Skew Deviation Revisited

I. Introduction 

According to Stedman's Medical Dictionary,184 skew deviation refers to “a hypertropia in which the eyes move in opposite directions equally; an acquired hypertropia, often fairly comitant, not fitting the characteristic pattern of trochlear nerve damage or of ocular muscle abnormality; often due to a brainstem or cerebellar lesion.” For many years, skew deviation was held to be a nonlocalizing sign and a diagnosis of exclusion.84, 112 Skew deviation usually presents as a comitant hypertropia in a patient with posterior fossa disease.44 In rare cases, however, it can increase in one horizontal direction of gaze, manifest as a paroxysmal hyperdeviation of one eye, or produce alternating hyperdeviations in gaze to either side.44, 181 The purpose of this review is to acquaint the reader with advances in our understanding of skew deviation as a clinical diagnostic entity, in terms of its clinical range of presentation, its underlying pathophysiology, and its clinical localizing value.

II. History 

Skew deviation was first recognized experimentally in animals by the experimental physiologist Francois Magendie in 1824.131 The following year, Henry Hertwig described skew deviation in a cat following an incision through the cerebellum into the medulla.100, 182 In 1904, Stewart and Holmes observed skew deviation in a man with a cerebellar tumor, and in other patients following craniotomies for cerebellar tumors.186 During World War I, Gordon Holmes documented skew deviation in 5 of 40 patients who had sustained cerebellar gunshot injuries.104 In 1921, Holmes theorized that skew deviation was observed only in patients with extensive cerebellar lesions and otherwise had no localizing value.103 In 1925, Pötzl and Sittig described skew deviation in a patient with a lesion in the ventral caudal portion of the vestibular complex and referred to it as the Hertwig-Magendiescher Schielstellung.155 In 1926, Brain reported skew deviation with head tilting in a patient with chronic otitis media.19

In his 1956 book Neurology of the Eye Muscles, Cogan observed that skew deviation was common with lesions of the cerebellum (tumors, abscesses, and vascular and post-surgical lesions) and in lesions of the vestibular nuclei, nerve, and end organ.44 He observed that the eye on the side of the lesion was directed downward and the opposite eye upward. Cogan attributed skew deviation to a lesion involving the vestibulo-ocular pathways but emphasized that, “evidence is scanty for localization, other than the general region of the posterior fossa.”44 In 1961, Smith et al noted that skew deviation may accompany internuclear ophthalmoplegia, in which case the higher eye is usually on the side of the lesion.181, 182 They considered skew deviation to fall into three clinical subtypes: comitant, laterally comitant (actually an incomitant skew deviation in which the hyperdeviation increases in one lateral field of gaze), and a laterally alternating skew deviation in which there is a hyperdeviation of the abducting eye in each lateral field of gaze.181

In 1975, Keane described 100 patients with skew deviation. Most patients had unilateral lesions involving the pons, but lesions within the medulla and midbrain were also common.116 As in previous reports, the hypotropic eye tended to be on the side of the lesion except in cases of unilateral internuclear ophthalmoplegia (INO), where the higher eye was on the side of the lesion. Keane attributed skew deviation to a lesion involving the otolithic pathways, which can be injured at any site as they ascend within the brainstem.115 He also noted that the natural history of skew deviation tended toward spontaneous resolution.

The role of the vestibular system and brainstem in the control of head-eye posture in the roll plane has been recognized for almost a century.19, 89, 102, 132, 143 In 1975, Westheimer and Blair provided what was to be a unifying explanation for skew deviation when they electrically stimulated the brainstem tegmentum of alert monkeys and noted a vertical deviation (skew deviation) and rotation (cyclotorsion) of the eyes conjugately and equally in the direction of the infraducted eye. They assigned the name ocular tilt reaction and stated that clinical skew deviation (Hertwig-Magendie phenomenon) and the ocular tilt reaction were identical phenomena.215, 216 In retrospect, the ocular tilt reaction had been produced by Muskins in 1914,143 documented in different species by Magnus et al,132 and described later by investigators in the scientific201 and veterinary literature.171, 214 These reports suggested that when skew deviation is due to a lesion in the rostral end of the medial longitudinal fasciculus (MLF), the ipsilateral eye may be higher.133

In 1977, Rabinovitch et al provided the first clinically recognized report of a human ocular tilt reaction.156 Two years later, Halmagyi et al documented an ocular tilt reaction in a woman following unilateral stapedectomy.91 They correctly attributed it to a compensatory response that followed unilateral injury to the vestibular pathway that arises in the utricle of the dependent ear and projected to the opposite brainstem. Numerous descriptions of the human ocular tilt reaction (Fig. 1) have since followed, and neuroimaging has provided exquisite anatomical confirmation of the site of injury.

Fig. 1. Ocular tilt reaction. Top Left: Facial photograph shows mild left head tilt. Top Right: Fundus photographs show intorsion of the right eye and extorsion of the left eye. Bottom left: MR imaging shows focal lesion involving the right medial longitudinal fasciculus. Bottom right: Diagram depicting causative lesion. (Reprinted from Vaphiades205 with permission of Wisconsin University Press.)

In summary, skew deviation was, until recently, considered to be a vertical misalignment of the eyes that was uncommon, usually seen in neurologically debilitated patients, and nonspecifically localizing except to the posterior fossa. In the past two decades, however, dedicated studies have shown that skew deviation is common, that its causative lesion can be focal, that it can be seen in otherwise intact ambulatory patients, and that it occurs in the more general context of an ocular tilt reaction.

III. Causes 

Skew deviation can result from any acute injury within the posterior fossa (ischemic infarction, multiple sclerosis, tumor, trauma, abscess, hemorrhage, syringobulbia, or neurosurgical procedures).12, 44, 116, 181 The majority of cases are seen in association with brainstem stroke.61, 181 A lesion need not involve the brainstem or cerebellum to cause skew deviation, however. Acute unilateral vestibular lesions can also cause skew deviation.61, 63, 90, 91, 113, 116, 167, 219

Numerous rarer causes of skew deviation have been documented.116 Several reports have documented skew deviation in patients with increased intracranial pressure.9, 76, 134 Skew deviation may accompany paroxysmal hemiparesis of childhood.66, 97 Cogan described skew deviation in one patient with Arnold-Chiari malformation and in two individuals with platybasia.45 Galimberti et al described paroxymal epileptic skew deviation in a patient who was otherwise neurologically intact.80 They attributed it to ictal activation of the vestibular cortex with secondary activation of descending projections to the vestibular nuclei. Suzuki et al described three patients who developed diplopia and skew deviation following cardiac catheterization.192 Negative neuroimaging studies were suggestive of minor ischemic damage to the brainstem. Yokota et al described skew deviation with alternating hypertropia of the abducting eye in three patients with Creutzfelt-Jakob disease.222

Ragge et al described an ocular tilt reaction in a 5-year-old girl with a mesencephalic lesion and polyarteritis nodosa.158 Skew deviation has also been reported in multifocal encephalopathy,17 CNS cryptococcus,56 hepatic coma,74 following Mandrax overdosage,151 from a unilateral cochleo-vestibular damage due to herpes zoster oticus,206 in paraneoplastic encephalomyelitis associated with benign ovarian teratoma,196 and in adult Leigh disease.93 Chueng et al diagnosed skew deviation on prenatal MR images in a fetus with association with glioblastoma involving the brainstem.43

