Disorders of the Fourth Cranial Nerve

Perspective Disorders of the Fourth Cranial Nerve Lanning B. Kline, MD, Joseph L. Demer, MD, Michael S. Vaphiades, DO, Mehdi Tavakoli, MD Abstract: This review of disorders of the fourth cranial nerve includes discussion on anatomy, examination techniques, congenital and acquired etiologies, differential diagnosis, and management options. The findings of the superior oblique muscle on orbital MRI in patients with fourth nerve palsy have had a major impact on our understanding of this cranial neuropathy. In addition, briefly reviewed are rare disorders of the fourth nerve: superior oblique myokymia, Brown syndrome, and ocular neuromyotonia. It behooves the clinician to have a clear understanding of the role that the fourth cranial nerve plays in a variety of neuro-ophthalmic conditions. Journal of Neuro-Ophthalmology 2021;41:176–193 doi: 10.1097/WNO.0000000000001261 © 2021 by North American Neuro-Ophthalmology Society C linicians are well aware that altered function of the ocular motor cranial nerves is the most frequent cause of diplopia. Although a myriad of causes may impair the function of these cranial nerves, some may be a manifestation of a life-threatening condition. For example, a third nerve palsy may signify the presence of the initial manifestation of an intracranial aneurysm, whereas a sixth nerve palsy may indicate the presence of increased intracranial pressure. By contrast, rarely is a fourth nerve palsy associated with a potential life-threatening disorder. In addition, detecting a fourth nerve palsy requires testing beyond assessment of the range of extraocular movements, the size and reactivity of the pupils, and position of the eyelids. The purpose of this review is to delineate the anatomy and physiology of the fourth nerve and superior oblique muscle, describe the examination and neuroimaging findings required to establish the correct diagnosis, discuss potential causes of Department of Ophthalmology, University of Alabama School of Medicine (LBK, MSV, MT), Birmingham, Alabama; The Shiley Eye Institute, University of California San Diego (LBK), San Diego, California; and The Jules Stein Eye Institute, University of California, Los Angeles (JLD), Los Angeles, California. The authors report no conflicts of interest. Address correspondence to Lanning B. Kline, MD, Department of Ophthalmology, University of Alabama School of Medicine, 700 South 18 Street, Birmingham, Alabama 35233; E-mail: lkline@uabmc. edu 176 fourth nerve palsy, and options for patient management. Finally, 3 clinical disorders related to superior oblique dysfunction will be discussed: Brown syndrome, superior oblique myokymia, and ocular neuromyotonia. ANATOMY The fourth (trochlear) nerve had 4 unique characteristics: it is the longest cranial nerve, the thinnest cranial nerve, the only cranial nerve to exit dorsally from the brainstem, and its fascicle decussates in the brainstem such that it innervates the contralateral superior oblique muscle (Fig. 1). On average, the fourth nerve is 60 mm in length with a diameter of 0.75– 1.0 mm, containing approximately 2,100 axons (1,2). The nerve can be divided into 5 anatomic segments: brainstem, subarachnoid space, tentorial, cavernous, and orbital. Within the midbrain, each fourth nerve nucleus lies in the ventral gray mater near the midline at the level of the inferior colliculi (Fig. 1). The medial longitudinal fasciculi are located just ventral to each nucleus. Efferent fibers from each nucleus travel posterolaterally, converge to decussate above the roof of the Sylvian aqueduct in the anterior medullary velum and emerge from the dorsal midbrain at the lower edge of the inferior colliculi. Within the subarachnoid space, each fourth nerve usually exits the midbrain as a single structure, although there are reports of it arising from the brainstem as multiple rootlets (3). Each nerve travels around the lower midbrain and curves through the quadrigeminal and ambient cisterns and the under the free edge of the tentorium. Just before its tentorial segment, each fourth nerve passes between the posterior cerebral and superior cerebellar arteries. The fourth nerve pierces the edge of the tentorium approximately 9–10 mm before entering the cavernous sinus. Within the tentorium, the nerves lie within an arachnoid sleeve, referred to as the trochlear cistern (2). The cavernous segment extends from the point where the fourth nerve inserts into the lateral dural wall of the cavernous sinus to the superior orbital fissure. The lateral wall of the cavernous sinus is composed of 2 layers: outer meningeal dura Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective FIG. 1. Anatomy of the fourth nerve. Top: sagittal view shows the ocular motor cranial nerve nuclei and course of the cranial nerves. Bottom left: posterior view demonstrates the fourth nerves decussating in the midbrain at the level of the inferior colliculi. Bottom center: coronal section reveals the fourth nerve in the lateral wall of the cavernous sinus. Bottom right: view from above illustrates the fourth nerve entering the orbit to innervate the superior oblique muscle. and inner periosteal dura. The fourth nerve lies in the interdural space approximately 1 mm below the third nerve and 2.5 mm above the ophthalmic nerve (4) (Fig. 1). As it passes through the superior orbital fissure, the fourth nerve travels laterally to medially and crosses above the third nerve. The orbital segment passes above the annulus of Zinn, through the orbital fat to innervate the dorsal surface of the superior oblique muscle. Although the nerve may terminate in the superior oblique as a single branch, more commonly it divides into 2 or 3 branches (Fig. 1) (5). This innervational pattern leads to compartmental innervation of the superior oblique that will be discussed below. The blood supply of the fourth nerve nucleus and fascicle is derived from perforating branches of the basilar artery (6). The subarachnoid segment is supplied by branches of the posterior cerebral and superior cerebellar arteries. The meningohypophyseal artery arising from the internal carotid supplies the cavernous segment while within the orbit contributions arise from the posterior ethmoidal and ophthalmic arteries (4). Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 SUPERIOR OBLIQUE MUSCLE The superior oblique originates at the orbital apex superomedial to the annulus of Zinn, on the lesser wing of the sphenoid bone medial to the optic canal (1). In primary gaze, the muscle becomes tendinous approximately 1 cm posterior to the trochlea (7). The trochlea is composed of cartilage and functions as the physiologic origin of the superior oblique. After passing through the trochlea, the superior oblique courses posteriorly and laterally to insert on the sclera below and temporal to the superior rectus muscle. The superior oblique contains approximately 14,000–19,000 muscle fibers compared with the rectus muscles which are composed of 17,000–24,000 fibers. Including its tendon, it is the longest (2.5 cm.) and thinnest of the extraocular muscles (1). Similar to other extraocular muscles, the superior oblique is composed of 2 layers, an outer orbital layer and an inner global layer (1). The orbital fibers have a mean diameter of approximately 10.4 mm, whereas the global fibers mean diameter is approximately 14.2 mm. Each layer contains 177 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective fibers that allow for either sustained contraction (gaze holding) or brief, rapid contraction (saccadic eye movements) (7). Approximately 40% of muscle fibers reside in the orbital layer and 60% in the global layer. The blood supply of the superior oblique is derived from branches of the anterior ciliary arteries that originate from the ophthalmic artery (2). The superior oblique muscle has 3 modes of action: incyclotorsion, depression, and abduction. Depending on the position of the eye, the role of these actions will vary (Fig. 2). In primary gaze, the superior oblique functions are primarily incyclotorsion and depression. With the eye in adduction, the muscle acts as a depressor, whereas in abduction, its function is incyclotorsion. Although the superior oblique also has abduction activity in primary gaze, its abduction function is most apparent with superior oblique overaction, often seen in patients with an A-pattern strabismus. At the insertion of the superior oblique on the globe, the anterior fibers impart a primarily incyclotorsional force, whereas the posterior fibers impart depressing and abducting forces (8). High-resolution MRI has provided anatomic details of the superior oblique muscle in vivo. These studies have been pioneered by Demer and Miller (9) in evaluating the muscle in both physiologic and pathologic settings. The normal superior oblique has its largest