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Invited Review

Ocular Motor and Vestibular Disorders in Brainstem Disease

Choi, Woo Young*; Gold, Daniel R.

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Journal of Clinical Neurophysiology: November 2019 - Volume 36 - Issue 6 - p 396–404
doi: 10.1097/WNP.0000000000000593
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Abstract

The brainstem contains ocular motor and vestibular structures that are associated with specific eye movement disorders when damaged (Fig. 1).1,2 Clinical observation of abnormal eye movements and working knowledge of the underlying anatomy are crucial for accurate localization. We will start with a brief overview of the brainstem structures involved in the three specific syndromes that will be discussed in this review (lateral medullary [Wallenberg] syndrome, medial longitudinal fasciculus [MLF] syndrome, and oculopalatal tremor [OPT]).

FIG. 1
FIG. 1:
Left—axial view of the medulla demonstrating structures that produce specific ocular motor and vestibular syndromes (discussed below). Right—sagittal view of the brainstem showing ocular motor nuclei (third, fourth, sixth), saccade generating (burst) neurons (paramedian pontine reticular formation for horizontal and riMLF for vertical/torsional), and gaze-holding (neural integrator) neurons (NPH-MVN for horizontal and INC for vertical/torsional). III, third nerve nucleus; IV, fourth nerve nucleus; VI, sixth nerve nucleus; CCN, central caudal nucleus (innervates bilateral levator palpebrae muscles); ICP, inferior cerebellar peduncle; INC, interstitial nucleus of Cajal; IVN, inferior vestibular nucleus; MLF, medial longitudinal fasciculus; MVN, medial vestibular nucleus; NPH, nucleus prepositus hypoglossi; PC, posterior commissure (involved in the dorsal midbrain or Parinaud's syndrome); PPRF, paramedian pontine reticular formation; riMLF, rostral interstitial nucleus of medial longitudinal fasciculus. Source: Neuro-Ophthalmology Virtual Education Library: NOVEL [Online]. Available at: https://collections.lib.utah.edu/ark:/87278/s6x38rgb and https://collections.lib.utah.edu/ark:/87278/s6j13x04. Accessed December 7, 2018.

BRAINSTEM STRUCTURES RESPONSIBLE FOR NORMAL OCULAR MOTOR AND VESTIBULAR FUNCTION

A lateral medullary lesion that involves the inferior cerebellar peduncle often results in asymmetry of the saccade excitation/inhibition pathways, resulting in ipsilesional ocular lateropulsion (or ipsipulsion), ipsilesional saccadic hypermetria, and contralesional saccadic hypometria.1,2 Afferents leaving the peripheral utricle to synapse in the vestibular nucleus may also be damaged in this vicinity, leading to an ocular tilt reaction (OTR) in the lateral medullary syndrome.

The MLF carries many of the fibers originating in the labyrinthine utricle and semicircular canals (SCCs) to their respective ocular motor nuclei.1,2 In addition to the well-known internuclear ophthalmoplegia (INO) where abducting nystagmus is a prominent feature, MLF lesions can cause other patterns of nystagmus. The MLF syndrome can also be associated with OTR and vestibulo-ocular reflex (VOR) deficits.

The inferior olivary nucleus is a nuclear complex found in the ventral medulla, dorsal to the pyramids and lateral to the medial lemniscus.1–3 It is thought to play a physiological role in adaptive motor control. Lesions involving the connections of the inferior olivary nucleus commonly lead to hypertrophic degeneration and the syndrome of OPT.

LATERAL MEDULLARY SYNDROME

The lateral medullary (or Wallenberg) syndrome is usually caused by occlusion of the ipsilateral vertebral artery or the posterior inferior cerebellar artery.1,4–6 Ischemia is the most common etiology, although a demyelinating lesion can also cause a Wallenberg syndrome.7,8 Classic neurologic findings include ipsilateral loss of pain and temperature sensation of the face (involvement of the descending nucleus and tract of the trigeminal nerve), contralateral loss of pain and temperature sensation in the trunk and limbs (spinothalamic tract), hoarseness, hiccups and dysphagia (nucleus ambiguous), ipsilateral Horner syndrome (descending oculosympathetic tract), ipsilateral limb ataxia, gait ataxia, and lateropulsion (inferior cerebellar peduncle) (video example of a complete Wallenberg syndrome—https://collections.lib.utah.edu/ark:/87278/s6963fhm).2,9 Ocular motor and vestibular symptoms and signs may include diplopia, vertigo, and nystagmus and can be some of the most disabling features. We will now review the major ocular motor and vestibular manifestations of the Wallenberg syndrome, including ipsilateral ocular lateropulsion (or ipsipulsion) and the OTR. While spontaneous nystagmus and involvement of the VOR are less common features (i.e., given the medial location of the medial vestibular nucleus [MVN]), they will also be discussed briefly.

