Chapter 14. Disorders of Ocular Movement and Pupillary Function

Ocular movement and vision are virtually inseparable. A moving object evokes movement of the eyes and almost simultaneously arouses attention and initiates the perceptive process. To look searchingly, i.e., to peer, requires stable fixation of the visual image on the center of the two retinas. One might say that the ocular muscles are at the service of vision.

Abnormalities of ocular movement are of three basic types. One category can be traced to a lesion of the extraocular muscles themselves, the neuromuscular junction, or to the cranial nerves that supply them (nuclear or infranuclear palsy). The second type is a derangement in the highly specialized neural mechanisms that enable the eyes to move together (supranuclear and internuclear palsies). This distinction, in keeping with the general concept of upper and lower motor neuron paralysis, hardly portrays the complexity of the neural mechanisms governing ocular motility. Perhaps more common but not primarily neurologic is a third group of disorders, strabismus, in which there is a congenital imbalance of the yoked muscles of extraocular movement that may lead to a developmental reduction in monocular vision (amblyopia), as discussed at the end of the previous chapter. Knowledge of the anatomic basis of normal movement is essential to an understanding of abnormal movement.

Anatomic and Physiologic Considerations

In no aspect of human anatomy and physiology is the sensory guidance of muscle activity more instructively revealed than in the neural control of coordinated ocular movement. Moreover, the entirely predictable and "hardwired" nature of the central and peripheral oculomotor apparatus allows for a very precise localization of lesions within these pathways. To focus the eyes voluntarily, to stabilize objects for scrutiny when one is moving, to bring into sharp focus near and far objects—all require the perfect coordination of six sets of extraocular muscles and three sets of intrinsic muscles (ciliary muscles, sphincters, and dilators of the iris). The neural mechanisms that govern these functions reside mainly in the midbrain and pons but are greatly influenced by centers in the medulla, cerebellum, basal ganglia, and the frontal, parietal, and occipital lobes of the brain. Most of the nuclear structures and pathways concerned with fixation and stable ocular movements are now known and much has been learned of their physiology both from clinical-pathologic correlations in humans and from experiments in monkeys.

Accurate binocular vision is actually achieved by the associated action of all the ocular muscles. The symmetrical and synchronous movement of the eyes is termed conjugate movement or gaze (conjugate meaning yoked or joined together). The simultaneous movement of the eyes in different directions, as in convergence, is termed dysconjugate or disjunctive. These two forms of normal ocular movements are also referred to as versions (versional) and vergence, respectively. Vergence movements have two components—fusional and accommodative. The fusional movements are convergence and divergence, which maintain binocular single vision and depth perception (stereopsis); they are necessary at all times to ensure that visual images fall on corresponding parts of the retinas. Convergent movements are brought into action when one looks at a near object. The eyes turn inward and at the same time the pupils constrict and the ciliary muscles relax to thicken the lens and allow near vision (the accommodative-near reflex, or triad). Divergence, albeit slight, is required for distant vision.

Rapid voluntary conjugate movements of the eyes to the opposite side are initiated in area 8 of the frontal lobe (see Fig. 22-1) and relayed to the pons. These quick movements are termed saccadic (peak velocity may exceed 700 degrees per second). Their purpose is to rapidly change ocular fixation and bring images of new objects of interest onto the foveae. Saccades are so rapid that there is no subjective awareness of movement during the change in eye position, essentially, a momentary blindness. Saccadic movements can be elicited by instructing an individual to look to the right or left (commanded saccades), or to move the eyes to a target (refixation saccades). These two movements are sometimes differently affected in neurologic disease. Saccades may also be elicited reflexively, as when a sudden sound or the appearance of an object in the peripheral field of vision attracts attention and triggers an automatic movement of the eyes in the direction of the stimulus. Saccadic latency, the interval between the appearance of a target and the initiation of a saccade, is approximately 200 ms.

The neurophysiologic pattern of pontine neurons that produces a saccade has been characterized as "pulse-step" in type. This refers to the sudden increase in neuronal firing (the pulse) that is necessary to overcome the inertia and viscous drag of the eyes and move them into their new position; it is followed by a return to a new baseline firing level (the step), which maintains the eyes in their new position by tonic contraction of the extraocular muscles (gaze holding).

Saccades are distinguished from the slower and smoother pursuit or following movements, for which the major stimulus is a moving target. The function of pursuit movements is to stabilize the image of a moving object on the foveae, and thus to maintain a continuous clear image of the object as the object changes position ("smooth tracking"). Unlike saccades, pursuit movements to each side are generated in the ipsilateral parietooccipital cortex, with modulation by the ipsilateral cerebellum, especially the vestibulocerebellum (flocculus and nodulus). Another portion of the cerebellum, the posterior vermis, also influences saccadic movements (see further on).

When following a moving target, as the visual image slips off the foveae, the firing rate of the governing motor neurons increases in proportion to the speed of the target, so that eye velocity matches target velocity. If the eyes fall behind the target, supplementary catch-up saccades are required for refixation. The pursuit movement is then not smooth, but becomes jerky ("saccadic" pursuit). A lesion of one cerebral hemisphere may cause pursuit movements to that side to break up into saccades. Diseases of the basal ganglia are also a common cause of a disruption of normally smooth pursuit into a ratchet-like saccadic pursuit in all directions.

If a series of visual targets enters the visual field, as when one is watching trees from a moving car or the stripes on a rotating drum, involuntary repeated quick saccades refocus the eyes centrally; the resulting cycles of pursuit and refixation are termed optokinetic nystagmus. This phenomenon is used as a bedside test, the main value of which is in revealing a lesion of the ipsilateral posterior parietal lobe. It may also be found that a frontal lobe lesion eliminates the quick nystagmoid refixation phase away from the side of the lesion, thereby causing the eyes to continue to follow the target until it is out of view. This optokinetic phenomenon is described more fully further on, in the section on nystagmus.

Vestibular influences are of particular importance in stabilizing images on the retina during head and body movement. By means of the vestibuloocular reflex (VOR), a prompt short latency movement of the eyes is produced that is equal and opposite to movement of the head. During sustained rotation of the head, the VOR is supplemented by the optokinetic system, which enables one to maintain compensatory eye movements for a more prolonged period. If the VOR is lost, as occurs with disease of the vestibular apparatus or eighth nerve, the slightest movements of the head, especially those occurring during locomotion, cause a movement of images across the retina large enough to impair vision. A unilateral loss of the VOR strongly implicates a disease of the vestibular apparatus on the side toward the rotation of the head. When objects are tracked using both eye and head movements, the VOR must be suppressed, otherwise the eyes would remain fixed in space; to accomplish this, the smooth pursuit signals cancel the unwanted vestibular ones (Leigh and Zee). It follows that the inability to suppress the VOR, while viewing a target as the patient is rotated, is indicative of a defect of supranuclear pursuit.

Horizontal Gaze

Saccades

As already mentioned, the signals for volitional horizontal gaze saccades originate in the eye field of the opposite frontal lobe (area 8 of Brodmann, see Fig. 22-1) and are modulated by the adjacent supplementary motor eye field and by the posterior visual cortical areas. Leichnetz traced the cortical-to-pontine pathways for saccadic horizontal gaze in the monkey. These fibers traverse the internal capsule and separate at the level of the rostral diencephalon into two bundles, the first being a primary ventral "capsular–peduncular" bundle, which descends through the most medial part of the cerebral peduncle. This more ventral pathway undergoes a partial decussation in the low midbrain, at the level of the trochlear nucleus, and terminates mainly in the vaguely defined paramedian pontine reticular formation (PPRF) of the opposite side, neurons of which, in turn, project to the adjacent sixth nerve nucleus (Fig. 14-1). A second, more dorsal "transthalamic" bundle is predominantly uncrossed and courses through the internal medullary lamina and paralaminar parts of the thalamus to terminate diffusely in the pretectum, superior colliculus, and periaqueductal gray matter. An off-shoot of these fibers (the prefrontal oculomotor bundle) projects to the rostral part of the oculomotor nucleus and to the ipsilateral rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) and to the interstitial nucleus of Cajal (INC), which are involved in vertical eye movements, as discussed in the next section.

Pursuit

The pathways for smooth pursuit movements are less well defined. One probably originates in the posterior parietal cortex and the adjacent temporal, and anterior occipital cortex (area MT of the monkey) and descends to the ipsilateral dorsolateral pontine nuclei. Also contributing to smooth pursuit movements are projections from the frontal eye fields to the ipsilateral dorsolateral pontine nuclei. The latter, in turn, project to the flocculus and dorsal vermis of the cerebellum, which provide stability for the pursuit movements. However, for the purposes of clinical work, lesions of the posterior parietal cortex are the ones known to impair pursuit toward the damaged side. Part of the frontal eye fields have been shown experimentally to participate in pursuit eye movements, but the influence of this area on pursuit is far less than that of the parietal lobes and is insignificant clinically.

Brainstem (Internuclear) Pathways and Oculomotor Nuclei

Conventionally, the term ocular motor nuclei refers to the nuclei of the third, fourth, and sixth cranial nerves; the term oculomotor nucleus refers to the third nerve nucleus alone. Ultimately, all the pathways mediating saccadic and pursuit movements in the horizontal plane, as well as for vestibular and optokinetic movements, converge on the pontine tegmental center for horizontal gaze, the PPRF. Also required for horizontal versional movements are the nuclei prepositus hypoglossi and their commissure, the abducens and medial vestibular nuclei, and pathways in the pontine and tegmentum of the brainstem that interconnect the oculomotor nuclei (Fig. 14-1).

The PPRF and the prepositus and medial vestibular nuclei are conceptualized as a "neural integrator" and relay station for horizontal saccade pathways. It is further considered that the PPRF projects to the sixth nerve nucleus to command horizontal eye movement. However, it is understood from animal experiments that supranuclear neural signals that encode smooth pursuit, and vestibular and optokinetic movements bypass the PPRF and project independently to the abducens nuclei (Hanson et al).

The fiber bundle connecting the third and sixth nerve nuclei, and connecting both these nuclei with the vestibular nuclei lies in the medial tegmentum of the brainstem; this pathway is the medial longitudinal fasciculus (MLF). The fibers of the MLF emanating from the sixth nerve nucleus cross in the pons and ascend to the contralateral medial rectus subnucleus of the third nerve. In this way, the abduction of one eye is yoked to adduction of the opposite one to produce conjugate horizontal gaze as described just below.

The abducens nucleus contains two groups of neurons, each with distinctive morphologic and physiologic properties: (1) the intranuclear abducens motor neurons, which innervate the ipsilateral lateral rectus muscle, and (2) abducens internuclear neurons, which project via the contralateral MLF to the medial rectus neurons of the opposite oculomotor nucleus. Conjugate lateral gaze is accomplished by the simultaneous activation of the ipsilateral lateral rectus, and the contralateral medial rectus, again, the latter through fibers that run in the medial portion of the MLF. Interruption of the MLF results in a discrete impairment or loss of adduction of the eye ipsilateral to the lesion, a sign referred to as internuclear ophthalmoplegia, the details of which are discussed further on (Fig. 14-1).

Two other ascending pathways between the pontine centers and the mesencephalic reticular formation have been traced: one traverses the central tegmental tract and terminates in the pretectum, in the nucleus of the posterior commissure; the other is a bundle separate from the MLF that passes around the nuclei of Cajal and Darkschewitsch to the riMLF. These nuclei are involved more in vertical gaze and are described below. In addition, each vestibular nucleus projects onto the abducens nucleus, and the MLF of the opposite side. This pathway is considered to generate the slow phase of the VOR.

Although direct projections from the frontal eye fields that bypass the PPRF and innervate the oculomotor nuclei, as described above, undoubtedly exist, indirect projections are more important in the voluntary control of conjugate eye movements. According to Leigh and Zee, a more accurate view of these various voluntary influences is one of a hierarchy of cell stations and parallel pathways that do not project directly to oculomotor nuclei but to adjacent premotor or burst neurons, which discharge at high frequencies immediately preceding a saccade. The premotor or burst neurons for horizontal saccades lie within the PPRF and those for vertical saccades in the riMLF (see below). Yet a third class of neurons (omnipause cells), lying in the midline of the pons, is involved in the inhibition of unwanted saccadic discharges. Nonetheless, in clinical work, the circuit that comprises in sequence (1) frontal lobe eye fields, (2) contralateral pontine PPRF, (3) abducens nucleus, (4) MLF, and (5) opposite oculomotor nucleus makes understandable a number of highly characteristic defects of horizontal ocular motion, as detailed in the remainder of the chapter.

Vertical Gaze

In contrast to horizontal gaze, which is generated by unilateral aggregates of cerebral and pontine neurons, vertical eye movements, with few exceptions, are under bilateral control of the cerebral cortex and upper brainstem. The groups of nerve cells and fibers that govern upward and downward gaze, as well as torsional saccades, are situated in the pretectal areas of the midbrain and involve three integrated structures—the riMLF, the INC, and the nucleus and fibers of the posterior commissure (Fig. 14-2).

The riMLF lies at the junction of the midbrain and thalamus, at the rostral end of the medial longitudinal fasciculus, just dorsomedial to the rostral pole of the red nucleus. It functions as the "premotor" nucleus with "burst cells" for the production of fast (saccadic) vertical versional and torsional movements. Input to the riMLF arises both from the PPRF and the vestibular nuclei. Each riMLF projects mainly ipsilaterally to the oculomotor and trochlear nuclei, but each riMLF is also connected to its counterpart by fibers that traverse the posterior commissure. Bilateral lesions of the riMLF or of their interconnections in the posterior commissure are more common than unilateral ones, and cause a loss either of downward saccades or of all vertical saccades.

The INC is a small collection of cells that lies just caudal to the riMLF on each side. Each nucleus projects to the motor neurons of the opposite elevator muscles (superior rectus and inferior oblique) by fibers that cross through the posterior commissure, and it projects ipsilaterally and directly to the depressor muscles (inferior rectus and superior oblique). The functional role of the INC appears to be in holding eccentric vertical gaze, especially after a saccade; it is also integral to the vestibuloocular reflex. Lesions of the INC produce a vertical gaze-evoked and torsional nystagmus, and an ocular tilt reaction and probably slow all conjugate eye movements, mainly vertical ones.

Lesions of the posterior commissure are common; they interrupt signals crossing to and from the INC and the riMLF. A lesion here characteristically produces a paralysis of upward gaze and of convergence, often associated with mild mydriasis, accommodative loss, convergence nystagmus, lid retraction (Collier "tucked lid" sign), and, less commonly, ptosis. This constellation is the Parinaud syndrome, also referred to as the pretectal, dorsal midbrain, or sylvian aqueduct syndrome (see "Vertical Gaze Palsy" further on). In some instances, only a restricted combination of these signs is seen. The same syndrome may be produced by unilateral lesions of the posterior commissure, presumably by interrupting bidirectional connections from the riMLF and INC. With acute lesions of the commissure, there is a tonic downward deviation of the eyes and lid retraction ("setting-sun sign").