cross-sectional area in midorbit tapering both posteriorly to its origin and anteriorly as it transitions to a tendon. As shown in Figure 3, the superior oblique can be visualized in primary gaze and its anatomic alterations demonstrated in upgaze and downgaze. CLINICAL EXAMINATION Because the fourth nerve innervates a single muscle, the superior oblique, the terms fourth nerve palsy and superior oblique palsy will be used interchangeably. HEAD POSITION/FACIAL ASYMMETRY Patients often adopt a head tilt to the side opposite the fourth nerve palsy (ocular torticollis) with a chin-down position. This moves the eye out of the field of action of the palsied superior oblique and diminishes diplopia. Rarely, patients may tilt their heads to the same side as the fourth nerve palsy. It has been speculated that this increases the distance between the diplopic images, which allows the patient to more easily ignore the 2 images. In addition, individuals with congenital fourth nerve palsies may develop midfacial hemihypoplasia, also on the side opposite the palsy. There also may be deviation of the nose and mouth toward the hypoplastic side (10). However, in a study of 79 subjects, Velez et al (11) quantitated 3 morphometric facial features and found that facial asymmetry was not useful in distinguishing congenital from acquired superior oblique palsy. RANGE OF EYE MOVEMENTS In contrast to third and sixth nerve palsies where some limitation in ductions is usually evident, patients with fourth nerve palsy generally have grossly full ocular motility. On occasion, the clinician may detect some impairment of depression with the eye in adduction, but often this is subtle and easily overlooked. The technique to assist in the diagnosis of a fourth nerve palsy is the Parks– Bielschowsky 3-step test. PARKS–BIELSCHOWSKY 3-STEP TEST Over a century ago, Nagel and later Hofmann and Bielschowsky recognized the importance of the cycloduction function of the oblique muscles (12). This led Hofmann and Bielschowsky to investigate why many patients with superior oblique palsy habitually tilt their head to one shoulder. They found that with head tilt toward the side of the palsied muscle, there was an increase in the vertical deviation, while tilting to the contralateral side caused either a decrease or resolution of the deviation. This became known as the Bielschowsky Head Tilt Test. FIG. 2. Action of the superior oblique muscle is shown in primary gaze (A), adduction (B), and abduction (C). 178 Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective FIG. 3. Quasicoronal MRI illustrates the appearance of the superior oblique (SO) in primary gaze and its increase in cross- section size from elevation to depression. IR, inferior rectus; MR, medial rectus; SR, superior rectus. Modified from (9). Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 Parks expanded on these observations and proposed a stepwise diagnostic schema in patients with vertical strabismus (13). As he pointed out, head tilt because of cyclovertical strabismus does not necessarily indicate binocular vision nor that the palsied muscle is an oblique. For example, head tilting may accompany a vertical rectus muscle palsy. In Parks’ schema, the first step reduces the possibility from 8 to 4 cyclovertical muscles, the second step from 4 to 2, and the third step will determine which of the remaining 2 muscles is weak. Figures 4 and 5 illustrate the results of the Parks– Bielschowsky 3-step test for a right and left hypertropia, respectively. The first step determines that the paretic muscle is either one of 2 depressors in 1 eye or 1 of 2 elevators in the other. With the second step, one determines if the vertical deviation increases in right or left gaze. At this point, the 2 suspected muscles are in different eyes, both are always superior or inferior muscles and both are either incyclotorters or excyclotorters. In the third step, the paretic muscle is unable to perform its torsional and vertical actions. Yet, the muscle of the same eye that is able to perform the appropriate torsional movement will also move the eye vertically, thus increasing the vertical misalignment. For example, in a patient with a right fourth nerve palsy and the head tilted to the right, excyclotorsion will occur in the left eye because of contraction of both the left inferior oblique and left inferior rectus muscles. However, the paretic right superior oblique cannot balance the torsional and elevating activity of the right superior rectus, and the right eye will move upward leading to an increase in the vertical deviation (right hypertropia). With head tilt to the left, the paretic right superior oblique is not involved, and there will be either no increase in the vertical misalignment or it will diminish or no longer be detectable. It has been proposed to add a fourth step, namely, measuring the vertical deviation in upgaze and downgaze (14). For example, with a right fourth nerve palsy, given that the superior oblique depresses the eye, the right hypertropia will increase in downgaze and lessen in upgaze. There are 3 important caveats regarding the Parks– Bielschowsky 3-step test: spread on commitance, the test’s sensitivity, and the test’s specificity. With a longstanding fourth nerve palsy, the amount of vertical deviation may become similar in all fields of gaze (12). This usually occurs when the fourth nerve palsy affects the dominant eye. For example, in a patient with a right fourth nerve palsy, the right inferior oblique (antagonist of the right superior oblique) requires less innervation to move the eye into its field of action. Following the Hering law, the left superior rectus (yoke muscle of the antagonist of the paretic muscle) also receives less innervation and will seem paretic. This will, in turn, diminish the amount of vertical misalignment. This has been referred to as inhibitional palsy of the contralateral antagonist. An alternate explanation for the spread of 179 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective FIG. 4. Results of the Parks–Bielschowsky 3-step test are shown for a patient with a right hypertropia. In primary gaze, the vertical deviation may be due to paresis of 1 of 4 muscles. Increase in the deviation in right vs. left gaze reduces the possibility to 2 muscles and with measurement in right vs. left head tilt, the paretic muscle can be detected. Potential paretic muscle: LIO, left inferior oblique; LSR, left superior rectus; RIR, right inferior rectus; RSO, right superior oblique. Reprinted with permission from (22). comitance may be found in the study by Suh et al (15). Using high-resolution orbital MRI, these investigators demonstrated that displacements in the pulley systems of the rectus muscles can alter motility patterns in superior oblique palsy. The Parks–Bielschowsky 3-step test lacks both sensitivity and specificity. In a series of 7 patients, Kushner (16) suggested that a number of other entities might simulate a fourth nerve palsy with the Parks–Bielschowsky 3-step test including paresis of more than one vertical muscle, dissociated vertical deviation, myasthenia gravis, and previous vertical muscle surgery. Using superior oblique atrophy on MRI as evidence of a fourth nerve palsy, Manchandia and Demer (17) performed the Parks– Bielschowsky 3-step test on 50 patients. They found that the test was diagnostic in only 70% of cases. By reducing the test to 2 steps, the sensitivity increased to 76%–84% but diminished the specificity. Lee et al (18) measured the sensitivity of the 3step test, depending on the presence or absence of the fourth nerve using high-resolution thin-section MRI. Testing sensitivity was 78% in patients with a fourth nerve and 72% in those without a fourth nerve. There was no statistically significant intergroup difference. Taken together, these reports demon180 strate that the Parks–Bielschowsky 3-step test is insensitive in 22%–30% of patients with fourth nerve palsy: CYCLOTORSION Because the primary action of the superior oblique muscle is incyclotorsion, detection of a torsional component of diplopia is helpful in establishing the diagnosis of fourth nerve palsy. In obtaining the history, the clinician should not only elicit the vertical orientation of the diplopic images, but also inquire if one of the images seems “tilted” or “slanted.” For confirmation and quantitation of cyclotorsion, a valuable technique is the double Maddox rod test. Each Maddox rod is composed of red, green, or white planoconvex cylinders that refract light rays such that a point light source is seen as a line or streak of light. Because of the optical properties of the parallel cylinders, the streak of light is seen perpendicular to the axis of the cylinders. Typically, red and/or white Maddox rods are placed in a trial frame (Fig. 6). The double Maddox rod test measures