Ocular Lateropulsion

Lateropulsion is the sensation of being pulled toward the side of the lesion.1,10 Commonly, patients with a Wallenberg syndrome have gait ataxia and veer or lean ipsilaterally, while the eyes will also deviate toward the side of the lesion (known as ipsipulsion) in the dark, behind closed lids or with a blink. Saccades are also affected and will be dysmetric—e.g., saccadic hypermetria (overshooting) ipsilaterally and saccadic hypometria (undershooting) contralaterally.11–14 Ipsipulsion can also be seen during vertical saccades—for example, an upward or downward saccade will have an ipsilesional (leftward) trajectory in the (left) Wallenberg syndrome (video example of saccadic hypermetria, ipsipulsion under closed lids, and lateropulsion of vertical saccades—https://collections.lib.utah.edu/ark:/87278/s64r24wd).

The hypothetical mechanism for this ocular lateropulsion has been developed in animal studies that showed ipsipulsion of saccades and deviation of the eyes toward the lesion side after inactivation of caudal fastigial nucleus.15,16 In this scheme (Fig. 2), the left inferior cerebellar peduncle carries climbing fibers from the right inferior olive to the left dorsal vermis, and these fibers have an inhibitory influence over the Purkinje cells. The inhibitory Purkinje cells project to the ipsilateral fastigial nucleus. Excitatory fibers from the left fastigial nucleus decussate and pass through the right fastigial nucleus (explaining why a unilateral fastigial lesion causes bilaterally hypermetric saccades) and on to the right inhibitory burst neuron (located caudal to the sixth nucleus, which will inhibit the contralateral [left] excitatory burst neuron/inhibitory burst neuron pair) and excitatory burst neuron (located in the paramedian pontine reticular formation) pair. Excitation of the right excitatory burst neuron activates the right sixth nucleus (directly facilitates rightward conjugate eye movements) while simultaneous excitation of the right inhibitory burst neuron inhibits the left sixth nucleus (indirectly facilitates rightward conjugate eye movements), thereby providing reciprocal innervation. In this scheme, the result of a lesion involving the climbing fibers within the left lateral medulla is hypoactive rightward saccades (contralesional hypometria) and overactive leftward saccades (ipsilesional hypermetria), and ipsipulsion (video example of ipsilesional hypermetria, contralesional hypometria, and ipsipulsion—https://collections.lib.utah.edu/ark:/87278/s65176w6).17–19 This scheme also explains contrapulsion and contralesional hypermetric saccades that would result from a lesion involving the right superior cerebellar peduncle (after the decussating fibers from the fastigial nucleus)20 or the right medial medulla (before the decussating climbing fibers).21,22

FIG. 2
FIG. 2:
Left—normal saccadic pathways in the brainstem and cerebellum resulting in reciprocal innervation of EBN/IBN pairs to facilitate or inhibit saccades to the right and left. Middle—imbalance in the saccadic pathways results in ipsipulsion and saccadic dysmetria with a left lateral medullary lesion (lightning bolt). Right—MR fluid attenuation inversion recovery demonstrating a left lateral medullary stroke. VI, sixth nerve nucleus; EBN, excitatory burst neuron; IBN, inhibitory burst neuron; ICP, inferior cerebellar peduncle; PPRF, paramedian pontine reticular formation; SCP, superior cerebellar peduncle. Source: Neuro-Ophthalmology Virtual Education Library: NOVEL [Online]. Available at: https://collections.lib.utah.edu/ark:/87278/s67h5cjg. Accessed December 2, 2018.

