Abnormal Eye Movements in Dizzy Patients

Neurol Clin 23 (2005) 675–703

Abnormal Eye Movements in Dizzy Patients Ki Bum Sung, MD, PhDa,*, Tae Kyeong Lee, MDa, Joseph M. Furman, MD, PhDb a

Department of Neurology, College of Medicine, Soonchunhyang University, 1174 Jung-Dong, Wonmi-Gu, Bucheon, Gyeonggi 420-607, Korea b Departments of Otolaryngology and Neurology, University of Pittsburgh, EEHOS 500, Pittsburgh, PA 15260, USA

Abnormalities of eye movements frequently are observed in patients who are dizzy. Most abnormal eye movements have a specific locus but not a specific cause. Therefore, thorough knowledge of the mechanism and careful observation of the abnormal eye movements are important aspects of evaluating patients who have dizziness. This article describes basics of normal eye movements first, followed by a discussion of abnormal eye movements occurring in peripheral and central vestibular disorders with an emphasis on their implicated sites and mechanisms.

Basics of eye movements Innervation of extraocular muscles There are six extraocular muscles that rotate each eye: four rectus (inferior, lateral, medial, and superior) and two oblique (inferior and superior). The superior oblique muscle is innervated by the trochlear nerve and the lateral rectus muscle is innervated by the abducens nerve. The other four muscles are innervated by the oculomotor nerve. The oculomotor nucleus is a paired structure lying ventral to the periaqueducal gray of the midbrain. The fascicles of the oculomotor nerve run ventrally to exit in the interpeduncular fossa as several rootlets. Each oculomotor nucleus

* Corresponding author. 1174 Jung-Dong, Wonmi-Gu, Bucheon-Si, Gyeonggi-Do 420-607, Korea. E-mail address: [email protected] (K.B. Sung). 0733-8619/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2005.01.006 neurologic.theclinics.com

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innervates only ipsilateral extraocular muscles except for the superior rectus muscle. Fibers to the superior rectus muscle decussate at the caudal third of the oculomotor nuclear complex and exit to join the fascicles of the other side [1]. The fascicles of the trochlear nerve arise from a pair of grouped motor neurons in the ventral mesencephalon at the level of the inferior colliculi and course dorsally to decussate in the anterior medullary vellum, emerging from the dorsal surface immediately caudal to the inferior colliculi. Therefore, superior oblique muscles are innervated by the contralateral trochlear nucleus. The abducens nucleus lies in the floor of the fourth ventricle ventral to the genu of the facial nerve and consists of two types of neurons: motoneurons innervating the ipsilateral lateral rectus muscle and internuclear neurons supplying the contralateral medial rectus muscle. Internuclear neurons, constituting 25% to 30% of the abducens nucleus, are distributed throughout the nucleus [2]. Axons of the internuclear neurons cross at the abducens nucleus level and in the region immediately rostral to it and then ascend in the medial part of the medial longitudinal fasciculus (MLF) [3,4]. Innervational patterns are depicted in Fig. 1. Terms for eye movements To describe the motion of the eye accurately, axes and planes must be defined. The eye rotates on three axes. These axes conventionally are referred to as X (parasagittal or nasooccipital), Y (transverse or interaural), and Z (vertical). The angular motions about these axes also are described according to the planes in which the rotations occur: horizontal (yaw, rotation about the Z axis), vertical (pitch, rotation about the Y axis), and torsional (roll, rotation about the X axis) (Fig. 2). Calling a torsional eye movement ‘‘rotatory’’ is a frequent misnomer. The primary position of the eye is the position in which pure horizontal or vertical rotation of the eye is associated with zero torsion. For clinical purposes, however, the primary position refers to the position assumed by the eye when looking straight ahead with body and head erect. A secondary position is reached by a solely horizontal or vertical rotation from the primary position. A tertiary position is reached when combined horizontal and vertical rotations take the eye away from the primary position. Torsional eye movements that rotate the upper poles of the eyes toward the subject’s right (ie, in a clockwise direction from the subject’s point of view) are called clockwise movements, although they seem counterclockwise to an observer. Torsional movements that rotate the upper poles of the eyes toward a certain side of the brain or toward the side of a brain lesion are called ipsiversive and ipsilesional, respectively. In addition, contrary to the usual convention for vertical tropias (misalignment of the visual axes), skew deviation (SD) is named after the side of the lower eye; for example, a left SD means a left hypotropia [5].

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Fig. 1. Innervation of the extraocular muscles. The abducens nucleus (VI) is composed of two types of neurons: (1) motoneurons (MN) innervating the ipsilateral lateral rectus muscle (LR) and (2) internuclear neurons (IN) crossing to ascend in the MLF to innervate the contralateral subnucleus of the oculomotor nucleus (III) that contains motoneurons destined for the medial rectus muscle (MR). The superior oblique muscle (SO) is innervated by the contralateral trochlear nucleus (IV), whose axons decussate in the anterior medullary velum. Axons for the superior rectus muscle (SR) cross within the oculomotor nucleus (III). The inferior oblique muscle (IO) and the inferior rectus muscle (IR) are innervated by the ipsilateral oculomotor nucleus.

Duction means a rotation of one eye when it alone is viewing. Naming conventions are as follows: adduction (toward nose horizontally), abduction (toward ear horizontally), sursumduction (elevation), deosursumduction (depression), intorsion (upper pole of the eye moves nasalward), and extorsion (upper pole of the eye moves temporal ward). Version means a rotation of both eyes, usually with both eyes viewing. Naming conventions are as follows: dextroversion (rightward), levoversion (leftward), sursumversion (upward), deorsursumversion (downward), dextrocycloversion

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Fig. 2. Axes and planes of eye movements. Linear movements of the head are called surge, sway, and heave along the X, Y, and Z axes, respectively. Angular movements (rotations) are called roll, pitch, and yaw around the X, Y, and Z axes, respectively.

