction (B) shows contraversive rightward ocular torsion (22.8° in the right eye and 210.9° in the left eye, normal range: 0-12.6°; the positive value indicates extorsion and the negative value indicates intorsion). C. Upbeat nystagmus with a dissociated (left eye . right eye) counterclockwise (upper poles of the eyes beating to the left ear) torsional component (D), and slow and limited rightward saccades in the left eye (arrows) (E). LH, horizontal movements of the left eye; LT, torsional movements of the left eye; LV, vertical movements of the left eye; RH, horizontal movements of the right eye; RT, torsional movements of the right eye; RV; vertical movements of the right eye; T, time. Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 401 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review pontine cleft (split pons sign), a butterfly configuration of the medulla, absence of major pontine crossing fiber tracts, and no decussation of the superior cerebellar peduncles (62,63). The sixth nerve fascicles course ventrally through the pontine tegmentum to exit ventromedially at the pontomedullary junction. According to concurrent damage to the nearby structures in the brainstem, nuclear or fascicular sixth nerve palsy may give rise to various combinations of neurological syndromes (Table 3) (64). Paramedian Pontine Reticular Formation The PPRF contains several different populations of neurons, which are important for generating saccades (1). The excitatory burst neurons, which provide premotor commands for horizontal saccades, lie in the dorsomedial portions of the nucleus pontis centralis caudalis, rostral to the sixth nerve nucleus (65). The excitatory burst neurons project to the ipsilateral sixth nerve nucleus. The nucleus raphe interpositus, located at the level of the sixth nerve nucleus, contains omnipause neurons that inhibit all burst neurons except during saccades (66). Caudal to the sixth nerve nucleus in the dorsomedial tegmentum of the rostral medulla, the inhibitory burst neurons receive inputs from the ipsilateral excitatory burst neurons and project to the contralateral sixth nerve nucleus (Fig. 4) (1). Unilateral lesions of the PPRF cause ipsilateral horizontal saccadic palsy (1,67). Ipsilaterally directed saccades and quick phases of the nystagmus are small and slow. Other horizontal and vertical eye movements also may be affected, but vergence, vestibular and pursuit eye movements typically are spared (68,69). During the acute phase, the eyes may be deviated contralaterally (Table 2). Isolated palsy of horizontal saccades in both directions may be observed after cardiac surgery (70) or in spinocerebellar ataxia type 2 or brainstem tumors (71,72), probably because of selective damage to the burst neurons in both PPRF. Internuclear Ophthalmoplegia Internuclear ophthalmoplegia (INO) is characterized by impaired adduction of the ipsilesional eye and dissociated abducting nystagmus of the contralateral eye because of a lesion involving the MLF that carries signals from contralesional sixth nerve nucleus to ipsilateral medial rectus subnucleus of the oculomotor nuclear complex (Fig. 7) (1,73-75). INO has been classified into anterior and posterior according to the presence of associated convergence palsy (76). In mild cases, only saccadic slowing of adduction is observed without gaze limitation (adduction lag) in the ipsilesional eye (73). In this case, abducting nystagmus of the contralateral eye is helpful for diagnosis. Several explanations have been proposed for 402 TABLE 4. Clinical characteristics of internuclear ophthalmoplegia (INO) Weakness or paralysis of adduction on the side of the MLF lesion during conjugate gaze when partial, best detected with saccadic slowing, giving the appearance of "adduction lag" Adduction may be preserved during convergence Dissociated abducting nystagmus on the contralesional eye during contralesional gaze Exotropia, usually in the contralesional eye Contraversive ocular tilt reaction Dissociated vertical-torsional nystagmus-usually upbeat and ipsiversive (top pole beating to side of the lesion) torsional components In bilateral INO, gaze-evoked vertical nystagmus, impaired vertical pursuit, and decreased vertical vestibular responses, especially for upward head movements Small-amplitude saccadic intrusions interrupting fixation INO, internuclear ophthalmoplegia; MLF, medial longitudinal fasciculus. dissociated abducting nystagmus of INO. One of them incorporates the brain's efforts to compensate for the adduction weakness (77). Such compensation induces an adaptive increase in innervation to the adducting eye, which must be accompanied by a commensurate change in the innervation of the abducting eye because of Hering