The MLF is the main conduit of signals that control vertical gaze from the vestibular nuclei in the medulla to the midbrain centers. For this reason, with internuclear ophthalmoplegia, along with the characteristic adductor paresis on the affected side, vertical pursuit and the VOR are impaired. This is most evident when there are bilateral internuclear ophthalmoplegias. Vertical deviation of the ipsilateral eye (skew) may be seen in cases of unilateral internuclear ophthalmoplegia, as discussed further on.

Vestibulocerebellar Influences on Eye Movements

There are important vestibulocerebellar influences on both smooth pursuit and saccadic movements (see also Chap. 5). The flocculus and posterior vermis of the cerebellum receive abundant sensory projections from proprioceptors of the cervical musculature (responsive to head velocity), the retinas (sensitive to target velocity), proprioceptors of eye muscles (eye position and eye velocity), auditory and tactile receptors, and the superior colliculi and PPRF. Cerebellar efferents concerned with ocular movement project onto the vestibular nuclei, and the latter, in turn, influence gaze mechanisms through several projection systems: one, for horizontal movements, consists of direct projections from the vestibular nuclei to the contralateral sixth nerve nucleus; another, for vertical movements, projects via the contralateral MLF to third and fourth nerve nuclei (Figs. 14-1 and 14-2).

Lesions of the flocculus and posterior vermis are consistently associated with deficits in smooth pursuit movements and an inability to suppress the vestibuloocular reflex by fixation (Baloh et al). Floccular lesions are also an important cause of downbeat nystagmus. As indicated in Chap. 5, patients with cerebellar (floccular) lesions are unable to hold eccentric positions of gaze and must make repeated saccades to look at a target that is away from the neutral position (gaze-paretic nystagmus, a term also applied to nystagmus arising from a lesion in the PPRF). This phenomenon is explained by the fact that with acute, one-sided lesions of the vestibulocerebellum, the inhibitory discharges of the Purkinje cells onto the ipsilateral medial vestibular nucleus are removed, and the eyes deviate away from the lesion. When gaze to the side of the lesion is attempted, the eyes drift back to the midline, and fixation can be corrected only by a saccadic jerk. The head and neck may also turn away from the lesion (the occiput toward the lesion and the face away). In addition, the vestibuloocular reflexes, which coordinate eye movements with head movements, are improperly adjusted (Thach and Montgomery). The interested reader can find further details concerning cerebellar influences on ocular movements in the monograph by Leigh and Zee and the review by Lewis and Zee.

Testing of Conjugate Gaze

It is apparent from the foregoing remarks that there is considerable clinical information to be obtained from an analysis of ocular movements. To fully examine the eye movements, the patient should be asked to look quickly to each side as well as up and down (saccades) and to follow a moving target (pursuit of a light, the examiner's finger, or an optokinetic drum). A patient with stupor and coma can be examined by passively turning the head or by irrigating the external auditory canals; these are vestibular stimuli to reflex eye movement as discussed in Chap. 17.

Most individuals make accurate saccades to a target. Alterations of saccadic movements, particularly overshooting of the eyes (hypermetria), are characteristic of a cerebellar lesion. Slowness of saccadic movements is mainly the result of disease of the basal ganglia such as Huntington and Wilson diseases, ataxia-telangiectasia, progressive supranuclear palsy, olivopontocerebellar degeneration, and certain lipid storage diseases. Lesions involving the PPRF may also be accompanied by slow saccadic movements to the affected side. Hypometric, slow saccades occurring only in the adducting eye indicate an incomplete internuclear ophthalmoparesis caused by a lesion of the ipsilateral MLF. When the earliest sign of a progressive eye movement disorder is slow saccades in the vertical plane, the likely diagnosis is progressive supranuclear palsy, but the same sign may occur in Parkinson disease and several less common processes that affect the basal ganglia, as discussed further on under "Vertical Gaze Palsy." Slow up-and-down saccades are also found in Niemann-Pick disease type C.

Yet another saccadic disorder takes the form of an inability to initiate voluntary movements, either vertically or horizontally. This abnormality may be congenital in nature, as in the ocular "apraxia" of childhood (Cogan syndrome, see below) and in ataxia-telangiectasia; an acquired difficulty in the initiation of saccadic movements may be seen in patients with Huntington disease or with a lesion of the contralateral frontal lobe or ipsilateral pontine tegmentum. The most common explanation for the inability to move the eyes is hysteria, a circumstance that can be exposed by noting the patient will follow his own eyes in a mirror.

In addition to abnormalities of the saccades themselves, saccadic latency or reaction time (the interval between the impulse to move and movement) is prolonged in Huntington chorea and Parkinson disease. Saccadic latency is also increased in corticobasal ganglionic degeneration (see Chap. 39), in which case it seems to correspond to the degree of motor apraxia. The obligate need to initiate eye movements with a blink is often a subtle sign of disordered supranuclear control of conjugate movements that is evident in these same diseases and in other processes including frontal lobe lesions.

Fragmentation of smooth pursuit movement, a frequent neuroophthalmic finding, is a jerky irregularity of tracking that has been called "saccadic pursuit". Two broad categories of disorders give rise to this phenomenon; a vestibulocerebellar and an extrapyramidal type. The former is commonly the result of sedative drug intoxication—with barbiturates, diazepam, and others as well as from a lesion of the vestibulocerebellar apparatus. In both, there is gaze directed nystagmus that seemingly interrupts pursuit movements as well. It is possible that sedatives cause this disturbance by affecting this same system.

A similar-appearing phenomenon, but one that does not manifest nystagmus, nicely called "cogwheel eye movements", is seen in certain extrapyramidal diseases such as Parkinson disease, Huntington disease, and progressive supranuclear palsy. In these diseases there is a ratchet-like impairment of smooth pursuit movements in association with slow, hypometric saccades ("saccadic pursuit"). Indeed, according to Vidailhet and colleagues, smooth pursuit movements are impaired in all types of basal ganglionic degenerations.

Asymmetrical impairment of smooth pursuit movements is indicative of a parietal or a frontal lobe lesion. Pursuit is impaired toward the side of a parietal lesion and away from a frontal lesion, as described earlier. This is not a common clinical phenomenon unless elicited by optokinetic testing as explained further on.

Vestibuloocular Reflex (VOR) Testing

This refers to involuntary conjugate eye movements that are contraversive to head turning and is manifest in unresponsive patients. Stimulation of the labyrinths by caloric or electrical activation elicits an identical phenomenon and can be performed in awake patients as well, as described in Chap. 17 on Coma.

Optic Fixation Reflex

The ability to suppress the VOR by visual fixation can provide considerable information and may be tested in various ways depending on the clinical need. One such test in the cooperative patient is performed by requesting that the patient fixate on a distant target and rapidly turning the head to one side by 5 to 10 degrees and (see "Tests of Labyrinthine Function" in Chap. 15). Slippage of fixation (impaired vestibuloocular reflex) is appreciated by observing a small corrective saccade in the direction opposite head turning. An alternative is to rotate the patient in a chair while he fixates on the thumb of his outstretched hand. There should be no loss of fixation at moderate rotational speeds; nystagmus during this maneuver is an abnormal sign. Zee has described yet another means of testing the VOR in which the examiner observes the optic nerve head while the patient rotates the head back and forth at a rate of one to two cycles per second. If the VOR is impaired, the optic nerve head appears to oscillate. Normally, movement of the head at this rate does not cause blurring of vision because of the rapidity with which the VOR accomplishes compensatory eye movements. As a result of inability to suppress the VOR, the patient experiences a feeling of instability.

Testing the Near Response (Accommodative Triad)

Combined convergence and accommodative movements are tested by asking the patient to look at his thumbnail, the examiner's finger, or object as it is brought toward the eyes. However, these fusional movements are frequently impaired in the elderly and in confused or inattentive patients and should not be interpreted as the result of disease in the ocular motor pathways. Otherwise, the absence or impairment of these movements should suggest a lesion in the rostral midbrain as a component of the Parinaud syndrome. Convergence spasms and retraction nystagmus may accompany paralysis of vertical gaze from a dorsal midbrain lesion. But when such convergent spasms occur alone, they are characteristic of hysteria, in which full horizontal movement can usually be obtained if each eye is tested separately. Also, cycloplegic eye drops will abolish accommodation and pupillary miosis.

Impairment of Conjugate Gaze

Horizontal Gaze Palsy

Strictly speaking, gaze palsy refers to a complete loss of both saccadic and pursuit movements to one side. Gaze paresis would then refer to an incomplete loss of the same capacity. Operationally, a distinction is made between supranuclear disorders of gaze that can be overcome by intense stimuli, and certain nuclear lesions that cause an insurmountable loss of gaze to one side that cannot be overcome except by physically moving the globes (forced ductions).

As a rule, the horizontal gaze palsies of cerebral and pontine origin are readily distinguished by the side of an accompanying hemiparesis. When there is a tonic deviation of the eyes ipsilateral to a cerebral lesion, this relationship is expressed as "the eyes look toward the lesion and away from the hemiparesis." The opposite pertains to brainstem gaze palsies, that is, gaze is impaired toward the side opposite the lesion, and if there is gaze deviation, the eyes are turned toward a hemiparesis. Palsies of pontine origin need not have an accompanying hemiparesis but are associated with other signs of pontine disease, particularly peripheral facial palsies and internuclear ophthalmoplegia on the same side as the paralysis of gaze. Pontine gaze palsies tend to be longer lasting than those of cerebral origin. Also, in the case of a cerebral lesion (but not a pontine lesion), the eyes turn to the paralyzed side if they are fixated on the target, and the head is rotated passively to the opposite side (i.e., by utilizing the VOR).

Cerebral Origin

An acute lesion of one frontal lobe, such as an infarct, usually causes impersistence or paresis of contralateral gaze (more so than an actual palsy of gaze), and the eyes may for a limited time turn involuntarily toward the side of the cerebral lesion. In most cases of acute frontal lobe damage, the gaze palsy is incomplete and temporary, lasting for a week or less. Almost invariably, it is accompanied by hemiparesis. Forced closure of the eyelids may cause the eyes to move paradoxically to the side of the hemiparesis rather than upward (the latter being the Bell phenomenon), as would be expected. Similarly, during sleep, the eyes may also deviate conjugately away from the side of the lesion toward the side of the hemiplegia. As indicated above, pursuit movements away from the side of the lesion tend to be fragmented or lost. Posterior parietal lesions reduce pursuit movements but do not cause gaze palsy.

With bilateral frontal lesions, the patient may be unable to turn his eyes voluntarily in any direction but retains fixation and following movements. Occasionally, a deep cerebral lesion, particularly a thalamic hemorrhage extending into the midbrain, will cause the eyes to deviate conjugately to the side opposite the lesion ("wrong-way" gaze); the basis for this anomalous phenomenon is not established, but interference with descending oculomotor tracts in the midbrain has been postulated by Tijssen. It should be emphasized that cerebral gaze paralysis is not attended by strabismus or diplopia, i.e., the eyes always move conjugately. The usual causes of gaze paresis are vascular occlusion with infarction, hemorrhage, and abscess or tumor of the frontal lobe.

A seizure originating in the frontal lobe may also drive the eyes to the opposite side. When the eyes are driven contralaterally from the cerebral focus they may not return to the midline, giving the impression of gaze palsy. Also, in the postictal period, the eyes may reside in the opposite direction, ipsilaterally to the seizure focus.

Brainstem Origin

The most common source of a nuclear-infranuclear gaze palsy is a lesion in the pontine horizontal gaze complex (PPRF; also involving the abducens nucleus), which causes ipsilateral gaze palsy and deviation of the eyes to the opposite side (Table 14-1). A unilateral lesion in the rostral midbrain tegmentum, by interrupting the cerebral pathways for horizontal conjugate gaze before their decussation, will also cause a paresis of gaze to the opposite side. Vestibulocerebellar lesions can cause yet another disorder of conjugate gaze that simulates a gaze palsy in which the eyes are forced, or driven to one side in a manner termed "pulsion" that prevents voluntary movement to the other side.

Vertical Gaze Palsy

Midbrain lesions affecting the pretectum and the region of the posterior commissure interfere with conjugate movements in the vertical plane. Paralysis of vertical gaze is a prominent feature of the Parinaud or dorsal midbrain syndrome described earlier. Upward gaze in general is affected far more frequently than downward gaze because, as already explained, some of the fibers subserving upgaze cross rostrally and posteriorly between the riMLF and INC and are subject to interruption before descending to the oculomotor nuclei, whereas the pathways for down-gaze apparently project directly downward to oculomotor nuclei from the two controlling centers.

The range of upward gaze is frequently restricted by extraneous factors, such as drowsiness, increased intracranial pressure, and particularly, aging. In a patient who cannot elevate the eyes voluntarily, the presence of reflex upward deviation of the eyes in response to flexion of the head ("doll's-head maneuver") or to voluntary forceful closure of the eyelids (Bell phenomenon) indicates that the nuclear and infranuclear mechanisms for upward gaze are intact and that the defect is supranuclear. However, useful this rule may be, in some instances of disease of the peripheral neuromuscular apparatus—such as Guillain-Barré syndrome and myasthenia gravis—in which voluntary upgaze may be limited, the strong stimulus of eye closure may cause upward deviation, whereas voluntary attempts at upgaze are unsuccessful, thereby spuriously suggesting a lesion of the upper brainstem. In addition, approximately 15 percent of normal adults do not show a Bell phenomenon; in others, deviation of the eyes is paradoxically downward.

In patients who during life had shown an isolated palsy of downward gaze, autopsy has disclosed bilateral lesions of the rostral midbrain tegmentum (just medial and dorsal to the red nuclei). An unusual case, described by Bogousslavsky and colleagues, suggests that a paralysis of vertical gaze may follow a strictly unilateral infarction that comprises the posterior commissure, riMLF, and INC. Hommel and Bogousslavsky have summarized the location of strokes that cause monocular and binocular vertical gaze palsies.

Several degenerative and related processes exhibit selective or prominent upgaze or vertical gaze palsies, as mentioned earlier (Table 14-1). In progressive supranuclear palsy, a highly characteristic feature is a selective paralysis of vertical gaze, with the more specific feature being downward paralysis beginning with impairment of saccades and later, restriction of all vertical movements. Parkinson and Lewy-body diseases (see Chap. 39), corticobasal ganglionic degeneration (see Chap. 39), and Whipple disease of the brain (see Chap. 40) may also produce vertical gaze palsies as these diseases progress.

