TABLE 1. Functional Classes Of Eye Movements

Prior to starting on this tour, we must recognize that when the brain initiates any type of eye movement, it must take into account the properties of the eyeball, its suspensory ligaments, and fascia. Although it is easy to take for granted that the brain will make adjustments, for example, when the eye turns to look out of the corner of the orbit, such eccentric “gaze-holding” demands an appropriate tonic contraction of the extraocular muscles, to prevent the eye from drifting back toward primary position. This gaze-holding function (sometimes referred to as the achievement of a neural integrator) is really a separate functional property affecting all eye movements that also has its own identified neural substrate.

A recent revolution in the field has been the rediscovery of pulleys that guide the tendons of the extraocular muscles.⁴ Thus, each muscle has an outer orbital layer that inserts into the muscles pulley; the inner global layer passes through the pulley to insert on the globe. With the exception of the superior oblique, all muscle pulleys move, which may be how Listing's law is imposed on eye rotations. Listing's law states that any eye position can be reached from primary position by rotation of the eye about a single axis lying in the equatorial plane. By delegating control of the geometry of eye rotations to the muscles and pulleys, the brain seems to simplify its role in controlling three dimensional eye rotations. Different populations of ocular motoneurons may supply the global and orbital layers, and their proprioception may differ⁵; these are topics of current research.

MOTOR COMMANDS FOR CONJUGATE (VERSIONAL) HORIZONTAL MOVEMENTS

The abducens nucleus is of central importance in the control of horizontal gaze because it governs conjugate movements of both the ipsilateral lateral rectus and the contralateral medial rectus muscles. It houses two populations of neurons: (1) abducens motoneurons, which supply the lateral rectus muscle and (2) abducens internuclear neurons, which project up the contralateral medial longitudinal fasciculus (MLF) to contact medial rectus motoneurons of the oculomotor nucleus (Fig. 1).^2,6 Thus, axons of the abducens nerve and axons of the abducens internuclear neurons that run in the MLF,⁷ together encode conjugate horizontal eye movements, and the mechanism for yoking of horizontal movements—Hering's law—has its neural basis in the abducens nucleus and its two populations of neurons. The abducens motoneurons and internuclear neurons show only minor morphological differences,⁸ but only the motoneurons contain acetylcholine.⁹ Both types of abducens neurons receive the same afferent input.

How do signals for each functional class of eye movement (Table 1) project to the abducens nucleus? The abducens nucleus receives vestibular and optokinetic inputs from the vestibular nuclei.¹⁰ Saccadic commands originate from burst neurons of the pontine and medullary reticular formation.¹¹ A descending smooth pursuit pathway probably projects to the abducens nucleus via the vestibular and cerebellar fastigial nuclei (see Pursuit System, below).² The signals that are important for gaze-holding (neural integrator) function reach the abducens nucleus from the nucleus prepositus hypoglossi and the medial vestibular nuclei.¹²

EFFECTS OF LESIONS OF THE PONS AND MEDULLA ON HORIZONTAL GAZE

Lesions of the abducens nucleus produce paralysis of both the ipsilateral lateral rectus and contralateral medial rectus for all conjugate eye movements,^13–16 but vergence movements are spared. Clinical lesions that affect only the abducens nucleus are rare, and usually there is also involvement of adjacent structures including the MLF, paramedian pontine reticular formation (PPRF), and particularly, the facial nerve fascicle.

Lesions of the medial longitudinal fasciculus produce internuclear ophthalmoplegia (INO), which is characterized by paresis of adduction for conjugate movements on the side of the lesion.^2,17 Another common feature of INO is dissociated nystagmus, characterized by abduction overshoot of the eye contralateral to the lesion (see Chapter 11). Dissociated nystagmus is probably an adaptive phenomenon; as the brain attempts to point the paretic adducting eye at the visual target, a series of saccades is only evident in the non-paretic, abducting eye.¹⁸ The MLF is paramedian in the pons and becomes slightly more lateral in the midbrain as it approaches the oculomotor nuclear complex. INO is often accompanied by skew deviation, probably because of disruption of the otolithic-ocular connections.¹⁹ In addition, the vertical vestibulo-ocular reflex (VOR) may show deficient downward eye movements when tested with “head impulses,” because the INO carries some but not all vertical vestibular signals.²⁰ Bilateral INO is usually associated with gaze-evoked vertical nystagmus, impaired vertical pursuit, and decreased vertical vestibular responses.²¹ Small-amplitude saccadic intrusions may interrupt fixation.²² The most frequent cause of INO in young adults, particularly when bilateral, is multiple sclerosis; other causes are summarized in Table 2.

TABLE 2. Causes Of Internuclear Ophthalmoplegia

1. Multiple sclerosis (commonly bilateral)
2. Brainstem infarction (commonly unilateral), including complication of arteriography and hemorrhage
3. Brainstem and fourth ventricular tumors
4. Arnold-Chiari malformation, and associated hydrocephalus and syringobulbia
5. Infection: bacterial, viral and other forms of meningo-encephalitis; in association with AIDS
6. Hydrocephalus, subdural hematoma, supratentorial arteriovenous malformation
7. Nutritional disorders: Wernicke's encephalopathy and pernicious anemia
8. Metabolic disorders: hepatic encephalopathy, maple syrup urine disease, abetalipoproteinemia, Fabry's disease
9. Drug intoxications: phenothiazines, tricyclic antidepressants, narcotics, propranolol, lithium, barbiturates
10. Cancer: either the result of carcinomatous infiltration, or remote effect
11. Head trauma, and cervical hyperextension or manipulation
12. Degenerative conditions: progressive supranuclear palsy
13. Syphilis
14. Pseudo-internuclear ophthalmoplegia of myasthenia gravis, and Fisher's syndrome

Strictly speaking, the term internuclear ophthalmoplegia should refer to absolute adduction paralysis during horizontal versions, and the term internuclear ophthalmoparesis should be used to describe those cases where adduction past the midline is present, but with limitation of amplitude or decreased velocity. When INO is subtle, two maneuvers may be useful for demonstrating it: the optokinetic and ocular dysmetria signs,²³ which rely on demonstrating impairment of innervation of the medial rectus muscle compared with its yoke, the contralateral lateral rectus, during horizontal saccades. With the optokinetic tape moving to the side of the involved medial rectus muscle, the nystagmus response in that eye is reduced (especially the adduction saccade) compared with the opposite eye. The ocular dysmetria sign necessitates repetitive horizontal saccadic refixations that disclose slow, hypometric refixation of the adducting eye (medial rectus) and concomitant overshoot of the abducting eye (lateral rectus). However, recent studies indicate that even experienced clinicians may miss INO,²⁴ and measurement of saccades to compare adducting and abducting movements is worthwhile when MS is suspected.^25–27 Magnetic resonance imaging (MRI) with proton-density high-resolution views of the brainstem may also aid in establishing MLF lesions.²⁸

Most cases of INO are orthotropic (or exophoric) in primary position without symptomatic diplopia unless accompanied by skew deviation. Occasionally, patients with bilateral INO show exotropia, designated the WEBINO (wall-eyed bilateral INO) syndrome. The explanation for this finding is unclear because monkeys with a lidocaine-induced internuclear ophthalmoplegia show an increased accommodative vergence to accommodation ratio, implying that the MLF actually carries signals that inhibit vergence.¹⁷ Thus, the cause of exotropia in INO is uncertain and we have observed it in patients with preserved convergence. Furthermore, the classification of INO into anterior and posterior types depending on the integrity of the convergence mechanism is not of localizing value in identifying the rostral-caudal location of the MLF lesion. The so-called posterior internuclear ophthalmoplegia of Lutz,²⁹ in which abduction (but not adduction) is impaired is rare. It has been difficult to conceptualize because the abducens contains neurons that innervate both lateral and medial rectus muscles for all conjugate eye movements.³⁰ One possible explanation concerns oculomotor internuclear neurons, which project from the third nerve nucleus down to the contralateral abducens nucleus; inactivation of these internuclear neurons causes impaired abduction.³¹

A combined lesion of one MLF and the adjacent abducens nucleus or PPRF produces paralysis of all conjugate movements except for abduction of the eye contralateral to the side of the lesion—”one-and-a-half” syndrome.^32–34 This occurs with brainstem infarction, hemorrhage, multiple sclerosis, and pontine glioma; rarer causes are brainstem arteriovenous malformation, basilar artery aneurysm, and posterior fossa tumor. When the lesion is acute, the patient may be profoundly exotropic.³⁵ The deviated eye may demonstrate marked nystagmus and is always on the side opposite that of the brainstem lesion.