law of equal innervation. Another possible mechanism is dissociated GEN that seems more prominent in the abducting eye because of the adduction weakness. Interruption of PMT that run near the MLF and carry the fibers to and from the flocculus and paraflocculus might be responsible for the GEN (27). INO is often accompanied by contraversive OTR (hypertropia of the ipsilesional eye, contraversive ocular torsion, and contraversive head tilt) that is due to interruption of central projections from contralateral utricle or vertical SCCs, which ascend in the MLF after decussation in the lower pons (78,79). Various patterns of skew-torsion of the eyes and dissociated vertical-torsional nystagmus (jerky seesaw nystagmus) may be observed and are explained by disruption of the neural pathways from contralateral vertical SCCs with or without concomitant damage to the fibers from contralateral utricle in or near the MLF (Fig. 7, Table 4) (80). SVV tilt is mostly contraversive but may be observed occasionally toward the lesion possibly because of involvement of the uncrossed vestibulothalamic tract (81). Asymmetry of the vertical VOR may be evident with rapid head rotations; thus, in a patient with right INO, the HITs for the left posterior SCC are mostly impaired, whereas those for the left anterior SCC are preserved (82). Bilateral INO often causes additional findings: gazeevoked vertical nystagmus, impaired vertical pursuit, and decreased vertical vestibular responses with a drop in Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review dynamic visual acuity when the head is rotating up and down (1). Upbeat nystagmus may be seen in association with bilateral INO, and it may be attributed to damage of the cell group of the PMT, the projections from the interstitial nucleus of Cajal (INC) to PMT, or the connections between the INC and the nucleus of Roller (83). However, the initial symmetric upbeat nystagmus and bilateral INO evolved into dissociated torsionalupbeat nystagmus, unilateral INO and contraversive OTR in a patient with a focal pontine tegmental lesion. These findings suggest that the initial upbeat nystagmus was due to bilateral disruption of the upward VOR pathways originating from the superior SCC, which are known to pass through the VTT or the MLF (84,85). Changes in vergence may be seen in INO with variable patterns because the MLF carries the signals related to convergence (1,86). A more common finding is exotropia, especially with bilateral INO ("wall-eyed bilateral INO" [WEBINO]). WEBINO should be differentiated from the exotropia (paralytic pontine exotropia) of one-and-a-half syndrome (73,87). Ataxia in association with INO indicates a dorsomedial pontine tegmental lesion at the pontomesencephalic junction (88). INO should be differentiated from medial rectus palsy (89). Diagnosis of INO is supported by other accompanying signs such as sparing of convergence, impaired HIT for the contralateral posterior SCC, dissociated verticaltorsional nystagmus, and coexistent contraversive OTR. In any patients with the features of an INO that cannot be explained by a lesion in the MLF, pseudo-INO due to ocular myasthenia gravis or Miller Fisher syndrome should be considered (86). Many disorders have been reported to cause INO (73- 75). In general, unilateral INO is most commonly observed in ischemia while bilateral INO is commonly due to multiple sclerosis. One-and-a-half Syndrome Combined damage to the sixth nerve nucleus or PPRF and adjacent MLF on 1 side causes an ipsilateral horizontal gaze palsy and INO, so that the only preserved horizontal eye movement is abduction of the contralateral eye (90,91). Such patients may show an exotropia of the contralesional eye, which is known as paralytic pontine exotropia (92). Besides one-and-a-half syndrome, various terms have been coined for the syndrome of horizontal gaze palsy in association with diverse patterns of cranial nerve involvement according to their combinations (Table 5) (93-97). Ocular Tilt Reaction in Brainstem Disorders The OTR consists of head tilt, skew deviation, and ocular torsion (98). It indicates a unilateral deficit of otolithic input or a unilateral lesion of the graviceptive brainstem pathway from the vestibular nucleus to the rostral midbrain, which crosses the midline at the pontine level. Along with SVV tilt, the OTR is a sensitive brainstem sign of localizing and lateralizing value (98). The OTR is invariably ipsiversive (hypotropia of the ipsilesional eye, ocular torsion toward the ipsilesional shoulder, and ipsiversive head tilt) with caudal pontomedullary lesions and contraversive in lesions located above the caudal pons (98). Nucleus Reticularis Tegmenti Pontis and Dorsolateral Pontine Nucleus The