Other Supranuclear Disorders of Gaze

The ocular tilt reaction, in which skew deviation (unilateral vertical separation of the eyes, discussed further on) is combined with ocular torsion and head tilt, is attributed to an imbalance of otolithic-ocular and otolithic-colic reflexes. In lesions involving the vestibular nuclei, as occurs in lateral medullary infarction, the eye is lower on the side of the lesion. With lesions of the MLF or INC, which can also cause skew and an ocular tilt reaction, the eye is higher on the side of the lesion.

Another unusual disturbance of gaze is the oculogyric crisis, or spasm, which consists of a tonic spasm of conjugate deviation of the eyes, usually upward and less frequently, laterally or downward. Recurrent attacks, sometimes associated with spasms of the neck, mouth, and tongue muscles and lasting from a few seconds to an hour or two, were pathognomonic of postencephalitic parkinsonism in the past. Now this phenomenon is observed as an acute reaction in patients being given phenothiazine and related neuroleptic drugs and in Niemann-Pick disease. The pathogenesis of these ocular spasms is not known. In the drug-induced form, upward deviation of the eyes is often associated with a report by the patient of peculiar obsessional thoughts; the entire syndrome can be terminated by the administration of an anticholinergic medication such as benztropine.

Congenital oculomotor "apraxia" (Cogan syndrome) is a congential disorder characterized by unusual eye and head movements that are obligately tied together during attempts to change the position of the eyes. The patient is unable to make normal voluntary horizontal saccades when the head is stationary. If the head is free to move and the patient is asked to look at an object to either side, the head is thrust to one side and the eyes turn in the opposite direction; the head overshoots the target, and the eyes, as they return to the central position, fixate on the target. Both voluntary saccades and the quick phase of vestibular nystagmus are defective. The pathologic anatomy is not understood but the condition abates over time. This same phenomenon is also seen in ataxia-telangiectasia (Louis-Bar disease, Chap. 37) and with agenesis of the corpus callosum, in which both horizontal and vertical saccades may be affected.

Anatomic Considerations

The third (oculomotor), fourth (trochlear), and sixth (abducens) cranial nerves innervate the extrinsic muscles of the eye. Because their actions are closely integrated and many diseases involve all of them at once, they are suitably considered together.

The oculomotor (third-nerve) nuclei consist of several paired groups of motor nerve cells adjacent to the midline, and ventral to the aqueduct of Sylvius at the level of the superior colliculi. A centrally located group of cells that innervate the pupillary sphincters and ciliary bodies (muscles of accommodation) is situated dorsally in the Edinger-Westphal nucleus that subserves pupillary reactions to light and the near vision response; this is the parasympathetic portion of the oculomotor nucleus. Ventral to this nuclear group are cells that mediate the actions of the levator of the eyelid, superior and inferior recti, inferior oblique, and medial rectus, in this dorsal–ventral order. This functional arrangement has been determined in cats and monkeys by extirpating individual extrinsic ocular muscles and observing the retrograde cellular changes (Warwick). Subsequent studies using radioactive tracer techniques have shown that medial rectus neurons occupy three disparate locations within the oculomotor nucleus rather than being confined to its ventral tip (Büttner-Ennever and Akert). These experiments also indicated that the medial and inferior recti, and the inferior oblique are innervated strictly ipsilaterally from the oculomotor nuclei, whereas the superior rectus receives only crossed fibers, and the levator palpebrae superioris (lid elevators) has bilateral innervations. Whether this precise arrangement is reproduced in humans is not known. Vergence movements are under the control of medial rectus neurons and not, as was once supposed, by an unpaired medial group of cells (nucleus of Perlia).

The fibers of the third-nerve nucleus course ventrally in the midbrain, crossing the medial longitudinal fasciculus, red nucleus, substantia nigra, and medial part of the cerebral peduncle successively. Lesions involving these structures therefore interrupt oculomotor fibers in their intramedullary (fascicular) course and give rise to several crossed syndromes of hemiplegia and ocular palsy. With regard to the oculomotor subnuclei, schematic arrangements of their projections have been derived from various sources, mainly experimental but some clinical, and are shown in the figure from Ksiazek and colleagues (Fig. 14-3). The emerging fibers can be considered as situated in medial, lateral and rostro-caudal groups, with the pupillary fibers occupying the rostro-medial aspect. This location of axons destined for the pupil continues through the third nerve. This information becomes useful in recognizing that combined pupillary and inferior and medial rectus palsies on one side may be the result of a fascicular lesion of the oculomotor nerve.

The sixth nerve (abducens) arises at the level of the lower pons from a paired group of cells in the floor of the fourth ventricle, adjacent to the midline. The intrapontine portion of the facial nerve loops around the sixth-nerve nucleus before it turns anterolaterally to make its exit; a lesion in this locality therefore causes a homolateral paralysis of the lateral rectus and facial muscles. It is important to note that the efferent fibers of the oculomotor and abducens nuclei have a considerable intramedullary extent, i.e., their fascicular portions (Fig. 14-4A and B).

The cells of origin of the trochlear nerves are just caudal to those of the oculomotor nerves in the lower midbrain. Unlike the third and sixth nerves, the fourth nerve emerges from the dorsal surface of the lower midbrain and then courses posteriorly (dorsally) and decussates a short distance from its origin, just caudal to the inferior colliculi.

The nerves proceed circumferentially and ventrally around the midbrain toward the entry of the nerve into the posterior cavernous sinus. Each nucleus therefore innervates the contralateral superior oblique muscle. The long extraaxial course and the position of the nerves adjacent to the brainstem is a putative explanation for the common complication of fourth-nerve palsy in head injury (see Chap. 35). The superior oblique muscle forms a tendon that passes through a pulley structure (the trochlea) and attaches to the upper aspect of the globe. When the eye is adducted, the muscle exerts an upward pull, but being attached to the globe behind the axis of rotation, it causes depression and intorsion of the eye; in abduction, it thereby pulls the ocular meridian toward the nose, thereby causing intorsion (i.e., clockwise in the right eye and counterclockwise in the left from the examiner's perspective).

The oculomotor nerve, soon after it emerges from the brainstem, passes between the superior cerebellar and posterior cerebral arteries. The nerve (and sometimes the posterior cerebral artery) may be compressed at this point by herniation of the uncal gyrus of the temporal lobe through the tentorial opening (see Chap. 17). The sixth nerve, after leaving the brainstem, sweeps upward along the clivus and then runs alongside the third and fourth cranial nerves; together they course anteriorly, pierce the dura just lateral to the posterior clinoid process, and run in the lateral wall of the cavernous sinus, where they are closely applied to the internal carotid artery and first and second divisions of the fifth nerve (Fig. 14-5 and "Cavernous Sinus Thrombosis" in Chap. 34).

When infraclinoid retrocavernous compressive lesions, such as aneurysms and tumors, affect the oculomotor nerve, they tend to also involve all three divisions of the trigeminal nerve. In the posterior portion of the cavernous sinus, the first and second trigeminal divisions are involved along with the oculomotor nerves; in the anterior portion, only the ophthalmic division of the trigeminal nerve is affected.

Just posterior and superior to the cavernous sinus, the oculomotor nerve crosses the terminal portion of the internal carotid artery at its junction with the posterior communicating artery. An aneurysm at this site frequently damages the third nerve; this serves to localize the site of compression or bleeding.

Together with the first division of the fifth nerve, the third, fourth, and sixth nerves enter the orbit through the superior orbital fissure. The oculomotor nerve, as it enters the orbit, divides into superior and inferior branches, although a functional separation of nerve bundles occurs well before this anatomic bifurcation. The superior branch supplies the superior rectus and the voluntary (striated) part of the levator palpebrae (the involuntary part is under the control of sympathetic fibers of Müller); the inferior branch supplies the pupillary and ciliary muscles and all the other extrinsic ocular muscles except, of course, two—the superior oblique and the lateral rectus which are innervated by the trochlear and abducens nerves, respectively. Superior branch lesions of the oculomotor nerve caused by an aneurysm or more commonly by diabetes, result in ptosis and uniocular upgaze paresis.

Diplopia and Strabismus

Under normal conditions, all the extraocular muscles participate in every movement of the eyes; for proper movement, the contraction of any muscle requires relaxation of its antagonist. Clinically, however, an eye movement can be thought of in terms of the one muscle that is predominantly responsible for an agonist movement in that direction, e.g., outward movement of the eye requires the action of the lateral rectus; inward movement, action of the medial rectus. The action of the superior and inferior recti and the oblique muscles varies according to the position of the eye. When the eye is turned outward, the elevator is the superior rectus and the depressor is the inferior rectus. When the eye is turned inward, the elevator and depressor are the inferior and superior oblique muscles, respectively. The actions of the ocular muscles in different positions of gaze are illustrated in Fig. 14-6 and Table 14-2.

The term binocular diplopia refers to the symptom of double vision caused by a misalignment of the visual axes of the two eyes. With very few exceptions, in order to experience diplopia there must be some vision in both eyes. Put another way, covering one eye usually obliterates double vision. If the visual axes are separated by a significant amount, the individual may suppress the image from one eye and not experience diplopia. There is a form of monocular diplopia that is due to lenticular or retinal disease and is also a manifestation of hysteria.

Strabismus, strictly speaking, refers to a muscle imbalance that results in misalignment of the visual axes, but the term is used most often by neurologists to describe a congenital variety of misalignment. Strabismus may be caused by weakness of an individual eye muscle (paralytic strabismus) or by an imbalance of muscular tone, presumably because of a faulty "central" mechanism that normally maintains a proper angle between the two visual axes (nonparalytic or pediatric strabismus, see below). Almost everyone has a slight tendency to strabismus, i.e., to misalign the visual axes when a target is viewed preferentially with one eye. This tendency is referred to as a phoria and is normally overcome by the fusion mechanisms. A misalignment that is manifest during binocular viewing of a target and cannot be overcome, even when the patient is forced to fixate with the deviant eye, is called a tropia. The ocular misalignment is then apparent by viewing the position of the patient's eyes while they fixate on a distant target. When tested monocularly, the range of movement in the affected eye are normal, or nearly so. The prefixes eso- and exo- indicate that the phoria or tropia is directed inward or outward, respectively, and the prefixes hyper- and hypo-, that the deviation is upward or downward. Paralytic strabismus is primarily a neurologic problem; nonparalytic strabismus (referred to as comitant strabismus if the angle between the visual axes is the same in all fields of gaze) is an ocular muscle problem that is managed by ophthalmologists, although it is associated with a number of congenital cerebral diseases and forms of developmental delay.

Pediatric Nonparalytic Strabismus

It is in this sense that the unqualified term strabismus is often used. The normal slight exotropia of neonates corrects by about 3 months of age. Large malalignments (greater than 15 degrees) are considered abnormal, even at birth. Most children with developmental esotropic strabismus present between ages 2 and 3 years, whereas those with exotropia show the condition in a broader range of preschool years. Esodeviations are initially intermittent and then become persistent; exodeviations are commonly intermittent. In both cases, eye movements are full and the child initially alternates fixation.

Esotropia is typically an acquired problem as a result of congenital farsightedness and the overengagement of the near response in order to see clearly, thereby driving the eyes to cross. Treatment with glasses within 6 months of the onset of the strabismus restores vision and usually leads to realignment of the axes. Large degrees of esotropia that are not the result of hypermetropia (farsightedness) are best treated by surgical realignment.

In contrast, persistent exotropic strabismus in a child is usually associated with a developmental delay, often as a component of a recognizable mental retardation syndrome, as detailed in Chap. 38, or with ocular pathology. It does, however, occur in neurologically normal children. If mild, intermittent exotropia is initially treated by one of a number of nonsurgical means such as patching and visual exercises to stimulate convergence; surgical correction is reserved for unresponsive cases. Donohue has written an informative review of the subject.

Once binocular fusion is established, usually by 6 months of age, any type of ocular muscle imbalance will cause diplopia, as images then fall on disparate or noncorresponding parts of the two functionally active retinas. After a time, however, the child eliminates the diplopia by suppressing the image from one eye. After another variable period, the suppression becomes permanent, and the individual retains diminished visual acuity in that eye, the result of prolonged disuse (amblyopia ex anopsia), as described in the last portion of Chap. 13.

Nonparalytic strabismus may create misleading ocular findings in the neurologic examination. Sometimes a slight phoric misalignment of the eyes is first noticed after a head injury or a febrile infection, or it may be exposed by any other neurologic disorder or drug intoxication that impairs fusional mechanisms (vergence). In a cooperative patient, nonparalytic strabismus may be demonstrated by showing that each eye moves fully when the other eye is covered. Tropias and phorias can also readily be detected by means of the simple "cover" and "cover–uncover" tests. When fusion is disrupted by covering one eye, the occluded eye will deviate; uncovering that eye results in a quick corrective movement designed to reestablish the fusion mechanism.

Clinical Effects of Lesions of the Third, Fourth, and Sixth Ocular Nerves

Third (Oculomotor) Nerve

A complete third nerve lesion causes ptosis, or drooping of the upper eyelid (as the levator palpebrae is supplied mainly by this nerve), and an inability to rotate the eye upward, downward, or inward. This corresponds to the weaknesses of the medial, superior, and inferior recti and the inferior oblique muscles. The remaining actions of the fourth and sixth nerves give rise to a position of the eye described by the mnemonic "down and out." The patient experiences diplopia in which the image from the affected eye is projected upward and medially. In addition, one finds a dilated, light-nonreactive pupil (iridoplegia), and paralysis of accommodation (cycloplegia) because of interruption of the parasympathetic fibers in the third nerve. However, the extrinsic and intrinsic (papillary) eye muscles may be affected separately in certain diseases. For example, infarction of the central portion of the oculomotor nerve, as occurs in diabetic ophthalmoplegia, typically spares the pupil, as the parasympathetic preganglionic pupilloconstrictor fibers lie near the surface. Conversely, compressive lesions of the nerve usually dilate the pupil as an early manifestation. After injury, regeneration of the third-nerve fibers may be aberrant, in which case some of the fibers that originally moved the eye in a particular direction now reach another muscle or the iris; in the latter instance the pupil, which is unreactive to light, may constrict when the eye is turned up and in.

Fourth (Trochlear) Nerve

A lesion of the fourth nerve, which innervates the superior oblique muscle, is the most common cause of isolated symptomatic vertical diplopia. Although oculomotor palsy was a more common cause of vertical diplopia in Keane's 1975 series, as stated earlier, in instances where this is the sole complaint, trochlear palsy (and brainstem lesions) have predominated in our material. Paralysis of the superior oblique muscle results in weakness of downward movement of the affected eye, most marked when the eye is turned inward (Fig. 14-7E), so that the patient complains of special difficulty in reading or going down stairs. The affected eye tends to deviate slightly upward when the patient looks straight ahead. This defect may be overlooked in the presence of a third-nerve palsy if the examiner fails to note the absence of an expected intorsion as the patient tries to move the paretic eye downward. Head tilting to the opposite shoulder (Bielschowsky sign) is especially characteristic of fourth-nerve lesions; this maneuver causes a compensatory intorsion of the unaffected eye and ameliorates the double vision. Lesions affecting the trochlear nucleus (rather than the nerve itself) will cause paresis of the contralateral superior oblique muscle; here, the patient will tilt their head toward the side of the lesion to ameliorate the diplopia.