Nystagmus

Given the lateral and caudal location of the Wallenberg syndrome, the rostral and medial (i.e., MVN) structures tend to be spared so that nystagmus may not be a prominent feature of the syndrome. However, when spontaneous nystagmus is present, it is usually horizontal or mixed horizontal—torsional with a small vertical component.2,23,24 In straight ahead gaze, the slow phase of the nystagmus is usually ipsilesional, and if the MVN-nucleus prepositus hypoglossi complex is involved, gaze-evoked nystagmus (i.e., right-beating in right gaze and left-beating in left gaze) results. After passive 2 to 3 Hz horizontal head-shaking in a Wallenberg syndrome, head-shaking-induced nystagmus can be ipsilesional (even when spontaneous nystagmus is contralesional), likely resulting from disinhibition of velocity storage connections between the unilateral vestibular nucleus and cerebellar nodulus/uvula.23 At the level of the medulla, spontaneous nystagmus can have features that are typically thought of as being “peripheral” including a unidirectional pattern; follows Alexander's Law (nystagmus increases in intensity in the direction of the fast phase); and suppresses with visual fixation.

VOR

The afferents originating in the horizontal SCCs of the labyrinth synapse in the MVN, so if these fibers are spared, the horizontal VOR will be intact. If the MVN is involved, an abnormal (positive) head impulse test (HIT) can be seen, which is typically suggestive of a peripheral vestibular disorder like vestibular neuritis.25,26 During a normal HIT, each time the patient's head is moved quickly to the right or to the left, the patient's eyes will remain on the visual target that is typically the examiner's nose (video example of a normal HIT [second half of video]—https://collections.lib.utah.edu/ark:/87278/s63b97tz). With an abnormal HIT, the patient's eyes will momentarily move with the head because of a deficient ipsilateral VOR, which will require the patient to make a catchup or refixation saccade to bring the eyes back to the visual target (video example of a bilaterally abnormal HIT [second half of video]—https://collections.lib.utah.edu/ark:/87278/s62z4z8g). Therefore, while an abnormal HIT is usually indicative of a peripheral cause of the acute vestibular syndrome, a normal HIT is highly suggestive of a central localization.27 A central localization of the acute vestibular syndrome should be assumed if any of the following are seen: normal HIT, gaze-evoked nystagmus, or a skew deviation per the “HINTS” examination (Head Impulse, Nystagmus, Test of Skew).28–31

OTR

The OTR is thought to be due to an imbalance in the roll plane involving the utriculo-ocular motor or graviceptive pathways (which modulate both otolithic [utricle] and vertical SCC afferents).32 While vestibular jerk nystagmus is a consequence of static SCC pathway imbalance (e.g., left-beating nystagmus because of acute right vestibular hypofunction from right-sided vestibular neuritis), the OTR is thought to represent static utricle/graviceptive pathway imbalance in the roll plane. The labyrinth contains the linear acceleration detectors (otoliths), including the saccule and utricle. The utricle responds not only to linear translation, but also to static head tilt. In the physiologic OTR, a motorcyclist, for example, going around a tight curve to the right will experience a rightward head and body tilt to the right, which excites the right utricle and causes an increase in its firing rate. The major component of the physiologic OTR will be a large head tilt to the left to reflexively reorient the head back to the gravitational vertical. These utricular afferents will synapse in the right vestibular nucleus in the medulla. The utriculo-ocular motor fibers that began on the right side then decussate at the level of the pontomedullary junction and ascend as part of the left MLF. Afferents travel via the MLF to the third and fourth nuclei in the left midbrain, as well as to the interstitial nucleus of Cajal (Fig. 3). The right eye elevates from contraction of the right (superior rectus, decussating fibers from the left third nucleus) and incycloducts from contraction of the right (superior oblique, decussating fibers from the left fourth nucleus). The left eye depresses from contraction of the left inferior rectus (fibers from the left third nucleus), and excycloducts from contraction of the left inferior oblique (fibers from the left third nucleus). Finally, some of the utricle afferents ascending in the left MLF will synapse in the left interstitial nucleus of Cajal, which is responsible for vertical and torsional gaze-holding. This ensures that the eyes will stay in the desired position while the head tilt is maintained.