Discrete lesions of the paramedian pontine reticular formation (PPRF)^36,37—which mainly corresponds to the nucleus pontis centralis caudalis and contains saccadic burst neurons—cause loss of saccades and quick phases of nystagmus to the side of the lesion. Vertical saccades are misdirected obliquely away from the side of the lesion.³⁸ Selective impairment of horizontal saccades occurs in degenerative conditions, such as some variants of olivopontocerebellar atrophy.³⁹ Other causes of slow or absent saccades are summarized in Table 3. Infarction of the paramedian pons usually but not always also involves adjacent fibers conveying vestibular and pursuit inputs to the abducens nucleus.³⁸ Pontine disease may cause a unilateral defect of smooth pursuit by affecting the dorsolateral pontine nuclei and their projections to the cerebellum (see below). More rostral brainstem lesions may cause ipsilateral smooth pursuit deficits, whereas caudal brainstem lesions tend to cause contralateral deficits²; this is discussed further below.

TABLE 3. Causes Of Slow Saccades

1. Olivopontocerebellar atrophy and spinocerebellar degenerations
2. Huntington's disease
3. Progressive supranuclear palsy
4. Parkinson's disease (advanced cases) and diffuse Lewy body disease
5. Whipple's disease
6. Lipid storage diseases
7. Wilson's disease
8. Drug intoxications: anticonvulsants, benzodiazepines
9. Tetanus
10. In dementia: Alzheimer's disease (stimulus-dependent) and in association with AIDS
11. Lesions of the paramedian pontine reticular formation
12. Internuclear ophthalmoplegia
13. Peripheral nerve palsy, diseases affecting the neuromuscular junction and extraocular muscle, restrictive ophthalmopathy

Bilateral experimental lesions of the nucleus prepositus hypoglossi and adjacent medial vestibular nucleus abolish the gaze-holding mechanism (neural integrator) for eye movements in the horizontal plane.^40,41 In health, the neural integrator generates the eye position command necessary to hold the eye steady in an eccentric orbital position. After damage to the neural integrator network (which includes connections with the vestibular cerebellum), the eye cannot be held in an eccentric position in the orbit and it drifts back to primary position. Corrective quick phases then produce gaze-evoked nystagmus (see Chapter 11). Thus, disease affecting the vestibular nuclei and nucleus prepositus hypoglossi cause vestibular imbalance—manifest as nystagmus or skew deviation—and impairment of gaze-holding. This occurs with lateral medullary infarction (Wallenberg's syndrome) in which the spontaneous nystagmus is usually horizontal or mixed horizontal-torsional with the slow phases directed toward the side of the lesion; the nystagmus may reverse direction in eccentric positions, suggesting coexistent involvement of the gaze-holding mechanism. Skew deviation, with an ipsilateral hypotropia, cyclodeviation (lower eye is more extorted), and ipsilateral head tilt (when present together, called the ocular tilt reaction) reflect an imbalance of otolithic inputs.⁴² In addition, patients with Wallenberg's syndrome show a characteristic lateropulsion in which the eyes deviate conjugately toward the side of the lesion if the lids are closed or with saccades.⁴³ A hypothetical explanation for lateropulsion is that infarction of the inferior cerebellar peduncle leads to increased inhibition of the fastigial nucleus by the cerebellar vermis⁴⁴; this is discussed further below in the section dealing with cerebellar influences on eye movements.

In the prerubral fields of the mesencephalon, rostral to the tractus retroflexus and caudal to the mammillothalamic tract, lies a nucleus that is important for the generation of vertical saccades (Fig. 2). This structure, now called the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF),^45,46 previously designated the nucleus of the prerubral fields, and the nucleus of the fields of Forel, contains burst neurons for vertical saccades and quick phases, and torsional quick phases. Each riMLF contains neurons that burst for upward and downward eye movements but for torsional quick phases in only one direction. Thus, the right riMLF discharges for quick phases that are directed clockwise with respect to the subject.⁴⁷ In addition, each riMLF is connected to its counterpart by the posterior commissure, and by a more rostrally located ventral commissure that lies ventral to the aqueduct. The riMLF projects to motoneurons innervating elevator muscles bilaterally but to motoneurons innervating depressor muscles ipsilaterally.^48,49 Furthermore, each burst neuron in the riMLF appears to send axon collaterals to motoneurons supplying yoke muscle pairs (e.g., superior rectus and inferior oblique); this is the neural substrate whereby Hering's law applies to saccades in the vertical plane.

The riMLF also projects to the interstitial nucleus of Cajal (INC), which has an important role in vertical gaze-holding (the neural integrator).⁵⁰ In addition, the INC also receives inputs from the vestibular nuclei. The INC projects to motoneurons of the vertical ocular motor subnuclei. The projections of the INC to the elevator ocular motor nuclei (superior rectus and inferior oblique) pass dorsally over the aqueduct in the posterior commissure and this might explain why lesions of the posterior commissure limit mainly upward eye movements.^50–52 The INC also contains neurons that project to motoneurons of the neck and trunk muscles and appears to coordinate combined torsional-vertical movements of the eyes and head.⁵³ The neural signals necessary for vertical vestibular and smooth pursuit eye movements ascend from the medulla and pons to the midbrain. The MLF is the most important route for these projections but the brachium conjunctivum and other pathways are also involved.⁵⁴

EFFECTS OF MIDBRAIN LESIONS ON VERTICAL AND TORSIONAL GAZE

Unilateral, experimental lesions of the riMLF cause a mild defect in vertical saccades, because each nucleus contains burst neurons for both upward and downward movements. On the other hand, unilateral riMLF lesions produce a specific defect of torsional quick phases.⁴⁷ For example, with a lesion of the right riMLF, torsional quick phases, clockwise from the point of view of the subject (extorsion of the right eye and intorsion of the left eye) are lost. Vertical saccadic deficits with unilateral lesions of the riMLF in humans are rare; such deficits probably reflect involvement of the commissural pathways of the riMLF that makes the lesion, in effect, bilateral.⁵⁵ In general, bilateral lesions are required to produce clinically apparent deficits of vertical eye movements.⁵⁶ Bilateral experimental lesions of the riMLF in monkeys cause a vertical saccadic deficit, that may be more pronounced for downward eye movements⁵⁷; this may be because upward saccadic projections are bilateral whereas downward saccadic projections are unilateral.^48,49,58 With bilateral riMLF lesions, vertical gaze-holding, vestibular eye movements and possibly pursuit are preserved, as are horizontal saccades, with the deficits limited to either downward or both upward and downward saccades.^58,59 Certain metabolic and degenerative disorders may lead to selective slowing or absence of vertical saccades (Table 3).

Unilateral experimental lesions of the INC are reported to impair gaze-holding function in the vertical plane.⁶⁰ In addition, there is skew deviation (ipsilateral hypertropia), extorsion of the contralateral eye, intorsion of the ipsilateral eye, and contralateral head tilt.¹⁹ Stimulation near the INC in the monkey produces an ocular tilt reaction that consists of an ipsilateral head tilt and a synkinetic ocular reaction: depression and extorsion of the eye ipsilateral to the stimulation and elevation and intorsion of the contralateral eye.^61,62 This ocular tilt reaction is similar to that produced by stimulation of the contralateral utricular nerve or an ipsilateral lesion of the vestibular nucleus (see Wallenberg's syndrome, above). Bilateral lesions of the medial longitudinal fasciculus (bilateral INO) impair vertical vestibular and pursuit movements but spare vertical saccades.⁶³ In addition, partial loss of the vertical eye position signal causes vertical gaze-evoked nystagmus.

Lesions of the posterior commissure cause loss of upward gaze⁵²; usually all types of eye movement are affected, although the VOR and Bell's phenomenon may sometimes be spared. Experimental inactivation of the posterior commissure with lidocaine impairs vertical gaze-holding (neural integrator) function.⁵¹ Other findings with posterior commissure lesions include slowing of vertical saccades below the horizontal meridian, disorders of convergence, convergence-retraction nystagmus, light-near dissociation of the pupils, and eyelid retraction (see Dorsal Midbrain Syndrome, below).