IV. Evolutionary Underpinnings 

Classical skew deviation occurs in the context of an ocular tilt reaction, in which bilateral otolithic input is leveraged by the central vestibular system to modulate extraocular muscle and postural tonus in the roll plane (the plane in which the head or body tilts from side to side).136, 176, 223 The ocular tilt reaction in humans is probably a vestigial remnant of the primitive otolithic righting reflex that is released only under pathological conditions.136 The relative preponderance of the individual components of head tilt, ocular torsion, and vertical eye movements, is dependent upon species differences in the range of head movement and the orientation of the optic axes.136 The head tilt component is most prominent in animals with little eye movements, such as owls.136, 185 The skew eye movement is most prominent in animals with mobile, laterally placed eyes, but no head movement in roll, such as fish.136 In these lateral-eyed animals, a body tilt around the long axis produces a rotation of the eyes that is purely vertical.11, 204 In the fish or a rabbit, for example, a rightward body tilt along its long axis causes the right eye to be lower in space than the left eye, which results in a compensatory skew deviation with upward rotation of the lowermost right eye and downward rotation of the uppermost left eye.89 The torsional eye movement (known as the ocular counter roll) is most prominent in frontal-eyed animals such as cat and humans.136

In humans, the head tilt is the major component of the physiological ocular tilt reaction (Fig. 2). Thus, motorcycle riders or skiers reflexively reorient the head back to the gravitational vertical during sharp turns that induce body tilt (Fig. 3). In humans, the gain of the static ocular counterroll (the torsional component of the ocular tilt reaction) is only about 0.1, as the need for a compensatory eye torsion reflex is reduced by a compensatory head tilt reflex.49, 59 Pansell et al found that humans show a transient skew deviation at the initiation of a head tilt that is opposite to the final skew deviation (i.e., right hypertropia during the initiation of a left head tilt).152 The subsequent dynamic skew deviation (left hypertropia during leftward tilt) is robust during whole body oscillations around the naso-occipital axis,113 but only a trace static skew deviation can be detected during static head or body tilt (on the order of 0.3 degrees).15, 119, 188 In the normal individual, for example, prism alternate cover testing during head tilt will not evoke a measurable hyperphoria.39 Given the magnitude of asymmetrical otolithic innervation evoked by a static head tilt, the virtual absence of a physiologic skew deviation must be taken as evidence that the frontal-eyed system has evolved to inhibit this reflex in the interest of single binocular vision.

Fig. 2. Figure showing physiologic and pathologic skew deviation. In the physiologic ocular tilt reaction (left), the compensatory head tilt predominates, with only a small skew deviation or static ocular counterroll. In the pathologic ocular tilt reaction (right), all three components of the ocular tilt reaction are present. (Reprinted from Brodsky37 with permission of the American Medical Association.)

Fig. 3. Physiologic ocular tilt reaction in a motorcycle rider when tilted in the roll plane. (Reprinted with permission from Bike magazine, p 74, August 2001.)

V. Neuroanatomy 

The primary functions of the vestibulo-ocular system are to maintain eye position and stabilize fixation during head movements. The labyrinthine receptors transduce the forces associated with head acceleration into a biological signal.136 The semicircular canals sense angular acceleration, while the otoliths (the saccules and utricles) respond to linear acceleration (i.e., head translation and the most pervasive form of linear acceleration, the pull of gravity).136 In lateral-eyed animals and in humans, the semicircular canals are roughly aligned with the long axis of the extraocular muscles (Fig. 4).176 When the head is rotated in a particular plane, the semicircular canal that lies in the plane of rotation detects acceleration and sends excitatory innervation to its corresponding extraocular muscles. In addition to serving to stabilize gaze, the vestibulo-ocular pathways also provide ascending input to the thalamo-cortical projections of spatial perception as well as descending input to vestibulo-spinal projections for adjustments of head and body posture (vestibulo-spinal reflexes).21

Fig. 4. Figure showing close anatomical correspondence between semicircular canals and extraocular muscles in man. (Reprinted from Simpson and Graf176 with permission of the New York Academy of Sciences.)

The ocular tilt reaction and its associated skew deviation represent a fundamental pattern of eye-head coordination in the roll plane.29, 61, 64 The otolith-ocular response to rotation is impaired in patients with skew deviations due to brainstem lesions.198 The ocular tilt reaction can be observed not only in patients with peripheral vestibular dysfunction but also in those with lesions of the graviceptive pathways, which run from the medulla to the mesencephalon.21, 24, 26, 27, 28, 29, 60, 63, 64, 89 Unilateral dysfunction due to either a peripheral or central vestibular pathway lesion results in a clinical syndrome characterized by a combination of phenomena involving perceptual (tilt in the subjective visual vertical) ocular motor (ocular torsion, skew deviation), and postural (head tilt) manifestations, which together constitute the ocular tilt reaction.29 Consequently, skew deviation is usually associated with lesions in the posterior fossa, particularly those involving the brainstem tegmentum from the diencephalon to the medulla.26 It is also seen clinically in lesions of the utricle or vestibular nerve.28

Each anterior semicircular canal provides excitatory input to the ipsilateral superior rectus and contralateral inferior oblique muscles (Fig. 5).48, 124, 190 Each posterior semicircular canal system provides excitatory innervation to the ipsilateral superior oblique and the contralateral inferior rectus muscles while inhibiting the ipsilateral inferior oblique and the contralateral superior rectus muscles (Fig. 5). Like their target extraocular muscles, the semicircular canals have a push–pull (yoke) relationship, so that activation of one canal inhibits the antagonist canal.48, 124, 190 Thus, injury to or inhibition of an anterior canal pathway causes functional activation of the ipsilateral posterior canal pathway.24

Fig. 5. Vesitibulo-ocular connections showing showing extraocular muscles activated by individual semicircular canals (I = ipsilateral; c = contralateral). Central connections through the vestibular nucleus are not shown.

In addition to the semicircular canals, each labyrinth contains otolithic sensors consisting of the utricle and the saccule.25, 124 Although some overlap exists,170 the semicircular canals respond to angular acceleration and produce dynamic vestibulo-ocular movements (phasic ocular deviations and nystagmus), whereas the parallel otolithic system responds to linear acceleration and is sensitive to changes in static head position.25, 63, 82, 124, 197 The otolithic pathways are not as well studied, but are believed to have similar projections to the corresponding canal pathways.124 Static eye positions, the ocular counterroll, sensory input for subjective vertical orientation, and conjugated vertical deviations such as skew deviation are mediated mainly by the utricles,25 although recent evidence suggests that a semicircular canal imbalance may contribute to the cyclotropia in unilateral vestibular patients.170 Graviceptive input from the otoliths converges with that from the vertical semicircular canals at the level of the vestibular nuclei.5, 8, 20, 85, 86, 172 Mathematical models of biological systems have recently been applied to the tonic and dynamic aspects of vestibulo-ocular function.20, 81, 82

VI. Symptomatology 

Unilateral lesions or stimulation of the utricles or vertical semicircular canal pathways cause an imbalance of vestibular tone in the roll plane, which results either in a complete (tonic or paroxysmal) ocular tilt reaction or in single components of the ocular tilt reaction such as cyclorotation of the eyes or skew deviation.64

In the pathological ocular tilt reaction, the eyes, head, and body are continuously adjusted to what the central nervous system erroneously computes as being vertical.29 This compensation causes a synkinetic rotation of the eyes, interpupillary axis, and head in the roll plane to realign with the perceived vertical (Fig. 6).27 When the patient's head is moved to the true vertical, the patient may perceive it as tilted in the opposite direction.29 However, the ocular torsion and head tilt are easily overlooked unless specifically sought.