the relative difference in torsion between the 2 eyes and may sometimes localize to the paretic eye (see below). In addition, the test is Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective FIG. 5. Results of the Parks–Bielschowsky 3-step test are shown for a patient with a left hypertropia. In primary gaze, the vertical deviation may be due to paresis of 1 of 4 muscles. Increase in the deviation in right vs. left gaze reduces the possibility to 2 muscles and with measurement in right vs. left head tilt, the paretic muscle can be detected. Potential paretic muscle: LSO, left superior oblique; LIR, left inferior rectus; RSR, right superior rectus; RIO, right inferior oblique. Reprinted with permission from (22). both subjective and prone to administrator and patient error and, in the literature, referred to as a “subjective method” of measuring cyclotorsion. At times, this test may give the clinician what seems to be paradoxical results and may not localize to the paretic eye. Olivier and von Noorden (19) found excyclotorsion of the nonparetic eye in 15 of 60 patients with unilateral superior oblique palsy. They noted that these patients fixated with their paretic eye when the 2 eyes were dissociated. However, torsional strabismus can be difficult to interpret. Normal ocular torsion varies with a different pattern in each of the 2 eyes according to horizontal and vertical eye position, vergence, and vestibular input. Hering law does not apply to torsion. Although the torsional positions of the 2 eyes are never identical, the torsional differences are almost never perceived as diplopia but are either interpreted as depth cures or ignored altogether. Individuals perceive constancy of visual space despite continuous variation of the torsional positions of the 2 eyes. Therefore, it should not be surprising that excyclotorsion associated with superior oblique palsy might be asymptomatic, or subjectively lateralized contralateral to the hypertropic eye even when a superior oblique muscle is Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 paretic. Thus, the clinician must interpret the results of the double Maddox rod test with these facts in mind. An alternate, and more reliable, method to detect in cyclotorsional paresis caused by fourth nerve palsy is with indirect ophthalmoscopy or fundus imaging. Normally, the fovea lies 6.3° ± 3° below a horizontal line from the center of the optic disc. The fovea will be located further below this level in a patient with a fourth nerve palsy (Fig. 7). Fundus photography has been designated as an “objective method” of measuring cyclotorsion. A number of studies have compared the “subjective” double Maddox rod test to the “objective” measurements obtained with fundus photography (8,20). Limitations of the double Maddox rod test include detection of torsion in one eye when there was bilateral involvement, underestimation of the total amount of cyclotorsion, and no statistically significant relationship between variation in double Maddox rod torsion vs. variation in torsion by fundus photography. BILATERAL FOURTH NERVE PALSIES A number of findings on physical examination support the diagnosis of bilateral fourth nerve palsies. Either eye may be 181 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective FIG. 6. Double Maddox rod test. In a patient with a right fourth nerve palsy, the red line will appear below the white line and in an incyclotorted position. This indicates excyclotorsion of the right eye, and by rotating the red Maddox rod until the 2 lines are parallel, the amount of excyclotorsion can be quantified. hypertropic in primary gaze or the patient may be orthophoric. There is a right hypertropia on gaze left and a left hypertropia on gaze right. A right hypertropia is present on right head tilt and a left hypertropia on left head tilt. Ocular cyclotorsion typically exceeds 10°. There is a V-pattern esotropia because of loss of abduction in downgaze. However, Muthusamy et al (21) have documented the difficulty, at times, in establishing the diagnosis of bilateral fourth nerve palsies because of lack of sensitivity of the Parks–Bielschowsky 3-step test and reversal of the hypertropia on lateral gaze. Head trauma is the most common cause of bilateral fourth nerve palsies (22). This is due to either avulsion of 182 the nerves at their exit from the midbrain or compression of the anterior medullary velum by the free edge of the tentorium. Other causes include hydrocephalus, stroke, and tumor (23). ADDITIONAL NEUROLOGIC FINDINGS Although the fourth nerve has a short course within the brainstem, on occasion, it may be accompanied by other neurologic signs. A fourth nerve palsy with a contralateral Horner syndrome would localize to the dorsal ponto–midbrain junction, whereas contralateral dysmetria would indicate Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective FIG. 7. Cyclotorsion on fundus photography. There is excyclotorsion of both eyes in a patient with bilateral fourth nerve palsies. The dashed line represents the normal position of the fovea relative to the center of the optic disc. The solid line reveals marked excyclotorsion of each eye (Modified from Martin TJ, Corbett JJ (eds). Practical Neuro-Ophthalmology. New York, NY: McGraw Hill, 2013). involvement of the superior cerebellar peduncle. The presence of an internuclear ophthalmoplegia would signify a lesion affecting the medial longitudinal fasciculus. Rarely, a fourth nerve palsy may be detected with an ipsilateral relative afferent pupillary defect. This is due to disruption of pupillomotor fibers from the third nerve within the brachium of the superior colliculus and not because of an optic neuropathy (24). Neurologic abnormalities may be detected with a fourth nerve palsy with disorders of the cavernous sinus including deficits of the ipsilateral third, sixth, and ophthalmic nerves. A Horner syndrome because of a lesion of the cavernous sinus would be ipsilateral to the fourth nerve palsy. Similar findings occur with orbital apex syndrome with the addition of signs of an optic neuropathy. Assessing the function of the fourth nerve can be challenging in the setting of an ipsilateral third nerve palsy. In this situation, if the eye cannot be adducted, then the ability of the superior oblique to depress the eye cannot be determined. The eye should be moved into abduction, and the patient asked to look down. In abduction, the superior oblique is primarily an incyclotorter (Fig. 2) and, by observing a landmark on the globe such as a conjunctival vessel, the clinician can look for inclyclotorsion, demonstrating that the fourth nerve is functional. CAUSES OF FOURTH NERVE PALSY Congenital Diagnosis of congenital superior oblique palsy in the infant or toddler can be challenging. The expected head tilt will not be present until neck strength and control have matured sufficiently, generally at 5–6 months after term birth. After the child is able to support the head, musculoskeletal torticollis is common and may confound the correct diagnosis. Patch testing with unilateral occluKline et al: J Neuro-Ophthalmol 2021; 41: 176-193 sion of each eye separately can be helpful, as torticollis because of strabismus will improve or resolve with monocular occlusion, whereas musculoskeletal torticollis will not. The patch need only be applied for 1–2 minutes to observe the result. In the first several years of life, children with incomitant strabismus of every kind vigorously adopt head and gaze positions that permit binocular fusion, and strongly resist the examiner’s efforts to gaze in directions where the strabismus is obvious. This behavior is reassuring for the presence of sensory binocular fusion and absence of dense amblyopia, but it makes it very difficult to examine and interpret ocular motility in willful toddlers. It usually is easier for the examiner to detect momentary overelevation in adduction than reduced depression in adduction in toddlers, and even this clinical finding may require more than one office visit. The toddler with unilateral superior oblique palsy will almost never tolerate ipsilateral head tilt, although sometimes the examiner can tilt the entire body en bloc toward each shoulder. It is rarely possible to make quantitative measurements of alignment in diagnostic gazes in infants or toddlers. Advances in MRI have led to a paradigm shift regarding the etiology of congenital fourth nerve palsy. Most patients have a congenital cranial dysinnervation disorder, defined as a development abnormality of either hypoplastic or aplastic cranial nerves with muscle dysinnervation. The initial evidence to support this concept was the finding of superior oblique hypoplasia in patients with a congenital fourth nerve palsy (9,25) (Fig. 8). The other piece of evidence became possible with further refinements in