SUSTAINED VERTICAL DEVIATIONS

A number of disparate conditions may lead to tonic upward or downward eye deviations. One dramatic example is the sustained upward deviation of oculogyric crisis (see below, under parkinsonian disorders). Otherwise, tonic up-gaze deviation is seen in unconscious patients, especially after hypoxic-ischemic brain injury, perhaps reflecting loss of cerebellar Purkinje cells that normally balance vestibular and gaze-holding mechanisms. This notion is supported by the observation that patients who survive such insults develop downbeating nystagmus.⁶⁴ Tonic downward deviation may occur transiently in neonates and does not necessarily indicate a neurologic abnormality; in such cases, the eyes can be easily driven above the horizontal meridian by the vertical doll's-head maneuver.⁶⁵ In comatose patients, sustained downward deviations, with small unreactive pupils, usually reflect bilateral thalamic infarction or hemorrhage.⁶⁶ The setting sun sign of infantile hydrocephalus is an analogous clinical phenomenon, with associated pathologic eyelid retraction. The reversibility of this sign with ventricular decompression indicates a dynamic mechanism secondary to acutely increased intracranial pressure.⁶⁷ Tonic downward deviation may occur with lesions that compress the posterior commissure but also in metabolic encephalopathies.⁶⁸ These sustained downward deviations are to be distinguished from “ocular bobbing,” an oscillatory disorder consisting of an abrupt downward jerk followed by a slow upward drift to midposition (see Chapter 11). Slow, spontaneously alternating skew deviations may occur with lesions of the dorsal midbrain.⁶⁹

DORSAL MIDBRAIN SYNDROME

Dorsal lesions in the rostral midbrain produce a distinctive constellation of neuro-ophthalmologic signs involving supranuclear control of vertical gaze, eyelids, pupils, accommodation, and vergence. This entity encompasses many eponymic and anatomical designations, such as Parinaud, Koerber-Salus-Elschnig, sylvian aqueduct, pretectal, and posterior commissural syndromes.⁷⁰ Pineal area tumors⁷¹ and midbrain infarction^58,59 are the most common causes. Other etiologies include congenital aqueductal stenosis, multiple sclerosis, syphilis, arteriovenous malformations, midbrain hemorrhage,⁷² encephalitis, midbrain or third ventricle tumors, herniation of the uncus,⁷³ and lesions resulting from stereotactic surgery.⁷⁴ The lesions are usually large and involve one or more of the sites previously described as causing up-gaze palsies. The pupils are mid-position or large and demonstrate light-near dissociation; that is, the light reaction is smaller than the near response. Pathologic lid retraction (Collier's sign) and lid lag are common findings. Paralysis of upward gaze is the hallmark sign. Upward saccades are affected initially, whereas pursuit is relatively spared. Both types of eye movements, as well as vestibulo-ocular responses and Bell's phenomenon, may ultimately become paralyzed. Attempts at upward saccades evoke convergence-retraction nystagmus that persists as long as the refixation effort is maintained. The nystagmus is best elicited with down-going optokinetic targets providing a stimulus for repetitive upward saccades; each fast phase is replaced by a convergence or retraction movement. There is debate as to whether it is a true form of nystagmus,⁷⁵ or a series of opposed adducting saccades, followed by slow divergence movements (see Chapter 11).⁷⁶ This is in contrast to normal subjects who show transiently convergence during downward saccades and divergence during upward saccades.⁷⁷ Rarely, a divergence-retraction nystagmus may occur in patients with dorsal midbrain syndrome.

Cerebral hemispheric lesions associated with focal motor seizures may cause retraction nystagmus temporally associated with periodic lateralized epileptiform discharges (PLEDs) on the electroencephalogram (EEG).⁷⁸

SKEW DEVIATION

Skew deviation may be defined as a vertical misalignment of the visual axes caused by a disturbance of prenuclear inputs. The misalignment may be the same in all positions of gaze (concomitant), may vary with gaze position, or may even alternate (e.g., right hypertropia on right gaze, left hypertropia on left gaze).^79–81 When skew deviation is nonconcomitant, it should be differentiated from vertical extraocular muscle palsy by the coexistence of signs of central neurologic dysfunction, and from trochlear nerve palsy by a negative head-tilt test. In some patients, skew deviation is accompanied by ocular torsion and head tilt—the ocular tilt reaction (OTR)¹⁹ (Fig. 3), which may be tonic (sustained)^82,83 or paroxysmal.^84,85 Such patients also show a deviation of the subjective vertical.¹⁹Rarely, skew deviation slowly alternates or varies in magnitude over the course of minutes.⁶⁹ These patients have midbrain lesions. The periodicity of the phenomena is reminiscent of periodic alternating nystagmus (see Chapter 11) and the two phenomena may coexist.⁸⁶

Skew deviation is seen with a variety of disorders of the brainstem and cerebellum,⁷⁹ and as a reversible finding with raised intracranial pressure. Current evidence suggests that skew deviation occurs whenever peripheral or central lesions cause an imbalance of otolithic inputs.¹⁹ Skew deviation also occurs with cerebellar lesions.⁸¹ The characteristics of the ocular tilt reaction caused by lesions of the vestibular labyrinth, vestibular nuclei, MLF, and the INC are summarized in Figure 10-3. In cases when the skew deviation is paroxysmal, the mechanism is thought to be irritative. This interpretation is supported by observations in one patient; stimulation of in the region of INC caused an ocular tilt reaction, with episodes of contralateral hypertropia and ipsilateral head tilt.⁶²

MOTOR COMMANDS FOR VERGENCE MOVEMENTS

Neurophysiologic studies in monkeys have shown that almost all oculomotor neurons subserving the medial rectus and the majority of neurons in the abducens nucleus discharge for both conjugate (version) and disjunctive (vergence) eye movements, although there is evidence that different neurons play relatively smaller or larger roles in conjugate versus vergence eye movements.^87–90 Premotor commands for vergence are found on neurons in the mesencephalic reticular formation, 1 to 2 mm dorsal and dorsolateral to the oculomotor nucleus.^89,91 Three main types of neurons are present; those that discharge in relation to vergence angle, vergence velocity,⁹² and both vergence angle and velocity. Evidence suggests that the nucleus reticularis tegmenti pontis (NRTP) houses neurons that are important for generating the vergence position signal (the vergence integrator).⁹³ Abducens and oculomotor interneurons (each of which has projections to the other nucleus via the MLF) contribute to the coordination of conjugate and vergence commands.^17,31

Most natural vergence movements are made in combination with a saccade, as we shift our fixation point between visual targets located at different distances and in different directions.⁷⁷ Clinicians traditionally test vergence with a smooth movement of a visual target that is brought along the patient's midsagittal plane toward the nose. These two types of vergence—saccadic vergence and pursuit vergence—depend, in part, on different anatomic circuits.²

DISORDERS OF VERGENCE

Midbrain lesions may disrupt convergence, accommodation, and pupillary constriction—the near reflex. In addition, they produce vertical gaze disturbances and so-called convergence-retraction nystagmus (see Dorsal Midbrain Syndrome, above). Convergence paralysis or paresis may be secondary to various organic processes such as encephalitis, multiple sclerosis, and occlusive vascular disease involving the rostral midbrain. The distinction between organic and functional convergence palsy is based primarily on the assumption that accommodation and pupillary constrictions are provoked during attempted convergence in the former, but not in the latter. Senescence and lack of effort are the most common causes of poor convergence. Overall, the most common disorders of vergence are congenital, causing strabismus in childhood. In many such cases, abnormality of the accommodative-convergence synkinesis can be demonstrated. In adults, the commonest disorders are spasm of the near reflex and divergence paresis (see below).

Testing of vergence eye movements has focused on movements that are either made with a saccade, or in response to a smoothly target moving in the depth plane. Vergence movements made with saccades may be slow in progressive supranuclear palsy (PSP; see Parkinsonian Disorders, below),⁹⁴ whereas patients with lesions involving the nucleus reticularis tegmenti pontis may have selective impairment of smooth vergence movements.⁹⁵ Applying this approach with reliable measurements of eye movements, is likely to provide new information on disorders of vergence.

SPASM OF THU NEAR REFLEX

Spasm of the near reflex (accommodative or convergence spasm) is most commonly psychogenic. Affected patients may appear to have unilateral or bilateral abducens paresis.⁹⁶ However, the pupillary miosis accompanying failure of abduction is a telltale sign. Volitional excessive near effort is uncomfortable and rarely can be maintained for more than seconds to minutes. Symptoms include blurred vision, eye strain, dizziness, headache, and diplopia. Rarely, a tonic near reflex may occur with organic disease, including generalized seizures, head trauma, the dorsal midbrain syndrome, craniocervical junction abnormalities, intoxications, and Wernicke's encephalopathy.^2,97

DIVERGENCE PARESIS OR PARALYSIS

Paresis (insufficiency) of divergence is a rare clinical syndrome characterized by orthophoria at near but relatively concomitant esotropia at distance, although abduction is normal. Diplopia while viewing distant objects is the principal complaint, although other vague symptoms may be emphasized. A prerequisite for the diagnosis of divergence paresis is the demonstration of normal abducting saccades, and this criteria has seldom been met. In many patients, the question of decompensation of a long-standing esophoria bias is usually raised, for example, in the setting of concussion or cervical hyperextension injury. Tests of vergence amplitudes and stereopsis may be equivocal and the possibility of mild abduction defects remains. Mild abducens nerve dysfunction occurs after head trauma or raised intracranial pressure. The possibility of raised intracranial pressure must be excluded. Divergence insufficiency has been reported in PSP, seizure disorder, acute brainstem dysfunction, vascular disease, and after viral infections.^98,99 Most patients do well with base-out prisms incorporated in distant spectacle correction and only rarely is ocular muscle surgery required.