Fig. 6. Graviceptive pathways from the otoliths and vertical semicircular canals mediating the vestibular reactions in the roll plane. The projections from the otoliths and the vertical semicircular canals to the ocular motor nuclei (trochlear nucleus IV, oculomotor nucleus III, abducens nucleus VI), and the supranuclear centers of the interstitial nucleus of Cajal (INC), and the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) are shown. They subserve vestibuloocular reflex (VOR) in three planes. The VOR is part of a more complex vestibular reaction that also involves vestibulospinal connections via the medial and lateral vestibulospinal tracts for head and body posture control. Note that graviceptive vestibular pathways for the roll plane cross at the pontine level. Ocular tilt reaction is depicted schematically on the right in relation to the level of the lesion (i.e., ipsiversive with peripheral and pontomedullary lesions, and a contraversive with pontomesencephalic lesions). In vestibular thalamus lesions, the tilts of the subjective visual vertical may be contraversive or ipsiversive. (Reprinted from Brandt and Dieterich25 with permission of Wiley.)

The fundamental association of skew deviation with ocular torsion and torticollis was overlooked for many years.25, 79 Although Trobe202 found no cyclodeviation in patients with skew deviation,79 the exclusion of patients with positive head tilt tests in this study may have foreordained that result.115 This classic triad of findings is absent in some patients.23, 90 The ocular tilt reaction rarely causes symptoms by itself; it does not cause disequilibrium and may only induce vertical diplopia.90

A skew deviation is usually comitant in different positions of gaze but can occasionally show horizontal incomitance and skew vertically in one lateral field of gaze.44, 182 The Bielschowsky Head Tilt Test is generally negative in comitant skew deviation, but can be positive in incomitant skew deviation and thereby simulate isolated oblique muscle paresis.7, 165 Skew deviation may be associated with a torsional jerk nystagmus. When this occurs, the upper poles of the eyes tend to beat away from the side of a medullary lesion and toward the side of a midbrain lesion.14, 63, 88, 92, 128 The ocular tilt reaction and its associated skew deviation tend to recover spontaneously over weeks to months.18, 115

VII. Subjective Visual Tilt 

The ocular tilt reaction is associated with a tilt in the subjective visual vertical. This term is often confusing to the uninitiated reader because the patient remains asymptomatic, and even when asked, states that his or her surroundings do not appear tilted. However, the patient's subjective visual world (which he or she perceives as upright) is indeed tilted with respect to the true earth vertical. In this sense, the patient can be said to experience a subjective visual tilt. It is as if you tilted a television set to one side and then imagined what the television characters perceived. Because their entire visual world is tilted together, they would tend to perceive themselves and their surroundings as normal. Despite their tilt, all visual cues would tell them that their internal world corresponds to true earth coordinates.

Such is the case in the patient with an ocular tilt reaction. In normal structured environments, our life-long experience persuades us as to horizontal and vertical orientations of rooms, houses, trees, and so on. For this reason, in the ocular tilt reaction the examiner can only determine the perceived tilt if a straight line is adjusted to “vertical” in darkness, or in surroundings which provide no cue for true vertical. A patient with a left ocular tilt reaction, for example, will experience a tilt in the subjective visual vertical that is counterclockwise (from the patient's perspective) because diminished input from the left utricle causes the brain to perceive the head as having been tilted to the right (Fig. 6). Under clinical conditions the patient's head reflexively rotates to align with the internally perceived vertical. Under testing conditions, the patient would adjust a vertical line in a counterclockwise direction until it corresponds to this altered internal sense of vertical. The subjective visual tilt can be identified using Double Maddox rods209 or by placing the patient's head in a half-spherical dome and instructing him or her to adjust a potentiometer to vertically situate an observed line.29 Either test must be performed separately with each eye occluded, and several measurements must be averaged. A tilt in the subjective visual vertical can also be suspected by observing the slant of personal photographs being taken or by observing the slant of handwriting with the eyes closed.29 In the ocular tilt reaction, the observed errors in tilt orientation are always in the same direction as the observed ocular torsion.

The ocular tilt reaction strives to realign the eyes and head to a tilted position that the brain erroneously computes as vertical (note that the ensuing cyclorotation of the eyes counterrotate the tilted subjective visual vertical back to true vertical (Fig. 6). With this disturbance, the patient's subjective sense of true vertical is rotated in the same direction as the ocular torsion, suggesting that the tilted perception of vertical provides the driving force for all components of the ocular tilt reaction, which strives to realign the eyes and body with the perceived vertical. This mechanism for torticollis differs from the more common contralateral head tilt in superior oblique palsy, which recruits otolithic innervation to restore vertical ocular alignment, all three components of the ocular tilt reaction realign the eyes and head to the tilted perception of true vertical. In the ocular tilt reaction, correction of the vertical ocular misalignment by prisms or by strabismus surgery should not eliminate the torticollis.

Following vestibular stimulation, some patients with skew deviation may experience a room-tilt illusion in which a room is perceived to be tilted on its side or even upside down.199 Slavin and LoPinto178 described an exceptional patient who experienced subjective visual tilt. Examination disclosed a bilateral rightward cyclodeviation and a corresponding tilt in the subjective visual vertical, but no hypertropia or head tilt in this patient who had compression of the left lateral medulla by a dolichoectatic carotid artery. These findings were consistent with a partial ocular tilt reaction (without skew deviation). Conversely, Strupp et al recently described a patient with unilateral anterior semicircular canal dehiscence who experienced ocular torsion but no displacement of the subjective visual vertical, suggesting that subjective visual tilt specifically requires asymmetrical otolithic input.189

To examine the effect of unilateral brainstem injury on perception of vertical in the roll plane, Dieterich and Brandt examined ocular torsion and tilt in the subjective visual vertical in 111 patients with acute vascular brainstem stroke.61 Of these patients, 104 (94%) showed a direction specific pathologic tilt of the static subjective visual vertical. Seventy-one of 86 patients (83%) exhibited a pathological static ocular torsion of one (47%) or both (36%) eyes. The tilt in the subjective visual vertical and ocular torsion were generally in the same direction. Caudal brainstem lesions caused ipsiversive tilts of the subjective visual vertical, whereas upper brainstem lesions caused contraversive tilts. Tilts in the subjective visual vertical were greatest with mesodiencephalic lesions and with lateral medullary lesions (i.e., Wallenberg syndrome). The mean tilt angle was 8.1 degrees, with a range of 2 to 26 degrees. All lesions caudal to the upper pons caused ipsiversive ocular torsion of one or both eyes, with concurrent ipsiversive tilts of the subjective visual vertical, whereas all lesions rostral to this pontine level cause contraversive tilts of ocular torsion and the subjective visual vertical. Some patients had significant tilts of the subjective visual vertical but no concurrent ocular torsion. When ocular torsion was present, it was always accompanied by a tilt of the subjective visual vertical in the same direction. The quantitative dissociation between a tilt in the subjective visual vertical and the corresponding ocular torsion shows that deviations in the subjective visual vertical are not simply the sensory consequence of the rotation of the eye, but represent the perceptual correlate of a vestibular tone imbalance in the roll plane.61 Some patients with brainstem injury can also experience brief, episodic tilting of the visual world as an apparently isolated phenomenon.163