Bilateral trochlear palsies, as may occur after head trauma, give a characteristic alternating hyperdeviation depending on the direction of gaze (unilateral traumatic trochlear paresis is still the more common finding with head injury). A useful review of the approach to vertical diplopia is given by Palla and Straumann.

Sixth (Abducens) Nerve

Lesions of the sixth nerve result in a paralysis of the abducens muscle and a resultant weakness of lateral or outward movement leading to a crossing of the visual axes. The affected eye deviates medially, i.e., in the direction of the opposing muscle. Diplopia is experienced as horizontal separation that is greatest at a distance form the patient and the image of the affected eye is projected outward. Fig 14-7A). With incomplete sixth-nerve palsies, turning the head toward the side of the paretic muscle overcomes the diplopia.

Many causes of oculomotor palsies and of combined palsies, which are discussed in a later section, are listed in Table 14-3 and are illustrated in Fig. 14-7 and below.

The Analysis of Diplopia

Almost all instances of diplopia (i.e., seeing a single object as double) are the result of an acquired paralysis or paresis of one or more extraocular muscles. The signs of the oculomotor palsies, as described above, are manifest in various degrees of completeness. With complete palsies, the affected muscle can often be surmised from the resting dysconjugate positions of the globes. With incomplete paresis, noting the relative positions of the corneal light reflections and having the patient perform common versional movements will usually disclose the faulty muscle(s) as the eyes are turned into the field of action of the paretic muscle. The muscle weakness may be so slight, however, that no strabismus or defect in ocular movement is obvious, yet the patient experiences diplopia. It is then necessary to use the patient's report of the relative positions of the images of the two eyes. Certain precautions should be taken in testing: one is cognizance of the above-mentioned absence of diplopia when the visual axes are widely separated and, the object or light used for testing should not be obscured by the patient's nose.

Two rules are applied sequentially to identify the affected ocular muscle in the analysis of diplopia:

1. The direction in which the images are maximally separated indicates the action of the pair of muscles at fault. For example, if the greatest horizontal separation is in looking to the right, either the right abductor (lateral rectus) or the left adductor (medial rectus) muscle is weak; if maximal when gazing to the left, the left lateral rectus and right medial rectus are implicated (Fig. 14-6A and B). As a corollary, if the separation is mainly horizontal, the paresis will be found in one of the horizontally acting recti (a small vertical disparity should be disregarded); if the separation is mainly vertical, the paresis will be found in the remaining vertically acting muscles, and a small horizontal deviation should be disregarded.

2. The second step in analysis identifies which of the two implicated muscles is responsible for the diplopia. The image projected farther from the center is attributable to the eye with the paretic muscle.

The simplest maneuver for the analysis of diplopia consists of asking the patient to follow an object or light into the six cardinal positions of gaze. When the position of maximal separation of images is identified, one eye is covered and the patient is asked to identify which image disappears. The red-glass test is an enhancement of this technique. A red glass is placed in front of the patient's right eye (the choice of the right eye is arbitrary, but if the test is always done in the same way, interpretation is simplified). The patient is then asked to look at a flashlight (held at a distance of 1 m), to turn the eyes sequentially to the six cardinal points in the visual fields, and to indicate the positions of the red and white images and the relative distances between them. The positions of the two images are plotted as the patient indicates them to the examiner (i.e., from the patient's perspective; Fig. 14-7). This allows the identification of both the field of maximal separation and the eye responsible for the eccentric image. If the white image on right lateral gaze is to the right of the red (i.e., the image from the left eye is projected outward), then the left medial rectus muscle is weak.

If the maximum vertical separation of images occurs on looking downward and to the left and the white image is projected farther down than the red, the paretic muscle is the left inferior rectus; if the red image (from the right eye) is lower than the white, the paretic muscle is the right superior oblique. As already mentioned, correction of vertical diplopia by a tilting of the head implicates the superior oblique muscle of the opposite side (or the ipsilateral trochlear nucleus). Separation of images on looking up and to the right or left will similarly distinguish paresis of the inferior oblique and superior rectus muscles. Most patients are attentive enough to open and close each eye and determine the source of the image thrown most outward in the field of maximal separation.

In the widely reproduced diagram analyzing diplopia from Cogan's 1956 book, we have noted the curiosity that the fields are shown from the perspective of the examiner rather than of the patient, as is the convention (and as incorrectly stated in the original legend). We have taken the liberty of repairing this reversal and showing the fields from the patient's perspective in Fig. 14-7.

There are several alternative methods for studying the relative positions of the images of the two eyes. One, a refinement of the red-glass test, is the Maddox rod, in which the occluder consists of a transparent red lens with series of parallel cylindrical bars that transform a point source of light into a red line perpendicular to the cylinder axes. The position of the red line is easily compared by the patient with the position of a white point source of light seen with the other eye. Another technique, the alternate cover test, requires less cooperation than the red-glass test and is, therefore, a passive maneuver that is more useful in the examination of children and inattentive patients. It does, however, require sufficient visual function to permit central fixation with each eye. The test consists of rapidly alternating an occluder or the examiner's hand from one eye to another and observing the deviations from and return to the point of fixation, as described earlier in the chapter in the discussion of tropias and phorias. Measuring the prismatic correction in each field of gaze with a prism bar allows the quantification of deviation and provides a method to follow diplopia over time.

The more sophisticated Lancaster test uses red/green glasses and a red and green bar of laser light projected on a screen to accomplish essentially the same result but has the advantage of reflecting the actual position and torsion of each eye. Detailed descriptions of the Maddox rod and alternate cover tests, which are the ones favored by neuroophthalmologists, can be found in the monographs of Leigh and Zee and of Glaser. In all these tests the examiner is aided by committing to memory the cardinal actions of the ocular muscles shown in Fig. 14-6 and Table 14-2.

Other Forms of Diplopia

The red-glass and other similar tests are most useful when a single muscle is responsible for the diplopia. If testing suggests that more than one muscle is involved, myasthenia gravis and thyroid ophthalmopathy are likely causes as they affect several muscles of ocular motility. Palsy of the oculomotor nerve causes a similar circumstance.

Monocular diplopia occurs most commonly in relation to diseases of the cornea and lens rather than the retina; usually the images are overlapping or superimposed rather than discrete. In most cases, monocular diplopia can be traced to a lenticular distortion or displacement but in some, no abnormality can be found and it is usually attributable to hysteria. Monocular diplopia has been reported in association with cerebral disease (Safran et al), but this must be a rare occurrence. Occasionally, patients with homonymous scotomas caused by a lesion of the occipital lobe will see multiple images (polyopia) in the defective field of vision, particularly when the target is moving.

Rarely, the acute onset of convergence paralysis gives rise to diplopia and blurred vision at all near points; most cases are a result of head injury, some to encephalitis or multiple sclerosis. Many instances of convergence paralysis do not have a demonstrable neurologic basis; they are caused by hysteria or remain unexplained. The ill-defined entity of divergence paralysis causes diplopia at a distance because of crossing of the visual axes; in such patients images fuse only at a near position. This disorder, the basis of which is unknown and for which there is no common lesion, is difficult to distinguish from mild bilateral sixth-nerve palsies and from convergence spasm, which is common in malingerers and hysterics. A special type of divergence paralysis is seen regularly with strokes in the rostral midbrain; these display an asymmetrical incompleteness of ocular abduction on both sides (pseudosixth palsy). Based on scant clinical data, a center for active divergence has been postulated to reside in the rostral midbrain tegmentum.

Causes of Individual Third-, Fourth-, and Sixth-Nerve Palsies (Table 14-3)

Ocular palsies may have a central cause—i.e., a lesion of the nucleus or the intramedullary (fascicular) portion of the cranial nerve—but more often they are peripheral. Weakness of ocular muscles because of a lesion in the brainstem is usually accompanied by involvement of other cranial nerves and by signs referable to the "crossed" brainstem syndromes of a cranial nerve palsy on one side and a hemiparesis on the opposite side (see Table 34-3 and Chap. 47). Peripheral lesions, which may or may not be solitary, have a great variety of causes.

In the series reported by Rucker (1958, 1966), who analyzed 2,000 cases of paralysis of the oculomotor nerves, the most common sources of individual ocular motor palsies were tumors at the base of the brain or skull (primary, metastatic, meningeal carcinomatosis), head trauma, ischemic infarction of a nerve (generally associated with diabetes), and aneurysms of the circle of Willis, in that order. The sixth nerve was affected in about half of the cases; third-nerve palsies were about half as common; and the fourth nerve was involved in less than 10 percent of cases. In 1,000 unselected cases reported subsequently by Rush and Younge, trauma was a more frequent cause than neoplasm and the frequency of aneurysm-related cases was fewer than in the aforementioned series; otherwise the findings were similar. Less-common causes of paralysis of the oculomotor nerves, but nonetheless seen by most practitioners, include variants of Guillain-Barré syndrome, herpes zoster, giant cell arteritis, ophthalmoplegic migraine, carcinomatous or lymphomatous meningitis, and the granulomatous disease sarcoidosis and Tolosa-Hunt syndrome, as well as fungal, tuberculous, syphilitic, and other forms of mainly chronic meningitis. Myasthenia gravis, discussed in Chap. 49, must always be considered in cases of ocular muscle palsy, particularly if several muscles are involved and if fluctuating ptosis is a prominent feature. Thyroid ophthalmopathy, discussed further on, presents in a similar fashion but without ptosis and is less common than myasthenia. Actually, in the above mentioned series, no cause could be assigned in 20 to 30 percent, although more cases are now being resolved with MRI.

Sixth-Nerve Palsy

Infarction of the sixth nerve is a common cause of sixth-nerve palsy in diabetics, in which case there is usually pain near the lateral canthus of the eye at the onset. An idiopathic form that occurs in the absence of diabetes—possibly atherosclerotic—is also well known. Isolated sixth nerve palsy with global headache, and more specifically when the sign is bilateral, sometimes proves to be caused by raised intracranial pressure from an intracranial neoplasm. In children, the most common tumor involving the sixth nerve is a pontine glioma; in adults, it is tumor arising from the nasopharynx. As the abducens nerve passes near the apex of the petrous bone it is in close relation to the trigeminal nerve. Both may be implicated by inflammatory or infectious lesions of the petrous (apex petrositis), manifest by facial pain and diplopia (Gradenigo syndrome). Among the causes of this syndrome is osteomyelitis of the petrous bone. Fractures at the base of the skull and petroclival tumors may have a similar effect, and sometimes head injury alone is the only assignable cause. Even in the absence of a fracture, fourth-nerve palsy is a more common complication of closed cranial injury (as noted below).

As mentioned, unilateral or bilateral abducens weakness may be a nonspecific sign of increased intracranial pressure from any source—including brain tumor, meningitis, and pseudotumor cerebri; rarely, it may appear after lumbar puncture, epidural injections, or insertion of a ventricular shunt. The type of bilateral weakness of ocular abduction that arises with infarction of the rostral mid-brain (pseudosixth) was described above. Occasionally, the nerve is compressed by a congenitally persistent trigeminal artery. A congenital form of bilateral abducens palsy is associated with bilateral facial paralysis (Mobius syndrome) as discussed in Chap. 38. Patients with the Duane retraction syndrome (absent sixth nerve) usually do not have diplopia and are aware of the retraction problem but an examiner may note a defect in unilateral abduction (this entity is discussed further on).

Fourth-Nerve Palsy

The fourth nerve is particularly vulnerable to head trauma (this was the cause in 43 percent of 323 cases of trochlear nerve lesions collected by Wray from the literature). The reason for this vulnerability has been speculated to be the long, crossed course of the nerves. A fair number of cases remain idiopathic even after careful investigation. The fourth and sixth nerves are practically never involved by aneurysm. This reflects the relative infrequency of carotid artery aneurysms in the infraclinoid portion of the cavernous sinus, where they could impinge on the sixth nerve. (In contrast, supraclinoid aneurysms commonly involve the third nerve.) Herpes zoster ophthalmicus may affect any of the oculomotor nerves but particularly the trochlear, which shares a common sheath with the ophthalmic division of the trigeminal nerve. Diabetic infarction of the fourth nerve occurs, but far less frequently than infarction of the third or sixth nerves. Trochlear-nerve palsy may also be a false localizing sign in cases of increased intracranial pressure, but again, not nearly as often as abducens palsy. Entrapment of the superior oblique tendon is a rare cause (Brown syndrome) in which, in addition to diplopia, there is focal pain at the superomedial corner of the orbit; hence it may be mistaken for the Tolosa-Hunt syndrome, discussed further on. Trochlear-nerve palsies have been described in patients with lupus erythematosus and with Sjögren syndrome, but their basic pathology is not known. Some cases of fourth-nerve palsy are idiopathic and most of these resolve.

Superior oblique myokymia is an unusual but easily identifiable movement disorder, characterized by recurrent episodes of vertical diplopia, monocular blurring of vision, and a tremulous sensation in the affected eye; in this way it simulates a palsy. The globe is observed to make small arrhythmic torsional movements, especially when viewed with an ophthalmoscope. The problem is usually benign and responds to carbamazepine but rare instances presage pontine glioma or demyelinating disease. Compression of the fourth nerve by a small looped branch of the basilar artery has been suggested as the cause of the idiopathic variety, analogous to several other better documented vascular compression syndromes affecting cranial nerves. This notion is supported by findings on MRI reported by Yousry and colleagues.

Third-Nerve Palsy

The third nerve is commonly compressed by aneurysm, tumor, or temporal lobe herniation. In a series of 206 cases of third-nerve palsy collected by Wray and Taylor, neoplastic diseases accounted for 25 percent and aneurysms for 18 percent. Of the neoplasms, 25 percent were parasellar meningiomas and 4 percent were pituitary adenomas. The palsy is usually chronic, progressive, and painless. As emphasized earlier, enlargement of the pupil is a sign of extramedullary third nerve compression because of the peripheral location in the nerve of the pupilloconstrictor fibers. By contrast, infarction of the nerve in diabetics usually spares the pupil, as the damage is situated in the central portion of the nerve. The oculomotor palsy that complicates diabetes (the cause in 11 percent in the Wray and Taylor series) develops over a few hours and is accompanied by pain, usually severe, in the forehead and around the eye. The prognosis for recovery (as in other nonprogressive lesions of the oculomotor nerves) is usually good because of the potential of the nerve to regenerate. Infarction of the third nerve occurs in nondiabetics as well.