FIG. 3
FIG. 3:
Left—primary and secondary actions of the cyclovertical extraocular muscles. Middle—normal utriculo-ocular motor pathways. Right—with a left lateral medullary lesion (lightning bolt), there is an imbalance in the utricle pathway tone, causing a left head tilt, skew deviation (ipsilesional hypotropia), and ocular counterroll (top poles toward the left ear), which makes up the pathologic OTR. III, third nerve nucleus; IV, fourth nerve nucleus; VI, sixth nerve nucleus; INC, interstitial nucleus of Cajal; IO, inferior oblique; IR, inferior rectus; LR, lateral rectus; MLF, medial longitudinal fasciculus; MR, medial rectus; SO, superior oblique; SR, superior rectus; VN, vestibular nucleus. Source: Neuro-Ophthalmology Virtual Education Library: NOVEL [Online]. Available at: https://collections.lib.utah.edu/ark:/87278/s6k97g27. Accessed December 2, 2018.

While the head tilt is the major component of the physiologic OTR, the skew (elevation in one eye and depression in the other) and ocular counterroll (cycloduction of both eyes—top poles rotate toward the same ear) are minute. In humans, a static head tilt causes counterrolling of the eyes that is equal to only about 10% of the head roll.33–38 This means that the static ocular response does not compensate for the head tilt and is thought to be vestigial. In contrast, central (rarely peripheral) lesions that disrupt utricle pathways can cause a pathological OTR with large amounts of skew deviation and ocular torsion (as much as 25°).1

In the case of a complete OTR resulting from a left Wallenberg syndrome (Fig. 3), the following will be seen: skew deviation with left (ipsilateral) hypotropia, left (ipsilateral) head tilt, leftward (ipsilateral) conjugate counterroll (top poles rotate toward the left ear—incycloduction right eye and excycloduction left eye), and the perceptual consequence of the OTR is the subjective visual vertical (SVV), which is tilted (ipsilaterally) toward the left.1 The SVV represents a patient's perception of vertical compared with true earth vertical, and at the bedside, the bucket test can be used to quantify (in degrees) the impairment.39 A tilted or abnormal SVV is a common perceptual consequence of the OTR. While the OTR and SVV will be ipsiversive when the utriculo-ocular motor pathway is damaged caudal to its decussation (e.g., Wallenberg), the OTR and SVV will be contraversive when these fibers are damaged rostral to the decussation (e.g., interstitial nucleus of Cajal or MLF—see below).

Although a substantial pathological OTR is almost always caused by a central lesion (video example of a skew deviation due to multiple sclerosis [second half of video]—https://collections.lib.utah.edu/ark:/87278/s6ck1p47), a peripheral etiology is possible. For example, a small transient skew deviation is rarely seen in acute vestibular neuritis (video example of a patient with vestibular neuritis causing unidirectional nystagmus, ipsilesional abnormal HIT, and small skew deviation [second half of video]—https://collections.lib.utah.edu/ark:/87278/s6ht70fx). Nevertheless, the presence of a skew deviation should be considered central until proven otherwise. A skew deviation should be distinguished from a fourth nerve palsy that also causes a vertical misalignment. A fourth nerve palsy will cause a compensatory head tilt to the contralesional side, although there will be excycloduction in the hypertropic eye because of a fourth nerve palsy, as opposed to the incycloduction seen in the hypertropic eye because of a skew deviation.

MLF SYNDROME

Medial longitudinal fasciculus lesions are most commonly seen as the result of stroke or demyelination.1 Other causes such as neoplasms, infections, metabolic disorders, neurodegenerative conditions and channelopathies are rare.40–42 Lesions affecting the MLF cause an INO. Clinically, an INO can be diagnosed when an adduction paresis is seen in combination with an abducting nystagmus in the contralateral eye. For example in a left INO, there will be a left adduction paresis and abducting nystagmus in the right eye, and this will almost always be ipsilesional (i.e., after the interneurons from the right sixth nucleus decussate and ascend the left MLF to reach the subnucleus of the left medial rectus in the midbrain). The adduction deficit can range from a total medial rectus paralysis to a mild paresis that is only apparent as slowing of adducting saccades (adduction lag) with a full range of adduction (video examples of INO in multiple sclerosis—https://collections.lib.utah.edu/ark:/87278/s6tj1wb3). The same eye may be able to adduct more fully during convergence movements if the lesion involves the caudal MLF. If the lesion is more rostral and in proximity to the medial rectus subnucleus in the midbrain, then convergence will not overcome the medial rectus weakness. Another cardinal sign of INO is dissociated or abducting nystagmus on contralateral gaze, which is thought to result from the brain's attempts to compensate for the adduction weakness.43,44 While an INO is the most easily recognized ocular motor feature of an MLF lesion, it is often accompanied (at least acutely) by the OTR, spontaneous nystagmus, and an abnormal VOR. These features of MLF syndrome are discussed below.