nucleus reticularis tegmenti pontis (NRTP) lies ventral to the nucleus reticularis pontis oris and caudalis, between TABLE 5. Variants of one-and-a-half syndrome Syndrome One-and-a-half syndrome Eight-and-a-half syndrome (93) Thirteen-and-a-half syndrome (94) Fifteen-and-a-half syndrome (95) Sixteen syndrome (96) Sixteen-and-a-half syndrome (97) Clinical Signs Ipsilateral horizontal gaze palsy and INO (1½) Ipsilesional facial palsy (7) One-and-a-half syndrome (1½) Ipsilesional trigeminal palsy (5) Ipsilesional facial palsy (7) One-and-a-half syndrome (1½) Contralateral facial palsy (7) Ipsilesional facial palsy (7) One-and-a-half syndrome (1½) Facial diplegia (7 + 7) Bilateral complete horizontal gaze palsies (2) Ipsilateral hearing loss (8) Ipsilesional facial palsy (7) One-and-a-half syndrome (1½) Causative Lesions MLF + sixth nerve nucleus or PPRF Facial nerve nucleus or fasciculus + 1½ syndrome Ipsilateral trigeminal nerve + 8½ syndrome Bilateral facial nerve nuclei or fasciculi and 1½ syndrome Bilateral facial nuclei or fasciculi and bilateral sixth nerve nuclei or PPRFs Cochlear nuclear complex (pons) + 8½ syndrome INO, internuclear ophthalmoplegia; MLF, medial longitudinal fasciculus; PPRF, paramedian pontine reticular formation. Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 403 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review the levels of the fourth nerve and sixth nerve nuclei in monkeys (1). The NRTP provides an important relay between the cortical eye fields/superior colliculus and the cerebellum, and mediates saccades, smooth pursuit, and vergence (99-101). The dorsolateral pontine nuclei (DLPNs) lie lateral to the lateral lemniscus in the pons at the level of and rostral to the sixth nerve nuclei in monkeys (1). It receives inputs from the posterior cortical areas concerned with smooth pursuit (102) and projects to the paraflocculus and uvula of the cerebellum (103). The DLPN provides an important relay from the cortical areas concerned with visual motion and contributes to maintenance of smooth pursuit and also to saccades (104). In humans, unilateral NRTP or DLPN lesions impair ipsilateral smooth pursuit (105) and lesions affecting the NRTP and also disrupt slow vergence (106,107). Ventral Tegmental Tract Excitatory vestibular projections arise mainly from the SVN and cross before reaching the elevator motoneurons either through the MLF or through the crossing VTT. Thus, the lesions affecting the crossing VTT may cause downward drift of the eyes and upbeat nystagmus (85). Excitatory pursuit signals arising from the dorsal Y group project to the elevator motoneurons through the crossed VTT (1,108). ABNORMAL EYE MOVEMENTS IN LESIONS INVOLVING THE MIDBRAIN AND MESODIENCEPHALIC JUNCTION The midbrain contains the third nerve and fourth nerve nuclei and fascicles, and the mesodiencephalic junction habors the key structures involved in the premotor control of vertical and torsional eye movements, especially the saccades and gaze-holding (Fig. 1). Thus, vertical ophthalmoplegia is characteristic of lesions involving the midbrain or mesodiencephalic junction and may be of supranuclear, nuclear, or fascicular origin. This area also contains the neural structures for vergence, pupillary responses and eyelid movements, and descending fibers for horizontal gaze. If any of these structures are damaged, their clinical manifestations will accompany abnormalities of vertical eye movements. Fourth Nerve Nucleus and Fascicle The fourth nerve nucleus lies caudal to the oculomotor nuclear complex, and the nerve fascicle courses posteroinferiorly around the aqueduct to decussate in the anterior medullary velum (109-111). Then, the fourth nerve emerges from the brainstem near the dorsal midline, just below the inferior colliculi. Nuclear or fascicular fourth nerve palsy may be isolated (109-111) but is more frequently accompanied by various 404 neurologic deficits, including Horner syndrome, INO, upbeat nystagmus, ataxia, or tinnitus, because of concurrent involvement of the neighboring structures including the descending sympathetic tract, MLF, brachium conjunctivum, ascending trigeminothalamic/spinothalamic tracts, and inferior colliculus (Fig. 8) (109-112). Nuclear lesions cause contralesional superior oblique palsy (SOP), but fascicular lesions may cause ipsilesional or contralesional SOP depending on the lesion location in the brainstem (Fig. 8). The lesions are more commonly located posterior to the cerebral aqueduct in patients with ipsilesional SOP than in those with contralesional SOP (109-111). Third Nerve Nuclei and Fascicles The cell bodies of the third nerve are located in the midbrain in a nuclear mass straddling the vertical midline (Fig. 1) (113). The