In chronic compressive lesions of the third nerve (distal carotid, basilar, or, most commonly, posterior communicating artery aneurysm; pituitary tumor, meningioma, cholesteatoma) the pupil is almost always affected by way of dilatation or reduced light response. However, the chronicity of the lesion may permit aberrant nerve regeneration. This is manifest by pupillary constriction on adduction of the eye or by retraction of the upper lid on downward gaze or adduction.

Rarely, children or young adults have one or more attacks of ocular palsy in conjunction with an otherwise typical migraine (ophthalmoplegic migraine). The muscles (both extrinsic and intrinsic) innervated by the oculomotor or less commonly, by the abducens nerve, are affected. Possibly, spasm of the vessels supplying these nerves or compression by edematous arteries causes a transitory ischemic paralysis but these are speculations. Arteriograms done after the onset of the palsy usually disclose no abnormality. The oculomotor palsy of migraine tends to recover; after repeated attacks, however, there may be permanent partial paresis.

Painful Ophthalmoplegia, Tolosa-Hunt Syndrome, Cavernous Sinus Syndrome, and Orbital Pseudotumor (Table 14-4)

Some of the diseases discussed above are associated with a degree of pain, often over the site of an affected nerve or muscle or in the immediately surrounding area. But the development over days or longer of a painful unilateral ophthalmoplegia constitutes a special syndrome that is usually traceable to an aneurysm, tumor, or inflammatory and granulomatous process in the anterior portion of the cavernous sinus or the adjacent superior orbital fissure. The idiopathic granulomatous painful condition has been termed Tolosa-Hunt syndrome; a similar but more extensive process is known as orbital pseudotumor. Although there is little pathologic material on which to base an understanding of these two diseases, they appear to be related orbital inflammations.

Orbital pseudotumor causes an inflammatory enlargement of the extraocular muscles, which often also encompasses the globe and other orbital contents accompanied by injection of the conjunctiva and lid and slight proptosis (Fig. 14-8). The Tolosa-Hunt syndrome lacks these features but is occasionally associated with additional signs of cavernous sinus disease, particularly sensory loss in the periorbital branches of the trigeminal nerve. In pseudotumor of the orbit, a single muscle or several may be involved and there is a tendency to relapse and later to involve the opposite globe. Visual loss from compression of the optic nerve is a rare complication of either condition. Associations with connective tissue disease have been reported in orbital pseudotumor but most cases in our experience have occurred in isolation. Ultrasonography examination or CT scans of the orbit show enlargement of the orbital contents in pseudotumor, mainly the muscles, similar to the findings in thyroid ophthalmopathy (which is not, however, painful unless there is secondary corneal ulceration).

The inflammatory changes of Tolosa-Hunt syndrome are limited to the superior orbital fissure and can sometimes be detected by MRI; coronal views taken after gadolinium infusion show the lesion to best advantage. However, sarcoidosis, lymphomatous infiltration, and a small meningioma may produce similar radiographic findings and granulomatous (temporal) arteritis rarely causes ophthalmoplegia. The sedimentation rate in our patients with orbital pseudotumor or Tolosa-Hunt syndrome has varied but it has been moderately elevated in reported cases, sometimes accompanied by a leukocytosis at the onset of symptoms. Sarcoidosis also can infiltrate the posterior orbit or cavernous sinus and cause a single or multiple unilateral nerve ophthalmoparesis as discussed in Chaps. 13 and 47.

Treatment

Both the Tolosa-Hunt syndrome and orbital pseudotumor are treated with corticosteroids. A marked response with reduction in pain and improved ophthalmoplegia in 1 or 2 days is confirmatory of the diagnosis; however, as pointed out in the review by Kline and Hoyt, tumors of the parasellar region that cause ophthalmoplegia may also respond, albeit not to the same extent. In both diseases, we have generally given prednisone 60 mg and tapered the medication slowly; although there are no data to guide the proper treatment, corticosteroids should be continued for several weeks or longer. The absence of a response to steroids should cause reconsideration of the diagnosis of Tolosa-Hunt syndrome.

Cavernous Sinus Syndrome

In the cavernous sinus syndrome, involvement of the oculomotor nerve on one or both sides is accompanied by periorbital pain and chemosis (Fig. 14-5B). In a series of 151 such cases reported by Keane, the third nerve (typically with pupillary abnormalities) and sixth nerve were affected in almost all and the fourth nerve in one-third; complete ophthalmoplegia, usually unilateral, was present in 28 percent. Sensory loss in the distribution of the ophthalmic division of the trigeminal nerve was often added, a finding that is helpful in the differentiation of cavernous sinus disease from other causes of orbital edema and ocular muscle weakness.

Trauma and neoplastic invasion are the most frequent causes of the cavernous sinus syndrome. Thrombophlebitis, intracavernous carotid aneurysm or fistula, fungal infection, meningioma, and pituitary tumor or hemorrhage account for a smaller proportion (see "Septic Cavernous Sinus Thrombophlebitis" and "Cavernous Sinus Thrombosis" in Chaps. 10 and 34). A dural arteriovenous fistula is another rare cause. Chapter 34 discusses this process more fully with other disorders of the cerebral venous sinuses; the optic neuropathy that sometimes accompanies the syndrome is noted in Chap. 13.

The other important considerations in older patients with painful ophthalmoplegia are temporal arteritis as mentioned above (see Chap. 10) and thyroid ophthalmopathy (although pain tends not to be prominent in the latter), which are discussed further on.

Acute Ophthalmoplegia (Table 14-5)

When a total or nearly complete loss of eye movements of both eyes evolves within a day or days, it raises a limited number of diagnostic possibilities. Keane, who analyzed 60 such cases, found the responsible lesion to lie within the brainstem in 18 (usually infarction and less often Wernicke disease), in the cranial nerves in 26 (Guillain-Barré syndrome or tuberculous meningitis), within the cavernous sinus in 8 (tumors or infection), and at the myoneural junction in 8 (myasthenia gravis and botulism). Our experience has tended toward the Guillain-Barré syndrome, as did Keane's later series (2007), and, somewhat less frequently in our material, myasthenia. The ophthalmoplegic form of Guillain-Barré syndrome is almost always associated with circulating antibodies to GQ1b ganglioside (see Chap. 46). There may be an accompanying paralysis of the dilator and constrictor of the pupil ("internal ophthalmoplegia") that is not seen in myasthenia.

Unilateral complete ophthalmoplegia has an even more limited list of causes, largely related to local disease in the orbit and cavernous sinus, mainly infectious, neoplastic, or thrombotic and most of which have already been mentioned.

Chronic and Progressive Bilateral Ophthalmoplegia

This is most often caused by an ocular myopathy (the mitochondrial disorder known as progressive external ophthalmoplegia), a restricted muscular dystrophy, thyroid ophthalmopathy (see below and Chap. 48), and, sometimes, myasthenia gravis or Lambert-Eaton syndrome. We have encountered instances of the Lambert-Eaton myasthenic syndrome that caused an almost complete ophthalmoplegia (but not as an initial sign, as it may be in myasthenia) and a patient with paraneoplastic brainstem encephalitis similar to the case reported by Crino and colleagues, but both of these are certainly rare as causes of complete loss of eye movements. Among the group of congenital myopathies, most of which are named for the morphologic characteristic of the affected limb musculature. A few of these—such as the central core, myotubular, and nemaline types, as well as the slow channel congenital myasthenic syndrome—may cause a generalized ophthalmoparesis (see Chap. 48). Among the chronic conditions, progressive supranuclear palsy may ultimately produce complete ophthalmoplegia, after first affecting vertical gaze. Thyroid ophthalmopathy as a cause of chronic ophthalmoparesis is discussed below.

The Duane retraction syndrome (so-called because of the retraction of the globe and narrowing of the palpebral fissure that is elicited by attempted adduction) occurs when the lateral rectus branches are aberrantly innervated by the third nerve. Cocontraction of the medial and lateral recti results in retraction of the globe in all directions of ocular movement.

Mechanical-Restrictive Ophthalmoparesis Including Thyroid Ophthalmopathy

Several causes of a pseudoparalysis of ocular muscles that are due to mechanical restriction of the ocular muscles are distinguished from the neuromuscular and brainstem diseases discussed above. Processes that infiltrate the orbit, such as lymphoma, carcinoma and granulomatosis may limit the range of motion of individual or all the ocular muscles. In thyroid disease, a swollen and tight inferior or superior rectus muscle may limit upward and downward gaze; less frequently, involvement of the medial rectus limits abduction. The frequency of involvement of the ocular muscles is given by Wiersinga and colleagues as inferior rectus 60 percent; medical rectus 50 percent; and superior rectus 40 percent. In most instances of thyroid ophthalmopathy, diagnosis is clear as there is an associated proptosis, but in the absence of the latter sign, and particularly if the ocular muscles are affected on one side predominantly, there may be difficulty. The extraocular muscle enlargement can be demonstrated by CT scans and ultrasonography. This disorder is discussed further in Chap. 48. In a significant number of cases, 10 percent according to Bahn and Heufelder, there are no signs of hyperthyroidism. However, most of these patients have laboratory evidence of thyroid autoimmune disease.

The mechanical restriction of motion is confirmed by forced duction tests in which the eye is physically pulled or pushed over by the examiner. In the past, the insertions of the extraocular muscles were anesthetized and grasped by toothed forceps and attempts to move the globe are palpably restricted; more often, a cotton swab applied to the sclera is used to manipulate the globe.

Mixed Gaze and Ocular Muscle Paralysis

We have already considered two types of neural paralysis of the extraocular muscles: paralysis of conjugate movements (gaze) and paralysis of individual ocular muscles. Here we discuss a third, more complex one—namely, mixed gaze and ocular muscle paralysis. The mixed type is always a sign of an intrapontine or mesencephalic lesion that may be caused by a wide variety of pathologic changes.

Internuclear Ophthalmoplegia and Other Pontine Gaze Palsies

These abnormalities have been mentioned previously because they are components of numerous tegmental brainstem syndromes affecting both horizontal and vertical gaze. A lesion of the lower pons in or near the sixth-nerve nucleus causes an ipsilateral paralysis of the lateral rectus muscle and a failure of adduction of the opposite eye, which is manifest simply as a gaze palsy to the side of the lesion. As already indicated, a presumed pontine center accomplishes horizontal conjugate gaze by simultaneously innervating the ipsilateral lateral rectus (via the abducens neurons) and the contralateral medial rectus via fibers that originate in the internuclear neurons of the abducens nucleus and cross at the level of the nucleus to traverse the MLF of the opposite side (Fig. 14-1).

With a complete lesion of the left MLF, the left ipsilateral eye fails to adduct when the patient looks to the right; this condition is referred to as internuclear ophthalmoplegia (INO; reciprocally, with a lesion of the right MLF, the right eye fails to adduct when the patient looks to the left—namely, right internuclear ophthalmoplegia). Quite often, rather than a complete paralysis of adduction, there are only slowed adducting saccades in the affected eye while its opposite quickly arrives at its fully abducted position. This can be brought out by having the patient make large side-to-side refixation movements between two targets or by observing the slowed corrective saccades induced by optokinetic stimulation. Typically, the affected eye at rest does not lie in an abducted position, but there are exceptions and in most cases the absence of exotropia most dependably differentiates INO from a partial third-nerve palsy with weakness of the medial rectus muscle. The exception is the WEBINO syndrome noted below. The two medial longitudinal fasciculi lie close together, each being situated adjacent to the midline, so that they are frequently affected together, yielding a bilateral internuclear ophthalmoplegia; this condition should be suspected when the predominant ocular finding is bilateral paresis of adduction.

A second component of INO is a nystagmus that is limited to, or most prominent in, the opposite (abducting) eye. The intensity of nystagmus varies greatly from case to case. Several explanations have been offered to account for this dissociated nystagmus, all of them speculative. The favored one invokes the Hering law in which activated pairs of yoked muscles receive equal and simultaneous innervation; because of an adaptive increase in innervation of the weak adductor there is a commensurate increase in innervation to the strong abductor (manifest as nystagmus). Whatever the afferent stimulus for this over-drive, it is probably proprioceptive (i.e., not visual), because occlusion of the affected eye does not suppress the nystagmus. The MLF also contains axons that originate in the vestibular nuclei and govern vertical eye position, for which reason an INO may also cause a skew (vertical deviation of one eye) or monocular vertical nystagmus with impairment of vertical fixation and pursuit (bilaterally with bilateral INO).

Lesions involving the MLF in the high midbrain cause a loss of convergence and an exotropia because of proximity to the medial rectus subnucleus. When the lesion is bilateral, both eyes are slightly abducted, giving rise to a "wall-eyed INO", or WEBINO. Abducting nystagmus tends to be slight in this mesencephalic type. More commonly, the MLF is involved by a lesion in the pons and convergence is spared and the globes are orthotopic, but there is sometimes an additional slight degree of horizontal gaze or sixth-nerve palsy as a result of disturbance of adjacent horizontal gaze centers. There may be yet another rare syndrome that has gone by the term "posterior INO of Lutz" (INO of abduction, in which the MLF is not involved); the lesion is proposed to be between the PPRF and the sixth nerve nucleus and the abduction paresis can be overcome by vestibular stimulation. The terms "anterior" and "posterior" INO have also been applied to these topographic syndromes but their meaning has been taken differently by various authors thus making them less useful.

The main cause of unilateral INO is a small paramedian pontine infarction. Other common lesions are lateral medullary infarction (where skew deviation is often a component), a demyelinating plaque of multiple sclerosis (more common as a cause of bilateral INO, as noted below), lupus erythematosus, and infiltrative tumors of the brainstem and fourth ventricular region. Occasionally, an INO is an unexplained finding after mild head injury or with subdural hematoma or hydrocephalus. Some of the more unusual causes are given in the experience of Keane (2005). Infarction and multiple sclerosis remained the most common in his series but trauma, transtentorial herniation, tumor, infection and hemorrhage were alternatives, the point being that a quarter were from unconventional processes. In addition, adductor weakness from myasthenia gravis can simulate an INO, even to the point of showing nystagmus in the abducting eye.

Bilateral INO is most often the result of a demyelinating lesion (multiple sclerosis) in the posterior part of the midpontine tegmentum. Pontine myelinolysis, pontine infarction from basilar artery occlusion, Wernicke disease, or infiltrating tumors are other causes. Brainstem damage following compression by a large cerebral mass has on occasion produced the syndrome.