OTR

The utriculo-ocular motor pathway crosses the midline at the pontomedullary junction and then ascends to the midbrain via the MLF to reach the third and fourth nuclei and the INC (Fig. 3). Medial longitudinal fasciculus lesions often cause a complete or partial OTR acutely, which rapidly improves.45 In addition to an exotropia from INO, a hypertropia of the ipsilesional eye due to skew deviation is commonly seen acutely and this is usually concomitant—i.e., the hypertropia is the same in all directions of gaze (straight ahead, right, left, up, down). Ocular counterroll, head tilt and SVV deviation are also commonly seen with an MLF lesion in the acute setting. In contrast to a Wallenberg in which the lesion is caudal to the decussation (pontomedullary region) of the utricle-ocular motor pathway so that the OTR and SVV are ipsiversive, the lesion is rostral to the decussation in the MLF syndrome, so that the OTR and SVV are contraversive. For example, a left MLF lesion is associated with hypertropia of the left eye, head tilt to the right, counterroll of both eyes (top poles) towards the right ear, and SVV tilted to the right.

Nystagmus

In addition to abducting nystagmus, an MLF lesion commonly causes other patterns of vertical and torsional nystagmus.1,46–48 Typically, such nystagmus due to an MLF lesion is seen acutely and will resolve within days. Four different patterns of vertical and torsional nystagmus can be identified (see below), each of which may cause oscillopsia. Of note, the spontaneous nystagmus in MLF syndrome can increase with removal of visual fixation, which is typically thought of as a peripheral feature of vestibular nystagmus, but may be seen in central vestibular nystagmus as well.49

Ipsiversive Conjugate Torsional Nystagmus

When vertical-torsional nystagmus is present and related to unilateral injury, it is always ipsiversive. In the case of left MLF syndrome, the anterior canal (AC) and posterior canal (PC) afferents that originated in the (contralateral) right labyrinth are involved (Fig. 4). However, those AC and PC afferents that originated in the (ipsilateral) left labyrinth and traversed the right MLF are unaffected. Therefore, the torsional nystagmus results from unopposed torsional slow phases (top poles of the eyes moving toward the right ear) generated by the normally functioning left AC and PC pathways, which is followed by a quick phase toward the left ear, and an ipsiversive (top poles toward the left ear) spontaneous nystagmus (video example of INO, skew and subtle ipsiversive nystagmus in acute MLF stroke—https://collections.lib.utah.edu/ark:/87278/s68m15w9).

FIG. 4
FIG. 4:
VOR pathways. Left—right HC pathway—afferents synapse in the right vestibular nucleus and then decussate to the left 6th nucleus, which innervates the LR, and send interneurons (travel through the right, MLF) from left sixth nucleus to right MR subnucleus. The ATD bypasses the MLF by sending afferents directly from the vestibular nucleus to the ipsilateral (right) MR subnucleus. Middle—right PC pathway—afferents synapse in the right vestibular nucleus, and then decussate and ascend in the left MLF to innervate the right SO and left IR. Right—right AC pathway—afferents synapse in the right vestibular nucleus, and ascend via three pathways: 1) MLF, 2) VTT, and 3) BC. The result is innervation of the right SR and left IO. III, third nerve nucleus; IV, fourth nerve nucleus; VI, sixth nerve nucleus; AC, anterior canal; ATD, ascending tract of Deiters; BC, brachium conjunctivum; HC, horizontal canal; INC, interstitial nucleus of Cajal; IO, inferior oblique; IR, inferior rectus; LR, lateral rectus; LVN, lateral vestibular nucleus; MLF, medial longitudinal fasciculus; MR, medial rectus; MVN, medial vestibular nucleus; PC, posterior canal; SO, superior oblique; SR, superior rectus; SVN, superior vestibular nucleus; VOR, vestibular-ocular reflex; VTT, ventral tegmental tract. Source: Neuro-Ophthalmology Virtual Education Library: NOVEL [Online]. Available at: https://collections.lib.utah.edu/ark:/87278/s63v3t3g. Accessed December 2, 2018.