The flocculi and ventral paraflocculi (tonsils), are paired structures that, in the human brain, lie ventral to the inferior cerebellar peduncle and next to the eighth cranial nerve. The flocculus receives bilateral inputs from the vestibular nuclei and the nucleus prepositus hypoglossi, and inputs from the dorsal cap of the contralateral inferior olive.¹⁰⁰ The main efferent pathways of the flocculus are to the ipsilateral superior, medial, and y-group of vestibular nuclei.¹⁰¹ The flocculus and ventral paraflocculus contain Purkinje cells that discharge during smooth pursuit and combined eye-head tracking to encode gaze-velocity.¹⁰² These floccular Purkinje cells may also contribute to vestibular eye movements during self-rotation,¹⁰³ and have an important role in the adaptive control of the VOR.¹⁰⁴

The nodulus, which is the midline portion of the flocculo-nodular lobe, lying immediately caudal to the inferior medullary velum, and the adjacent ventral uvula receive afferents from the vestibular nuclei and inferior olive.¹⁰⁵ The nodulus and uvula project to the vestibular nuclei and probably to other structures via the fastigial nucleus. Together, these structures affect the temporal response of the VOR, so that a sustained, constant-velocity rotation induces nystagmus that out-lasts by two or three times the duration of displacement of the cupula of the labyrinthine semicircular canals (a process called velocity storage).¹⁰⁶

Lobules IV to VII of the vermis (the culmen, folium, tuber, declive, and part of the pyramis) receive mossy fiber inputs from the PPRF, NRTP, dorsolateral pontine nuclei, vestibular nuclei and nucleus prepositus hypoglossi, and climbing fiber inputs from the inferior olive.¹⁰⁷ The projection from NRTP may relay information from the frontal eye fields necessary for the planning of saccades. The dorsal vermis projects to the fastigial nucleus, which also receives inputs from the inferior olive.¹⁰⁸ The fastigial nucleus sends contralateral projections via the uncinate fasciculus (which runs in the dorsolateral border of the brachium conjunctivum) to the PPRF, and riMLF. Current concepts are that feedback of motor commands (efference copy) steers the eye to its target during saccades. This feedback circuit includes the dorsal vermis and fastigial nuclei, and timing of the discharge of neurons at these sites influences initial acceleration of the eye and deceleration when the eye approaches its target.^109–111

EFFECTS OF CEREBELLAR LESIONS ON EYE MOVEMENTS

Experimental lesions of the flocculus and paraflocculus in monkeys produce a syndrome that is similar to that encountered clinically in patients with the Arnold-Chiari malformation.^2,112 This includes impaired smooth pursuit and eye-head tracking,¹¹³ and impaired gaze-holding (deficient neural integrator). The gaze-holding deficit most probably reflects the contribution that the cerebellum makes to enhance the brainstem neural integrator, which lies in the medial vestibular nuclei and the nucleus prepositus hypoglossi. Another deficit caused by floccular lesions is loss of the ability to adapt the properties of the VOR in response to visual demands^104,114; consequently, patients with disease involving the vestibular cerebellum may have vestibulo-ocular eye movements that are hypoactive or hyperactive, and they may complain of impaired vision and oscillopsia with head movements. Downbeat nystagmus (see Chapter 11) is another common finding, and probably reflects an imbalance in central vestibular connections due to loss of floccular modulation of the vertical VOR.

In monkeys, lesions of the nodulus and uvula maximize the velocity-storage effect¹¹⁵; maneuvers that would usually minimize the effect, such as pitching the head forward during postrotational nystagmus, are rendered ineffectual. Similar effects are seen in patients with midline cerebellar tumors that involve the nodulus.¹¹⁶ In addition, when monkeys that have nodular lesions are placed in darkness, they may develop periodic alternating nystagmus.¹¹⁵ Patients with periodic alternating nystagmus often have lesions involving the nodulus and ventral uvula.¹¹⁷

Experimental lesions of the dorsal vermis produce dysmetria of saccades, especially hypometria.¹¹⁸ Experimental inactivation of the caudal fastigial nuclei with the GABA agonist muscimol causes hypermetria of ipsilateral saccades and hypometria of contralateral saccades.¹¹⁹ This mechanism of saccadic dysmetria may account for the ipsipulsion of saccades encountered in patients with Wallenberg's syndrome; loss of inputs from an infarcted inferior cerebellar peduncle cause an increase in Purkinje cell activity that inhibits the ipsilateral fastigial nucleus.⁴⁴ Disease processes that involve the fastigial nucleus in humans often produce a severe form of saccadic dysmetria in which the eye may repetitively overshoot a stationary target, so-called macrosaccadic oscillations (see Chapter 11); this also is reported with a genetic disorder (spinocerebellar ataxia with saccadic intrusions).¹²⁰ The posterior vermis also contributes to smooth pursuit; it has reciprocal connections with the dorsolateral pontine nuclei, and neurons encode target velocity during pursuit. Lesions of the posterior vermis impair smooth pursuit.¹²¹ Unilateral lesions of the fastigial nucleus cause a defect of contralateral smooth pursuit, but bilateral lesions may leave smooth pursuit preserved, reflecting directional (acceleration-deceleration) influences of this nucleus on tracking.¹²²

COMMON VASCULAR SYNDROMES OF THE CEREBELLUM

The cerebellum receives its blood supply from the three branches of the posterior circulation: the posterior-inferior cerebellar artery (PICA), anterior-inferior cerebellar artery (AICA), and superior cerebellar artery (SCA). Occlusion in these vessels often also produces brainstem infarction, making precise clinicopathologic correlation difficult. Infarction in the distribution of the distal PICA may cause acute vertigo and nystagmus that often simulates an acute peripheral vestibular lesion.¹²³ These symptoms probably reflect a central vestibular imbalance, created by asymmetrical infarction in the vestibulocerebellum that normally has a tonic inhibitory effect on the vestibular nuclei. Affected patients may have gaze-evoked nystagmus that differentiates this cerebellar lesion from an acute peripheral vestibulopathy. The AICA supplies portions of the vestibular nuclei, adjacent dorsolateral brainstem and inferior lateral cerebellum (including the flocculus); in addition the AICA is the origin of the labyrinthine artery in most individuals. Consequently, ischemia in the AICA distribution may cause vertigo, vomiting, hearing loss, facial palsy, and ipsilateral limb ataxia.¹²⁴ Infarction in the territory of the SCA causes ataxia of gait and limbs, and vertigo. A characteristic finding is saccadic contrapulsion. This consists of an overshooting of contralateral saccades and an undershooting of ipsilateral saccades; attempted vertical saccades are oblique, with a horizontal component away from the side of the lesion.^125–127 Thus, the saccadic disorder is the opposite of the saccadic ipsipulsion seen in Wallenberg's syndrome and probably reflects interruption of crossed outputs from the fastigial nucleus running in the uncinate fasciculus adjacent to the superior cerebellar peduncle.

THE SACCADIC SYSTEM

Several Roles for Saccades

To appreciate the role of the cerebral hemispheres in the control saccadic movements, one must understand that rapid eye movements serve several distinct functions.³

1. At the lowest level are the fast phases of nystagmus, which reset the eyes after vestibular or optokinetic slow-phase movements.
   
2. Spontaneous saccades occur at a frequency of approximately 20 per minute and serve the purpose of visual search of the environment, although they also occur in darkness.
   
3. Reflexive or nonvolitional saccades, characterized by short reaction times, occur in response to new visual, auditory, or tactile cues.
   
4. Voluntary (intentional or volitional) saccades carry the eyes to a predetermined location corresponding to the position of a visual target or sound; they direct the fovea at a goal. Such voluntary saccades can also be made in a predictive fashion when the target is moving in a regular pattern: the eye movement anticipates the change in target position. Voluntary saccades can also be made toward imagined or remembered target locations, or in response to commands (e.g., “Look right”). A special case of voluntary saccades is the antisaccade, when the subject is required to respond to a visual stimulus by looking to the corresponding position in the opposite visual hemifield.
   
5. Saccades can be voluntarily suppressed when it is necessary to maintain steady foveal fixation.
   

Thus, saccades respond to the full range of sensory inputs (visual, vestibular, auditory, somatosensory) and to internal cognitive factors. Each of these distinct functions of saccades depends on different cortical and subcortical areas; by examining each function, at the bedside or in the laboratory, it is possible to evaluate the separate neural substrates.