In addition to brainstem injury, acute peripheral vestibular loss can also cause an ipsiversive tilt of the subjective visual vertical and ocular torsion, as shown by Friedman following labyrinthectomy,75 and by Curthoys following unilateral vestibular neurectomy.52 Curthoys et al found a high correlation between the direction and magnitude of changes in ocular torsion and the subjective visual vertical one week after unilateral vestibular neurectomy in many patients,52 suggesting that peripheral lesions cause a tilt of the subjective visual vertical with an ocular torsion of similar magnitude while, in central vestibular lesions, the magnitude of the effect on these two parameters may differ, with a tendency of the subjective visual vertical to be affected to a greater degree.

VIII. Localizing Value 

To ascertain the localizing value of skew deviation, Brandt and Dieterich reviewed 155 patients with the clinical diagnosis of acute unilateral brainstem infarction.26 Fifty-six (36%) of these patients demonstrated skew deviation. Skew deviation was always associated with ocular torsion, which affected both eyes in 50%, the lowermost eye in 31%, and the uppermost eye in 19%. The direction of the ocular torsion inevitably corresponded to the direction of skew (i.e., intorsion of the right eye and/or extorsion of the left eye with a left hypotropia, and intorsion of the left eye and extorsion of the right eye with a right hypotropia). Skew deviation was associated with a complete ocular tilt reaction toward the lowermost eye in 61%. In all cases, unilateral pontomedullary lesions induced ipsiversive skew deviations (toward the side of the lower eye) which were probably caused by injury to the medial or superior vestibular nucleus, while unilateral pontomesencephalic and mesodiencephalic lesions all caused contraversive skew deviations, probably from involvement of the interstitial nucleus of Cajal in the rostral midbrain tegmentum or the medial longitudinal fasciculus along its pontomesencephalic route. These findings confirmed that skew deviation usually occurs as a component of the ocular tilt reaction. It also identified the localizing value of skew deviation in patients with acute brainstem infarction. If the level of brainstem damage is known from the clinical syndrome, then skew deviation indicates the side of the lesion. Conversely, if the side of the lesion is evident from the clinical syndrome, then the level of the brainstem injury is indicated by the direction of skew, ipsiversive with caudal and contraversive with rostral brainstem lesions.26

From these studies,26 the following conclusions can be drawn:

IX. Sites of Injury 

The ocular tilt reaction indicates a unilateral peripheral deficit of otolithic input or a unilateral lesion of graviceptive brainstem pathways from the vestibular nucleus (crossing midline at the pontine level) to the interstitial nucleus of Cajal in the rostral midbrain.25 The resultant head tilt, torsion of the eyes, skew deviation, and tilt of the subjective visual vertical are the postural, ocular motor, and perceptual manifestations of a single lesion of those vestibular pathways subserving the vestibulo-ocular reflex in the roll plane.25 Because these pathways are difficult to injure in isolation, lesions along each site of the vestibulo-ocular pathways may be associated with specific clinical disorders depending on their location which determine the contiguous areas of injury. Lesions causing the ocular tilt reaction can be subdivided in to peripheral and central injuries to the otolithic pathways.

B. Central Injury to Otolithic Pathways 

1. Medulla 

Clinical29 and experimental203 unilateral medullary lesions can produce a tonic ipsiversive OTR.142 Skew deviation is a frequent accompaniment of Wallenberg (lateral medullary) syndrome.63, 73, 114, 138, 139, 175, 197 Patients with Wallenberg syndrome present with ipsilateral impairment of pain and temperature sensation over the face, ipsiversive lateropulsion (a compelling sensation of being pulled toward the side of the lesion), skew deviation, saccadic eye movements that are larger toward the side of the lesion (causing vertical saccades to have an oblique configuration), Horner syndrome, limb ataxia, and bulbar disturbance causing dysarthria and dysphagia.13, 33, 197 Contralateral pain and temperature sensation is impaired over the limbs and trunk. Some patients experience a room tilt illusion, in which the entire room is tilted on its side or even upside down.33, 105 The disorder is usually caused by occlusion of the intradural segment of the ipsilateral vertebral artery, or occlusion of the perforating branches which supply the dorsolateral medulla and cause injury to the vestibular nucleus or its cerebellar, semicircular canal, or otolithic connections.

In patients with lateral medullary infarction, the ocular torsion is usually unequal, with greater extorsion of the ipsilateral eye than incyclotorsion of the contralateral eye.79, 90 In a study of 36 patients with Wallenberg syndrome, Dieterich and Brandt63 noted ipsiversive cyclorotation of one or both eyes in most patients, especially extorsion of the eye ipsilateral to the brainstem lesion (suggesting an isolated lesion of posterior canal pathways) (Fig. 7). Only one third of patients had a complete ocular tilt reaction but all patients had a tilt of the subjective visual vertical.28, 139 Torsional nystagmus is also common in Wallenberg syndrome, with the upper poles of the eyes beating away from the side of the lesion.33 In Wallenberg syndrome, the deviation in the subjective visual vertical, lateropulsion of the body, and cyclorotation of the eyes are the perceptual, ocular motor, and postural consequences of a common lesion of central vestibulo-ocular pathways that subserve graviceptive tone in the roll plane.33 The disconjugate ocular torsion in this syndrome presumably reflects selective injury to otolithic pathways corresponding to the posterior semicircular canals.23, 29, 33 Medial medullary lesions that cause skew deviation can be associated with upbeating nystagmus.142

Fig. 7. Figure showing different types of skew deviation that can result from selective unilateral injury to otolithic either the anterior or posterior semicircular canals. These asymmetric injuries provide an explanation for incomitant forms of skew deviation.

2. Cerebellum 

Otolith input to the cerebellum has been demonstrated extensively.10, 42, 47, 83 Animal studies have demonstrated pathways not only from the vestibular nuclei via the inferior olive to the cerebellar vermis (uvula-nodulus), but also primary otolith projections to the uvula-nodulus via mossy fibers.11 Furthermore, single-cell recordings suggest that the otoliths influence neural activity in the rostral fastigial nucleus.42 The otolith signals are relayed from the vestibular nuclei, medullary reticular formation, inferior olive, and lateral reticular nucleus to the cerebellar nodulus and uvula, and influence the deep cerebellar nucleus.42 Skew deviation has been produced experimentally in animals by lesions of the cerebellum,104, 149, 217 restiform body,212 and inferior and middle cerebellar peduncle.2, 44, 149 Burde and colleagues found lateral alternating skew deviation in two monkeys after total cerebellectomy;41 however, most studies of ocular motor function following stimulation or destruction of the cerebellum in humans116, 145 and monkeys47, 162, 218 have not noted skew deviation.