third nerve nuclear complex is divided into subnuclei, each devoted exclusively to an individual muscle function. The medial rectus has 3 subnuclei, whereas the remaining muscles have only 1. Most rostral and dorsal are the visceral nuclei (Edinger- Westphal nuclei) that supply parasympathetic innervation to the pupillary sphincters and ciliary muscles through the ciliary ganglia (113). Dorsocaudally, the single caudal central nucleus, in the midline innervates the levator palpebrae superioris bilaterally, subserving upper lid elevation. The neurons for the superior rectus send their axons immediately across the midline to join the contralateral third nerve fascicles. The other subnuclei project ipsilaterally to their individual extraocular muscles (Fig. 9) (1). Owing to these anatomic characteristics of the third nerve nuclei, nuclear involvements should be considered in patients with: 1) unilateral third nerve palsy with paresis of contralateral superior rectus or bilateral partial ptosis, 2) bilateral third nerve palsy with spared levator function (internal ophthalmoplegia may be present or absent) (73). On the contrary, nuclear involvement is unlikely in 1) unilateral third nerve palsy with normal function of the contralateral superior rectus, 2) unilateral internal ophthalmoplegia, 3) unilateral ptosis, 4) isolated unilateral or bilateral weakness of the medial rectus (1). Because of the topographical arrangement of the third nerve fascicles, various combinations of internal and external ophthalmoplegia may occur in lesions involving the third nerve fascicles in the brainstem (73,114,115). Furthermore, fascicular third nerve palsy gives rise to distinct syndromes according to the neural structures additionally involved along the path of the fascicles through the red nucleus, substantia nigra, and cerebral peduncle (Table 6) (113). The Rostral Interstitial Nucleus of the MLF The rostral interstitial nucleus of the MLF (riMLF) is located dorsomedial to the rostral pole of the red nucleus, Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 8. A patient with right superior oblique palsy (A) shows abnormal extorsion (15°, normal range: 0-12.6°) of the right eye (B) and a small infarction (C) in the area of left fourth nerve fascicle (D). IV, fourth nerve nucleus; SCP, superior cerebellar preduncle. medial to the fields of Forel, lateral to the periaqueductal gray and the nucleus of Darkschewitch (Fig. 1) (1). The riMLF contains the excitatory burst neurons that generate vertical and ipsiversive torsional saccades (116). Each Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 burst neuron in the riMLF sends axon collaterals to the motoneurons supplying yoke muscle pairs (117). Thus, unilateral or bilateral lesions involving the riMLF cause vertical saccadic palsy that is mainly conjugate. Although 405 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 9. Topographic arrangements of the third nerve nuclei and fascicles in the midbrain. EWN, Edinger-Westphal nuclei; CCN, central caudal nucleus; DN, dorsal nucleus; PN, paramedial nucleus; IN, intermediate nucleus; VN, ventral nucleus; RN, red nucleus; III, nucleus of the third cranial nerve; IR, inferior rectus; IO, inferior oblique; MR, medial rectus; and SR, superior rectus. each riMLF contains burst neurons for both upward or downward saccades, the riMLF on 1 side is responsible for ipsiversive torsional saccades (118,119). Thus, the right riMLF generates clockwise torsional saccades from the subject's point of view (extorsion of the right eye and intorsion of the left eye). Torsional saccades can be induced at the bedside by oscillating the head in the roll plane or by inducing torsional OKN (1). Unilateral riMLF lesion gives rise to contraversive (top poles of the eyes beating to the contralesional ear) torsional nystagmus, limited and slowed vertical saccades and loss of ipsiversive torsional nystagmus during torsional VOR (Table 7) (118,119). mainly through the posterior commissure but also through the ipsilateral projections (123). The INC plays a key role in gaze-holding for vertical and torsional eye position (124). Thus, bilateral lesions of INC typically show vertical GEN, impaired torsional and vertical VOR, and limited vertical saccades but with normal speed within the limited range. Unilateral INC lesions produce contraversive OTR and ipsiversive torsional nystagmus that helps differentiate it from contraversive torsional nystagmus in unilateral riMLF lesions (Table 7) (125). However, in monkeys, the OTR and hemiseesaw nystagmus were observed when the area caudal to the INC was inactivated (126). The Interstitial Nucleus of Cajal Dorsal Midbrain Syndrome The INC lies immediately caudal to the riMLF (Fig. 