Several Cortical Areas that Contribute to Saccade Generation

In addition to the classic frontal and parietal eye fields (PEF), several other cortical areas contribute to the control of saccades; these include the supplementary eye fields (SEF), and dorsolateral prefrontal cortex (Fig. 4). How do sensory and cognitive signals reach these areas?

The different attributes of vision reaching striate cortex (Brodmann area 17, visual area V1), such as the fine features, color, spatial location, and motion of a viewed object, are mainly processed separately in different cortical areas.¹³¹ Thus, striate cortex projects to many separate secondary visual areas, each of which is mainly concerned with analysis of certain features of vision. Important for the planning of saccades is the inferior parietal lobule. In monkeys, area 7a is important for localizing an object in space by taking into account the location of a stimulus within the visual field and the direction in which the eyes are pointing.¹³² Neurons here discharge after saccades, and seem more concerned with visuospatial integration than with eye movements per se. In humans, the homologue of area 7a is probably close to the intraparietal sulcus (posterior parietal cortex [PPC]). In the posterior insula and adjacent superior temporal gyrus lies an area of multisensory vestibular cortex (MVC) that may contribute information of head or body movements.¹³³ Together, this information is important for planning accurate saccadic eye movements and eye-head movements to objects in extrapersonal space. Also important for eye movements are the middle temporal (MT, or V5) and medial superior temporal (MST) visual areas that, in humans, probably lie at the junction of temporal, parietal, and occipital lobes posterior to the superior temporal sulcus, at the junction of Brodmann areas 19, 37, and 39, close to the intersection of the ascending limb of the inferior temporal sulcus and the lateral occipital sulcus.^131,134 In monkeys, area MT contains neurons that encode the speed and direction of moving visual targets; experimental lesions here cause a selective defect of motion vision.¹³⁵ Area MST, to which MT projects, contains neurons that combine visual motion information with eye movement.¹³⁶ Areas MT and MST are important for generating smooth pursuit (see below), and also provide important information to cortical areas concerned with saccade generation because we often make saccades toward moving targets.

The PEF in monkeys lie in the lateral intraparietal area (LIP), within the intraparietal sulcus. Neurons here discharge before saccades.^132,137 LIP projects to frontal eye fields and the superior colliculus, but not directly to the PPRF or riMLF.¹³⁸ Experimental lesions of LIP delay the onset of saccades made to visual stimuli.¹³⁹ In humans, the homologue of LIP, the PEF, probably lies within or close to the horizontal portion of the intraparietal sulcus.¹⁴⁰ Parietal lesions in humans also cause an increase in the response time from presentation of a visual stimulus until the generation of a saccade (increased saccadic latency). Unilateral parietal disease may cause bilateral increases in saccadic latency, and the effect is more marked for right hemisphere lesions.¹⁴¹ This defect in the initiation of saccades often coexists with disorders of hemivisual attention; however, the saccadic defect may occur alone, supporting the notion that the human homologue of LIP is distinct from areas concerned with directing visual attention. The most impressive disturbance of saccades with parietal lobe lesions occurs when patients are required to respond to a double-step stimulus, in which the target jumps twice before there is time for the subjects to respond.^142,143 If the target first jumps into the contralateral hemifield and then into the ipsilateral field, patients cannot make accurate saccades to the final target position, even though it lies in the intact hemifield. This suggests that the parietal lobe plays an important role in computing target position from both visual stimuli and an efference copy of eye movements (in this case, the change in eye position due to the first saccade).

The frontal eye fields (FEF) in monkeys lies along the posterior bank of the arcuate sulcus, corresponding to part of Brodmann area 8. The FEF receive input from visual areas MT and MST, dorsolateral prefrontal cortex, PEF, SEF, and from the intralaminar thalamic nuclei.¹⁴⁴ Neurons in the monkey FEF discharge before volitional but not reflexive saccades.¹⁴⁵ Furthermore, the FEF seem important in suppressing saccades and maintaining steady fixation. Pharmacologic inactivation of the FEF in monkeys causes a contralateral ocular motor scotoma with abolition of all reflex visual and voluntary saccades with sizes and directions corresponding to the site of injection on the FEF map.¹⁴⁶ The homologue of FEF in humans probably lies in the precentral gyrus and sulcus, close to the intersection with the superior frontal sulcus.¹⁴⁷ The FEF project caudally to the superior colliculus, caudate nucleus, and brainstem reticular formation (see below). Disease involving the FEF in humans causes bilaterally increased latency of saccades to visual targets if the previous (fixation) target remains visible. If, however, the fixation target disappears before the new target is presented (gap paradigm), then there is no increase in the response time.¹⁴⁸ This evidence suggests that the FEF are important for disengagement of fixation. In addition, unilateral FEF lesions cause increased saccadic latency to remembered target locations bilaterally.¹⁴⁹ Also impaired is the ability to generate predictive saccades, and antisaccades that are directed into the visual hemifield opposite to that of the test stimulus.¹²⁹ Thus, the FEF seem important for the programming of saccades concerned with intentional exploration of the visual environment.

The SEF, in monkeys, are located in the dorsomedial frontal lobes, in the anterior part of the supplementary motor area.¹⁵⁰ The SEF receive input from FEF, parietal cortex, and intralaminar thalamic nuclei, and project to the FEF, caudate nucleus, superior colliculus and brainstem reticular formation.¹⁵¹ In humans, the SEF lies in the posteromedial portion of the superior frontal gyrus, anterior to the supplementary motor area (SMA) in the upper part of the paracentral sulcus.¹⁵² One important difference between SEF and FEF is that the former but not the latter is important for generating saccades to specified spatial (rather than retinal) locations.¹⁴⁹ Another function that is impaired by disease affecting the SEF, especially on the left side, is the ability to make a sequence of saccades to several target lights that are turned on, and remain on in a specified order.¹⁵³ The SEF may be aided by anterior cingulate in learning new motor sequences.¹⁵⁴ One patient with a discrete lesion affecting one SEF had difficulty in changing the direction of his saccadic eye movements, especially when he had to reverse the direction of a previously established pattern of response.¹⁵² The SEF and the adjacent pre-supplementary motor area (pre-SMA) seem to work together to coordinate sequential movements. ¹⁵⁵

The dorsolateral prefrontal cortex (PFC; Brodmann area 46) makes an important contribution to voluntary control of saccades. Although not a classic eye field, it is important for making accurate motor responses (including saccades) to the remembered spatial locations of targets.^156,157 Experimental lesions of PFC, including pharmacologic blockade of D1 dopamine receptors,¹⁵⁸ interfere with this working memory area so that targets that are out of sight, are also “out of mind.” Patients with disease involving PFC show impaired accuracy of saccades to remembered target locations, increased errors on the antisaccade task, impaired predictive saccades, and impaired visual search.^3,129

CORTICAL PROJECTIONS TO BRAINSTEM SACCADE CIRCUITS

Parallel descending pathways connect these cortical regions with brainstem and cerebellar structures concerned with the generation of saccades. No direct projection exists from cortical neurons to ocular motoneurons or even to saccade-generating burst neurons in the PPRF and riMLF.^159–161 Instead, several intermediate structures play important roles, including the caudate nucleus, substantia nigra, superior colliculus, and brainstem reticular formation. These are summarized in Figure 4.

Parietal area LIP projects to the superior colliculus, and to the FEF, but not to the brainstem reticular formation concerned with saccade generation.¹³⁸ The FEF projections run in the internal capsule; clinical lesions involving the anterior portion of the internal capsule and adjacent deep frontal region are reported to increase saccadic latency.¹⁶² Below the level of the internal capsule, several separate pathways can be discerned: one to the caudate nucleus; a second to the intralaminar thalamic nuclei and the ipsilateral superior colliculus; and a third, the pedunculopontine pathway that runs in the most medial aspect of the cerebral peduncle, and projects to the NRTP, which in turn, projects to the cerebellum.^160,161,163 A partial ocular motor decussation may occur between the levels of the trochlear and abducens nuclei,¹⁶⁴ although this has not been confirmed. The SEF also project to the caudate nucleus, where convergence with FEF projections occurs, and to the superior colliculus and pontine omnipause neurons.¹⁶⁵ The dorsolateral prefrontal cortex projects to parts of the caudate nucleus, and to the superior colliculus.¹⁶⁶ The caudate nucleus sends inhibitory projections to the nondopaminergic, substantia nigra pars reticulata (SNpr), which in turn, inhibits neurons in the superior colliculus. Thus, this basal ganglia system is composed of two serial, inhibitory links: a caudo-nigral inhibition that is only phasically active and a nigro-collicular inhibition that is tonically active.¹⁶⁷ If the frontal cortex causes caudate neurons to fire, then the nigro-collicular inhibition is removed and the superior colliculus is able to activate a saccade. Disease affecting the caudate nucleus could impair the ability to make saccades to complex tasks. On the other hand, disease affecting the SNpr might disinhibit the superior colliculus, causing excessive, inappropriate saccades. Both deficits occur in patients with disorders affecting the basal ganglia, such as Huntington's disease.¹⁶⁸