highresolution, thin-section MRI to consistently visualize the fourth nerve. Kim and Hwang (26) detected absence of the fourth nerve with associated superior oblique hypoplasia in 10 of 12 individuals with fourth nerve palsy (mean age: 14 years; range: 4–47 years) and no such findings in 12 183 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective controls (Fig. 9). This has been confirmed in subsequent reports (27,28). In a systematic review of MRI findings in 22 patients with head tilt–dependent hypertropia, Demer et al (29) found that about half exhibited superior oblique atrophy characteristic of fourth nerve denervation. In another study of 97 patients diagnosed with congenital fourth nerve palsy, the ipsilateral fourth nerve was absent in 73% with the superior oblique muscle being hypoplastic (26). These patients also had a higher prevalence of a head tilt and developed it at an early age. The other 27% had normal fourth nerves, symmetric size of the superior oblique muscles, prominent overelevation in adduction of the affected eye, and more frequently had dissociated vertical deviation. Of interest is the finding by Lee et al (27) that when imaging demonstrated superior oblique atrophy concordant with absence of the ipsilateral fourth nerve, the contralateral fourth nerve diameter was mildly, but significantly, subnormal. It seems that denervation of the superior oblique muscle may be progressive over many years. This is illustrated in Figure 10, where a presumed congenital fourth nerve palsy was associated with progressive atrophy of the superior oblique over 18 years of follow-up. It is also possible that denervation may progress because of slow growth of a benign neoplasm such as a fourth nerve schwannoma or a congenital sclerosing hemangioma of the cavernous sinus (30). To minimize risk in the pediatric population, it is reasonable to reserve MRI with sedation to situations where prompt diagnosis is important. One example would be consideration of early strabismus surgery for significant ocular torticollis, or if there are findings of craniosynostosis that may be associated with other orbital abnormalities. If, in the older child, there are no associated neurological findings, and the incomitant strabismus pattern is straightforward, strabismus surgery is often performed without imaging confirmation of atrophy of the superior oblique muscle. However, neuroimaging also is warranted when a suspected superior oblique palsy is associated with other neurological, motility, or craniofacial abnormalities, or when strabismus surgery is required despite equivocal FIG. 8. Coronal T2 orbital MRI demonstrates hypoplasia the left superior oblique muscle in a patient with a left fourth nerve palsy. SO, superior oblique. 184 examination findings. Such imaging may avert futile surgical maneuvers, such as attempted operation on an aplastic superior oblique muscle, or manipulation of a superior oblique tendon that is in continuity with a severely hypoplastic superior oblique muscle. Acquired Although there are a variety of causes of an acquired fourth nerve palsy, initially the clinician must exclude the possibility of a decompensated congenital fourth nerve palsy. In a number of retrospective reports, a congenital etiology was presumed in approximately 50% of patients (31,32). With increasing age, as fusional amplitudes diminish or after head trauma or a major systemic illness, an individual may no longer be able to maintain single binocular vision with a congenital or longstanding fourth nerve palsy. It is critical to obtain a careful history and review head and eye positions from old photographs of the patient. Demonstrating spread on comitance during the Parks– Bielschowsky 3-step test would suggest a deviation of long duration or a masquerade syndrome mimicking a superior oblique palsy (15). Large vertical fusional amplitudes (.3 prism diopters) also support the diagnosis of a longstanding fourth nerve palsy. Taken together, these clinical findings support the likely diagnosis of a congenital or longstanding fourth nerve palsy that has become symptomatic, and unnecessary hematologic and neuroimaging studies can be avoided. It has been proposed that hypertropia greater in up— than downgaze, or equal to it—is characteristic of a decompensated congenital fourth nerve palsy and never present in ischemic, traumatic of tumorous causes (33). Although this was the case in a neuro-ophthalmic clinic enriched with patients having a relatively small hypertropia, we have not found this clinical finding reliable for identifying cases of congenital fourth nerve palsy in a strabismus surgical practice where typically the hypertropia in 2–3-fold larger (Demer JL, ARVO abstract, 2021). If the clinical findings do not support a congenital or longstanding fourth nerve palsy, then the patient must be evaluated for an acquired cause (Table 1). One approach is based on the potential anatomic location of the pathology: brainstem, subarachnoid space, cavernous sinus, and orbit. Within the brainstem, the fascicular portion of the fourth nerve is short, so it is virtually impossible to distinguish a nuclear vs. fascicular lesion. As discussed above under “Associated Neurologic Findings,” brainstem localization is likely if there are additional neurologic signs such as a contralateral Horner syndrome or an ipsilateral internuclear ophthalmoplegia. Brainstem causes include stroke, demyelination tumor, and arteriovenous malformation. Within the subarachnoid space, a fourth nerve palsy is often isolated. After the nerves decussate in the anterior Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective FIG. 9. MRI of a patient with a congenital right superior oblique palsy with ipsilateral hypoplastic superior oblique muscle and absent trochlear nerve. A, B. Coronal T2 orbital images show the right superior oblique muscle (thin arrows) is smaller than the right (thick arrows). C–H. Contiguous high-resolution MRI from rostral to caudal reveals that the left fourth nerve (arrows) is clearly identified in the perimesencephalic cistern. The right fourth nerve is not detected, and only vessels are found. IC, inferior colliculus. Reprinted with permission from (26). medullary velum, they are vulnerable to injury from contrecoup forces transmitted by the free edge of the tentorium. This is a likely mechanism in many cases of head trauma. Microvascular ischemia because of decreased perfusion from the vasa nervorum may lead to impaired function of the fourth nerve, as seen in individuals with vasculopathic risk factors such as diabetes mellitus, hypertension, hyperlipidemia, and smoking. However, an ischemic mononeuropathy should completely resolve within 3–6 months. If this does not occur, the patient must be evaluated for an alternate cause. Any inflammatory, infectious, or neoplastic process involving the subarachnoid space (cerebrospinal fluid) is a potential cause of a fourth nerve palsy. On occasion, compression of the fourth nerve may be due Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 to a mass lesion including meningioma, pinealoma, or schwannoma (Fig. 11). Schwannomas of the fourth nerve are rare (43). They have been well documented in patients with neurofibromatosis but can occur in healthy individuals as well. They most often involve the cisternal portion of the fourth nerve but may, at times, affect the cavernous segment. Schwannomas that exceed 0.5 cm in size may compress the brainstem causing hemiparesis, ataxia, and sensory abnormalities. Although these findings often warrant neurosurgical intervention, with smaller tumors resulting in an isolated fourth nerve palsy management options include prisms, eye muscle surgery, and radiosurgery or a combination of these modalities. 