An ipsilateral gaze palsy is the simplest oculomotor disturbance that results from a lesion in the paramedian tegmentum. More complex is the one-and-a-half syndrome that involves the pontine center for gaze plus the adjacent ipsilateral MLF on one side that combines an INO and a horizontal gaze palsy on the same side. It is usually of vascular or, less often, demyelinative cause. The gaze palsy is, of course, on the side of the lesion and the eyes are deviated contrawise. As a result, one eye lies fixed in the midline for all horizontal movements; the other eye makes only abducting movements and may be engaged in horizontal nystagmus in the direction of abduction (see Fisher; also Wall and Wray). Unlike the situation of an INO alone, the mobile eye rests abducted because of the gaze palsy, a sign that has been termed "paralytic pontine exotropia." In some cases the patient is able to adduct the eye ("nonparalytic exotropia," a condition which has other causes).

An incomplete version of the bilateral INO displays only bilateral nystagmus on gaze in one direction (due to paresis of gaze) and nystagmus only in the abducting eye with gaze directed to the other side (due to the lesion in the MLF on the same side). This has been summarized the mnemonic of nystagmus in both eyes looking toward the pontine lesion and in one eye looking away from the lesion.

Caplan has summarized the features of mixed oculomotor defects that occur with thrombotic occlusion of the upper part of the basilar artery ("top of the basilar" syndromes). These include upgaze or complete vertical gaze palsy and so-called pseudoabducens palsy, mentioned earlier. The latter is characterized by bilateral incomplete esotropia that simulates bilateral sixth nerve paresis (pseudoabducens palsy) but appears to be a type of sustained convergence or a paresis of divergence; it can be overcome by vestibular stimulation.

Skew Deviation

Skew deviation is a disorder in which there is vertical deviation of one eye above the other that is caused by an imbalance of the vestibular inputs to the oculomotor system. The patient may complain of similar degrees of diplopia in all fields of gaze (comitant), or diplopia may vary with different directions of gaze. In either case, the patient complains of vertical diplopia. A noncomitant vertical deviation of the eyes, most pronounced when the affected eye is adducted and turned down, is characteristic of fourth-nerve palsy, described further on. Skew deviation does not have precise localizing value and is associated with a variety of lesions of the cerebellum and the brainstem, particularly those involving the MLF. With skew deviation due to cerebellar disease, the eye on the side of the lesion usually rests lower (in a ratio of 2:1 in Keane's series), but sometimes it is higher than the other eye. The corresponding image, of course, rests higher in the first instance and lower with the latter, which is most often a component of an INO.

The hypertropic eye has been known to alternate with the direction of gaze ("alternating skew") and has also been seen with the condition known as periodic alternating nystagmus. A cerebellar or other posterior fossa lesion is the usual cause. A mechanism for this sign has been proposed based on otolithic influences on cerebellar centers. Ford and coworkers have described a rare form of skew deviation caused by a monocular palsy of elevation stemming from a lesion immediately rostral to the ipsilateral oculomotor nucleus; a lesion of upgaze efferents from the ipsilateral riMLF was postulated but an abnormality of the vertical gaze holding mechanism related to the function of the INC is an alternative explanation.

Among the most unusual of the complex ocular disturbances is a subjective tilting of the entire visual field that may produce any angle of divergence but most often creates an illusion of environmental tilting of 45 to 90 degrees (tortopia) or of 180-degree vision (upside-down vision). Objects normally on the floor, such as chairs and tables, are perceived to be on the wall or ceiling. Although this symptom may arise as a result of a lesion of the parietal lobe or in the otolithic (utricular) apparatus, it has most often been associated in our experience with an internuclear ophthalmoplegia and slight skew deviation. Presumably the vestibular-otolithic nucleus or its connections in the MLF that maintain the vertical position of the ipsilateral eye are impaired. Lateral medullary infarction has been a common cause; other cases may be migrainous (Ropper, 1983). Ocular lateropulsion, in which the eyes are driven to one side and the patient feels pushed or pulled in the same direction, is another component in some cases of lateral medullary infarction as discussed in Chap. 34.

Nystagmus

Nystagmus refers to involuntary rhythmic movements of the eyes and is of two general types. In the more common jerk nystagmus, the movements alternate between a slow component and a fast corrective component, or jerk, in the opposite direction. In pendular nystagmus, the oscillations are roughly equal in rate in both directions, although on lateral gaze the pendular type may be converted to the jerk type with the fast component to the side of gaze. Nystagmus reflects an imbalance in one or more of the systems that maintain stability of gaze. The causes may therefore be viewed as originating in (1) structures that maintain steadiness of gaze in the primary position; (2) the system for holding eccentric gaze—the so-called neural integrator; or (3) the VOR system, which maintains foveal fixation of images as the head moves. For the purposes of clinical work, however, certain types of nystagmus are identified as corresponding to lesions in specific structures within each of these systems, and it is this approach that we take in the following pages. One classification considers nystagmus as the result of a disturbance in the vestibular apparatus or its brainstem nuclei, the cerebellum, or a number of specific regions of the brainstem such as the MLF.

In testing for nystagmus, the eyes should be examined first in the central position and then during upward, downward, and lateral movements. Jerk nystagmus is the more common type. It may be horizontal or vertical and is elicited particularly on ocular movement in these planes, or it may be rotatory and, rarely, retractory or vergent. By custom the direction of the nystagmus is designated according to the direction of the fast component (referred to as "beating" to that side). There are several varieties of jerk nystagmus. Some occur spontaneously; others are readily induced in normal persons by drugs or by labyrinthine or visual stimulation.

Drug intoxication is certainly the most frequent cause of nystagmus. Alcohol, barbiturates, other sedative-hypnotic drugs, phenytoin, and other antiepileptic drugs are the common ones. This form of nystagmus is most prominent on deviation of the eyes in the horizontal plane, but occasionally it also may appear in the vertical plane. For no known reason, it may occasionally be asymmetrical in the two eyes.

Oscillopsia is the symptom of illusory movement of the environment in which stationary objects seem to move back and forth, up and down, or from side to side. It may be caused by ocular flutter (a cerebellar sign as discussed later) or coarse nystagmus of any type. With lesions of the labyrinths (as in aminoglycoside toxicity), the symptom of oscillopsia is only provoked by motion—e.g., walking or riding in an automobile—and indicates an impaired ability of the vestibular system to stabilize ocular fixation during body movement (i.e., impaired VOR function). In these circumstances, cursory examination of the eyes may disclose no abnormalities; however, if the patient's head is rotated slowly from side to side or moved rapidly in one direction while attempting to fixate a target, impairment of smooth eye movements and their replacement by saccadic or nystagmoid movements is evoked (see Chap. 15 for further discussion of these tests). If episodic and involving only one eye, oscillopsia is usually caused by myokymia of an ocular muscle (usually the superior oblique).

Nystagmus of Labyrinthine Origin (See Also Chap. 15)

This is predominantly a horizontal or vertical unidirectional jerk nystagmus, often with a slight torsional component, that is evident when the eyes are close to the central position and changes minimally with the direction of gaze. It is more prominent when visual fixation is eliminated (conversely, it is suppressed by fixation). The observation of suppression with visual fixation is facilitated by the use of Frenzel lenses, but most instances are evident without elaborate apparatus. Vestibular nystagmus of peripheral (labyrinthine) origin beats in most cases away from the side of the lesion and increases as the eyes are turned in the direction of the quick phase (the Alexander law). In contrast, as noted below, nystagmus of brainstem and cerebellar origin is most apparent when the patient fixates upon and follows a moving target and the direction of nystagmus changes with the direction of gaze. Labyrinthine-vestibular nystagmus is horizontal, vertical, or oblique, and that of purely labyrinthine origin characteristically has an additional torsional component. Tinnitus and hearing loss are often associated with disease of the peripheral labyrinthine mechanism; also, vertigo, nausea, vomiting, and staggering may accompany disease of any part of the labyrinthine-vestibular apparatus or its central connections. These points are elaborated in Chap. 15. As a characteristic example, the intense nystagmus of benign positional vertigo (described fully in Chap. 15) is evoked by moving from the sitting to the supine position, with the head turned to one side. In this condition, nystagmus of vertical-torsional type and vertigo develop a few seconds after changing head position and persist for another 10 to 15 s. When the patient sits up, the nystagmus changes to beat in the opposite direction.

In many normal individuals, a few irregular jerks are observed when the eyes are moved far to one side ("nystagmoid" jerks), but the movements cease once lateral fixation is attained. A fine rhythmic nystagmus may also occur normally in extreme lateral gaze, beyond the range of binocular vision; but it is bilateral and disappears as the eyes move a few degrees toward the midline. These latter movements are probably analogous to the tremulousness of skeletal muscles when maximally contracted.

Nystagmus Caused by Brainstem and Cerebellar Disease

Brainstem lesions often cause a coarse, unidirectional, gaze-dependent nystagmus, which may be horizontal or vertical, meaning that the nystagmus is exaggerated when the eyes sustain an eccentric position of gaze; vertical nystagmus, for example, is brought out usually on upward gaze, less often downward. Unlike the vestibular nystagmus discussed above, the central type usually also changes direction depending on the direction of gaze. The presence of bidirectional vertical nystagmus usually indicates disease in the pontomedullary or mesencephalic tegmentum. Vertigo is less common or less intense than with labyrinthine nystagmus, but signs of disease of other nuclear structures and tracts in the brainstem are frequent.

Spontaneous upbeat nystagmus is observed frequently in patients with demyelinating or vascular disease, tumors, or Wernicke disease. There is still uncertainty about the anatomic basis of coarse upbeat nystagmus. According to some authors, it has been associated with lesions of the anterior cerebellar vermis or another cerebellar site. Kato and associates cite cases with a lesion at the pontomedullary junction involving the nucleus prepositus hypoglossi, which receives vestibular connections and projects to all brainstem and cerebellar regions concerned with oculomotor functions. Bilateral internuclear ophthalmoplegia is also a cause.

Downbeat nystagmus, which is always of central origin, is characteristic of lesions in the medullary–cervical region such as syringobulbia, Chiari malformation, basilar invagination, and demyelinating plaques. It has also been seen with Wernicke disease and may be an initial sign of either paraneoplastic brainstem encephalitis or cerebellar degeneration with opsoclonus. Downbeat nystagmus, usually in association with oscillopsia, has also been observed in patients with lithium intoxication or with profound magnesium depletion (Saul and Selhorst). Halmagyi and coworkers, who studied 62 patients with downbeat nystagmus, found that half were associated with the Chiari malformation and various forms of cerebellar degeneration; in most of the remainder, the cause could not be determined. Cases associated with antibodies against glutamic acid decarboxylase (GAD), a substance that has a documented relationship to the stiff man syndrome have been reported by Antonini and colleagues and by other groups. Whether this antibody explains the idiopathic cases of downbeat nystagmus is not known.

Nystagmus of several types—including gaze-evoked nystagmus, downbeat nystagmus, and "rebound nystagmus" (gaze-evoked nystagmus that changes direction with refixation to the primary position)—occurs with cerebellar disease, particularly with lesions of the vestibulocerebellum or with brainstem lesions that involve the nucleus prepositus hypoglossi and the medial vestibular nucleus. Characteristic of cerebellar disease are several closely related disorders of saccadic movement that appear as nystagmus (opsoclonus, flutter, dysmetria) described below. Tumors situated in the cerebellopontine angle may cause a coarse bilateral horizontal nystagmus that is higher amplitude to the side of the lesion.

Nystagmus that occurs only in the abducting eye is referred to as dissociated nystagmus and is a common sign of internuclear ophthalmoplegia, as discussed earlier.

Infantile (Congenital, Pendular) Nystagmus

This is found in a variety of conditions in which central vision is lost early in life, such as albinism and various other diseases of the retina and refractive media. Occasionally it is observed as a congenital abnormality, even without poor vision. The defect is postulated to be an instability of smooth pursuit or gaze-holding mechanisms. The nystagmus is always binocular and in one plane; i.e., it will remain horizontal even during vertical movement. It is mainly pendular (sinusoidal) except in extremes of gaze, when it comes to resemble jerk nystagmus. Head oscillation may accompany the nystagmus and is probably compensatory. With eye movement recordings it displays a feature unique among nystagmus, an exponentially increasing velocity of the slow phase.

Indications as to the congenital nature of nystagmus are that it remains horizontal in all directions of gaze; it is suppressed during convergence and may be associated with odd head positions or with head oscillations and with strabismus. Also characteristic is a paradoxical response to optokinetic testing (see below), in which the quick phase is in the same direction as the drum rotation.

The related condition of latent nystagmus is the result of a lack of normal development of stereoscopic vision and may be detected by noting that the nystagmus changes direction when the eyes are alternately covered. In a few individuals who later in life lose vision in one eye, the latent nystagmus becomes a manifest latent nystagmus.

In addition, severe visual loss or blindness of acquired type that eliminates the ability to accurately direct gaze, even in adulthood, produces nystagmus of pendular or jerk variety. Both horizontal and vertical components are evident and the characteristic feature is a fluctuation over several seconds of observation in the dominant direction of beating. We have seen this sign a number of times in patients who became blind from severe optic neuritis few years back. The formerly common syndrome of "miner's nystagmus" is an associated condition that occurs in patients who have worked for many years in comparative darkness. The oscillations of the eyes are usually very rapid, increase on upward gaze, and may be associated with compensatory oscillations of the head.

Spasmus nutans, a specific type of pendular nystagmus of infancy, is accompanied by head nodding, and occasionally by wry positions of the neck. Most cases begin between the fourth and twelfth months of life, never after the third year. The nystagmus may be horizontal, vertical, or rotatory; it is usually more pronounced in one eye than the other (or limited to one eye) and can be intensified by immobilizing or straightening the head. Most infants recover within a few months or years. Most cases are idiopathic, but symptoms like those of spasmus nutans betray the presence of a perichiasmal or third ventricular tumor (see also seesaw nystagmus below in "Other Types of Nystagmus"); rare cases accompany childhood retinal diseases. Although there is no direct connection to this syndrome, the rare condition of bobble-head doll syndrome, consisting of rhythmic head movements caused by lesions in or adjacent to the third ventricle as described in Chap. 30.

Acquired forms of pendular nystagmus may occur with adult leukodystrophies (see Chap. 37), multiple sclerosis (see Chap. 36), toluene intoxication, and in the oculomasticatory myorhythmia of Whipple disease, in which the nystagmus is conjoined to rhythmic jaw movements (see Chap. 32).

Other Types of Nystagmus

Convergence nystagmus has already been alluded to in several contexts—it refers to a rhythmic oscillation in which a slow abduction of both eyes is followed by a quick movement of adduction, usually accompanied by quick rhythmic retraction movements of the eyes (nystagmus retractorius, retraction nystagmus) and by one or more features of the Parinaud–dorsal midbrain syndrome discussed earlier in the chapter. There may also be rhythmic movements of the eyelids or a maintained spasm of convergence, best brought out on attempted elevation of the eyes on command or downward rotation of an OKN drum (see below for discussion of optokinetic nystagmus, OKN). These unusual phenomena all point to a lesion of the upper midbrain tegmentum and are usually manifestations of vascular disease, traumatic damage, or tumor, notably pinealoma that compresses this region.