Upbeat Nystagmus, More in the Contralesional Eye

The most common pattern is upbeat-torsional (ipsiversive) nystagmus, where there is more upbeat in the contralesional eye than in the ipsilesional eye (video example of spontaneous upbeat-torsional nystagmus in acute MLF stroke, more upbeat in contralesional eye, and more torsion in ipsilesional eye—https://collections.lib.utah.edu/ark:/87278/s6rz39rq). To explain this pattern, consider the AC or upward/antigravity pathways (Fig. 4). In the case of a left MLF syndrome, the excitatory fibers from the right AC decussate at the pontomedullary junction and ascend in the left MLF (in addition to the brachium conjunctivum and ventral tegmental tract) to innervate the right superior rectus and left inferior oblique muscles. Injury to the left MLF that mainly involves AC pathways would therefore cause more PC or downward tone/slow phase and upbeat nystagmus. Because the primary action of right superior rectus is supraduction, there should be more upbeat nystagmus in the right (contralesional) eye. Because the primary action of left inferior oblique is excycloduction, there should be more torsion in the left (ipsilesional) eye.

Downbeat Nystagmus, More in the Ipsilesional Eye

To explain this pattern, consider the PC or downward/gravity pathways (Fig. 4). In the case of left MLF syndrome, the excitatory fibers from the right PC decussate at the pontomedullary junction and ascend in the left MLF to innervate the right superior oblique and left inferior rectus. Injury to the left MLF that mainly involves PC pathways would therefore cause more AC or upward tone/slow phase and downbeat nystagmus. Because the primary action of right superior oblique is incycloduction, there should be more torsion in the right (contralesional) eye. Because the primary action of left IR is infraduction, there should be more downbeat in the left (ipsilesional) eye.

Hemi- or Jerky Seesaw Nystagmus

In hemi- or jerky seesaw nystagmus, the vertical components are in opposite directions (downbeat in the ipsilesional eye and upbeat in the contralesional eye), but with a conjugate ipsiversive fast phase. Damage to utricle and/or vertical SCC pathways is thought to be responsible for this nystagmus (Figs. 3 and 4). In the case of left MLF syndrome, the utricle fibers originating in the right labyrinth will decussate and ascend in the left MLF to innervate right superior rectus superior rectus and left inferior rectus inferior rectus. Because a skew deviation is a common consequence of an acute MLF lesion (left MLF lesion will result in the left eye being too high and the right eye being too low), the upward movement of the left eye and downward movement of the right eye due to the skew can be thought of as the slow phases, so that the fast phases are downward for the left (ipsilesional) eye and upward for the right (contralesional) eye. Another theory is that symmetric involvement of the vertical SCC pathways could cause ipsilesional downbeat (PC) and simultaneous contralesional upbeat (AC), resulting in a jerky seesaw pattern.1,48

VOR

Vertical VOR

It has been demonstrated that central pathways that originate in the contralateral vertical SCCs traverse the MLF.1,48,50 The posterior SCC pathway is much more affected by a unilateral MLF injury as compared to the anterior SCC pathway.50 This is because the fibers originating in the anterior SCC also travel through the brachium conjunctivum and ventral tegmental tract (Fig. 4). Therefore, anterior SCC function may be relatively spared while posterior SCC function is impaired. Patients with bilateral (more often than unilateral) MLF injuries may experience oscillopsia with head movements because of vertical VOR impairment. Objectively, this can be demonstrated by a significant decrement in dynamic visual acuity vertically but not horizontally or with vertical HIT in the planes of anterior and posterior SCCs. Vertical HIT may also be abnormal in the plane of the anterior SCC, possibly from additional involvement of the brachium conjunctivum if the MLF was affected more laterally.

Horizontal VOR

During horizontal VOR testing using the HIT, the velocity of the adducting eye (ipsilateral to an MLF lesion) movement can be relatively preserved, so that it is much better than what would be expected based on bedside testing with a significant adduction lag due to an INO. This is proposed to be caused by an extra-MLF pathway, the ascending tract of Deiters, which goes directly from the vestibular nuclei to the oculomotor nucleus (Fig. 4).1 For example, an adducting saccade of the left eye with leftward HIT in the setting of a left INO may look normal because of an extra-MLF pathway. However, if the gain is subnormal so that a refixation saccade is necessary to bring the eyes back to the target during the HIT (fixation target is usually the examiner's nose), a much slower adducting saccade of the left eye will be generated because this is using the MLF pathway.