THE SUPERIOR COLLICULUS

Much of what know about the superior colliculus is based on studies in monkeys. Saccades can be produced by electrical stimulation in its ventral layers.¹⁶⁹ In this “motor map,” the direction and size of the saccade are mainly functions of the site of stimulation, not its strength. Small saccades are elicited rostrally, large saccades caudally. Stimulation of the rostral pole of the motor map inhibits saccades; this fixation zone of the superior colliculus suppresses saccades.¹⁷⁰ Electrophysiologic activity of more caudally placed collicular neurons indicates that they encode the overall gaze displacement,¹⁷¹ which is consistent with the notion that they indirectly drive burst neurons in the brainstem reticular formation. The superior colliculus has reciprocal connections with the mesencephalic reticular formation.^172,173 The importance of the superior colliculus is demonstrated by the finding that inactivation of collicular burst neurons blocks the effects of frontal eye field stimulation.¹⁷⁴ Lesions restricted to the superior colliculus in humans are uncommon, but existing reports indicate that unilateral collicular lesions impair the ability to initiate contralateral saccades at short-latency (express saccades)¹⁷⁵ a finding consistent with animal lesion studies.¹⁷⁶ Degenerative disorders, such as PSP (discussed below), that involve the superior colliculus, also affect the adjacent central mesencephalic reticular formation and riMLF, and initially cause slow vertical saccades; subsequent involvement of the pons and PPRF leads to saccadic slowing in all directions.¹⁷⁷

Thus, current evidence indicates that the superior colliculus is important for initiating saccades and specifying saccade direction and size. Similar to cortical areas, superior colliculus neurons encode this information in a “place map.” The location of discharging collicular burst cells remains constant throughout the eye movement, encoding the overall gaze displacement.¹⁷¹

The Role of Descending Parallel Projections

The relative importance of descending pathways for saccade generation has been elucidated by studies of the effects of restricted, experimental lesions. Chronic lesions of the superior colliculus, in monkeys, cause relatively minor deficits such as an increase in saccadic latency.¹⁷⁸ Chronic FEF lesions, in monkeys, also cause minor deficits that affect saccades to remembered targets.¹⁷⁹ In contrast, combined lesions of the FEF and superior colliculi produce a severe and lasting deficit of eye movements, with a restricted range of movement.¹⁸⁰ Severe deficits of saccadic and pursuit eye movements also follow combined, bilateral lesions of parietal-occipital and frontal cortex in monkeys.¹³⁹ With unilateral, combined parieto-frontal lesions, saccades to visual targets in contralateral hemispace are impaired;¹⁸¹ with hemidecortication, the deficit is more enduring.¹⁸² In humans, combined bilateral lesions of frontal and parietal cortex cause loss of ability to make voluntary saccades—ocular motor apraxia.¹⁸³

THE PURSUIT SYSTEM

As indicated above, neurons in the secondary visual areas MT encode the speed and direction of a moving target.¹⁸⁴ MT projects to the adjacent visual area MST, where neurons encode not only visual information, but also a corollary discharge (efference copy) of the eye movement command.¹³⁶ Adjacent parietal cortex also influences smooth pursuit, probably by enhancing attention on the moving target. The FEF also contribute to both the initiation and maintenance of smooth pursuit.¹⁸⁵ From MST, projections descend to the dorsolateral pontine nuclei (DLPN),¹⁸⁶ and subsequently to the flocculus, paraflocculus, and vermis of the cerebellum.¹⁸⁷ The flocculus projects to the ipsilateral vestibular nuclei,¹⁰¹ which, in turn, project to the ocular motor nuclei; the vermis projects to the underlying fastigial nucleus.

The effects of experimental or discrete clinical stimuli can be interpreted with reference to the above scheme (Fig. 5). Lesions of striate cortex abolish smooth pursuit of targets presented in the blind hemifield, but pursuit is normal in both directions in the seeing hemifield.¹⁸⁹ Lesions of MT do not cause a conventional visual field defect but produce a selective abnormality in target speed estimation; both saccades and smooth pursuit are consequently impaired.¹⁸⁸ Lesions of MST in monkeys cause a disturbance much like the ipsilateral pursuit deficit encountered with unilateral cortical lesions in humans (Fig. 6); horizontal pursuit is impaired for targets moving toward the side of the lesion.^{135,189–192} Experimental lesions of DLPN cause a similar impairment of ipsilateral smooth pursuit.^193,194 Lesions of the cerebellar flocculus, paraflocculus, and dorsal vermis also impair ipsilateral smooth pursuit.¹⁹⁵ However, experimental or clinical lesions of the vestibular or fastigial nuclei produce a defect of contralateral smooth pursuit.^196,197 Lesions of the PPRF that impair or abolish saccades do not necessarily affect smooth pursuit.^36,37 Hence, the PPRF lesions that affect smooth pursuit probably do so because of involvement of axons that traverse it.

A large number of conditions bilaterally impair smooth pursuit eye movements so that the eyes consequently “fall behind” the moving target and require “catch-up” saccades to regain fixation. Such saccadic or cogwheel pursuit occurs with age, sedative drugs, inattention,¹⁹⁸ fatigue, and impaired consciousness, as well as in diffuse cerebral,¹⁹⁹ cerebellar, or brainstem disease. A pursuit defect, difficult to distinguish from that of inattention, is found in schizophrenia.²⁰⁰

VESTIBULO-OCULAR SYSTEM

The VOR, during brief, natural head rotations, is probably unaffected by cortical lesions²⁰¹; only when vestibular responses are supplemented by pursuit eye movements—to enhance or suppress the response—may asymmetric deficits become evident. The posterior insula and adjacent superior temporal gyrus house an area of multisensory vestibular cortex (MVC) contributes information of head or body movements¹³³; lesions affecting this region impair patients' ability to judge the direction of earth-vertical.¹⁹

GAZE-HOLDING

Gaze-holding—sustaining the eyes conjugately in eccentric positions in the orbits—is dependent on vestibular nuclei, nucleus prepositus hypoglossi, and their cerebellar connections.^2,41 However, the cerebral hemispheres, particularly the parietal lobes, influence this ability by encoding the location of a target in space. Parietal neurons respond not simply to the location of a visual stimulus on the retina, but also to the direction of gaze.²⁰² Thus, unilateral parietal lobe lesions are manifest not only by hemispatial neglect, but also by a “gaze preference” ipsilateral to the side of the lesion.¹⁸²

COMMON DISTURBANCES OF GAZE WITH UNILATERAL HEMISPHERIC LESIONS

With acute lesions, the patient's eyes are often deviated conjugately toward the side of the lesion. Such deviations are more common after large strokes involving right post-Rolandic cortex²⁰³ visual hemineglect is a common accompaniment.²⁰⁴ Conjugate deviation of the patient's eyes away from the side of the lesion (wrong-way deviation) occurs with subfrontal or thalamic lesions.^32,205

Acutely, patients may not voluntarily direct their eyes toward the side of the intact hemisphere, but vestibular stimulation usually produces a full range of horizontal movement (with the slow phase), in contrast to gaze palsies associated with pontine lesions.⁷⁰ Sometimes, in addition to ipsiversive deviation of the eyes, there is a small amplitude nystagmus with ipsilateral quick phases; the slow phases of this nystagmus may reflect unopposed pursuit drives directed away from the side of the lesion. Vertical saccades may be dysmetric with an inappropriate horizontal component toward the side of the lesion. Because both hemispheres are normally activated to elicit a purely vertical saccade, the loss of one hemisphere may be the cause of such oblique saccades.

Chronically, there usually is no resting deviation of the eyes, and persistence of gaze deviation is associated with only a prior lesion in the contralateral hemisphere.²⁰⁶ Attempted forced eyelid closure may cause a contralateral conjugate eye movement, the mechanism of which is not understood.²⁰⁷ In primary position, a small-amplitude nystagmus may be present (best seen during ophthalmoscopy), with slow phases directed toward the side of the intact hemisphere²⁰⁸; it may represent an imbalance in smooth pursuit tone. Horizontal pursuit is impaired for tracking of targets moving toward the side of the lesion^209,210; a convenient way to demonstrate this asymmetry of pursuit is with a hand-held optokinetic drum or tape.²¹¹ The response is decreased when the stripes are moved toward the side of the lesion. At the bedside this optokinetic response is usually judged by the frequency and amplitude of quick phases. A variety of defects in the control of saccades can be brought out by special testing, as outlined above. However, when prolongation of saccadic reaction time is evident at the bedside, it may reflect defects in visual detection, visual attention, or abnormal programming of saccades.