Seesaw nystagmus is a torsional-vertical oscillation in which the intorting eye moves up and the opposite (extorting) eye moves down, then both move in the reverse direction. It is occasionally observed in conjunction with chiasmatic bitemporal hemianopia caused by sellar or parasellar masses and after pituitary surgery. Spasmus nutans has some similarities, as mentioned above, and alternating skew may be a related phenomenon.

Periodic alternating nystagmus is a remarkable horizontal jerking that periodically (every 90 seconds or so) changes direction, interposed with a brief neutral period during which the eyes show no nystagmus, or jerk downward. Alternating nystagmus is seen with lesions in the lower brainstem but has also been reported with Creutzfeldt-Jakob disease, hepatic encephalopathy, lesions of the cerebellar nodulus, carcinomatous meningitis, anti-GAD antibodies, and varied other processes. A congenital form is associated with albinism. It differs from ping-pong gaze, which is a saccadic variant with a more rapid alternating of gaze from side to side and usually the result of bilateral cerebral strokes.

So-called palatal nystagmus, which is really a tremor, is caused by a lesion of the central tegmental tract and may be accompanied by a convergence–retraction nystagmus that has the same beat as the palatal and pharyngeal muscles, as discussed in Chap. 4.

Optokinetic Nystagmus

When one is watching a moving object (e.g., the passing landscape from a train window, a rotating drum with vertical stripes, or a strip of cloth with similar stripes), a rhythmic jerk nystagmus, optokinetic nystagmus (OKN), normally appears. This phenomenon is explained by a slow component of nystagmus that represents an involuntary pursuit movement to the limit of comfortable conjugate gaze followed by a quick saccadic movement in the opposite direction in order to fixate the next new target that is entering the visual field. With unilateral lesions of the parietal region, the slow pursuit phase of the OKN may be lost or diminished when the stimulus—e.g., the striped OKN drum—is moving toward the side of the lesion, whereas rotation of the drum to the opposite side elicits a normal response. (A prominent neurologist of our acquaintance in past days correctly made the diagnosis of parietal lobe abscess on the basis of fever and absent pursuit to the side of the lesion.) It is remarkable that patients with hemianopia caused by an occipital lobe lesion show a normal optokinetic response. The loss of the pursuit phase with a parietal lesion is presumably because of interruption of efferent pathways from the parietal cortex to the brainstem centers for conjugate gaze. On the other hand, frontal lobe lesions allow the eyes to tonically follow in the direction of the target but with little or no fast-phase correction in the direction opposite the lesion. In recent years, however, it has been suggested from primate experiments that there is a subcortical relay station for OKN in the geniculate nucleus of the optic tract contralateral to the slow phase of nystagmus.

An important additional fact about OKN is that the ability to evoke it in all directions proves that the patient is not blind. Each eye can be tested separately to exclude monocular blindness. Thus the test is of particular value in the examination of hysterical patients and malingerers who claim that they cannot see, and of neonates and infants (a nascent OKN is established within hours after birth and becomes more easily elicitable over the first few months of life).

Caloric-Induced Nystagmus

Labyrinthine stimulation—e.g., irrigation of the external auditory canal with warm or cold water, or "caloric testing"—produces a marked nystagmus. Cold water induces a slow tonic deviation of the eyes toward the irrigated ear and a compensatory nystagmus in the opposite direction; warm water does the reverse. Thus the acronym taught to generations of medical students: COWS, or "cold opposite, warm same," to refer to the direction of the fast phase of the induced nystagmus. The slow tonic component reflects impulses originating in the semicircular canals, and the fast component is a corrective movement. Chapter 15 discusses the production of nystagmus by labyrinthine stimulation and other features of vestibular nystagmus.

Other Spontaneous Ocular Movements

Roving conjugate eye movements are characteristic of light coma. Slow horizontal ocular deviations that shift every few seconds from side to side (ping-pong gaze) is a form of roving eye movement that occurs with bihemispheric infarctions or sometimes with posterior fossa lesions. Fisher has noted a similar slower, side-to-side pendular oscillation of the eyes ("windshield-wiper eyes"). This phenomenon has been associated with bilateral hemispheric lesions that have presumably released a brainstem pacemaker.

Ocular bobbing is a term coined by Fisher to describe a distinctive spontaneous fast downward jerk of the eyes followed by a slow upward drift to the midposition. It is observed in comatose patients in whom horizontal eye movements have been obliterated by large destructive lesions of the pons, less often of the cerebellum. The movements may be disconjugate in the vertical plane, especially if there is an associated third-nerve palsy on one side.

Other spontaneous vertical eye movements have been given a variety of confusing names: atypical bobbing, inverse bobbing, reverse bobbing, and ocular dipping. For the most part, they are observed in coma of metabolic or anoxic origin and in the context of preserved horizontal eye movements (in distinction to ocular bobbing). Ocular dipping is the term we have used to describe an arrhythmic slow conjugate downward movement followed in several seconds by a more rapid upward movement; it occurs spontaneously but may at times be elicited by moving the limbs or neck. Anoxic encephalopathy has been the most common cause, but a few cases have followed drug overdose (Ropper, 1981).

Oculogyric crisis, formerly associated with postencephalitic parkinsonism, is now most often caused by phenothiazine drugs, as discussed earlier.

Saccadic Intrusions (Opsoclonus and Ocular Dysmetria)

This group of phasic or repetitive eye movements is distinguished from nystagmus in that the first movement is a fast saccade, in contrast to jerk nystagmus, where by definition the movement starts with a slow phase. Opsoclonus is the term applied to rapid, conjugate oscillations of the eyes in horizontal, rotatory, and vertical directions, made worse by voluntary movement or the need to fixate the eyes. These movements are continuous and chaotic, without an intersaccadic pause (hence the colorful term saccadomania), and are almost unique among disorders of ocular movement in that they persist in sleep. As indicated in Chap. 6, they are sometimes part of a widespread myoclonus associated with parainfectious disease, occasionally with AIDS, poststreptococcal infection, West Nile virus encephalitis, and rickettsial infections, but most characteristically as a paraneoplastic manifestation with severe ataxia ("Paraneoplastic Cerebellar Degeneration" discussed in Chap. 31). Opsoclonus may also be observed in patients who are intoxicated with antidepressants, anticonvulsants, organophosphates, cocaine, lithium, thallium, and haloperidol; in the nonketotic hyperosmolar state; and in cerebral Whipple disease, where the eye movements are coupled with rhythmic jaw movements (oculomasticatory myorhythmia). A childhood form, associated with limb ataxia and myoclonus that is responsive to adrenocorticotropic hormone (ACTH), may persist for years without explanation, as in the "dancing eyes" of children (Kinsbourne syndrome). However, a distant (paraneoplastic) effect of neuroblastoma remains the main consideration in children with this ocular disorder. There is also a self-limited benign form in neonates. Similar movements have been produced in monkeys by creating bilateral lesions in the pretectum.

Ocular dysmetria, the analogue of limb dysmetria, consists of an overshoot or undershoot of the eyes on attempted fixation followed by several cycles of oscillation of diminishing amplitude until fixation is attained. The dysmetria may occur on eccentric fixation or on refixation to the primary position of gaze. It probably reflects dysfunction of the anterosuperior vermis and underlying deep cerebellar nuclei.

Ocular flutter refers to occasional bursts of very rapid horizontal oscillations around the point of fixation; this abnormality is also associated with cerebellar disease. Flutter at the end of a saccade, called flutter dysmetria ("fish-tail nystagmus") has the appearance of dysmetria, but careful analysis indicates that it is probably a different phenomenon. Whereas the inaccurate saccades of ataxia are separated by normal brief pause (intersaccadic interval), flutter dysmetria consists of consecutive saccades without an intersaccadic interval (Zee and Robinson). Nonetheless, all those movements have the same implication of cerebellar cortical disease.

Opsoclonus, ocular dysmetria, and flutter-like oscillations may occur together, or a patient may show only one or two of these ocular tremors, either simultaneously or in sequence. One hypothesis relates opsoclonus and ocular flutter to a disorder of the saccadic "pause neurons" (see above), but their exact anatomic basis has not been elucidated. Some normal individuals can voluntarily induce flutter.

An eye movement difficult to classify is ocular neuromyotonia that is found after radiation that includes the field of the ocular motor nerves (and less characteristically from vascular or tumor compression). There is intermittent contraction of one or more ocular muscles that may cause paroxysmal diplopia. The similar syndrome of superior oblique myokymia was discussed in an earlier section of the chapter.

Disorders of the Eyelids and Blinking

A consideration of oculomotor disorders would be incomplete without reference to the eyelids and blinking. In the normal individual, the eyelids on both sides are at the same level with respect to the limbus of the cornea and there is a variable prominence of the eyes, depending on the width of the palpebral fissure. The function of the lids is to protect the delicate corneal surfaces against injury and the retinae against glare; this is done by blinking and lacrimation. Eyelid movement is normally coordinated with ocular movement—the upper lids elevate when looking up and descend when looking down. Turning the eyes quickly to the side is sometimes attended by a single blink, which is necessarily brief so as not to interfere with vision. When the blink duration is prolonged, it is indicative of an abnormally intense effort required to initiate the saccade; usually this is because of frontal lobe or basal ganglionic disease.

Closure and opening of the eyelids is accomplished through the reciprocal action of the levator palpebrae and orbicularis oculi muscles. Relaxation of the levator and contraction of the orbicularis effect closure; the reverse action of these muscles effects opening of the closed eyelids. Opening of the lids is aided by the tonic innervation of the superior tarsal (Müller) muscle, which is innervated by sympathetic fibers. The levator is innervated by the oculomotor nerve, and the orbicularis by the facial nerve. The trigeminal nerves provide sensation to the eyelids and are also the afferent limbs of corneal and palpebral reflexes. Central mechanisms for the control of blinking, in addition to the reflexive brainstem connections between the third-, fifth-, and seventh-nerve nuclei, include slower and polysynaptic circuits of the cerebrum, basal ganglia, and hypothalamus. Voluntary lid closure is initiated through frontobasal ganglionic connections.

The eyelids are kept open by the tonic contraction of the levator muscles, which overcomes the elastic properties of the periorbital muscles. The eyelids close during sleep and certain altered states of consciousness as a result of relaxation of the levator muscles. Facial paralysis causes the closure to be incomplete.

Blinking occurs irregularly at a rate of 12 to 20 times a minute, the frequency varying with the state of concentration and with emotion. The natural stimuli for the blink reflex (blinking is always bilateral) are corneal contact (corneal reflex), a tap on the brow or around the eye, visual threat, an unexpected loud sound, and, as indicated above, turning of the eyes to one side. There is normally a rapid adaptation of blink to visual and auditory stimuli but not to corneal stimulation.

Electromyography of the orbicularis oculi reveals two components of the blink response, an early and late one, features that are readily corroborated by clinical observation. The early response consists of only a slight movement of the upper lids; the immediately following response is more forceful and approximates the upper and lower lids. Whereas the early part of the blink reflex is beyond volitional control, the second part can be inhibited voluntarily.

Blepharospasm, an excessive and forceful closure of the lids, is a common disorder that is seen in isolation or as part of a number of dyskinesias and drug-induced movement disorders. Extremes of this condition may result in functional blindness. Increased blink frequency is a subtle part of the same condition but also occurs with corneal irritation. The opposite sign, reduced frequency of blinking (<10/min), is characteristic of progressive supranuclear palsy and Parkinson disease. In these cases, adaptation to repeated supraorbital tapping at a rate of about 1/s is impaired; therefore the patient continues to blink with each tap on the forehead or glabella, referred to as the glabellar, or Myerson sign.

A lesion of the oculomotor nerve, by paralyzing the levator muscle, causes ptosis, i.e., drooping of the upper eyelid. A lesion of the facial nerve, as in Bell palsy, results in an inability to close the eyelids because of weakness of orbicularis oculi, retraction of the upper lid (as a result of the unopposed action of the levator), and loss of the blink reflex on the affected side. In some instances of Bell palsy, even after nearly full recovery of facial movements, blink frequency and amplitude may be reduced on the previously paralyzed side. A trigeminal nerve lesion on one side, by reducing corneal sensation, interferes with the blink reflex on both sides, whereas Bell palsy does not abolish the contralateral blink. Aberrant regeneration of the third nerve after an injury may result in a condition wherein the upper lid retracts on lateral or downward gaze (pseudo-von Graefe sign). Aberrant regeneration of the facial nerve after Bell palsy has an opposite effect—closure of the lid with jaw movements or speaking (one of the Marcus Gunn phenomena, the other being an afferent pupillary defect to light). There is also a congenital and sometimes hereditary anomaly in which a ptotic eyelid retracts momentarily when the mouth is opened or the jaw is moved to one side. In other cases, inhibition of the levator muscle and ptosis occurs with opening of the mouth ("inverse Marcus Gunn phenomenon," or Marin Amat syndrome).

A useful clinical rule is that a combined paralysis of the levator, and orbicularis oculi muscles (i.e., the muscles that open and close the lids) indicates a myopathic disease such as myasthenia gravis or myotonic dystrophy. This is because the third and seventh cranial nerves are rarely affected together in peripheral nerve or brainstem disease. An infrequent but overlooked cause of unilateral static ptosis is a dehiscence of the tarsal muscle attachment; it can be identified by the loss of the upper lid fold just below the brow.

Bilateral ptosis is a characteristic feature of certain muscular dystrophies and of myasthenia gravis; congenital ptosis and progressive sagging of the upper lids in the elderly are other common forms as well botulism whether naturally acquired of after botulinum toxin treatments. An effective way of demonstrating that mild ostensibly unilateral ptosis is in fact bilateral is to lift the ptotic side and observe that the opposite lid promptly droops. This reflects the enhanced effort required to maintain patency of the lids. Unilateral ptosis is a notable feature of third-nerve lesions (see above) and of sympathetic paralysis, namely, the Horner syndrome. It may be accompanied by an overaction (compensation) of the frontalis and the contralateral levator palpebrae muscles. In patients with myasthenia, Cogan has described a "lid twitch" phenomenon, in which there is a transient retraction of the upper lid when the patient moves visual fixation from the down position to straight ahead. Brief fluttering of the lid margins upon moving the eyes vertically is also characteristic of myasthenia.