OPT

Anatomy and Clinical Features

Hypertrophic olivary degeneration (HOD) manifests as OPT (formerly called oculopalatal myoclonus), where palatal tremor (PT) is synchronous with pendular nystagmus.1,3 Synchronous contractions of other muscles from the branchial arches such as larynx, pharynx, diaphragm, facial muscles, and rarely skeletal muscles may also be seen.51–53 The most reported and studied cases are the development OPT and HOD weeks to months after a structural brainstem or cerebellar lesion, commonly related to a hemorrhage. In these cases, OPT is said to be “symptomatic” and results from a destructive lesion in the Guillain-Mollaret pathway, also referred to as the dentato-olivary pathway (Fig. 5). This imaginary triangle has three points: dentate nucleus, red nucleus, and inferior olivary nucleus. The right inferior olive sends decussating climbing fibers through the contralateral (left) inferior cerebellar peduncle to densely contact the inhibitory Purkinje cells, which then travel from the cerebellar cortex to the left dentate nucleus. The dentate nucleus sends decussating fibers through the superior cerebellar peduncle, which wrap around the contralateral (right) red nucleus. These fibers then descend to the ipsilateral inferior olive via the right central tegmental tract (CTT). Lesions involving the CTT are commonly associated with OPT as compared to lesions of the dentate nucleus or brachium conjunctivum, which in some cases may only be associated with PT.54–56 The most common structural brainstem or cerebellar lesion is hemorrhagic stroke,3,57 often from a pontine or midbrain cavernous angioma involving the unilateral or bilateral descending CTT. Other causes include ischemic stroke, brainstem tumors, surgical or gamma knife removal of brainstem cavernoma,58 multiple sclerosis,59 and sarcoid.60

FIG. 5
FIG. 5:
Left—the Guillain-Mollaret triangle has three points: dentate nucleus, red nucleus, and inferior olivary nucleus. Right—MRI T2 image showing bilateral hypertrophic olivary degeneration (arrow points to hyperintense right inferior olive although there is bilateral involvement). Source: Neuro-Ophthalmology Virtual Education Library: NOVEL [Online]. Available at: https://collections.lib.utah.edu/ark:/87278/s62n8zjg. Accessed December 2, 2018.

Involuntary rhythmic contraction of the levator veli palatini muscle61 is seen in symptomatic PT. It is commonly bilateral and symmetric62 and persists during sleep.63 In contrast to essential PT (see below), patients with symptomatic PT rarely complain of ear click,62,63 nor do they have symptoms referable to PT. The rhythmic frequency of PT is about 2 Hz, which is a similar frequency to that observed in the ocular oscillations of OPT. In OPT, in addition to PT, patients have pendular nystagmus with vertical, torsional, or seesaw components56,64 that can be of large amplitude and high velocity.56 The pendular nystagmus is often vertical–torsional and can be conjugate, dissociated or disjunctive.54 In contrast to patients with PT who are mostly asymptomatic, patients with OPT can be very symptomatic with bothersome oscillopsia (video example of OPT after dorsal pontine cavernoma hemorrhage involving the CTT—https://collections.lib.utah.edu/ark:/87278/s6mh1mnm).56,65

In addition to symptomatic PT/OPT, a syndrome of progressive ataxia and PT has been described.66–68 In this syndrome, a progressive ataxia and PT/OPT develops in patients without history of structural brainstem or cerebellar lesion. In most cases, HOD is seen on MRI, although there is no visible structural lesion along the dentato-olivary pathway. An essential form of PT has also been described for which there is neither structural lesion nor HOD,69 and in many cases, this is thought to represent a functional or psychogenic disorder.70 In contrast to the symptomatic PT/OPT that involves the levator veli palatini muscle, the tensor veli palatini muscle is involved and a bothersome ear click is often found in the essential PT.62