ACUTE BILATERAL FRONTO-PARIETAL LESIONS: OCULAR MOTOR APRAXIA

Large bihemispheric lesions produce a disturbance of ocular motility called acquired ocular motor apraxia. It is characterized by loss of voluntary control of eye movements, with preservation of reflex movements, including the VOR and quick phases of nystagmus. Acquired apraxia limited to the vertical plane implies bilateral lesions at the mesencephalic-diencephalic junction.²¹²

When acquired ocular motor apraxia is associated with acute optic ataxia and disturbance of visual attention, the eponym Balint's syndrome is used.^183,213 Voluntary movements of the eyes are limited in the horizontal and vertical planes. Gaze shifts are usually achieved by combined movements of eyes and head.¹⁸³ Both slow and quick phases of vestibular nystagmus are largely preserved, confirming the intact brainstem mechanisms. The defect of voluntary eye movements probably reflects disruption of descending pathways both from both the frontal and the PEF, so that the superior colliculus and brainstem reticular formation lack their supranuclear inputs; similar results have been produced experimentally in monkeys.¹⁸⁰

Sometimes the term “spasm of fixation” is applied to such patients with difficulties in voluntarily shifting gaze. Holmes²¹⁴ described a group of such patients, and noted that if the visual scene was a homogenous white screen, then voluntary eye movements became possible. As reviewed above, one effect of FEF lesions is difficulties in disengagement of fixation. Thus, it appears that spasm of fixation might have a real physiologic basis, but before applying the term to patients, it would seem necessary to demonstrate difference in saccadic latency between trials in which the fixation stimulus disappeared before the new visual stimulus appeared (gap stimulus) and trials in which the fixation stimulus remained visible.²¹⁵ Brainstem disorders that affect the saccade-generating reticular formation should not be included in this category. Another factor in evaluating such patients is the nature and size of the visual stimulus. We have seen a patient with extreme difficulty making saccades on command who did so only after prolonged tight eyelid closure; there was slightly less difficulty with small refixation targets, and with larger targets the saccades were initiated with more ease until, finally, normal command saccades occurred as the patient alternately refixated on close faces.

Congenital oculomotor apraxia is characterized by absence of horizontal saccadic refixations and smooth pursuit movement, although some patients show normal smooth pursuit. During childhood, fast phases of nystagmus are absent during either optokinetic or caloric stimulation. This implicates a basic saccadic, rather than apraxic, disorder and the condition is better designated congenital saccadic palsy or congenital gaze palsy, depending on the integrity of smooth pursuit eye movements. The most striking feature of this syndrome is head thrusts used to accomplish ocular refixations. The head thrust may not be present in early infancy but develops between 4 and 8 months of age.^216,217 These head movements are more exaggerated than those in patients with acquired saccadic palsy. The head moves toward the position of the eccentric new target, and the eyes, responding to the active vestibulo-ocular system, rotate conjugately in the opposite direction (Fig. 7). The eyelids often close at the onset of the head movement, which may promote saccade generation. Head rotation may overshoot the intended target, enabling the contraversively deviated eyes to fixate the target. While maintaining fixation, the head slowly moves back until the eyes are straight forward. With advancing age, the head thrust becomes less prominent and saccadic eye movements, albeit abnormal, may emerge.²¹⁸ In one patient who was reexamined in adulthood, head thrusts were noted only rarely.²¹⁹ This syndrome may be familial, and significant developmental central nervous system (CNS) defects such as hypoplasia of the corpus callosum and cerebrum may be associated.^220–222 Apraxia of vertical gaze is usually not congenital but acquired.

PARKINSONIAN DISORDERS AND PROGRESSIVE SUPRANUCLEAR PALSY (PSP)

A broad range of parkinsonian disorders are now recognized, and examination of eye movements, especially saccades, often contributes to accurate clinical diagnosis.

Idiopathic Parkinson's Disease

Most patients with Parkinson's disease (PD) show only minor abnormalities on clinical examination that may also occur in healthy elderly subjects. Thus, steady fixation may be disrupted by saccadic intrusions (square-wave jerks),^223–225 but these are also seen in healthy elderly subjects. Moderate restriction of the range of upward gaze is common in elderly individuals,²²⁶ with or without parkinsonism, and may be caused by changes in the orbital tissues.²²⁷ Smooth pursuit may be impaired in PD as in some healthy normals.²²⁸ Convergence insufficiency occurs commonly.²²⁹ Patients with advanced PD may show slowing of vertical saccades, but PSP should always be considered in such cases. One characteristic sign in PD is hypometria that becomes more marked when patients are asked to rapidly perform self-paced refixations between two continuously visible targets (e.g., index fingers of the examiner's right and left hand positioned to test large horizontal saccades).

Laboratory studies have shown that the phenomenon of hypometria during self-paced saccades is not simply the result of persistence of the visual targets, because saccades made in anticipation of the appearance of a target light at a remembered location are also hypometric.^230,231 Patients with PD also have difficulty in generating sequences of memory-guided saccades.^232–234 However, saccades made reflexively to novel visual stimuli are normal in size and promptly initiated.²³⁵ Moreover, visually guided adaptation of saccades is preserved whereas memory-guided adaptation of saccades is impaired.²³⁶ Thus, patients with PD seem to have difficulty generating internally guided saccades to accurately shift gaze.^235,237 Despite this hypometria, patients are still able to shift their gaze with a series of saccades to the location of a briefly flashed target; this finding indicates a retained ability to encode the location of objects in extrapersonal space.^225,230

During tracking of a predictable, sinusoidal target motion, eye speed is less than target speed, leading to catch-up saccades.^225,238 In addition, the catch-up saccades are hypometric; thus, the cumulative tracking eye movement is less than that of the target.²³⁹ Despite these impairments, the phase relationship between eye and target movement is normal,²³⁷ which implies a normal predictive smooth tracking strategy. This is in contrast to saccadic tracking of predictive target jumps that, as described above, is deficient.

Caloric and low-frequency rotational vestibular responses, in darkness, may be hypoactive in patients with PD.^240,241 However, at higher frequencies of head rotation, and especially during visual fixation, the VOR adequately compensates for head perturbations, which explains the lack of oscillopsia complaints in patients with PD.

Treatment of PD with L-dopa does not generally improve the ocular motor deficits except that saccades tend to become larger.^238,242 Newly diagnosed patients with idiopathic PD may show improved smooth pursuit after starting dopaminergic therapy.²⁴² Memory-guided saccades are impaired after pallidotomy for Parkinson's disease²⁴³ but improve with subthalamic nucleus stimulation.²⁴⁴ Pallidotomy increases saccadic intrusions on steady fixation (square wave jerks).^224,245 In parkinsonism caused by methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, saccadic latency is reduced and saccadic accuracy improved by dopaminergic agents.²⁴⁶ Similarly, in monkeys that received MPTP, saccadic abnormalities, including increased latency, increased duration, decreased rate of spontaneous saccades, and inappropriate saccades, all are reversed by dopaminergic therapy.^247,248

Oculogyric crisis, first encountered as a feature of postencephalitic parkinsonism, now usually occurs as a side effect of drugs, especially neuroleptic agents.²⁴⁹ A typical attack is ushered in by feelings of fear or depression, which give rise to an obsessive fixation or a thought. The eyes usually deviate upward and sometimes laterally; they rarely deviate downward. During the period of upward deviation, the movements of the eyes in the upper field of gaze appear normal. Affected patients have great difficulty in looking down, except if they combine a blink and downward saccade. Thus, the ocular disorder may reflect an imbalance of the vertical eccentric gaze-holding mechanism. Anticholinergic drugs promptly terminate the thought disorder and ocular deviation, a finding suggesting that the disorders of thought and eye movements are linked by a pharmacologic imbalance common to both.²⁴⁹ Oculogyric crises have also been described after striatocapsular infarction, and with bilateral putaminal hemorrhage.²⁵⁰ Oculogyric crises are distinct from the brief upward ocular deviations that may occur in Tourette's syndrome,²⁵¹ Rett's syndrome,²⁵² children with benign paroxysmal tonic up-gaze,⁶⁵ and in patients with tardive dyskinesia.²⁵³ Episodic brief spells of tonic up-gaze have also been reported after bilateral lentiform lesions.²⁵⁴

PSP is a degenerative disease of later life characterized by abnormal eye movements, frequent falls, axial rigidity, difficulties with swallowing and speech, and mental slowing.²⁵⁵ Median survival time is approximately 6 years. The disturbance of eye movements is usually present early in the course, but occasionally develops late, or is not noted by the patient's physicians.²⁵⁶ Patients may present with the complaints of blurred vision, double vision, or photophobia,²⁵⁵ and have often been fitted with several different spectacle refractions, without improvement. These visual complaints are caused by the loss of the ability to voluntarily shift gaze downward so that patients have difficulty looking down to see a plate of food, tying their shoes, or walking down stairs with confidence.