(upper poles toward subject’s right), and levocycloversion (upper poles to subject’s left). Version also is used frequently to mean conjugate eye movements, that is, movements that rotate the eyes in the same direction by the same amount. Vergence or disjunctive movements are those that rotate the eyes simultaneously in opposite, typically horizontal, directions, such as convergence (left eye to the right and right eye to the left) and divergence (left eye to the left and right eye to the right). Actions of extraocular muscles Actions of the extraocular muscles are described in Table 1 and depicted in Fig. 3. The primary action of the extraocular muscles refers to the principal rotation of the eye when that muscle contracts; the secondary and tertiary actions mean lesser rotations.

Table 1 Actions of the extraocular muscles Muscle

Primary action

Secondary action

Tertiary action

Medial rectus Lateral rectus Superior rectus Inferior rectus Superior oblique Inferior oblique

Adduction Abduction Elevation Depression Intorsion Extorsion

Intorsion Extorsion Depression Elevation

Adduction Adduction Abduction Abduction

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Fig. 3. Scheme of functions of the extraocular muscles. The action of each extraocular muscle is illustrated by the direction of the arrows. IO, inferior oblique muscle, IR; inferior rectus muscle; LR, lateral rectus muscle; MR, medial rectus muscle; SO, superior oblique muscle; SR, superior rectus muscle.

Synergistic muscles in the two eyes, that is, muscles that cause the two eyes to move in the same direction, are called yoke muscles. The horizontally acting recti (ie, the medial and lateral rectus) are yoke muscles. The yoke muscle pairs for the other four muscles are more complex (see Fig. 3). Pulleys The four rectus and superior oblique muscles arise from the annulus of Zinn in the apex of the orbit, whereas the inferior oblique muscle arises from the inferior nasal aspect of the orbit. The four rectus muscles insert into the sclera anterior to the equator of the globe, whereas both oblique muscles insert into the sclera posterior to the equator of the globe. Recent studies reveal, however, that the direction of pull is not determined entirely by the origins and insertions of the extraocular muscles. Radiologic imaging using MRI and histologic examination of the orbit reveal that the four rectus [6] and inferior oblique muscles [7] pass through pulleys (ie, sleeve-like encircling collagen rings stiffened by elastin and smooth muscle). They are located near the equator of the globe in the posterior Tenon’s capsule firmly attached to each other and to the orbital wall. All the extraocular muscles consist of orbital and global layers and each layer contains approximately equal numbers of fibers [8]. The orbital layer of each extraocular muscle inserts on its corresponding pulley, whereas the global layer inserts into the sclera as recognized classically [8,9]. The orbital layer of the inferior oblique muscle inserts on the pulleys of the lateral rectus and inferior rectus muscles and on its own [8]. Compared with other muscles, the superior oblique

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muscle is a special case, because it has the trochlea, a fibrous, cartilaginous rigid ring in the superior medial part of the orbital rim. Sheath and tendon of the superior oblique muscle pass through the trochlea. The sheath of the superior oblique muscle inserts on the pulley of the superior rectus muscle, whereas the tendon continues inferior to the pulley of the superior rectus muscle to insert broadly on the posterior lateral sclera [9]. The pulleys have important implications; the functional origin of each extraocular muscle is at its pulley. The pulleys prevent the extraocular muscles from side slipping in relation to the orbital walls during eye movements [6,7,9–13]. The active pulley hypothesis states that the global layer of each extraocular muscle rotates the globe, whereas the orbital layer is inserted on its pulley to position it linearly and thus shift the ocular rotational axis to result in more precise eye movements [9–13]. Vestibulo-ocular reflex The vestibulo-ocular reflex (VOR) is a neural network that enables holding the image of concern constant in space during head movements. It is composed of a three-neuron arc reflex. The excitatory pathways from the secondary vestibular neurons cross the midline to reach ocular motor neurons, which activate a pair of extraocular muscles acting in the plane of the corresponding semicircular canals from which they receive the stimuli. The inhibitory pathways ascend ipsilaterally to reach the ocular motor nuclei, which innervate a pair of the corresponding antagonistic muscles. These threeneuron arcs are depicted in Fig. 4. Excitation of a horizontal semicircular canal causes the eyes to deviate horizontally to the contralateral side as a result of activation of the ipsilateral medial rectus and contralateral lateral rectus muscles. Excitation of an anterior canal activates the ipsilateral superior rectus muscle and its yoke muscle, the contralateral inferior oblique muscle. Excitation of a posterior canal stimulates the ipsilateral superior oblique muscle and the contralateral inferior rectus muscle. In posterior semicircular canal–type benign paroxysmal positional vertigo (BPPV), nystagmus usually is described as beating toward the undermost affected ear with a torsional component when it is evoked by the Dix-Hallpike test. In reality, however, it is more complex. For example, in patients who have right-sided posterior canal BPPV, torsional nystagmus is seen when patients look to the right, whereas vertical nystagmus is observed when patients look to the left. This phenomenon results from the fact that the function of the superior oblique muscle is dependent on eye position in the orbit; it is a depressor when the eye is adducted and it is an intorter when the eye is abducted. Nystagmus in the superior canal dehiscence syndrome is caused by the excitation of the ipsilesional superior rectus and contralesional inferior oblique muscles because the anterior canal is activated in this condition. The induced nystagmus primarily is vertical when the ipsilesional eye is abducted.

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Fig. 4. Extraocular muscles activated by the stimulation of the semicircular canals can be inferred because muscle planes of the extraocular muscles excited by the canals lie in planes similar to those of canals; an anterior canal, when stimulated, excites the ipsilateral superior rectus muscle and the contralateral inferior oblique muscle (thin dotted lines); a posterior canal, when stimulated, excites the ipsilateral superior oblique muscles and the contralateral inferior rectus muscles (solid dotted lines); a horizontal canal excites the ipsilateral medial rectus muscle and the contralateral lateral rectus muscle (thick dotted lines). AC, anterior semicircular canal; HC, horizontal semicircular canal; IO, inferior oblique muscle, IR; inferior rectus muscle; LR, lateral rectus muscle; MR, medial rectus muscle; PC, posterior semicircular canal; SO, superior oblique muscle; SR, superior rectus muscle.