Because early reports of skew deviation in humans were so frequently associated with large cerebellar lesions,41, 103, 153, 181, 207 it is curious that the causal association of skew deviation with cerebellar disease has been a matter of some controversy. As discussed below, lateral alternating skew deviation (resulting from bilateral injury to the vestibulo-ocular tracts)140, 141, 207, 224 is recognized in patients with Arnold Chiari malformation and other types of cerebellar disease, but clinical reports of unilateral skew deviation in patients with pure cerebellar disease are surprisingly rare.140 In retrospect, most cerebellar lesions purported to cause skew deviation with comitant hypertropia have been large,181 and have probably involved adjacent brainstem vestibulo-ocular pathways, and this was the cause of the observed skew deviation.115, 157

Recent evidence has confirmed that isolated cerebellar lesions can indeed cause skew deviation. Mossman and Halmagyi documented two patients with tonic contraversive partial ocular tilt reactions attributable to unilateral cerebellar lesions. Radtke described paroxysmal alternating skew deviation in a patient who underwent biopsy of the inferior cerebellar vermis resulting in destruction of the uvula. The localization of these lesions suggested that the ocular tilt reaction may be under inhibitory control of the ipsilateral caudal cerebellum.140 Wong and Sharpe described five patients with probable skew deviations caused by focal cerebellar lesions involving the vermis or hemisphere.220

3. Medial Longitudinal Fasciculus 

Because focal lesions of the medial longitudinal fasciculus can also produce an ocular tilt reaction, careful examination for skew deviation is especially important in patients with demyelinating disease.225 When skew deviation accompanies internuclear ophthalmoplegia, the higher eye is usually on the affected side, suggesting a rostral lesion of the medial longitudinal fasciculus after it crosses in the pons.84, 182 Patients with an unilateral internuclear ophthalmoplegia should also be examined for ocular torsion and a head tilt to the contralateral side.46, 180, 200, 225 In a retrospective series, Smith et al identified skew deviation in 43% of patients with unilateral internuclear ophthalmoplegia (mostly secondary to ischemic vascular disease) and in 13% of patients with bilateral internuclear ophthalmoplegia (mostly secondary to multiple sclerosis).182 In 10 of 12 unilateral cases, the higher eye was on the side of the MLF lesion.

Patients with unilateral internuclear ophthalmoplegia may also have a conjugate torsional nystagmus in which the upper poles of the eyes cyclorotate so as to beat toward the side of the lesion.55 When internuclear ophthalmoplegia is associated with diplopia, it is often incorrectly assumed that the diplopia is horizontal secondary to deficient adduction. In this setting, a patient may have a clinically nonevident skew deviation that is sufficient to prevent fusion. Placement of a small vertical prism may be all that is necessary to relieve the diplopia and restore binocular vision.

4. Midbrain 

It was noted long ago that skew deviation can be produced in monkeys by unilateral electrolytic lesions in the midbrain tegmentum.58 In experimental animals, electrical stimulation of the meso-diencephalon in the region of the interstitial nucleus of Cajal elicits a phasic (i.e., transient) ipsiversive head tilt and eye torsion, whereas lesions in the region of the interstitial nucleus of Cajal produce tonic (i.e., persistent) contraversive head tilt and eye torsion.3, 70, 89, 96, 101, 102, 109, 110, 111, 130, 201 Electrical stimulation in the region of the INC produces a phasic ipsiversive OTR.77, 78, 96, 129, 169 Patients with unilateral stereotactic midbrain lesions have also developed skew deviation.144

In humans, mesodiencephalic lesions involving the interstitial nucleus of Cajal produce an ocular tilt reaction that is contraversive if the lesion is inhibitory and ipsiversive and paroxysmal if the lesion is excitatory.89 The interstitial nucleus of Cajal is the most rostral midbrain structure in which a unilateral lesion induces the ocular tilt reaction or skew deviation.25 It is an important structure in the control of vertical and torsional head and eye position,193 and an essential component of the neural (velocity-to-position) integrator for both vertical and torsional eye movements.3, 4, 25, 51, 77, 99, 117

The current functional concept is that there are two distinct and separate brainstem structures controlling eye–head coordination in roll and pitch: the bilateral caudal vestibulo-ocular reflex with inputs from the otoliths and the vertical semicircular canals, and the bilateral rostral integration center (the interstitial nucleus of Cajal). If the ascending medullary graviceptive pathways are lesioned at the pontomesencephalic level, rostral to the downward branching of the vestibulo-spinal tracts, skew deviation and ocular torsion can occur in the absence of a head tilt.23 This mechanism explains some partial forms of ocular tilt reaction that are seen. Other mesencephalic lesions selectively affect descending pathways for eye–head coordination and produce a complete ocular tilt reaction with conjugate ocular torsion. These lesions involve descending pathways such as the tectoreticulospinal neurons that originate in the interstitial nucleus of Cajal and run through the medial longitudinal fasciculus to couple eye and head roll motion by excitatory projections.

When skew is accompanied by dorsal midbrain syndrome the lesion can be localized to the mesencephalon.50, 89, 148, 159, 168, 180, 213 Medially situated or bilateral midbrain lesions can produce lateral alternating skew deviation.118, 164, 165 Because the half cycles of see-saw nystagmus are identical to the eye movement abnormalities of the ocular tilt reaction,92 it is not surprising that jerk see-saw nystagmus and the ocular tilt reaction sometimes occur concomitantly in patients with midbrain lesions involving the interstitial nucleus of Cajal.14, 88, 92, 159 Rambold et al described a patient with congenital nystagmus who developed intermittent see-saw nystagmus with visible head oscillations that were synchronized to the nystagmus, suggesting a common oscillating signal for the generation of head and eye movements.159 Unilateral mesodiencephalic lesions that activate the rostral interstitial nucleus of the medial longitudinal fasciculus can produce an ocular tilt reaction or a jerk see-saw nystagmus with torsional fast phases that rotate the upper poles of the eyes toward the side of the lesion.14, 88

5. Thalamus 

Reports of skew deviation in patients with thalamic injury reflect injury to subthalamic structures.71, 121 Ischemic lesions involving the interstitial nucleus of Cajal often occur in association with paramedian thalamic infarctions. When a skew deviation occurs in association with pretectal extension of a thalamic hemorrhage, the higher eye is usually ipsilateral.72 Kumral et al found skew deviation in 17 of 55 (31%) patients with posterior thalamic hemorrhage, 14 of who had a large thalamic hemorrhage.120

In 1993, Brandt and Dieterich examined 35 patients with acute thalamic infarctions and found that 8 of 14 patients with paramedian infarctions had a complete ocular tilt reaction.60 The ocular tilt reaction in these patients was due to ischemia of the rostal midbrain tegmentum (including the interstitial nucleus of Cajal) and not to thalamic injury per se. Eleven of 17 patients with posterolateral infarctions of the thalamic nuclei exhibited tilts of the subjective visual vertical that were either ipsiversive or contraversive. Anteromedial infarctions did not affect vestibular function in the roll plane. These results indicate that the interstitial nucleus of Cajal and the rostral interstitial nucleus of the MLF are the most rostral brainstem structures mediating eye-head coordination in roll.60 Unilateral lesions of vestibular structures rostral to the interstitial nucleus of Cajal manifest with deviations of perceived vertical without concurrent eye-head tilt.25, 60

6. Vestibular Cortex 

Unilateral lesions of vestibular structures rostral to the INC (i.e., the vestibular thalamus and vestibular cortex) cause mostly contraversive tilts in the subjective visual vertical without concurrent eye-head tilt.22, 25 Tilts in the subjective visual vertical caused by lesions in the vestibular cortex may be associated with a compulsory lateropulsion.22 The overlapping areas of infarction centered on the posterior insula, suggesting that the parieto-insular vestibular cortex seems to represent the integration center of the multisensory vestibular cortex areas within the parietal lobe.30

X. Clinical Subtypes 

Smith et al divided skew deviation into three classic subtypes (comitant, laterally comitant, and lateral alternating skew deviation).181 Additional forms such as paroxysmal skew deviation, alternating skew deviation, and transient neonatal skew have since been recognized.