185 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective FIG. 10. Quasicoronal T1 orbital MRI over an 18-year interval of a woman with a presumed right congenital superior oblique palsy. During both scans, the patient fixated in depression to maximize superior oblique cross section by active contraction. Note interval progression of right superior oblique atrophy. The fellow left superior oblique remained normal, whereas neuroimaging of the fourth nerve through the midbrain, cavernous sinus, and orbit demonstrated no abnormality. SO, superior oblique. Disorders of the cavernous sinus typically give rise to multiple cranial neuropathies including the third, fourth, sixth, and ophthalmic nerves. The oculosympathetic pathway (ipsilateral Horner syndrome) also may be affected. These signs may occur in various combinations. Causes include tumor, aneurysm, vascular fistula, infection, inflammation, and thrombosis. Neuroimaging (including vascular studies) provide critical information in narrowing the differential diagnosis of cavernous sinus disease. Orbital syndromes affecting the fourth nerve generally also affect multiple ocular motor cranial nerves. Orbital signs are evident including proptosis, chemosis, conjunctival injection, and eyelid edema. The most common etiologies are tumor, infection, inflammation, and trauma. Imaging plays a critical role in evaluating patients with an acquired fourth nerve palsy. Brain MRI is required to exclude a lesion anywhere along the course of the fourth nerve. In addition, orbital imaging may provide additional information. This initially was demonstrated by Horton et al (44) in a 62-year-old man with an acquired fourth nerve palsy whose MRI showed atrophy of the right superior oblique muscle. There also is evidence that selective fourth nerve palsies may arise from pathologies of the 2 divisions of the nerve innervating the superior oblique. This has been termed “compartmental” superior oblique palsy. When MRI shows that the atrophic superior oblique cross section is nearly circular, the morphology is termed “isotropic,” and the neuropathy is presumed to involve both the medial and lateral divisions of the fourth nerve; when the cross section is elliptical, the morphology is termed “anisotropic,” and the neuropathy is presumed to involve only one division (Fig. 12) (45). Current MRI resolution does not permit identification which of the 2 divisions is more involved in anisotropic superior oblique palsy. However, some evidence suggests that the lateral compartment is more commonly 186 involved in anisotropic superior oblique palsy (46) perhaps because deficiency in vertical action associated with weakness in this compartment is more likely to manifest clinically as hypertropia that would be weakness limited to the medial compartment whose major action is torsion. Selective compartmental superior oblique pathology may explain some of the variability in ocular motility findings in patients with acquired fourth nerve palsy. However, at this time, it is unclear how to make specific clinical use of the distinction between isotropic and anisotropic superior oblique palsy. DIFFERENTIAL DIAGNOSIS Of the entities that can simulate a fourth nerve palsy, skew deviation may prove to be most challenging for the clinician. Skew deviation is a vertical and torsional misalignment of the eyes because of brainstem lesions that interrupt the utricular– ocular motor pathway (Fig. 13). Occasionally, skew deviation also may arise from peripheral vestibular or cerebellar lesions. It may be comitant or incomitant and virtually always occurs with other brainstem or cerebellar signs. Skew deviation may be part of the ocular tilt reaction which includes head tilt and ocular cyclotorsion. With damage to one utricle, the tonic signal from the other side is unopposed and leads to alteration in the appearance of the subjective vertical. This results in a head tilt and rotation of the upper poles of both eyes toward the affected side and a skew deviation (Fig. 14). Donahue et al (47) have addressed the issue of distinguishing between ocular tilt reaction and fourth nerve palsy. Given that both entities have vertical strabismus, head tilt, and ocular cyclotorsion, care must be taken when interpreting the results of the Parks–Bielschowsky 3-step test, specifically step 3. With ocular tilt reaction, there is bilateral cyclotorsion toward the lower eye (incyclotorsion of the Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 3 38 0 49 2 8 0 31 0 37 4 28 4 26 1 14 20 35 5 37 0 0 37 21 4 32 2 18 4 36 0 44 0 33 8 15 21 39 3 18 9 6 higher eye), whereas in fourth nerve palsy, cyclotorsion is unilateral, with excyclotorsion of the higher eye. The upright-supine test also has been proposed as a means to differentiate skew deviation from fourth nerve palsy. Wong et al (48) found that the hypertropia improved at least 50% in the supine position only in patients with skew deviation. However, in the 25 patients studied, the mean duration of symptoms was 48 months, with a minimum of 15 months. Lemos et al (49) were unable to reproduce these results. Their 37 patients were examined within 60 days of onset of symptoms, with 91% tested within 30 days. These investigators speculated that, over time, adaptive mechanisms take place leading to the findings of Wong and colleagues. However, they argue that their findings are of greater clinical value in the acute setting when distinguishing skew deviation from fourth nerve palsy is of critical importance. Ocular myasthenia gravis may also mimic any cranial nerve palsy and should always be considered in a patient with fourth nerve palsy. Myasthenia gravis is an autoimmune (antibody-driven) disease targeting acetylcholine receptors located at the postsynaptic junction. Autoantibodies block or destroy acetylcholine receptors, effectively decreasing the number of sites for acetylcholine binding. Myasthenia gravis may be divided into purely ocular or generalized forms. Among patients presenting with ocular symptoms, 20%–50% remain purely ocular myasthenia, whereas the remainder progress to generalized disease (50). Ocular involvement eventually occurs in 90% of myasthenics and accounts for the initial complaint in 75%. Ocular manifestations can masquerade as cranial nerve and gaze palsies with or without nystagmus. A history of variable and fatigable ocular muscle weakness in the presence of normal pupillary function 8 27 0 15 15 33 4 36 0 36 10 13 2.5 67.5 0 2.5 7.5 20 37 46 248 19 172 36 33 40 84 Rucker (34) 67 Total patients Etiologies (%) Neoplasm Trauma Aneurysm Ischemia Miscellaneous Undetermined Khawan et al (36) Rucker et al (35) TABLE 1. Etiologies of acquired fourth nerve palsy Burger et al (37) Younge and Sutula (38) Rush and Younge (39) Kodsi and Younge (children) (40) Richards et al (41) Park et al (42) Dosunmu et al (32) Perspective Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 FIG. 11. Fourth nerve schwannoma. Postcontrast axial T1 MRI reveals an enhancing mass along the subarachnoid portion of the left fourth nerve. 187 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective FIG. 12. Quasicoronal T1 orbital MRI obtained in a healthy control and in 2 patients with fourth nerve palsies. Compartmental bisectors of muscles are indicated with white dashed lines (top row). Note the rounder left superior oblique muscle in isotropic atrophy (middle row) comparted with the elongated superior oblique in anisotropic atrophy (bottom row). IR, inferior rectus; LPS, levator palpebrae superioris; LR, lateral rectus; MR, medial rectus; SO, superior oblique; SR, superior rectus. should raise the suspicion for ocular myasthenia gravis. Ocular myasthenia may give rise to a Parks–Bielschowsky consistent with a fourth nerve palsy (51). In addition, on examination, other signs of ocular myasthenia should be looked for including ptosis, lid fatigue, Cogan lid twitch sign, and orbicularis oculi weakness. Thyroid eye disease is another immune-mediated disorder in which orbital fibroblasts seem to play a critical role. They express 2 autoantigens, thyrotropin-receptor and insulin-like growth factor-1. These autoantigens lead to activation of orbital fibroblasts precipitating an inflammatory process resulting in increased volume of the extraocular muscles and orbital fat (52). Diplopia in thyroid eye disease is due to a restrictive myopathy. Typically, the inferior rectus muscle initially is affected, giving rise to impaired upward gaze and vertical diplopia. In well-established cases, there are a host of clinical signs supporting the diagnosis of thyroid eye disease including proptosis, chemosis, periorbital edema, lid retrac188 FIG. 13. Skew deviation. The utricular–ocular motor pathway is depicted by the dashed lines. Axons from the utricle run to the vestibular nucleus. The vestibular nucleus (VN) is connected to the contralateral cyclovertical muscle subnuclei through the medial longitudinal fasciculus (MLF). Subnuclei for the superior rectus (SR) and the fourth nerve nucleus (4N) innervate the contralateral SR and superior oblique (SO) muscles. 