Gaze holding and neural integrator To hold gaze steady in an eccentric position, extraocular muscles must contract tonically to counteract elastic forces of the orbital contents that tend to take the eyes back to the primary position. Gaze holding calls on more than visual fixation, because eccentric gaze remains relatively steady even in darkness [14]. In contrast to ocular motor neurons, which encode velocity and position commands, unprocessed premotor inputs, from which the final ocular motor command is assembled, encode velocity signals only. Because an eye position signal is required to hold the eyes steady, a mathematic integration is necessary to generate a position signal from velocity-encoded information. For horizontal gaze holding, the nucleus prepositus hypoglossi (NPH) [15] and the medial vestibular nucleus (MVN) [16] are of prime importance. For vertical eye movements, the interstitial nucleus of Cajal (INC) is believed the site of neural integration (ie, the generator of the eye

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position command) [17]. In addition to the structures described previously, the cerebellum plays an important role in gaze holding. It is suggested that one of the functions of the cerebellum is to improve the performance of an inherently leaky (ie, imperfect) neural integrator [18,19]. A positive feedback loop between the cerebellum and the brainstem enables neurons to perseverate their own activity, thereby improving integration. When the integrator does not work perfectly, the eye position signal decays with time because of the elastic restoring forces of the orbit, which pull the eyes into the primary position. As the eyes drift back to the primary position, corrective quick phases beating opposite to the slow drift occur. This is called gazeevoked nystagmus (GEN). Lateral gaze can change the characteristics of vestibular nystagmus; looking in the direction of the fast component increases the amplitude and frequency of the spontaneous nystagmus, whereas looking in the opposite direction has the reverse effect. This phenomenon is called Alexander’s law and may be the result of a central strategy to cope with vestibular imbalance. Faced with a vestibular imbalance, the nervous system makes the neural integrator less efficient and, thus, the time constant of centripetal drift short. In this way, centripetal drift from an imperfect integrator can counteract the vestibular imbalance in one field of gaze [20]. The effect of the horizontal position of the eye in the orbit on the slow component velocity is the basis for the classification of vestibular nystagmus. It is called first degree if it is present only on looking in the direction of the fast phase, second degree if it is present in the primary position and with lateral gaze toward the fast phase, and third degree if it is present in all fields of gaze. Mechanism of conjugate gaze Horizontal conjugate gaze The abducens nucleus is the keystone for all horizontal conjugate eye movements, because it contains two kinds of neurons: abducens motor neurons innervating the ipsilateral lateral rectus muscle and abducens internuclear neurons crossing to innervate the contralateral medial rectus subnucleus of the oculomotor nucleus by way of the MLF. This crossed connection is the neural basis for Hering’s law in the horizontal plane. All functional classes of horizontal eye movements send signals to the abducens nucleus: vestibular, optokinetic [21,22], and smooth pursuit [23] systems via the vestibular nucleus; the saccadic system via the pontine and medullary reticular formation [1,24]; and the neural integrator [25] via MVN and NPH. In addition, the abducens nucleus receives inputs from the cerebellum during horizontal eye movements [26]. Vertical conjugate gaze The oculomotor and trochlear nuclei receive inputs related to vertical and torsional conjugate eye movements. Inputs for saccades and gaze holding

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arise from the midbrain, whereas those for vestibular and smooth pursuit originate from the lower brainstem. The rostral interstitial nucleus of the MLF (riMLF), lying in the prerubral fields of the midbrain, generates vertical and torsional saccades. Each riMLF houses neurons that fire for upward and downward saccades. They fire in only one direction for torsional saccades, however. That is, the right riMLF fires for quick phases directed clockwise with respect to the subject, whereas the left riMLF fires for those directed counterclockwise [27]. Therefore, intactness of the riMLF can be evaluated by checking the torsional quick phase of torsional nystagmus elicited by ipsilateral head roll at the bedside. Subdivision of eye movements The ocular motor system consists of two major subdivisions: version and vergence. The ocular motor system serves to place the images of the object onto the fovea and to keep the image on the fovea during movements of the viewed object. The optokinetic and fixation systems serve to hold gaze, whereas saccades and smooth pursuit systems act to shift gaze. The vergence system has gaze-holding and gaze-shifting properties [26]. Conjugate eye movements also can be divided into 1) fast voluntary eye movements (ie, saccades), 2) quick phases of evoked and pathologic nystagmus, 3) rapid eye movements of sleep, 4) slow eye movements (ie, smooth pursuit), 5) fixation, 6) vestibular-induced slow movements, and 7) optokinetic eye movements. Most naturally occurring eye movements are in fact a combination of various versional and vergence movements. Functional over- or underactivity in any subsystem will result in both static and dynamic eye movement disturbances, which may result in dizziness. Functional classifications of eye movements are described in Table 2.

Table 2 Functional classes of human eye movements Class of eye movement

Main function

Vestibular Visual fixation Optokinetic Smooth pursuit

Holds images steady on the retina during brief head rotations Holds the image of a stationary object on the fovea Holds images steady on the retina during sustained head rotation Holds the image of a small moving target on the fovea or holds the image of a small near target on the retina during linear self-motion; with optokinetic responses, aids gaze stabilization during sustained head rotation Reset the eyes during prolonged rotation and direct gaze toward an oncoming visual scene Bring objects of interest onto the fovea Moves the eyes in opposite directions so that images are placed or held simultaneously on both foveas