E. Lateral Alternating Skew Deviation 

Lateral alternating skew deviation refers to a reversing hypertropia that is present in each lateral position of gaze. Most commonly the abducting eye is higher but sometimes the adducting eye can be higher.115, 141 It has long been suspected that laterally alternating skew deviation results from bilateral rather than unilateral involvement of central otolithic pathways.24, 84, 115, 116, 144 Only recently, however, has evidence accumulated to explain the specific ocular motor effects of bilateral brainstem lesions.

Cogan first reported bilateral abduction hypertropia in a patient with downbeating nystagmus and basilar invagination.45 In 1985, Keane examined 408 patients with skew deviation and found that 47 (12%) had a skew deviation that alternated on gaze to either side.115 Pretectal lesions were responsible for 29 cases and lower brainstem lesions were seen in 5 cases. Acute hydrocephalus, tumors, strokes, and multiple sclerosis were the most common causes, followed by spinocerebellar disease and tectal herniation. In 23 patients the adducting eye was higher, in 22 it was lower, and in 2 it reversed on repeat examination. This suggested that bilateral alternating skew deviation may localize to the pretectal area.115 In 1988, Moster et al described 53 patients with alternating skew deviation in lateral gaze with hypertropia of the abducting eye.141 Most patients had associated downbeating nystagmus and ataxia and were diagnosed as having lesions of the craniocervical junction. The localization of these lesions contrasted sharply with those in Keane's report, where lesions were found mainly in the midbrain pretectum. It is now established that lateral alternating skew deviation results from bilateral injury to central graviceptive pathways which extend from the medulla to the midbrain.24 Because these pathways can be injured at any point along their course, it should be expected that bilateral lesions at many positions along the brainstem can produce this ocular motility disorder.24

In 1995, Brandt and Dieterich suggested that overlapping pathways modulate roll and pitch function of the vestibulo-ocular reflex, making efficient use of the vestibular network.24 According to their hypothesis, a unilateral skew deviation reflects a central graviceptive imbalance in the roll plane, while bilateral paramedian lesions or bilateral dysfunction of the cerebellar flocculus produces a tone imbalance in the pitch plane. The principle behind this operation resembles the guidance system of airplanes, in which unilateral activation of a brake flap causes the plane to roll but bilateral activation results in downward pitch. In a bilateral ocular tilt reaction, the vertical components summate to produce the slow phase vertical drift of both eyes while the torsional components cancel each other. Thus, a unilateral roll imbalance manifests as an ocular tilt reaction, while bilateral otolithic imbalance produces vertical nystagmus in conjunction with an alternating skew on lateral gaze.24

Because central otolithic pathways corresponding to the anterior and posterior semicircular canals (which subserve forward and backward body pitch) are segregated in the brainstem, the clinical characteristics of bilateral alternating skew deviation may simply reflect the pattern of injury to these pathways. A bilateral neurologic lesion that selectively inhibits those otolithic pathways corresponding to the anterior semicircular canals would lead to a predominance of output from otolithic pathways corresponding to the posterior semicircular canals (Fig. 8). 24 Brandt and Dieterich coined the term posterior canal predominance for this type of central vestibular imbalance, which would increase tonus to the inferior rectus and superior oblique muscles of both eyes.67 Because the vertical action of the superior oblique muscles is more prominent in adduction, the abducting eye would display a hypertropia on gaze to either side (Fig. 8). A recent evolutionary hypothesis by Zee similarly invokes the innervational effects of body pitch during lateral gaze in lateral eyed animals to similarly explain why lateral alternating skew deviation could result from a central pitch imbalance.224

Fig. 8. Lateral alternating skew deviation. Top: Diagram depicting the ocular motor affects of bilateral prenuclear lesions affecting otolithic pathways corresponding to the anterior semicircular canals. These lesions would activate the posterior semicircular canals which excite all four depressors. The greater torsional actions of the superior oblique muscles in primary position also produces static intorsion of the globes. Bottom: Because the vertical actions of the oblique and rectus muscles summate in adduction (the oblique muscles have mainly a torsional effect in abduction), this disorder results in laterally alternating skew deviation with overdepression of the adducting eye. (Reprinted from Brodsky and Donahue38 with permission of the American Medical Association.)

XI. Differential Diagnosis 

A. General 

Skew deviation and its associated ocular tilt reaction are usually readily differentiated from the vertical ocular misalignment caused by restriction (blow out fracture, congenital fibrosis syndrome, Brown syndrome, orbital fibrous bands, paretic disease—some forms of double elevator palsy, superior or inferior division third nerve palsy, etc.), neuromuscular junction disease (myasthenia gravis), innervational disorders (dissociated vertical divergence), and rare disorders such as extraocular muscle aplasia1, 32, 183 (Table 1). In the patient with acute neurologic disease, however, the prenuclear ocular tilt reaction must be carefully distinguished from nuclear or peripheral oculomotor and trochlear lesions, especially when the midbrain tegmentum is involved.62, 150 In a cranial nerve palsy, any perceived tilt in the subjective visual vertical is secondary to the ocular torsion, whereas in the ocular tilt reaction, the ocular torsion is secondary to the subjective visual tilt (or both may be secondary to the underlying central vestibular disturbance). Unilateral oculomotor or trochlear palsy should be suspected when ocular torsion and tilt in the subjective visual vertical are measurable in one eye only.62 In bilateral fourth nerve palsy, monocular measurements show subjective visual tilts for both eyes in opposite directions.25 A prenuclear tegmental lesion can rarely injure the cranial nerve nucleus or nerve fascicle and produce a combined prenuclear and fascicular lesion,62 resulting in a skew deviation plus an oblique muscle palsy. These disorders produce complicated ocular motility findings depending upon the relative damage to each structure.