Pathologic and Radiological Features

Hypertrophic olivary degeneration is the main pathologic finding in OPT.1 A lesion involving the dentato-rubral pathway (i.e., before the decussation of fibers from brachium conjunctivum to contralateral red nucleus) is associated with hypertrophy of the contralateral inferior olivary nucleus, whereas a lesion along the CTT between the red nucleus and the medulla is associated with hypertrophy of the ipsilateral inferior olivary nucleus because this descending tract remains uncrossed (video example of a patient with OPT due to unilateral cerebellar cavernoma causing contralateral HOD—https://collections.lib.utah.edu/ark:/87278/s6rc1227).71 The olivary nucleus is enlarged because of hypertrophy of neurons,72 which usually begins within a month of the stroke, reaching its peak in about 6 months. Synaptic and axonal remodeling as well as astrocytosis is found along with the neuronal hypertrophy. Corresponding radiological changes can be seen on MRI as increased T2/fluid attenuation inversion recovery signal and enlargement of the inferior olive (Fig. 5).54 The MRI hyperintensity may appear within one month and tends to persist, but the hypertrophy appears usually after about 6 months and disappears after about 3 years.73 The HOD on MRI is unilateral or bilateral in cases of symptomatic PT and bilateral in cases of progressive ataxia and PT.74 Consistent with the pathological findings, the HOD on MRI appears contralaterally with cerebellar/dentate lesions and ipsilaterally with CTT lesions.54,73,74 The HOD on MRI may be seen before the clinical manifestations of PT/OPT,75 or PT/OPT may not be seen at all in some cases.76

Pathogenesis

The main explanation of PT/OPT associated with the development of HOD is that the abnormal inferior olive plays a significant role.3 Because the CTT normally inhibits the ipsilateral inferior olive, damage to the CTT results in decreased inhibition of the ipsilateral olive resulting from transsynaptic degeneration. Hypertrophic inferior olivary degeneration occurs as swollen and vacuolated neurons come into contact with each other and corresponds to MRI T2/fluid attenuation inversion recovery hyperintensity (Fig. 5). Cells of the inferior olive are electrically coupled by dendrodendritic gap junctions and are normally capable of generating spontaneous oscillations, but are inhibited by the CTT. When olivary denervation occurs, there is aberrant conduction between the soma of adjacent cells, causing synchronized oscillatory signals that are transmitted to the cerebellum where they are modulated and augmented.64,77 These rhythmic outputs generate nystagmus and PT.

Treatments

Although OPT occasionally resolves spontaneously,59 it tends to persist for many years and MRI shows persistent signal change in the inferior olivary nucleus.54 The most bothersome consequence of OPT is oscillopsia related to the pendular nystagmus, which can be difficult to treat. Previous studies have shown a positive effect of gabapentin and memantine on reduction of nystagmus amplitude, frequency, and velocity.65,78,79 Trihexyphenidyl was found to improve eye and palate movements and reduce complaints in patients with OPT after a structural lesion, patients with essential PT, and in multiple sclerosis.80 Clonazepam and antimalarial agents have been used with variable success.1,81 Botulinum toxin has been tested with variable success on pendular nystagmus in OPT and in clicking tinnitus in PT.3,82,83 In the authors' experience, the nystagmus and oscillopsia associated with OPT can be very difficult to treat, as benefits of the medications listed above are commonly limited by their side effects.

CONCLUSION

The brainstem contains ocular motor and vestibular structures that are associated with specific eye movement disorders when damaged. The combination of ocular lateropulsion and saccadic dysmetria with a partial or complete OTR (hypotropic eye will be ipsilateral to the direction of lateropulsion) is suggestive of a lateral medullary localization. In the MLF syndrome, while an INO is the most easily recognized ocular motor feature, other acute signs include spontaneous vertical-torsional nystagmus, an OTR, and an abnormal vertical VOR, which can cause oscillopsia acutely or chronically. Hypertrophic olivary degeneration can manifest as OPT, commonly developing weeks to months after a brainstem hemorrhage that involves the CTT. Understanding the neural structures involved in ocular motor and vestibular control allows the clinician to accurately localize a variety of brainstem syndromes.

ACKNOWLEDGMENTS

The authors thank Dr. David Zee and Dr. Ari Shemesh for critically reading our manuscript.

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Keywords:

Brainstem; Ocular motor; Vestibular; Oculopalatal tremor; Medial longitudinal fasciculus; Lateral medullary stroke

© 2019 by the American Clinical Neurophysiology Society