Nystagmus quick phases Saccades Vergence

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Saccades Saccades, the fastest of eye movements, bring images of objects of interest onto the fovea by rapidly redirecting the line of sight. Although no cortical neuron projects directly to ocular motor neurons [28], parietal cortical areas have two important functions in saccades: (1) shifts of visual attention and (2) programming of saccades to a visual target. The parietal area projects to the frontal eye field (FEF) and to the superior colliculus but not directly to burst neurons [29]. Three frontal cortical areas (ie, the FEFs, supplementary eye fields, and dorsolateral prefrontal cortex) are important for volitional saccades. The FEFs project through the anterior limb of the internal capsule to (1) basal ganglia, (2) thalamus, and (3) nucleus reticularis tegmenti pontis (NRTP) [30,31]. The caudate nucleus phasically inhibits the pars reticulata of the substantia nigra, which tonically inhibits the superior colliculus [32]. This pathway inhibits extraneous reflexive saccades during fixation. It also facilitates memory or prediction-guided saccades. The intralaminar nucleus of the thalamus is the probable site for efference copy [33]. The pulvinar is important for the process of saccadic suppression [34] and shift of attention [35]. NRTP receives signals from the FEFs via the most medial part of the cerebral peduncle and projects to the dorsal vermis and caudal fastigial nucleus [36,37]. NRTP neurons encode the three-dimensional eye displacement vectors [38] and contain long-lead burst neurons that project to the

Fig. 5. Block diagram of the major structures involved in the generation of saccades. The caudate nucleus phasically inhibits the substantia nigra pars reticulata, which tonically inhibits the superior colliculi. Thick lines are main pathways; thin lines are less important pathways. DLPC, dorsolateral prefrontal cortex; FEF, frontal eye field; IML, intramedullary lamina of the thalamus; NRTP, nucleus reticularis tegmenti pontis; PEF, parietal eye fields; PPC, posterior parietal cortex; SEF, supplementary eye field; SNpr; substantia nigra pars reticulata.

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cerebellum and paramedian pontine reticular formation (PPRF) [39]. The superior colliculus projects to excitatory burst neurons (EBN), inhibitory burst neurons (IBN), and omnipause neurons [40]. Pathways described previously are summarized in Fig. 5. EBN for horizontal saccades lying in the PPRF project to the ipsilateral abducens nucleus innervating motoneurons and internuclear neurons and to the ipsilateral IBN. They also, however, discharge during vertical and oblique saccades [41]. IBN lying in the rostral dorsal medulla project across the midline to inhibit the contralateral abducens nucleus during ipsilateral saccades [42]. EBN and IBN for vertical and torsional saccades are located in the riMLF [27,43]. Omnipause cells lying in the nucleus raphe interpositus of the pons send inhibitory projections to EBN and IBN of all kinds of saccades [44]. Omnipause cells tonically inhibit burst neurons except immediately before and during a saccade in any directions (see Fig. 6). Disorders of saccades consist of abnormalities of initiation, velocity, amplitude, and accuracy. Also, saccades can occur inappropriately. Only abnormalities of accuracy and inappropriate saccades are discussed. Generally, inaccurate (dysmetric) saccades can be classified into two groups: (1) saccadic pulse dysmetria and (2) postsaccadic drift (glissade). Saccadic pulse dysmetria occurs when the size of the pulse command is too large or too small. This leads to a normal looking saccade of the wrong size. Pulsestep mismatch dysmetria occurs when there is a mismatch between the pulse

Fig. 6. Brainstem structures involved in generating horizontal conjugate saccades. Excitatory secondary vestibular neurons (EVN) innervate the contralateral abducens nucleus, whereas inhibitory secondary vestibular neurons (IVN) innervate the ipsilateral abducens nucleus. Solid lines represent excitatory pathways; dotted lines represent inhibitory pathways. III, oculomotor nucleus; VI, abducens nucleus; VIII, vestibular nucleus; EBN, excitatory burst neurons; HC, horizontal semicircular canal; IBN, inhibitory burst neurons; IN, internuclear neurons; LR, lateral rectus muscle; MLF, medial longitudinal fasciculus; MN, motor neurons; MR, medial rectus muscle; P, omnipause neurons; PPRF, paramedian pontine reticular formation.

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and step. This results in postsaccadic drift. The dorsal ocular motor vermis and the fastigial nucleus control pulse size [45,46]; the flocculus and paraflocculus control pulse-step matching [47,48]. The combination of hypermetric saccades in one horizontal direction and hypometric saccades in the opposite direction is called saccadic lateropulsion. There are two types of saccadic lateropulsion: ipsipulsion and contrapulsion. An increase of the Purkinje’s cell activity after inferior cerebellar peduncle disruption, as in Wallenberg’s syndrome (Fig. 7), inhibits the ipsilateral fastigial neurons that innervate the contralateral PPRF and medullary reticular formation (MRF). This creates a bias toward ipsilesional saccades; saccades toward the lesioned side are hypermetric and saccades away from the lesioned side are hypometric. This abnormality is called saccadic ipsipulsion. If fastigial output is blocked after its decussation, however, as in lesions of the superior cerebellar peduncle (SCP) (Fig. 7), the ipsilesioinal PPRF and MRF are disfacilitated as a result of a loss of excitatory input from the contralesional fastigial nucleus. This creates a bias toward the contralesional side; thus, saccades toward the lesioned side are hypometric and saccades away from the lesioned side are hypermetric. This abnormality is called saccadic contrapulsion. Ocular oscillations can be divided into three types according to the characteristics of the initiating movements causing a deviation of the eye: (1) nystagmus initiated by slow eye movements, (2) inappropriate saccades

Fig. 7. Connections responsible for saccadic lateropulsion. The symbol, þ, indicates excitatory and
inhibitory connections. Lesion A induces a transient increase of Purkinje’s cell activity, which results in increased inhibition of the ipsilesional fastigial activity causing disfacilitation of the contralesional PPRF; lesion B induces disfacilitation of the ipsilesional PPRF.