The initial ocular motor findings are of slowing of vertical saccades and quick phases, either down, or up, or both. Sometimes vertical saccades take a curved or oblique trajectory (“round the houses”).^228,257 Vertical smooth pursuit is relatively preserved but of decreased gain.²⁵⁸ Larger targets may elicit greater responses²⁵⁹ and should be used to evaluate the range of eye movements in patients in whom neck stiffness makes testing the VOR technically difficult. Full-field optokinetic stimuli may induce responses that are useful for analysis.²⁶⁰ Combined eye-head tracking may also be relatively spared. As the disease progresses, the range of movements with vertical saccades and pursuit declines, and eventually no voluntary vertical eye movements are possible. Usually the VOR is preserved until late in the disease (although a characteristic rigidity of the neck may make the vertical doll's head maneuver difficult to elicit).

Steady fixation is disrupted by horizontal square-wave jerks,^223,228 which are more common than in other parkinsonian disorders. Horizontal saccades are hypometric but initially normal in speed.¹⁷⁷ In some patients, the involvement of horizontal saccades may resemble internuclear ophthalmoplegia, although vestibular stimulation may overcome the limitation of adduction.²⁶¹ Horizontal smooth pursuit is impaired, partly because of square-wave jerks. Convergence eye movements are commonly impaired.⁹⁴ Late in the disease, there is complete ophthalmoplegia. Patients with absent quick phases but intact vestibular eye movements may also show tonic deviation of the eyes in the orbit during body rotation; if the head is free to move, it may also deviate opposite to the direction of body rotation.²⁶²

A range of eyelid abnormalities occur in PSP: blepharospasm, lid-opening apraxia, eye-closing apraxia, lid retraction, and lid lag.²²⁸ Patients usually show an inability to suppress a blink to a bright light, which is a visual Meyerson's (glabella) sign.²⁶² Bell's phenomenon is usually absent.

Laboratory studies of saccades in PSP have demonstrated that vertical saccades are slower than horizontal saccades of similar size.^177,228 The latency of horizontal saccades in PSP is prolonged in some patients, but others retain the ability to make short-latency or express saccades.²⁶³ Patients with PSP also make errors when they are required to look in the opposite direction to a suddenly appearing target (the antisaccade task). Both the presence of express saccades and errors on the antisaccade task suggest defects in frontal lobe function and, although frontal neuropathological changes are mild, positron emission scanning indicates profound frontal hypometabolism.²⁶⁴

Vestibular eye movements during horizontal rotation, either in darkness, or during fixation of a stationary target, confirms that PSP patients show similar slow phases to controls but abnormal quick phases, commonly leading to contraversive deviation of gaze.²⁵⁸

Smooth pursuit is usually impaired both horizontally and vertically.²²⁸ In the vertical plane, no corrective catch-up saccades occur. The combined impairment of vertical saccades and pursuit constitutes a voluntary gaze palsy. During large-field, vertical optokinetic stimulation, patients with PSP show tonic deviation of the eyes in the direction of stripe motion, with small or absent resetting quick phases.²⁶⁰ When patients with PSP shift their fixation point between distant and near targets, the vergence movement is slowed compared to normal subjects.⁹⁴

Pathologically, PSP is a diffuse disorder, and although the midbrain bears the brunt of the early pathology, accounting for the relative vulnerability of vertical saccades, other parts of the brainstem, cerebellum, and forebrain are affected.²⁶⁵ Treatment is unsatisfactory, having little effect on the ocular motor syndrome or the general neurologic disorder

CONTRIBUTION OF EYE MOVEMENT EXAMINATION IN THE DIFFERENTIAL DIAGNOSIS OF PARKINSONISM

Careful examination of eye movements, especially saccades, can often contribute to accurate diagnosis in parkinsonism. Thus, most patients with PD have normal eye movements for their age, whereas most patients with PSP do not. A number of other parkinsonian disorders may mimic PSP. These include multiple infarcts affecting the basal ganglia, internal capsule, and midbrain (in the distribution of the perforating vessels arising from the proximal portions of the posterior cerebral artery)²⁶⁶; infiltrative disorders such as lymphoma; and paraneoplastic syndromes.⁵⁸ Diseases causing the dorsal midbrain syndrome, such as tumor and hydrocephalus, can also present like PSP, with vertical gaze palsy.

Whipple's disease can closely mimic PSP, with vertical saccadic gaze palsy,^267,268 in addition to oculomasticatory myorhythmia, a pendular vergence oscillation with concurrent contractions of the masticatory muscles; rarely limb muscles also show rhythmic contractions.²⁶⁹ Whipple's disease can be diagnosed using polymerase chain reaction (PCR) analysis of involved tissues,²⁷⁰ and be treated with antibiotics.²⁷¹ Pure akinesia is characterized by profound slowness of speech, handwriting, and gait, and affected patients may suffer episodes during which they stand “frozen” for hours on end.²⁷² Tremor, limb rigidity, akinesia, or responsiveness to levodopa are absent. Such patients may show slow and hypometric vertical saccades, and the disorder may be a restricted form of PSP with a longer, more benign course.

Cortical-basal ganglionic degeneration (CBGD) may cause a defective range of vertical eye movements, but it does not cause marked slowing of saccades. The main ocular motor defect is an increased saccadic reaction time (latency), which is evident at the bedside.^228,273 The other features of this degeneration—focal dystonia, apraxia, alien hand syndrome, myoclonus, asymmetric akinetic-rigid syndrome, with late onset of balance disturbances—are more important in making the diagnosis.^274,275 Multiple system atrophy (MSA) causes a parkinsonian syndrome with characteristic autonomic findings. Some patients may show slowing of vertical saccades as well as hypometria.^177,228 Cerebellar eye movement findings, including downbeat nystagmus during positional testing,²⁷⁶ impaired smooth ocular and eye-head pursuit may occur. Diffuse Lewy body disease, characterized by parkinsonism and fluctuating dementia with florid visual hallucinations, may sometimes be associated with a vertical gaze paralysis.^277,278 Slow saccades, with a supranuclear gaze palsy are reported in Creutzfeldt-Jakob disease²⁷⁹; cerebellar findings, including periodic alternating nystagmus, rebound nystagmus and centripetal nystagmus (slow phases directed eccentrically) on lateral gaze also may occur.^279,280

HUNTINGTON'S DISEASE

Huntington's disease (HD) is caused by a genetic defect of the IT15 gene (huntingtin) on chromosome 4, leading to increased CAG triplet repeat length. Disturbances of voluntary gaze are common.^{168,281–283} Saccades are initiated with difficulty and with prolonged latencies, especially when made to command. An obligatory blink or head thrust may be used to start the eye moving.²⁸⁴ Saccades may be slow horizontally or vertically. Longitudinal studies have documented progressive slowing of saccades with prolongation of reaction time.²⁸⁵ Saccades may be slower in patients who become symptomatic at an earlier age, and who have inherited the disease from their father.¹⁶⁸

Fixation is disrupted in some patients by saccadic intrusions.²⁸³ Smooth pursuit may be impaired, but often is relatively spared compared with saccades. Eccentric gaze holding and the VOR are usually normal. Late in the disease, rotational stimulation causes the eyes to deviate tonically because of impaired quick phases.

Individuals studied at a presymptomatic point in their disease may have normal eye movements.^281,286,287 Thus, testing of eye movements cannot be regarded as a reliable method for determining which offspring of affected patients will go on to develop the disease. Improvement of saccadic eye movement abnormalities in HD has been reported with sulpiride.²⁸⁸

FUNCTIONAL DISTURBANCES OF GAZE

Spasm of the near reflex (convergence spasm), which may mimic a lateral rectus paresis, has been discussed above. Rarely, patients may present with a psychogenic paralysis of horizontal gaze. Pursuit and saccades are usually symmetrically restricted. Sophisticated neuro-ophthalmologic testing using passive head rotations, optokinetic stimuli, and pursuit stimulation with the large mirror test should demonstrate the full ability to make fast and slow eye movements and uncover the psychogenic nature of the disturbance.²⁸⁹ In the mirror test, the patient is asked to look into a large hand-held mirror that is then tilted right and left or up and down. The patient's eyes readily moved with the moving reflection of the visual environment.

TABLE 4. Ocular Motor Disorders Caused By Lesions Of The Cerebellum

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