Table 1. Skew Deviation: Differential Diagnosis

	Neurologic
	• Superior Oblique Palsy
	• Inferior Oblique Palsy
	• Superior Division 3rd Nerve Palsy
	• Third Nerve Palsy
	• Ocular Neuromyotonia
	Neuro-Muscular
	• Myasthenia Gravis
	• Systemic Botulism
	• Lambert-Eaton Syndrome
	Restrictive (positive forced ductions)
	• Thyroid Eye Disease
	• Monocular Elevation Deficiency
	• Congenital Fibrosis Syndrome
	• Acquired Brown Syndrome
	• Chronic Progressive External Ophthalmoplegia
	• Orbital Fibrous Bands
	Congenital
	• Brown Syndrome
	• Superior Oblique Palsy
	• Monocular Elevation Deficiency
	• Extraocular Muscle Aplasia

B. Skew Deviation Simulating Superior Oblique Palsy 

Kushner has noted that skew deviation can sometimes simulate superior oblique palsy during Bielschowsky Three-step testing.122 Because both disorders can result from traumatic or neurological injury to the posterior fossa,32, 184 skew deviation should always be a diagnostic consideration in patients with apparent superior oblique palsy. Superior oblique palsy with spread of comitance can also mimic a comitant skew deviation since both conditions are associated with a head tilt that is directed toward the side of the lower eye. In this setting, the positive Bielschowsky Head Tilt test and the ocular torsion, as measured by fundus observation, must be used to distinguish the two disorders (Table 2).

Table 2. Ocular Tilt Reaction Versus Superior Oblique Palsy

	Prenuclear Lesion (Ocular Tilt Reaction)	Superior Oblique Palsy
	Intorsion of higher eye/extorsion of the lower eye	Extorsion of higher eye
	Binocular tilt of subjective visual vertical	Monocular tilt of subjective visual vertical
	Head tilt compensatory for altered subjective visual vertical	Head tilt compensatory for vertical diplopia

In 1999, Donahue et al described 5 patients with hypertropia and contralateral head tilt, in whom the Bielschowsky Head Tilt test suggested superior oblique palsy68 (Fig. 9). Although extorsion of the higher eye characterizes superior oblique palsy, these patients had extorsion of the lower eye and/or intorsion of the higher eye, indicating an ocular tilt reaction. All patients had other neurologic features consistent with more widespread brainstem disease. The authors interpreted the findings from the three-step test to be indicative of selective injury to the otolithic pathways corresponding to the anterior semicircular canals, and cautioned that examination of objective fundus torsion in both eyes is necessary to rule out an ocular tilt reaction and differentiate the incomitant hypertropia of apparent superior oblique palsy from skew deviation. Mechanical anomalies within the orbital pulley system (a lower lateral rectus muscle pulley on one side) can also manifest as unilateral superior oblique palsy.57

Fig. 9. Ocular tilt reaction simulating superior oblique palsy. Top left: Facial photograph demonstrates a left head turn and a slight head tilt. Top right: Field measurements are consistent with right superior oblique palsy (HT = hypertropia). Bottom left and right: Retinal photographs show intorsion of the higher eye and extorsion of the lower eye which signifies an ocular tilt reaction. (Reprinted from Donahue et al68 with permission of the American Medical Association.)

XII. Expanding the Definition of Skew Deviation 

Our traditional application of the term skew deviation to patients with neurologic disease leaves us with a hemianopic view of this disorder and its underlying physiology. In lower animals, the central vestibular system uses weighted graviceptive input from the two labyrinths and weighted visual input from the two eyes to establish subjective vertical orientation in the roll and pitch plane.38 These primitive reflexes can be detected in normal humans, wherein a cycloversion movement (a conjugate torsional rotation of both eyes as occurs in the ocular tilt reaction) is evoked by visual or graviceptive imbalance in the roll plane, while a cyclovergence movement (a disconjugate torsional rotation of both eyes resulting in intorsion or extorsion of both eyes) is evoked by a visual or graviceptive imbalance in the pitch plane.35 Although the binocular visual system is normally subordinate to the peripheral vestibular system in establishing extraocular muscle tone, these primitive reflexes manifest in the setting of congenital strabismus.38 Thus, a unilateral or asymmetrical loss of otolithic tone secondary to brainstem, cerebellar, or utricular injury causes a skew deviation, while asymmetrical visual input in the setting of congenital strabismus evokes dissociated vertical divergence.36, 37 The same interrelationship is evident in the pitch plane, where a bilateral loss of otolithic tone causes lateral alternating skew deviation while asymmetrical visual input can produce primary inferior oblique muscle overaction.35, 38

A. Dissociated Vertical Divergence 

Dissociated vertical divergence (DVD) is an ocular motor disorder characterized by a slow upward drift of either eye, followed, after a variable period of time, by a slow descent of the higher eye back to the neutral position (Fig. 10). The hyperdeviating eye extorts during its ascent and intorts as it descends to resume fixation. Dissociated vertical divergence most commonly accompanies congenital esotropia, but is also seen with rarer forms of congenital strabismus.37

Fig. 10. Dissociated vertical divergence. In the patient with congenital strabismus, unequal binocular visual input exerts the same physiologic effect as unbalanced utricular input, producing a combined vertical divergence and cycloversion of the eyes. In DVD, however, the cycloversion movement is opposite in direction to that seen with the utricular ocular tilt reaction. (Reprinted from Brodsky36 with permission of the American Medical Association.)

Dissociated vertical divergence recapitulates the primitive dorsal light reflex, wherein asymmetrical visual input to the two eyes evokes a vertical divergence movement.37 Like the otolithic ocular tilt reaction, this visuo-vestibular reflex also functions as a righting reflex in lateral-eyed animals to restore vertical orientation by equalizing visual input to the two eyes.37 Brodsky has proposed that dissociated vertical divergence is a human dorsal light reflex, which is normally suppressed except when early onset strabismus precludes the development of single binocular vision in infancy (Fig. 10).36, 37 In this setting, the two eyes revert to their primitive ancestral function as sensory balance organs. Dissociated vertical divergence appears to be a second type of ocular tilt reaction that produces a vertical divergence with intorsion of the lower eye and extorsion of the higher eye.37 This vertical divergence can be conceptualized as an inverse skew deviation that is driven by unequal visual input to the two eyes rather than unequal graviceptive input to the two labyrinths.37 Vertical divergence of the eyes with these inverse torsional characteristics seems to be a signature of abnormal binocular vision.37 Dissociated vertical divergence may also contribute to the physiologic hyperphoria that is evoked in normal individuals by occlusion or Maddox rod testing.127, 147, 179

C. Acquired Comitant Esotropia 

Acquired comitant esotropia is a perplexing disorder that is also produced by structural lesions within the posterior fossa. Because these lesions affect neurologic pathways subserving horizontal rather than vertical vergence mechanisms, they bear a pathophysiologic resemblance to skew deviation. Acquired comitant esotropia can be produced by structural lesions localized to the posterior fossa such as cerebellar vermal tumors or Arnold Chiari malformations.106, 107, 125, 218 Some patients may also have divergence insufficiency.44, 125 Because these prenuclear lesions presumably disrupt central vestibular pathways subserving horizontal rather than vertical vergence, the resulting esodeviation can be by conceptualized as a horizontal skew deviation, recognizing its mechanistic overlap with other forms of skew deviation.34

The physiologic underpinnings of horizontal skew deviation may lie in the translational vestibulo-ocular reflex. During fore-and-aft translation, vestibularly driven eye movements use radial optic flow and binocular disparity vergence to minimize head movement induced modulation of the fixation plane.135 Visual tracking mechanisms that address translational disturbances are most accurately tuned for headings in the fore-aft axis (i.e., the surge plane) (Table 3).6 Disconjugate vergence movements during fore-and-aft translations exhibit much higher gains (at or above unity) than conjugate version movements during lateral translation in the lateral plane (approximately 0.5), suggesting that the translational vestibulo-ocular reflex is tuned to stabilize binocular gaze in the same depth plane during translational movements.6