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initiated by fast eye movements, and (3) ocular bobbing-like eye movements. Nystagmus is described later. In ocular bobbing, the oscillation of the eyes consists of a fast downward drift from the primary position followed by a slow upward drift to the primary position with an interval of few seconds between two [49]. There are three variants of ocular bobbing: (1) inverse bobbing or ocular dipping (a slow downward and fast upward movement), (2) reverse bobbing (a fast upward and slow downward movement), and (3) converse bobbing or reverse dipping (a slow upward and fast downward movement). If fast eye movements disrupt foveal fixation, they are called inappropriate saccades. These are sporadic biphasic oscillations in which the saccade takes the eyes off target. These are classified into two types: (1) saccadic intrusions when they are sporadic and (2) saccadic oscillations when they are sustained (Table 3) [50]. Some of them are site specific, whereas some of them are disease specific [26,50]. Smooth pursuit Smooth pursuit eye movements hold the image of a small moving object of interest on the fovea and help to stabilize gaze during sustained or low frequency head rotation with the help of the VOR and the optokinetic system. There is some controversy regarding the exact pathways of the smooth pursuit systems. It generally is believed, however, that smooth pursuit signals from the cortex cross two times before reaching the ocular motoneurons and move the eyes ipsilaterally (Fig. 8). In brief, primary visual cortex projects to the middle temporal area (MT), which lies at the temporal-occipital-parietal junction in humans. It projects to the medial superior temporal visual area (MST) and also to the FEF. The descending pathways from the posterior cortex run along the surface of the lateral ventricle in the internal sagittal stratum and turn toward the retrolenticular portion of the internal capsule and lateral part of the cerebral peduncle [51,52]. Pathways from the anterior cortex run along the most medial aspect of the cerebral peduncle to reach the dorsolateral pontine nucleus (DLPN) of the pons [30]. Pursuit projections from the DLPN decussate in the middle cerebellar peduncle first as mossy fibers that activate basket cells and stellate cells of the flocculus that, in turn, inhibit Purkinje’s cells [53]. The main

Table 3 Classification of inappropriate saccades Saccadic intrusion

Saccadic oscillation

Square wave jerks Macro square wave jerks Saccadic pulse Saccadic impersistence of gaze

Micro saccadic oscillation Macro saccadic oscillation Square wave oscillation Ocular flutter Opsoclonus

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Fig. 8. Putative pathways for horizontal smooth pursuit. The first decussation is through middle cerebellar peduncle and the second is through projections from the flocculus to the ipsilateral vestibular nuclei (VN), which send signals to the contralateral abducens nucleus. See text for details.

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efferent pathways of the flocculus and paraflocculus are to the ipsilateral superior and MVN and to the y-group [23,30]. From the functional point of view, it is this double inhibition that enables the cortical pursuit signal to produce an ipsilateral pursuit, because axons of the activated MVN cross the midline and innervate the contralateral abducens nucleus (Fig. 8). Smooth pursuit defects can be caused by cerebellar lesions. A right-sided cerebellar lesion that affects only the mossy fiber projections from the pons after their decussation produces a contralateral (leftward) pursuit defect by disrupting excitatory inputs to basket cells and stellate cells that inhibit right hemisphere Purkinje’s cells. This results in a disinhibition of right-sided floccular Purkinje’s cells, which inhibit the right MVN. Whereas right-sided damage to cerebellar outflow projections from Purkinje’s cells, which are inhibitory, produces an ipsilateral (rightward) defect by reducing Purkinje’s cell inhibition of the right MVN, unilateral cerebellar lesions that interrupt mossy fiber inflow and Purkinje’s cell outflow might produce bidirectional pursuit defects. The deficit following lesions of the flocculus and paraflocculus is a low-pursuit gain, differing from that after total cerebellectomy, which abolishes smooth pursuit totally [54,55]. In addition to floccular lesions, experimental lesions of the posterior vermis also can cause a partial defect of smooth pursuit [56]. Optokinetic reflex The optokinetic system serves to stabilize retinal images when the VOR fails to function successfully, such as during sustained rotation. The optokinetic reflex to a full-field moving visual stimulus has two stages. First, the eyes begin to follow in the same direction and the eye velocity rapidly builds to a value approximating that of the stimulus. This initial response is accomplished by the smooth pursuit system. Second, there is a slower buildup in the neural activity. This second stage can be discerned only as optokinetic after nystagmus (ie, when the subject is placed in darkness after undergoing optokinetic stimulation for approximately 30 seconds or more). In foveate and afoveate animals, visual information from the retina is transmitted in succession to the accessory optic tract, the central tegmental tract (CTT), the inferior olive, and through the ICP to the flocculus, nodulus, and other adjacent parts of the cerebellum, which receive primary and secondary vestibular fibers. This pathway is called indirect. In foveate animals, including humans, cortical pathways are more important than the accessory optic system. The aforementioned pathway from the striate cortex through MT, MST, DLPN, and ICP to the flocculus and cerebellar vermis is called the direct pathway [57,58]. These two stages are compared in Table 4. Humans use a combination of eye and head movements to acquire or track targets visually. The rapid combined eye-head movement to acquire a target is called a gaze saccade or eye-head saccade. Slow gaze shifts are called gaze pursuit or eye-head pursuit. During gaze shifts, the VOR causes the eyes to move in the opposite direction of the head movements.

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Table 4 Two stages of the optokinetic reflex Nucleus of optic tract component

Smooth pursuit component

Stare nystagmus Slow component Late Velocity storage Indirect Involuntary Slow rise Subcortical

Look nystagmus Fast component Early Smooth pursuit Direct Voluntary Rapid rise Cortical

Therefore, the VOR must be nullified during combined eye-head movements. Negation of the VOR during combined eye-head tracking is achieved by two separate mechanisms: cancellation of the VOR, presumably accomplished by a smooth pursuit signal causing the eyes to move in the same direction as that of the head movements [59,60], and VOR suppression, accomplished by a partial reduction of VOR gain [61–63]. Flocculus and paraflocculus lesions can produce impairment in fixation of a target rotating with the head.