3N, third nerve nucleus; 6N, sixth nerve nucleus; IO, inferior oblique; IR, inferior rectus; INC, interstitial nucleus of Cajal; riMLF, rostral interstitial nuclei of medial longitudinal fasciculus. tion, and lid lag. However, Moster et al (53) have reported that, early in the disease, many of these clinical findings may be very subtle or absent, and the Parks–Bielschowsky 3-step test may simulate a fourth nerve palsy. Ocular cyclotorsion may be present as well. In addition to a careful physical examination and hematological studies for thyroid function, 3 other findings would suggest thyroid eye disease as the correct diagnosis. These are increase in vertical misalignment in upward gaze, elevation of intraocular pressure in upward gaze, and positive-forced duction testing. Orbital imaging to detect enlargement of the extraocular muscles will confirm the presence of thyroid eye disease (Fig. 15). Skew deviation, ocular myasthenia gravis, and thyroid eye disease are the principal disorders in the differential diagnosis of fourth nerve palsy. As noted previously, other conditions to consider with a Parks–Bielschowsky test consistent with a fourth nerve palsy are paresis of more than one vertical muscle, previous vertical muscle surgery, dissociated vertical deviation, and, more recently, sagging eye syndrome. The sagging eye syndrome results from degeneration of the ligaments suspending the rectus muscle pulleys, usually because of aging (54,55). With degeneration of the lateral Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective tropic eye has greater excyclotorsion, in contrast to fourth nerve palsy where the hypertropic eye has greater excyclotorsion. Sagging eye syndrome should be suspected in the setting of adnexal features of ptosis, superior sulcus defects, lid laxity, and a history of prior blepharoplasty or facelift surgery. Management Indications for treatment of superior oblique palsy include significant misalignment of the eyes in primary position, ocular torticollis, and diplopia. Although the surgery is the mainstay of treatment, the use of prisms and botulinum toxin might be considered in certain cases. Prisms FIG. 14. With the ocular tilt reaction, apparent tilt of the environment (B) is compensated for (C) to achieve the appearance of normal upright orientation (A). Reprinted with permission from (22). rectus–superior rectus band ligament, there is inferior displacement of the lateral rectus muscle path, creating a depressing action of the lateral rectus at the expense of some abducting action. When lateral rectus sag is bilaterally symmetrical, the vertical actions of the 2 lateral rectus muscles are balanced and have no net effect on vertical muscle balance. However, when asymmetrical, the lateral rectus with greater sag causes hypotropia with greater excyclotropia than does the lateral rectus with lesser sag. It should be noted that in sagging eye syndrome, the hypo- Prism may be helpful in some patients with a fourth nerve palsy and small-angle vertical deviation. However, the effectiveness of prisms in superior oblique palsy is limited because of the incomitant nature of the deviation and associated torsional component (56). Botulinum Toxin-A Injection of botulinum toxin-A into the antagonist inferior oblique muscle has been used in a variety of clinical settings of acquired fourth nerve palsy including acute or chronic, unilateral or bilateral, and with different underlying etiologies including microvascular and traumatic. Studies have shown the efficacy of botulinum toxin-A in alleviating diplopia and improve the vertical and torsional deviation (57,58). Bagheri and Eshaghi (59) introduced a FIG. 15. Thyroid eye disease. A. Sixty-four–year-old man developed vertical diplopia with a left hypertropia and was referred with a presumptive diagnosis of a left fourth nerve palsy. The pupils are pharmacologically dilated. B. Coronal T1 MRI with fat suppression reveals enlargement of the right inferior and medial rectus muscles. On examination, the patient had limited elevation of the right eye. Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 189 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective transconjunctival approach to injecting 2.5–5 units of botulinum toxin-A into the belly of the inferior oblique muscle in the inferotemporal quadrant of the eye and 20 mm from the limbus. Limitations of this treatment modality include relatively difficult technique, possible diffusion of the toxin to the other extraocular muscles, and less efficacy in larger angles of deviation in longstanding cases (58,60). Surgery Decisions regarding surgery are made on a case-by-case basis, and, in many instances, there is no consensus on the best surgical approach. Although the details of specific surgical procedures are beyond the scope of this review, some general guidelines are presented. 1. Overaction of the inferior oblique muscle: overelevation in adduction is noted in many patients with superior oblique palsy. In such cases, a weakening procedure is required and can correct up to 15 prism diopters of vertical deviation in primary position (61,62). Different inferior oblique weakening procedures such as myectomy, recession, and anteriorization have been used with comparable results. Studies have shown that the inferior oblique muscle has a “self-grading” feature, as a single weakening procedure can address a wide range of vertical ocular misalignment (62). 2. Large vertical deviation: in vertical deviations larger than 20 prism diopters in the primary position, a single inferior oblique weakening procedure usually is inadequate. In the absence of vertical comitance and superior oblique tendon laxity (see below), recession of the contralateral inferior rectus frequently is the procedure of choice (63). Overcorrection is uncommon, but in many patients, a stepwise surgical approach is warranted (64). 3. Vertical comitance: it has been suggested that hypertropia in the abducted and inferior fields in an eye with superior oblique palsy may indicate tightness of the ipsilateral superior rectus muscle. This is present in many longstanding cases and, occasionally, mistakenly interpreted as overaction of the contralateral superior oblique. In these patients, superior rectus recession is an appropriate additional procedure combined with ipsilateral inferior oblique weakening or superior oblique tuck to address the significant vertical deviation in the primary position (65). 4. Laxity of superior oblique tendon: this is observed in patients with atrophy of the superior oblique muscle and can be detected with the exaggerated forced duction test. These patients often have a larger vertical hypertropia in the field of action of the superior oblique muscle. Superior oblique tuck in these patients has provided favorable results, and intraoperative adjustment is recommended to avoid iatrogenic Brown syndrome (see below) (66). 5. Cyclotorsion: when cyclotorsion is the main issue, previously mentioned procedures usually are not adequate. 190 The Harada–Ito procedure or its modifications are helpful in this scenario. These procedures include splitting and advancing the anterior part of the superior oblique tendon that has a major torsional effect (67). Another surgical option is nasal transposition of the inferior rectus muscles. 6. Bilateral superior oblique palsies: in these patients, ocular vertical misalignment is often minimal, and diplopia mainly arises from significant excyclotorsion. In the absence of a vertical deviation, bilateral symmetric Harada–Ito procedures can be performed. If a vertical deviation is present, then bilateral but asymmetric Harada–Ito procedures possibly with adjustable suture techniques can be performed (68). In many patients with bilateral superior oblique palsies, there is a V-pattern esotropia and chin-up posture. This can be managed with bilateral inferior rectus recessions with or without nasal transposition. However, all of these procedures have limited success. In patients with bilateral superior oblique palsies who previously had binocular fusion, there is no optimal surgical solution. SUPERIOR OBLIQUE MYOKYMIA Superior oblique myokymia is an infrequent disorder of the fourth nerve typically affecting healthy individuals (69). Although initially described by Duane (70) over a century ago, it was named and further characterized by Hoyt and Keane in 1970 (71). Superior oblique myokymia occurs monocularly with paroxysmal episodes of high-frequency, low-amplitude vertical and torsional movements of the eye. Patients generally complain of monocular oscillopsia with images moving vertically and often accompanied by vertical diplopia. The episodes last seconds to minutes, may occur multiple times a day and then remit for weeks, months, and possibly years. Although superior oblique myokymia may be precipitated by looking into the field of action of the superior oblique muscle, most often there is no identifiable precipitating factor. The diagnosis is primarily made by obtaining a detailed history. If it occurs during the clinical examination, the eye movement is subtle and is best detected using the slit lamp. Three theories have been proposed regarding the cause of superior oblique myokymia (69). The first stems from the observation that atrophy of the superior oblique muscle has been seen in some patients. This is presumed because of previous trauma to the fourth nerve, and, with regeneration of the nerve, there is either aberrant supranuclear control or alteration in function of cellular membranes of the nerve. This latter mechanism is termed ephaptic transmission whereby there is lateral contact between nerve fibers across which impulses are