1). It receives vertical and torsional saccadic inputs from the riMLF and vestibular inputs through the MLF and other ascending pathways. The INC contains neurons that encode burst-tonic (velocity-position) signals (120,121), and neurons that project to motoneurons of the neck and trunk muscles, and coordinate combined eye-head movements in torsional and vertical planes (122). The INC projects to the ocular motoneurons The pretectum is located just rostral to the superior colliculus below the brachium of the superior colliculus, where it forms the transition region between the brainstem and diencephalon. It contains several nuclei that are specialized for visual motor function (43). Lesions involving this area are characterized by various combinations of pupillary, eyelid, and horizontal eye movement abnormalities in addition to vertical ophthalmoplegia (Fig. 10, Table 8). This ocular motor syndrome has TABLE 6. Fascicular third nerve palsy Syndrome Weber Benedikt Claude Nothnagel 406 Associated Sign Contralateral hemiplegia Contralateral hemiplegia, contralateral involuntary movement or tremor Contralateral ataxia Ipsilateral ataxia Lesion Cerebral peduncle Cerebral peduncle, substantia nigra, red nucleus Superior cerebellar peduncle, red nucleus Superior cerebellar peduncle Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review TABLE 7. Topodiagnosis of lesions involving INC and riMLF INC Unilateral Inactivation OTR Torsional nystagmus GEN VOR Torsional Vertical Saccades Tosional Vertical Bilateral inactivation GEN VOR Torsional and vertical Saccades Torsional Vertical Unilateral stimulation OTR Torsional nystagmus riMLF Contraversive Ipsiversive Vertical and torsional GEN Contraversive Contraversive No Little effects on VOR gain and phase Little effects on VOR gain and phase Loss of ipsitorsional nystagmus Reduced or abolished contralesional fast phases Reduced amplitudes and normal velocity All ipsitorsional components are lost Slowed Vertical and torsional GEN No Severely reduced gain and phase lead Preserved Loss of all vertical and torsional saccades Reduced amplitudes and normal velocity Ipsiversive Contraversive Adapted from (119). GEN, gaze-evoked nystagmus; INC, interstitial nucleus of Cajal; OTR, ocular tilt reaction; riMLF, rostral interstitial nucleus of the medial longitudinal fasciculus; VOR, vestibulo-ocular reflex. been given various designations including Parinaud syndrome, Koeber-Salus-Elschig syndrome, pretectal syndrome, and Sylvian aqueduct syndrome (1). Pupillary Abnormalities The pupils are mid-dilated and react better with a near stimulus than to light (light-near dissociation). It may be explained by a lesion that interrupts fibers of the light reflex pathway but spares the more ventrally located fibers of the near reflex pathway (1). Eyelid Abnormalities The most common eyelid abnormality is eyelid retraction (Collier lid sign) (1,127), but ptosis may occur. Eyelid retraction may result from dysfunction of the nucleus of the posterior commissure (nPC), which normally provides inhibitory inputs to the central caudal nucleus within the third nerve nuclear complex (127). Ptosis may be ascribed to disruption of the corticofugal stimulatory fibers for the levator function, damage to the oculosympathetic fibers, or extension of the lesion to the third nerve nuclei. Transient eyelid lag during downward gaze, but without sustained eyelid retraction may occur because of involvement of the midbrain M group that normally coordinates vertical saccades and lid movements (128). Nystagmus and Involuntary Eye Movements Ipsiversive or contraversive torsional nystagmus may occur depending on selective involvement of the riMLF or INC (125,129,130). Convergence-retraction nystagmus is well Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 recognized in dorsal midbrain syndrome and often is elicited by inducing upward saccades. It has been ascribed to disjunctive saccades that converge and retract the eyes (131) or to TABLE 8. Clinical characteristics of the dorsal midbrain syndrome Nystagmus and other involuntary eye movements Upbeat, downbeat, convergence-retraction nystagmus Torsional, see-saw or hemiseesaw nystagmus Vertical gaze-evoked nystagmus Paroxysmal ocular tilt reaction Ophthalmoplegia Vertical: upgaze, downgaze, both up- and down-gaze palsy, vertical one-and-a-half syndrome, monocular elevation palsy Horizontal: pseudo-sixth nerve palsy, contralateral saccadic palsy, ipsilateral pursuit impairment Vergence: convergence or divergence insufficiency, convergence spasm Ocular misalignment Exotropia, esotropia Skew deviation: contralateral, alternating, intermittent Sustained upgaze or downgaze Pupillary abnormalities Anisocoria No or diminished light