Abnormalities of eye movements in vestibular disorders Peripheral vestibular disorders To understand the mechanism of the abnormalities of eye movements in vestibular disorders, the concept of resting discharge, that is, continuous spontaneous activity, of vestibular afferents is essential [64,65]. The most obvious function of the resting discharge is that it permits a bidirectional response. Two other functions may be ascribed to the resting discharge. First, it provides the basis for the tonic influence exerted by the labyrinth on the central nervous system [66]. Second, the resting discharge may serve to decrease the sensory threshold. If there are any differences of resting discharge between both sides, irrespective of being caused by an increase or decrease of one side, vestibular tone imbalance and bias ensue. Vestibular symptoms and signs may reflect static (ie, head still) or dynamic (ie, head moving) disturbances. Static disturbances come about because of the tonic imbalance of vestibular tone when the head is still; dynamic disturbances reflect abnormalities in gain, phase, and direction in response to rotation or translation of the head. Because abnormal eye movements in vestibular disorders are described in an article by Tusa elsewhere in this issue, only some of them are discussed here. Nystagmus is an involuntary, rhythmic oscillation of the eyes. Jerk nystagmus has clearly defined slow and quick phases. Although the slow

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component of jerk nystagmus reflects the underlying pathology, by convention the direction of the fast component defines the direction of the nystagmus. Jerk nystagmus can be classified into physiologic and pathologic types. There are three types of physiologic nystagmus: (1) vestibular induced (caloric and rotational), (2) visually induced (optokinetic), and (3) extreme of gaze induced (endpoint). Pathologic jerk nystagmus can be spontaneous, gaze evoked, or positional. Examination for pathologic nystagmus must include observation of the effects of fixation, eye position in the orbit, and head position. In addition to the effect of removal of fixation on nystagmus, characteristics of the direction of the nystagmus are important in determining its origin. Purely vertical or torsional spontaneous nystagmus suggests a central origin. Stimulation of a single canal produces slow deviation of the eyes in the plane in which the stimulated canal lies, primarily by the excitation of a pair of extraocular muscles: anterior canal–ipsilateral superior rectus and contralateral inferior oblique, posterior canal–ipsilateral superior oblique and contralateral inferior rectus, and lateral canal–ipsilateral medial rectus and contralateral lateral rectus. The directions of the slow eye movements (tonic deviation) produced by stimulation of the canals are depicted schematically in Fig. 9. Purely vertical or torsional nystagmus seldom is seen in labyrinthine disorders. Large cerebellopontine angle tumors can produce asymmetric GEN from compression of the brainstem and cerebellum. The combination of low frequency, large-amplitude GEN on looking ipsilesionally and high frequency, small-amplitude vestibular nystagmus on looking contralesionally

Fig. 9. Schematic summary of semicircular canal excitation and corresponding eye movements. Arrows indicate the direction of the slow phase of the eye movements, not the fast phase of the induced nystagmus. L, left; R, right; AC, anterior semicircular canal; HC, horizontal semicircular canal; PC, posterior semicircular canal.

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is called Bruns’ nystagmus. Contralesional vestibular nystagmus is produced because of a decrease of ipsilateral vestibular tone. It is postulated that, faced with a vestibular imbalance, the brain intentionally makes the neural integrator leaky so that GEN can be used counteract the vestibular imbalance [20]. In this way, there is at least one null position in the orbit in which the eyes do not drift and vision is stable. As the tumor grows, the neural integrator may be compromised because of structural abnormalities and more severe GEN combined with the vestibular nystagmus leading to Bruns’ nystagmus (see Fig. 10). Central vestibular disorders Central vestibular disorders may be classified according to anatomic location and according to the three major planes of action of the VOR. Brainstem disorders Yaw plane disorders. Rotational vertigo, past pointing, rotational and lateral body falls, and horizontal nystagmus represent vestibular tone imbalance in the yaw plane. Horizontal nystagmus. Horizontal nystagmus in the lateral medullary syndrome is one of the most typical forms of vestibular tone imbalance in the yaw plane. Typically, in this disorder, horizontal nystagmus beats away from the side of the medullary infarction (so-called ‘‘pseudo-vestibular neuritis’’) [67], but it may beat ipsilaterally during gaze toward the side of

Fig. 10. Pathophysiology and characteristics of Bruns’ nystagmus with a right cerebellopontine angle mass. The sum of the two types of slow phases is nearly zero in center gaze, rightward in left gaze, and leftward on right gaze. The nystagmus has the character of vestibular nystagmus, however, when gazing to the left (ie, away from the side of the lesion) and the character of GEN when gazing to the right (ie, toward the side of the lesion). CPA, cerebellopontine angle; NI, neural integrator.

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the infarction [68] or during eye closure [69]. In addition to the horizontal nystagmus, other forms of nystagmus (ie, torsional or mixed types) can occur in medullary lesions [70]. Because the area of a lesion causing tone imbalance in the yaw plane not only is small but also overlaps the areas subserving tone in the pitch or roll plane, a pure horizontal syndrome in the yaw plane occurs less frequently than those in the pitch or roll plane. Experimental lesions of the caudal end of the vestibular nuclei or vestibular root entry zone cause torsional nystagmus with a large horizontal component [71]. Thus, some central vestibular disorders mimic unilateral peripheral labyrinthine disorders. Lateropulsion of saccades. Lateropulsion, described previously, typically occurs in the yaw plane. Periodic alternating nystagmus. Periodic alternating nystagmus (PAN) is a spontaneous horizontal nystagmus, present in primary gaze, that periodically changes direction approximately every 2 minutes in the absence of a change in eye or head position. There are null periods between each half cycle that vary from 2 to 20 seconds [72]. Because the period of oscillation is longer than 4 minutes, PAN easily is missed, unless the nystagmus is observed for several minutes. Pharmacologic evidence suggests that the nodulus and uvula maintain inhibitory control on vestibular responses by using c-aminobutyric acid [73]. Therefore, dysfunction of the nodulus and uvula can cause PAN because of excessive vestibular activity [74]. Pitch plane disorders. In contrast to the vestibular tone imbalance in the yaw or roll plane caused by unilateral lesions, pitch plane disorders are caused by bilateral lesions of paired pathways in the brainstem or cerebellar flocculus. This can explain the fact that upbeat or downbeat nystagmus usually is caused by various intoxications or metabolic disorders. They are not observed in unilateral brainstem infarctions [75]. Palatal tremor. Acquired vertical pendular nystagmus is seen in association with palatal tremor. It usually is associated with a similar oscillation, at approximately 2 Hz, of the face, palate, pharynx, larynx, trunk, and extremities. The ocular oscillations often are vertical but may have horizontal or torsional components. When palatal tremor is unilateral, oscillation is similar to that of one eye in seesaw nystagmus; the eye of the involved side rises and intorts synchronously, then falls and extorts. The contralesional eye intorts as it rises and extorts as it falls [26]. Palatal tremor usually develops several months after lesions involving the Guillain Mollaret triangle, which is composed of three anatomic structures: the dentate nucleus, the red nucleus, and the inferior olivary nucleus [76]. The efferents from the dentate nucleus run through the SCP, cross in the decussation of the SCP, pass dorsal and inferior to the contralateral red nucleus, descend to