transmitted rather than transmission at the synapse. A second potential etiology is neurovascular compression of the fourth nerve by the superior cerebellar Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective artery or its branches at its root exit zone from the brainstem. However, vascular compression of the fourth nerve may be an incidental finding in asymptomatic individuals. Finally, a structural lesion has, on occasion, been associated with superior oblique myokymia including posterior fossa astrocytoma (72) and dural arteriovenous fistula (73). Given that in most overwhelming patients superior oblique myokymia is a benign condition, treatment with reassurance will often suffice. Obtaining brain MRI with high-resolution sequences (fast imaging employing steady-state acquisition [FIESTA] and three-dimensional constructive interference in steady state [CISS]) is decided on a case-by-case basis. A variety of treatment options are available. Topical betablocker eye drops seem to be efficacious with the advantages of being simple to use and noninvasive although the mechanism of action is unknown (69). Similarly, beta-blockers such as propranolol have been prescribed as a systemic medication. Use of membrane stabilizing agents often are used including carbamazepine and gabapentin. Eye muscle surgery is reserved for patients refractory to medical therapy. Various procedures have been used. There are reports of successful use of a large superior oblique tenectomy coupled with an inferior oblique weakening procedure. The Harada–Ito procedure has been modified with some success, with nasal transposition of anterior fibers of the superior oblique muscle. Neurosurgical intervention also has been reported with a Teflon graft placed between the fourth nerve and the arterial loop compressing the nerve (74–76). BROWN SUPERIOR OBLIQUE TENDON SHEATH SYNDROME Originally described in 1950 (77), this disorder consists of absence of elevation of the eye in adduction and, in that position of gaze, positive forced ductions. There is normal or near normal elevation of the globe in primary gaze and abduction and, frequently, depression of the eye in adduction with widening of the palpebral fissure. A large exotropia is present in upgaze. Brown syndrome is a congenital disorder in most patients but, if acquired, may be caused by inflammatory, traumatic, or surgical lesions of the superior oblique tendon or trochlea. Approximately 90% of cases are unilateral, and the right eye is more frequently affected. Brown syndrome may occur on either an innervational or structural basis (78). If because of an innervational cause, this disorder may be classified as a congenital cranial dysinnervation syndrome. Supporting evidence includes electromyographic studies showing paradoxical innervation of the superior oblique muscle, absence of the ipsilateral fourth nerve on high-resolution MRI without superior oblique atrophy, and lack of physiologic relaxation of the superior oblique on upgaze. Yet, many patients with Brown syndrome do not have these findings and likely have a structural abnormality of the superior oblique muscle, tendon, or trochlea. Patients with Brown syndrome develop an anomalous head position with head tilt and the chin up. This avoids Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 diplopia and allows for binocular vision. Therefore, amblyopia is rare. Management depends on the degree of ocular misalignment. In mild cases, observation may be all that is required. Surgical options include superior oblique tenotomy and superior oblique recession with placement of a silicone expander in the superior oblique muscle. In cases of Brown syndrome because of an inflammatory cause, locally injected or systemic corticosteroids have been used as have nonsteroidal anti-inflammatory agents. OCULAR NEUROMYOTONIA Ocular neuromyotonia is a rare disorder of ocular motility. It is characterized by spasm of one or more of the extraocular muscles, occurring either spontaneously or after maintaining eccentric gaze (79). It is believed to be the result of episodic discharge of one of the ocular motor cranial nerves producing sustained and inappropriate contraction of extraocular muscles. Ephaptic transmission may play role leading to failure of the extraocular muscles to “relax” after sustained eccentric gaze. Ocular neuromyotonia most frequently has been described in patients after radiation therapy to the skull base, although it also has been reported in the setting of thyroid eye disease, intracranial neoplasm, ingestion of alcohol, and spontaneously (80). When ocular neuromyotonia affects the superior oblique muscle, the patient develops a hypotropia of the affected eye with an associated exotropia and inability to elevate the eye in adduction. Medications that stabilize cellular membranes are effective in the treatment of ocular neuromyotonia. These include carbamazepine, gabapentin, phenytoin, and lacosamide. CONCLUSION The fourth cranial nerve and the muscle that it innervates, the superior oblique, have many unique anatomic and physiologic features. Although some disorders affecting this nerve and muscle are rare, fourth nerve/superior oblique palsy is a very common cause of vertical strabismus. Establishing the diagnosis of fourth nerve/superior oblique palsy requires meticulous attention to the patient’s history, clinical examination findings, and neuroimaging results. A number of successful medical and surgical options are available for treatment. REFERENCES 1. Miller NR, Newman NJ, eds. Walsh & Hoty’s Clinical NeuroOphthalmology. Vol. 1, 6th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2005. 2. Joo W, Rhoton AL. Microsurgical anatomy of the trochlear nerve. Clin Anat. 2015;28:857–864. 3. Nathan H, Goldhammer Y. The rootlets of the trochlear nerve. Acta Anat (Basel). 1973;84:590–596. 191 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective 4. Agarwal N, Ahmed AK, Wiggins RH, McCulley TJ, Kontzialis M, Macedo LL, Choudhri AF, Ditta LC, Ishii M, Gallia GL, Aygun N, Blitz AM. Segmental imaging of the trochlear nerve: anatomic and pathologic considerations. J Neuroophthalmol. 2021;41:e7–e15. 5. Nan YS, Park Y, Kim I-B, Shin SY. Detailed anatomy of the trochlear nerve in the superior oblique muscle. Graefe’s Arch Clin Exp Ophthalmol. 2019;257:2173–2178. 6. Hendrix P, Griessenauer CJ, Foreman P, Shoja MM, Loukas M, Tubbs RS. Arterial supply of the upper cranial nerves: a comprehensive review. Clin Anat. 2014;27:1159–1166. 7. Kono R, Poukens V, Demer JL. Superior oblique muscle layers in monkeys and humans. Invest Ophthalmol Vis Sci. 2005;46:2790–2799. 8. Lee JJ, Chun KI, Baek S-H, Kim US. Relationship of hypertropia and excyclotorsion in superior oblique palsy. Korean J Ophthalmol. 2013;27:39–43. 9. Demer JL, Miller JM. Magnetic resonance imaging of the functional anatomy of the superior oblique muscle. Invest Ophthalmol Vis Sci. 1995;36:906–913. 10. Akbari MR, Nejad MK, Askarizadeh F, Pour FF, Pazooki MR, Moeinitabar MR. Facial asymmetry in oculr torticollis. J Curr Ophthalmol. 2015;27:4–11. 11. Velez FG, Clark RA, Demer JL. Facial asymmetry in superior oblique muscle palsy and pulley heterotopy. J AAPOS. 2000;4:233–239. 12. Von Noorden GK. Burian-Von Noorden’s Binocular Vision and Ocular Motility. 2nd edition. St. Louis, MO: CV Mosby, 1980. 13. Parks MM. Isolated cyclovertical muscle palsy. Arch Ophthalmol. 1958;60:1027–1035. 14. Brazis PW. Palsies of the trochlear nerve: diagnosis and localization—recent concepts. Mayo Clin Proc. 1993;68:501– 509. 15. Suh SY, Le A, Clark RA, Demer JL. Rectus pulley displacements without abnormal oblique contractility explains strabismus in superior oblique palsy. Ophthalmology. 2016;123:1222– 1231. 16. Kushner BJ. Errors in the three-step test in the diagnosis of vertical strabismus. Ophthalmology. 1989;96:127–132. 17. Manchandia AM, Demer JL. Sensitivity of the three-step test in the diagnosis of superior oblique palsy. J AAPOS. 2014;18:567–571. 18. Lee JE, Yang HK, Kim JH, Hwang J-M. Diadnostic utility of the three-step test according to the presence of the trochlear nerve in superior oblique palsy. J Clin Neurol. 2018;14:66–72. 19. Olivier P, Von Noorden GK. Excyclotropia in the nonparetic eye in unilateral superior oblique muscle paralysis. Am J Ophthalmol. 1982;93:30–33. 20. Roh Y-R, Hwang J-M. Comparison of subjective and objective torsion in patients with acquired unilateral superior oblique muscle palsy. Br J Ophthalmol. 2011;95:1583–1587. 21. Muthusamy B, Irsch K, Chang H-YP, Guyton DL. The sensitivity in diagnosing acquired bilateral superior oblique paresis. Am J Ophthalmol. 2014;157:901–907. 22. Kline LB, Foroozan R. Neuro-Ophthalmology Review Manual. 7th edition. Thorofare, NJ: Slack Inc., 2013. 23. Brodsky MC. Pediatric Neuro-Ophthalmology. 2nd edition. New York, NY: Springer, 2016. 