reflex Light-near dissociation Lid abnormalities Collier sign (lid retraction) Ptosis 407 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 10. Both upward and downward gaze palsy in a patient with a small infarction in the area of right pretectum (arrow). The patient also shows a mildly impaired convergence and lid retraction. synchronous convergence although the mechanisms require further elucidation (132). Paroxysmal OTR or skew-torsion may repeat because of episodic hyperactivity of the neurons in the INC or riMLF, mostly due to hemorrhagic lesions involving these structures (119,133). Paroxysmal OTR may respond to gabapentin or carbamazepine (119). Vertical Gaze Palsy Pretectal lesions may give rise to various patterns of vertical gaze palsy including selective upgaze palsy, selective downgaze palsy, both up- and down-gaze palsy, vertical one-and-a-half syndrome, and double elevator palsy. These may be due to involvements of the neurons in the riMLF, INC, M group, and nPC, and their afferent and efferent fibers (134). The nPC may be important for the control of vertical gaze and eyelid movements. Cells in the nPC project through the posterior commissure and may contact the riMLF, INC, and the M group of neurons, which are relayed to the central caudal subdivision of the third nerve nucleus and may coordinate vertical eye and lid movements (135). The vertical gaze palsy in posterior commissural lesions usually affects all types of eye movements although the VOR and Bell phenomenon may be spared (1). Acutely, the eyes may be tonically deviated downward (setting sun sign), which is prominent in infants with intraventricular hemorrhage. Many disease processes may affect the region of the posterior commissure and disrupt vertical gaze. Pineal tumors produce the dorsal midbrain syndrome either by direct pressure on the posterior commissure or by causing obstructive hydrocephalus (136). Vertical one-and-a-half syndrome refers to either loss of downward movements in both eyes and selective loss of upward movements in 1 eye (137) or impaired upward eye movements in both eyes and a selective deficit of downward motion in 1 eye (138). Both have been described in 408 association with thalamomesencephalic infarctions (137,138). Rarely, both elevator muscles (superior rectus and inferior oblique) of 1 eye may be selectively impaired in midbrain lesions. This double elevator palsy may be a supranuclear paresis of mononuclear elevation because the eyes are nearly orthotropic in primary gaze, and the inferior oblique is innervated by the ipsilateral third nerve nucleus and the superior rectus is supplied by the contralateral one (139). The lesions may be located on either ipsilateral or contralateral side of the palsy (139). Otherwise, it may be due to a selective damage to the third nerve fascicles supplying the inferior oblique and superior rectus (140). Horizontal Ophthalmoplegia Pretectal lesions may show disturbance of horizontal eye movements, especially abnormalities of vergence. Convergence may be paralyzed or excessive (convergence spasm). During horizontal saccades, the abducting eye may move more slowly than its adducting fellow eye or even show a complete loss of abduction because of excess of convergence tone (pseudo-sixth nerve palsy) (141). Otherwise, unilateral paramedian midbrain lesion also may cause paresis of horizontal gaze with impairment of ipsilateral smooth pursuit and sometimes contralateral saccades by affecting the descending pathways (142). CONCLUSION Numerous structures located in the brainstem generate distinct patterns of abnormal eye movements when damaged. Recognition of ocular motor abnormalities from damage of each structure allows topographic diagnosis of the lesions from various disorders involving the brainstem. Although diverse patterns of eye movements may be observed in lesions anywhere along the brainstem, Lee et al: J Neuro-Ophthalmol 2018; 38: 393-412 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review medullary lesions mostly present various patterns of nystagmus and impaired vestibular eye movements without obvious ophthalmoplegia. Pontine ophthalmoplegia is characterized by abnormal eye movements in the horizontal plane, while midbrain lesions typically show vertical ophthalmoplegia in addition to pupillary and eyelid abnormalities. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J.-S. Kim and S.-H. Lee; b. Acquisition of data: J.-S. Kim, S.-H. Lee, and H.-J. Kim; c. Analysis and interpretation of data: J.-S. Kim and S.-H. Lee. Category 2: a. Drafting the manuscript: J.-S. Kim and S.-H. Lee; b. Revising it for intellectual content: J.-S. Kim and H.-J. Kim. Category 3: a. 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