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the inferior olivary nucleus by way of the CTT, and then cross over to the dentate nucleus of the original side through the inferior cerebellar peduncle. Although it is an anatomic triangle, palatal tremor is associated with lesions of the first two limbs of the triangle, but not with the third limb (ie, the olivodentate fiber within the inferior cerebellar peduncle) [77]. A spontaneous remission is uncommon. Upbeat nystagmus. The pathophysiology of upbeat nystagmus is believed related to an imbalance in vertical VOR pathways. This imbalance may occur as a result of a reduction of upward VOR tone from the anterior semicircular canal by lesions in the SCP, the ventral tegmental tract (VTT), or the NPH. The eyes thus are deflected downward. Then, as a compensatory mechanism, upbeat nystagmus develops. Upbeat nystagmus, therefore, can

Fig. 11. Schematic representation of the structures causing upbeat nystagmus. Brachium conjunctivum (BC) and ventral tegmental tract (VT) relay excitatory inputs from the anterior semicircular canal (AC) through the vestibular nuclei (VIII) to the contralateral oculomotor nucleus (III), which innervates the ipsilateral superior rectus muscle (SR) and the contralateral inferior oblique muscle (IO). Ascending excitatory pathways from the perihypoglossal nuclei (PHN) possibly modulate the vestibular tone of the vertical VOR. Lesions in the three connections depicted above the ’s result in upbeat nystagmus by inducing bilateral downward bias in the vertical VOR. IV, trochlear nucleus.

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arise from two separate intraaxial brainstem lesions in the tegmentum of the pontomesencephalic (either the SCP or VTT) or the pontomedullary junction (NPH) (Fig. 11) [78]. Downbeat nystagmus. First-order otolith afferents are known to project to Purkinje’s cells of the nodulus [79], which exert a weak but definite inhibitory effect on otolith-ocular reflexes [80]. An imbalance in otolithocular reflexes secondary to a lesion of the vestibulocerebellum, perhaps the nodulus, can cause downbeat nystagmus [81]. Downbeat nystagmus is believed caused either by disinhibition of anterior SCC projections secondary to bilateral lesions of the flocculi or by disruption of posterior SCC projections secondary to lesions in the floor of fourth ventricle (see Fig. 12) [82]. Roll plane disorders. Torsional nystagmus, tilt of the subjective visual vertical (SVV), SD, ocular torsion (OT), and the ocular tilt reaction (OTR) are clinical signs of vestibular tone imbalance in the roll plane. Graviceptive input from the otolith organs and the vertical SCCs subserve vestibular function in the roll plane. Graviceptive pathways from the utricle decussate at a caudal pontine level just above the vestibular nuclei and ascend via the MLF to the INC [17]. The INC has extensive connections to rostral and caudal structures, especially the vestibular nuclei and spinal cord and the

Fig. 12. Schematic representation of the structures causing downbeat nystagmus. Either interruption of the excitatory pathways from the posterior semicircular canals to the depressors of the eyes or disinhibition of excitatory pathways from the anterior semicircular canal to the elevators of the eyes as a result of loss of inhibition from the flocculus causes upward bias in the vertical VOR, which results in downbeat nystagmus.
, inhibitory pathway (dark lines); þ, excitatory pathway (light lines); III, oculomotor nucleus; IV, trochlear nucleus; VIII, vestibular nuclei; AC, anterior semicircular canal; IO, inferior oblique muscle; IR, inferior rectus muscle; PC, posterior semicircular canal; SO, superior oblique muscle; SR, superior rectus muscle.

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ocular motoneurons. Therefore, the INC coordinates combine verticaltorsional movements of the eye and head in addition to the neural integration for the position command of vertical-torsional eye movements. Torsional nystagmus. Tone imbalance in the roll plane can be caused by three conditions: (1) a vestibular nucleus lesion (Wallenberg’s syndrome), (2) deficient vertical and torsional neural integrator function (an INC lesion), and (3) deficient vertical and torsional saccadic command (riMLF lesion). When there is tonic torsional drift of the eyes because of tonic imbalance in the roll plane, compensatory torsional nystagmus beating opposite to the deviation occurs. With pontomedullary lesions, fast phases of torsional nystagmus are contralesional (ie, the upper pole of the eye beats to the side opposite the lesion) [70,83]. With MLF [84] and INC [85,86] lesions, fast phases of torsional nystagmus are ipsilesional. Tilts of the subjective visual vertical. Tilts of the SVV occur in disorders involving vestibular structures from the labyrinth to the vestibular cortex and represent the most sensitive sign of an active vestibular tone imbalance in roll plane [75,87]. Unilateral brainstem lesions lying caudal to the crossing of the graviceptive pathway cause ipsiversive OT of one or both eyes, with concurrent ipsiversive tilt of the SVV. Lesions rostral to the decussation, however, cause contraversive OT and contraversive tilt of SVV [87]. Tilts of the SVV occur in thalamic and cortical lesions but occur without concurrent SD, OT, and head tilt [88]. Skew deviation. SD, Hertwig-Magendie syndrome, is a vertical misalignment of the eyes resulting from supranuclear lesions. There is evidence to suggest that SD and OT indicate a vestibular tone imbalance in the roll plane secondary to lesions in the graviceptive pathways [70,89,90]. The direction-specific coincidence of SD, OT, and tilts of SVV toward the lowermost eye is observed only in supranuclear lesions: SD is ipsiversive with caudal pontomedullary lesions and contraversive with rostral pontomesencephalic lesions [91]. Whereas SD does not manifest itself without OT, monocular or binocular torsion frequently is seen without concurrent SD. Ocular tilt reaction. The OTR consists of a triad of head tilt, conjugate OT, and SD, all toward the same side. The OTR indicates dysfunction of the graviceptive pathways anywhere from the peripheral labyrinth to the INC of the rostral midbrain. Structures, pathways, and syndromes related to the roll plane are depicted in Fig. 13. Thalamic disorders Some investigators report contraversive OTR in some paramedian thalamic infarctions [75,92]. In these cases, OTR is, in fact, a result of the