24. Girkin CA, Perry JD, Miller NR. A relative afferent pupillary defect without any visual sensory deficit. Arch Ophthalmol. 1998;116:1544–1545. 25. Ozkan SB, Aribal ME, Sener EC, Sanac AS, Gurcan F. Magnetic resonance imaging in evaluation of congenital and acquired superior oblique palsy. J Pediatr Ophthalmol Strabismus. 1997;34:29–34.26. 26. Kim JH, Hwang JM. Absence of the trochlear nerve in patients with superior oblique hypoplasia. Ophthalmology. 2010;117:2208–2213. 27. Yang HK, Kim JH, Hwang J-M. Congenital superior oblique palsy and trochlear nerve absence: a clinical and radiological study. Ophthalmology. 2012;119:170–177. 192 28. Lee DS, Yang HK, Kim JH, Hwang J-M. Morphometry of the trochlear nerve and superior oblique muscle volume in superior oblique palsy. Invest Ophthalmol Vis Sci. 2014;55:8571– 8575. 29. Demer JL, Clark RA, Kung J. Functional imaging of human extraocular muscles in head tilt dependent hypertropia. Invest Ophthalmol Vis Sci. 2011;52:3023–3031. 30. Gesite-de Leon B, Demer JL. Sclerosing cavernous hemangioma of the cavernous sinus mimicking congenital fibrosis of the extraocular muscles. J AAPOS. 2014;18:299–301. 31. Tarczy-Hornoch K, Repka MX. Superior oblique palsy or paresis in pediatric patients. J AAPOS. 2004;9:133–140. 32. Dosunmu EO, Hatt SR, Leske DA, Hodge DO, Holmes JM. Incidence and etiology of presumed fourth cranial nerve palsy: a population-based study. Am J Ophthalmol. 2018;185:110– 114. 33. Ivanir Y, Trobe JD. Comparing hypertropia in upgaze and downgaze distinguishes congenital from acquired fourth nerve palsies. J Neuroophthalmol. 2017;37:365–368. 34. Rucker CW. Paralysis of the third, fourth, and sixth cranial nerves. Am J Ophthalmol. 1958;46:787–794. 35. Rucker CW. The causes of paralysis of the third, fourth, and sixth cranial nerves. Am J Ophthalmol. 1966;61:1293–1298. 36. Khawam E, Scott AB, Jampolski A. Acquired superior oblique palsy. Arch Ophthalmol. 1967;77:567–574. 37. Burger LJ, Kalvin NH, Smith JL. Acquired lesions of the fourth cranial nerve. Brain. 1970;93:567–574.. 38. Younge BR, Sutula F. Analysis of trochlear nerve palsies. Mayo Clin Proc. 1977;52:11–18. 39. Rush JA, Younge BR. Paralysis of cranial nerves III, IV and VI. Cause and prognosis in 1,000 cases. Arch Ophthalmol. 1981;99:76–79. 40. Kodsi SR, Younge BR. Acquired oculomotor trochlear and abducent cranial nerve palsies in pediatric patients. Am J Ophthalmol. 1992;114:568–574. 41. Richards BW, Jones FR, Younge BR. Cause and prognoses of 4278 cases of paralysis of oculomotor, trochlear and abducens cranial nerves. Am J Ophthalmol. 1992;183:489–496. 42. Park UC, Kim SJ, Hwang JM, Yu YS. Clinical features and natural history of acquired third, fourth, and sixth cranial nerve palsy. Eye. 2008;22:691–696. 43. Gupta A, Lee ECH, Kelly HR, Chen RC. Clinical and imaging manifestations of trochlear nerve schwannomas—a case series. J Neuroophthalmol. [published online ahead of print September 11, 2020] doi: 10.1097/WNO.0000000000001059. 44. Horton JC, Tsai R-K, Truwit CL, Hoyt WF. Magnetic resonance imaging of superior oblique muscle atrophy in acquired trochlear nerve palsy. Am J Ophthalmol. 1990;110:315–316. 45. Shin SY, Demer JL. Superior oblique extraocular muscle shape in superior oblique palsy. Am J Ophthalmol. 2015;159:1169–1179. 46. Suh SY, Clark RA, Le A, Demer JL. Extraocular muscle compartments in superior oblique palsy. Invest Ophthalmol Vis Sci. 2016;57:5535–5540. 47. Donahue SP, Lavin PJM, Hamed LM. Tonic ocular tilt reaction simulating a superior oblique palsy. Arch Ophthalmol. 1999;117:347–352. 48. Wong AMF, Sharpe JA, Tweed D. Adaptive neural mechanism for Listing’s law revealed in patients with fourth nerve palsy. Invest Ophthalmol Vis Sci. 2002;43:1796– 1803. 49. Lemos J, Subei A, Sousa M, Nenes C, Cunha L, Glisson C, Eggenberger E. Differentiating acute and subacute vertical strabismus using different head positions during the uprightsupine test. JAMA Ophthalmol. 2018;136:322–328. 50. Weinberg DA, Lesser RL, Vollmer TL. Ocular myasthenia: a protean disorder. Surv Ophthalmol. 1994;39:169–210. 51. Rush JA, Shafrin F. Ocular myasthenia presenting as superior oblique weakness. J Clin Neuroophthalmol. 1982;2:125–127. 52. Shan JCS, Douglas RS. The pathophysiology of thyroid eye disease. J Neuroophthalmol. 2014;34:177–185. Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Perspective 53. Moster ML, Bosley TM, Slavin ML, Rubin SE. Thyroid ophthalmolpathy presenting as superior oblique paresis. J Clin Neuroophthalmol. 1992;12:94–97. 54. Rutar T, Demer JL. Heavy eye syndrome in the absence of high myopia: a connective tissue degeneration in elderly strabismic patients. J AAPOS. 2009;13:36–44. 55. Chaudhuri Z, Demer JL. Sagging eye syndrome: a connective tissue involution as a cause of horizontal and vertical strabismus in elderly patients. JAMA Ophthalmol. 2013;131:619–625. 56. Tamhankar MA, Ying GS, Volpe NJ. Success of prisms in the management of diplopia due to fourth nerve palsy. J Neuroophthalmol. 2011;31:206–209. 57. Carden SM. Botulinum toxin chemodenervation of the inferior oblique muscle for chronic and acute IV nerve palsies: results in 15 cases. Binocul Vis Strabismus Q. 1998;13:8. 58. Telebnejad MR, Tahamtan M, Nowroozzadeh MH. Botulinum Toxin Injection for treatment of acute traumatic superior oblique muscle palsy. J Ophthalmic Vis Res. 2015;10:263–267. 59. Bagheri A, Eshaghi M. Botulinum toxin injection of the inferior oblique muscle for the treatment of superior oblique muscle palsy. J AAPOS. 2006;10:385–388. 60. Garnham L, Lawson JM, O’Neill D, Lee JP. Botulinum toxin in fourth nerve palsies. Aust N Z J Ophthalmol. 1997;25:31– 35. 61. Hatz KB, Brodsky MC, Killer HE. When is isolated inferior oblique muscle surgery an appropriate treatment for superior oblique palsy? Eur J Ophthalmol. 2006;16:10–16. 62. Elhusseiny AM, Gore C, Ali A, Sadiq M, Dagi LR, Kazlas M. Selfgrading effect of inferior oblique myectomy and recession. J AAPOS. 2020;24:218.e1–218.e6. 63. Nejad M, Thacker N, Velez FG, Rosenbaum AL, Pineles SL. Surgical results of patients with unilateral superior oblique palsy presenting with large hypertropias. J Pediatr Ophthalmol Strabismus. 2013;50:44–52. 64. Nash DL, Hatt SR, Leske DA, May L, Bothun ED, Mohney BG, Brodsky MC, Holmes JM. One- versus two-muscle surgery for presumed unilateral fourth nerve palsy associated with moderate angle hyperdeviations. Am J Ophthalmol. 2017;182:1–7. 65. Cogen MS, Roberts B. Combined superior oblique tuck and adjustable suture recession of the ipsilateral superior rectus for long-standing superior oblique palsy. J AAPOS. 2003;7:195–199. Kline et al: J Neuro-Ophthalmol 2021; 41: 176-193 66. Helveston EM, Mora JS, Lipsky SN, Plager DA, Ellis FD, Sprunger DT. Surgical treatment of superior oblique palsy. Trans Am Ophthalmol Soc. 1996;94:315–334. 67. Bradfield YS, Struck MC, Kushner BJ, Neely DE, Plager DA. Outcomes of Harada- Ito surgery for acquired torsional diplopia. J AAPOS. 2012;16:453–457. 68. Bata BM, Leske DA, Holmes JM. Adjustable bilateral superior oblique tendon advancement for bilateral fourth nerve palsy. Am J Ophthalmol. 2017;178:115–121. 69. Zhang M, Gilbert A, Hunter DG. Superior oblique myokymia. Surv Ophthalmol. 2018;63:507–517. 70. Duane A. Unilateral rotary nystagmus. Trans Am Ophthalmol Soc. 1906;11:63–67. 71. Hoyt WF, Keane JR. Superior oblique myokymia. Report and discussion on five cases of benign intermittent uniocular microtremoe. Arch Ophthalmol. 1970;84:461–467. 72. Dehaene L, Casselman J. Left superior oblique myokymia and right superior oblique paralysis due to a posterior fossa tumor. J Neuroophthalmol. 1993;13:13–16. 73. Geis TC, Newman NJ, Dawson RC. Superior oblique myokymia associated with a dural arteriovenous fistula. J Neuroophthalmol. 1996;16:41–43. 74. Samii M, Rosahl SK, Carvalho GA, Krzizok T. Microvascular decompression for superior oblique myokymia: first experience. J Neurosurg. 1998;86:1020–1024. 75. Mikami T, Minamida Y, Ohtsuka K, Houkin K. Resolution of superior oblique myokymia following microvascular decompression of trochlear nerve. Acta Neurochir (Wein). 2005;147:1005–1008. 76. Fam MD, Scott C, Forster A, Kamel MH. Microvascular decompression for superior oblique myokymia: a case report. Br J Neurosurg. 2014;28:552–555. 77. Brown HW. Congenital structural muscle abnormalities. In: Strabismus Ophthalmic Symposium. Allen JH, ed. St. Louis, MO: CV Mosby, 1950. 78. Kaeser P-F, Brodsky MC. Fourth cranial nerve palsy and Brown syndrome: two interrelated congenital dysinnervation disorders?. Cur Neurol Neurosci Rep. 2013;13:352. 79. Soares-dos-Reis R, Martins AI, Bras A, Matos A, Bento C, Lemos J. Ocular neuromyotonia. Pract Neurol. 2018;18:389–390. 80. Roper-Hall G, Chung SM, Cruz OA. Ocular neuromyotonia: differential diagnosis and treatment. Strabismus. 2013;21:131–136. 193 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.