Table 3. The Three Dimensions of Skew Deviation

	Clinical Disorder	Plane	Laterality	Pathways
	Skew deviation	Roll plane	Unilateral	Brain stem graviceptive pathways modulating otolithic tone
	Lateral alternating skew deviation	Pitch plane	Bilateral	Brain stem graviceptive pathways modulating otolithic tone
	Horizontal skew deviation	Surge plane	? Midline	Cerebellar pathways mediating translational VOR

While prenuclear lesions that disrupt vertical vergence generally localize to the brainstem, those that disrupt horizontal vergence tend to localize to the cerebellum.207 Although little is known about the neurologic substrate of the translational vestibulo-ocular reflex, monkeys with lesions involving the dorsal cerebellar vermis develop an esotropia that is greater at distance than at near fixation.194, 195 Similar observations are made clinically in adults with cerebellar disease who develop a divergence insufficiency-type esotropia. The dorsal vermis projects to the fastigial oculomotor region, which has been implicated in the control of vergence.195 Neurons have been identified within the cerebellar vermis that modulate with convergence alone (Zhang HY, Gamlin PDR: Single-unit activity within the posterior fastigial nucleus during vergence and accommodation in the alert primate. Soc Neurosci Abstr 1996:22) Humans with global cerebellar dysfunction can have an esophoria during monocular viewing and a smaller esotropia during binocular viewing, suggesting an increase in esotonus to the extraocular muscles with a relatively preserved ability to use horizontal disparity cues to drive motor fusion.194 Further study will be necessary to determine whether patients with acquired comitant esotropia or divergence insufficiency experience an altered internal representation of proximity (Table 3).34

XIII. Prognosis and Treatment 

Because most ocular tilt reactions are transient and spontaneous recovery is the rule,18, 123 surgical therapy should be deferred for several months. During this period, prismatic treatment or botulinum therapy can provide adequate symptomatic relief of vertical diplopia. Prisms, botulinum toxin, and vertical rectus muscle recession have all been touted as effective treatments for vertical diplopia secondary to persistent skew deviation.40, 123, 146, 160, 174 The resolution of the ocular tilt reaction after unilateral vestibular deafferentation may be an index of vestibular compensation.90

It is important to recognize that these treatments will not eliminate the head tilt component (which is secondary to a central tilt in the subjective visual vertical and not compensatory for the vertical diplopia). As noted above, the patient is usually unaware of the head tilt and grateful to be relieved of vertical diplopia following successful treatment. Treatment of a persistent head tilt poses a paradoxical therapeutic dilemma. Because the head tilt serves to realign the head to a tilted subjective vertical, any effort to simultaneously treat the head tilt would require surgically augmenting the torsional deviation to rotate the eyes further in the direction of the head tilt. This surgical cyclorotation of the eyes would serve to counter-rotate the visual world in the opposite direction (i.e., back toward the true earth vertical) and thereby eliminate the need for a compensatory head tilt. This therapeutic principle also underlies the use of horizontal transposition of the vertical rectus muscles or oblique muscle surgery in children with idiopathic torticollis and head tilts associated with congenital nystagmus. In patients with ocular tilt reactions, this procedure could be combined with vertical rectus muscle recessions to treat both components of the ocular tilt reaction.

XIV. Questions 

Our enormous progress in elucidating the pathophysiology of skew deviation raises a number of new questions. Because skew deviation is often associated with conjugate ocular torsion, are some patients with unilateral otolithic dysfunction using a combination of horizontal and vertical convergence to fuse a hyperphoria? Perhaps patients with manifest hypertropia represent the most severe end of the spectrum. Is the subjective visual tilt necessarily the cause of the skew deviation, ocular torsion, and head tilt? Although these three ocular motor phenomena accompany subjective visual tilt in the context of an ocular tilt reaction, recovery of all these ocular motor phenomena is not necessarily coincident with normalization of the subjective visual vertical. It is therefore possible that neurologic disease causes the ocular tilt reaction and the subjective visual tilt together, with the subjective sense of vertical the most easily disrupted and the last to return to normal. Why is there so little physiologic skew deviation? What are the antivestibular forces independent of fusion that minimize physiologic skew deviation during physiologic head tilt? Do some idiopathic head tilts (without strabismus) result from a central or peripheral otolithic imbalance? It is well to remember that, when we treat idiopathic head tilts by torsional rotating the eyes in the direction of the head tilt, we are surgically inducing a contraversive subjective visual tilt to neutralize the head tilt.

XV. Conclusions 

Skew deviation has evolved from a descriptive term to a precise physiological mechanism of injury. Skew deviation results from a unilateral lesion that unilaterally injures the otolithic pathways and thereby causes the brain to perceive the world as tilted. The resulting vertical deviation is but one part of an ocular tilt reaction which rotates the eyes and head toward the tilted visual world to restore vertical orientation. Skew deviation can be caused by a lesion to utricular pathways anywhere from the utricle to midbrain. Partial injury that involves only those pathways corresponding to the anterior or posterior semicircular canals produces incomitant skew deviation, while lateral alternating skew deviation results from symmetric bilateral lesions involving these same pathways. While unilateral skew deviation corresponds to central graviceptive dysfunction of otolithic pathways in the roll plane, lateral alternating skew deviation corresponds to a central graviceptive dysfunction of otolithic pathways in the pitch plane. A developmental imbalance in visual input between the two eyes produces a constellation of ocular motility abnormalities that is strikingly similar to those produced by the two labyrinths, suggesting that our eyes retain their primitive evolutionary function as balance organs. By expanding our clinical definition of skew deviation to include those central vestibular imbalances induced by binocular imbalance, we can broaden our physiologic perspective of skew deviation.

Several challenges face the ophthalmologist who is evaluating a vertical ocular deviation of neurologic origin. First, the clinician must look for associated signs and symptoms of skew deviation (tilt of the subjective visual vertical, head tilt, torsion). Second, the clinician must measure the hyperdeviation in different fields of gaze to not only identify clinical subtypes of skew deviation, but to recognize incomitant forms of skew deviation that are due to selective patterns of injury to the anterior or posterior semicircular canals, and to distinguish them from isolated superior or inferior oblique muscle palsy. Third, it should be remembered that lesions producing skew deviation can also compromise ocular motor nerve function to produce a complex clinical picture. Finally, developmental aberrations in binocular alignment can produce equivalent ocular motility disturbances and must be considered in the differential diagnosis.

XVI. Method of Literature Search 

References were obtained from English and non-English references for skew deviation, and ocular tilt reaction. English references from 1966 to 2005 were obtained from MEDLINE, and older English and non-English references were obtained from neuro-ophthalmology textbooks and major articles that addressed the topic of skew deviation. Due to the large number of experimental animal studies investigating the ocular motor consequences of brainstem or cerebellar lesioning on vertical ocular alignment, only the seminal neurophysiologic studies that related directly to the mechanism of skew deviation and the ocular tilt reaction were cited.