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Fig. 13. Structures and pathways important for eye movement syndromes in the roll plane. Graviceptive pathways from the otoliths and pathways from vertical semicircular canals are conveyed in the MLF to reach more rostral contralateral structures, including the INC and the riMLF. The nucleus ventrooralis intermedius (Vim), nucleus ventrocaudalis externus (Vce) of the thalamus, area 2v (tip of intraparietal sulcus), area 3a (ventral part of central sulcus), and PIVC (posterior end of the insula) also receive graviceptive inputs (dotted lines). The OTR is induced only in the lesions below the level of INC; it is ipsiversive when the lesion is below the decussation of the MLF (horizontal line traversing lower brainstem), whereas it is contraversive when the lesion is above the decussation but below the level of INC (horizontal line traversing upper brainstem). Lesions above the level of INC result only in tilts of the SVV without either SD or ocular tilt. Curved arrows on the right indicate the direction of the tilts of the SVV; bars on the eyes indicate the upper pole of each eye. III, oculomotor nucleus; IV, trochlear nucleus; VI, abducens nucleus; VIII, vestibular nucleus.

additional paramedian rostral midbrain infarction. The paramedian thalamic arteries and paramedian superior midbrain arteries often arise jointly from the basilar artery. Thus, occlusion of the basilar artery can cause a concurrent paramedian thalamic and rostral midbrain infarction. Thalamic lesions can cause perceptual tilts of SVV but neither SD nor OT. In unilateral thalamic infarctions, tilts of the SVV, either contraversive or ipsiversive, are seen only when the posterolateral thalamus, which contains vestibular relay nuclei to the cortex [75,92], is involved. Thalamic astasia refers to an inability to stand in the absence of motor weakness or marked

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sensory loss. It usually is caused by the involvement of the superiolateral portion of the ventrolateral thalamic nucleus [93]. Cortical disorders Even though great progress in understanding the vestibular system has been made, little is known about vestibular function in the cortex. At least four different areas of the parietal and temporal cortex are identified in animal studies as receiving vestibular afferents: area 2V (tip of the intraparietal sulcus) [94], area 3aV (ventral part of the central sulcus) [95], parietoinsular vestibular cortex (PIVC) (posterior end of the insula) [96], and area 7 (inferior parietal lobule) [97]. Lesions of the posterior insula cause pathologic tilts of the SVV, mostly contraversive, but no SD and slight monocular torsion [96]. These findings support the view that vestibular projections to the cerebral cortex are important for perception of verticality and localization of the objects but not for brainstem vestibular reflexes. Epileptic nystagmus refers to recurrent attacks of nystagmus caused by a cortical seizure activity. The conjugate deviation of the eyes during the seizure may be tonic or clonic; in the latter, the resulting eye movements present as epileptic nystagmus. The mechanism of epileptic nystagmus is not understood completely but may be explained by one of the following three mechanisms: epileptic activation of a cortical (1) saccadic, (2) pursuit, or (3) optokinetic region [98,99]. Cerebellar disorders The cerebellum affects almost every type of eye movement by making immediate, on-line correction and by ensuring long-term adaptation. Cerebellar lesions can be challenging to diagnose. Caution must be used in analyzing eye movement abnormalities and concluding that they are a result of cerebellar dysfunction, because coincident involvement of the brainstem is frequent in patients who have cerebellar disorders. Because the cerebellum is the structure responsible for adaptive behavior, a silent brain lesion may be unmasked by subsequent cerebellar dysfunction and produce an eye sign not present with either lesion alone. Certain cerebellar signs cannot be produced in animal models because human cerebellar lesions often evolve slowly or diffusely. Eye movement abnormalities with cerebellar disease are classified into three syndromes: (1) the syndrome of the flocculus and paraflocculus (impaired smooth pursuit; impaired VOR cancellation and fixation suppression; gaze-evoked, downbeat, centripetal, and rebound nystagmus; postsaccadic drift or glissades; and impaired VOR adaptation and learning); (2) the syndrome of the nodulus and ventral uvula (prolonged VOR time constant resulting from maximized velocity storage; impaired habituation of the VOR; positional, downbeat, and PAN; impaired tilt suppression of postrotational nystagmus; and the OTR); and (3) the syndrome of the dorsal vermis and underlying fastigial nucleus

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(saccadic dysmetria; mild deficits of smooth pursuit; and impaired motion perception) [26,100]. OTR and apparent vestibular neuritis can result from a unilateral cerebellar lesion [101]. The mechanism of a tonic contraversive OTR and for pseudoneuritis with a unilateral cerebellar lesion is an increase in tonic resting activity of secondary vestibular neurons in the ipsilesional vestibular nucleus resulting from loss of inhibition from the lesioned nodulus.

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