The opposite of ptosis, i.e., retraction of the upper lids, with a staring expression (Collier sign) is observed with orbital tumors and in thyroid disease, the latter also being the most common cause of unilateral and bilateral proptosis. A staring appearance alone is observed in Parkinson disease, progressive supranuclear palsy, and hydrocephalus in young children, in which there may be downturning of the eyes ("sunset sign"), and paralysis of upward gaze. Retraction of the eyelids may also be part of a dorsal midbrain syndrome and is accompanied by a light-near pupillary dissociation; it is not accompanied by a lid lag (von Graefe sign) on downward gaze, in distinction to what is observed in thyroid ophthalmopathy. Slight lid retraction has been observed in a few patients with hepatic cirrhosis, Cushing disease, chronic steroid myopathy, and hyperkalemic periodic paralysis. Lid retraction can be a reaction to ptosis on the other side; this is clarified by lifting the ptotic lid manually, and observing the disappearance of contralateral retraction as mentioned above.

Myotonic dystrophy features ptosis as a component of the myopathic facies. In myotonia congenita, forceful closure of the eyelids may induce a strong aftercontraction. In certain extrapyramidal diseases, particularly progressive supranuclear palsy, and Parkinson disease, even gentle lid closure may elicit blepharoclonus and blepharospasm on attempted opening of the lids; or there may be a delay in the opening of the tightly closed eyelids. Acute right parietal or bifrontal lesions often produce a peculiar disinclination to open the eyelids, even to the point of offering active resistance to forced opening. The closed lids give the false impression of diminished alertness and has incorrectly been called an apraxia of lid opening.

The testing of pupillary size and reactivity, which can be accomplished by the use of a flashlight and simple gauge (we favor the circular laminated card—the Iowa pupil gauge), yields important, often vital clinical information. Essential, of course, is the proper interpretation of pupillary reactions, and this requires some knowledge of their underlying neural mechanisms.

The diameter of the pupil is determined by the balance of innervation between the constricting sphincter and radially arranged dilator muscles of the iris, the sphincter muscle playing the major role in the light response. The pupilloconstrictor (parasympathetic) fibers arise in the Edinger-Westphal nucleus in the high midbrain, join the third cranial (oculomotor) nerve, and synapse in the ciliary ganglion, which lies in the posterior part of the orbit. The postganglionic fibers then enter the globe via the short ciliary nerves; approximately 3 percent of the fibers innervate the sphincter pupillae and 97 percent the ciliary body, which is primarily responsible for accommodative constriction of the pupil. The sphincter of the pupil comprises 50 motor units, according to Corbett and Thompson.

The pupillodilator (sympathetic) fibers arise in the posterolateral part of the hypothalamus and descend, uncrossed, in the lateral tegmentum of the midbrain, pons, medulla, and cervical spinal cord to the eighth cervical, and first and second thoracic segments, where they synapse with lateral horn neurons. The latter give rise to preganglionic fibers, most of which leave the cord by the second ventral thoracic root and proceed through the stellate ganglion to synapse in the superior cervical ganglion. The postganglionic fibers course along the internal carotid artery and traverse the cavernous sinus, where they join the first division of the trigeminal nerve, finally reaching the eye as the long ciliary nerve that innervates the dilator muscle of the iris. Some of the postganglionic sympathetic fibers also innervate the sweat glands and arterioles of the face, and Müller's muscle in the eyelid.

The Pupillary Light Reflex

The most common stimulus for pupillary constriction is exposure of the retina to light. Reflex pupillary constriction is also part of the act of convergence and accommodation for near objects (near synkinesis).

The pathway for the pupillary light reflex consists of three parts (Fig. 14-9). There is an afferent limb, fibers of which originate in the retinal receptor cells, pass through the bipolar cells, and synapse with the retinal ganglion cells; axons of these cells run in the optic nerve and in the ipsilateral tract. The light reflex fibers leave the optic tract just rostral to the lateral geniculate body and enter the high mid-brain, where they synapse in the pretectal nucleus. The special intercalated neurons, which pass ventrally to the ipsilateral Edinger-Westphal nucleus and, via fibers that cross in the posterior commissure, go on to the contralateral Edinger-Westphal nucleus (labeled "pretecto-oculomotor" tract in Fig. 14-9). The effector arm of the reflex consists of an efferent two-neuron pathway from the Edinger-Westphal nucleus that synapses in the ciliary ganglion, from which the short ciliary nerves innervate the sphincter to cause pupillary constriction.

Alterations of the Pupils

The pupils tend to be large in children and small in the aged, sometimes markedly miotic but still reactive (senile miosis). An asymmetry of the pupils of 0.3 to 0.5 mm is found in 20 percent or more of normal individuals. A lesion that destroys only a small number of nerve cells in the Edinger-Westphal nucleus or ciliary ganglion will cause paralysis of a sector or sectors of the iris and deform the pupil to a pear or elliptical shape.

Normally the pupil constricts under a bright light (direct reflex), and the other unexposed pupil also constricts (consensual reflex). With complete or nearly complete interruption of the optic nerve, the pupil will fail to react to direct light stimulation; however, the pupil of the blind eye will still show a consensual reflex, i.e., it will constrict with illumination of the healthy eye. Contrariwise, lack of direct and consensual light reflex with retention of the consensual reflex in the opposite eye places the lesion in the efferent limb of the reflex arc, i.e., in the homolateral oculomotor nerve or its nucleus. A lesion of the afferent limb of the light reflex pathway will not affect the near responses of the pupil, and lesions of the visual pathway caudal to the point where the light reflex fibers leave the optic tract will not alter the pupillary light reflex (Fig. 14-9).

Following initial constriction, the pupil may normally dilate slightly in spite of a light shining steadily in one or both eyes. Slowness of response along with failure to sustain pupillary constriction, or "pupillary escape," is sometimes referred to as the Marcus Gunn pupillary sign; a mild degree of it may be observed in normal persons, but it is far more prominent in cases of damage to the retina or optic nerve. The unilateral inadequacy of pupillary response may be used to expose mild degrees of retrobulbar optic neuropathy. This relative "afferent pupillary defect" is tested always in a dimly lighted room with the patient fixating on a distant target. If a light is shifted quickly from the normal to the impaired eye, the direct light stimulus is no longer sufficient to maintain the previously evoked consensual pupillary constriction and both pupils dilate. A variant of this maneuver is the "swinging-flashlight test," in which each pupil is alternately exposed to light at 3-s intervals and the pupil on the side of an optic neuropathy displays a paradoxical dilatation just as the light is brought to it.

Hippus, a rapid fluctuation in pupillary size, is common in metabolic encephalopathy but otherwise has no particular significance and is occasionally seen in normal persons. To distinguish hippus from the Marcus Gunn afferent pupillary defect one carefully observes the first movement of the pupil as the light is repeatedly moved to the affected eye; in hippus, half of the initial responses will be dilation and half, constriction, whereas in a deafferented pupil all the initial movements are dilation.

Horner Syndrome

Interruption of the sympathetic fibers results in miosis and ptosis (because of paralysis of the pupillary dilator muscle and of Müller muscle, respectively). The lesion may be central, between the hypothalamus and the points of exit of sympathetic fibers from the spinal cord (C8 to T3, mainly T2), or peripheral, in the cervical sympathetic chain, superior cervical ganglion, or along the carotid artery. A congenital form caused by perinatal injury, usually of the sympathetic chain in the neck is seen regularly in our clinics (Fig. 14-10). A hereditary form of the Horner syndrome (autosomal dominant) is also known, usually but not always associated with a congenital absence of pigment in the affected iris (heterochromia iridis) (Hageman et al).

To the ophthalmic findings may be added loss of sweating on the same side of the face and redness of the conjunctiva. The entire complex is called the Horner syndrome, Bernard-Horner syndrome, or oculosympathetic palsy. The pupillary change may be subtle and may require covering the eyes or dimming the room lights to observe the lack of expected mydriasis on one side.

Most cases are caused by peripheral interruption of the sympathetic chain but the same effect may be produced by ipsilateral lesions of the sympathetic tract in the medulla or cervical cord. The pattern of sweating may be helpful in localizing the lesion in the following manner: With lesions at the level of the common carotid artery, loss of sweating involves the entire side of the face. With lesions distal to the carotid bifurcation, loss of sweating is not found or is confined to the medial aspect of the forehead and side of the nose (Morris et al). Retraction of the eyeball (enophthalmos), considered a component of the syndrome, is probably an illusion created by narrowing of the palpebral fissure.

Bilateral Horner syndrome is a rare occurrence; usually it is found in autonomic neuropathies and in high cervical cord transection. Although difficult to appreciate, bilateral miosis may be detected (using pupillometry or direct observation) by noting a lag in the redilation of the initially small pupils when light is withdrawn (Smith and Smith, 1999).

Stimulation or irritation of the sympathetic fibers, a rare phenomenon, has the opposite effect, i.e., lid retraction, dilatation of the pupil, and apparent proptosis. Use is made of this phenomenon in the testing of the ciliospinal pupillary reflex, which is evoked by pinching the neck (afferent, C2, C3) and effecting pupillary enlargement through cervical efferent sympathetic fibers.

Extreme bilateral constriction of the pupils (miosis) is commonly observed with pontine lesions, presumably because of interruption of the pupillodilator fibers but the mechanism is not entirely clear. Narcotic ingestion is the most common cause of bilateral miosis in clinical practice except in the elderly, who often acquire small pupils, particularly if medication drops for glaucoma are being used.

Interruption of the parasympathetic fibers causes an abnormal dilatation of the pupils (mydriasis), often with loss of pupillary light reflex; in cases of coma, this is the result of a midbrain lesion (the "blown" or Hutchinson pupil, described in Chap. 17 in the context of cerebral masses causing coma) and with direct compression of the oculomotor nerve, as by aneurysm of the circle of Willis, tumor, or temporal lobe herniation. Other signs of oculomotor palsy are usually conjoined.

As an ancillary test to determine the cause of changes in the size of the pupils, the functional integrity of the sympathetic and parasympathetic nerve endings in the iris may be determined by the use of certain drugs detailed in the next section. Atropinics dilate the pupils by paralyzing the parasympathetic nerve endings; physostigmine and pilocarpine constrict the pupils, the former by inhibiting cholinesterase activity at the neuromuscular junction and the latter by direct stimulation of the sphincter muscle of the iris. Epinephrine and phenylephrine dilate the pupils by direct stimulation of the dilator muscle. Cocaine dilates the pupils by preventing the reabsorption of norepinephrine into the nerve endings. Morphine and other narcotics act centrally to constrict the pupils. More recently, the alpha-agonist drug, apraclonidine, has been shown to reliably reverse the anisocoria of Horner syndrome and has become the preferred drug for testing. One drop (0.5 percent solution) is placed in each eye, the eyes are kept closed for 1 min and the drops are repeated 5 min later. Enlargement of the miosis with the affected pupil becoming larger than the unaffected one 30 to 45 min after instillation is definite evidence of a Horner syndrome. Ptosis is also reduced, sometimes to a remarkable extent. It was originally developed as a treatment for glaucoma (Koc et al).

In diabetes mellitus, where autonomic spinal and cranial nerves are often involved, the pupils are affected in the majority of cases. They are smaller than would be expected for age because of involvement of pupillodilator sympathetic fibers, and mydriasis is excessive upon instillation of sympathomimetic drugs. The light reflex, mediated by parasympathetic fibers (which are also damaged), is reduced, usually to a greater degree than constriction on accommodation (Smith and Smith, 1987). Some of these abnormalities require special methods for their demonstration.

Argyll Robertson Pupil (Table 14-6)

In almost all the forms of late syphilis, particularly tabes dorsalis, the pupils are bilaterally small, irregular, and unequal; they fail to react to light, although they do constrict on accommodation (light-near dissociation) and do not dilate properly in response to mydriatic drugs. Atrophy of the iris is associated in some cases. This is known as the Argyll Robertson pupil. The exact locality of the lesion is not certain but it is generally believed to be in the tectum of the midbrain proximal to the oculomotor nuclei where the descending pupillodilator fibers are in close proximity to the light reflex fibers (Fig. 14-9). This putatively explains the sparing of the afferent accommodative pathways from the retina to the Edinger-Westphal nuclei. The possibility of a partial third-nerve lesion extending to the ciliary ganglion seems as plausible to us. A similar pupillary abnormality has been observed in the meningoradiculitis of Lyme disease and in diabetes. A dissociation of the light reflex from the accommodation-convergence reaction is also sometimes observed with a variety of midbrain lesions—e.g., pinealoma, multiple sclerosis; in these diseases, miosis, irregularity of pupils, and failure to respond to a mydriatic are usually not present. S.A.K. Wilson referred to this condition as the Argyll Robertson pupillary phenomenon.

Adie Tonic Pupil (Holmes-Adie Syndrome) (Table 14-6)

Another interesting pupillary abnormality is the tonic reaction, also referred to as the Adie pupil. This syndrome is caused by a degeneration of the ciliary ganglia and the postganglionic parasympathetic fibers that normally constrict the pupil and effect accommodation. The patient may complain of unilateral blurring of vision or photophobia or may have noticed that one pupil is larger than the other. The affected pupil is slightly enlarged in ambient light and the reaction to light is absent at the outset of the syndrome or greatly reduced if tested in the customary manner, although the pupil will slowly constrict with prolonged bright light stimulation. Characteristically, there is a light-near dissociation, i.e., like the Argyll Robertson pupil, the Adie pupil responds better to near (accommodation) than it does to light. The most characteristic feature is that once the pupil has constricted, it tends to remain tonically constricted and redilates very slowly (the "tonic' aspect of the syndrome). Once dilated, the pupil remains in this state for many seconds, up to a minute or longer. Light and near paralysis of a segment or segments of the pupillary sphincter is also characteristic of the syndrome; this segmental irregularity can be seen with the high plus lenses of an ophthalmoscope. The affected pupil constricts promptly in response to the common miotic drugs and is unusually sensitive to a 0.1 percent solution of pilocarpine, a concentration that has only minimal effect on a normal pupil (due to denervation supersensitivity).

The tonic pupil usually appears during the third or fourth decade of life and is much more common in women than in men; it may be associated with absence of knee or ankle jerks (Holmes-Adie syndrome) and hence be mistaken for tabes dorsalis. From all available data, it represents a special form of mild inherited polyneuropathy. There is a familial tendency to the syndrome, in some cases associated with a mutation in the myelin protein zero (MP0) gene that is implicated in one of the less-common forms of Charcot-Marie-Tooth inherited polyneuropathy (see Chap. 46).

An acquired type of tonic pupil has also been associated, sometimes on uncertain grounds, with diabetes, viral infection, and trauma. We have observed it in migraine and following recovery from the Guillain-Barré syndrome.

Springing Pupil

Mention should be made of this rare pupillary phenomenon characterized by transient episodes of unilateral mydriasis for which no cause can be found (the springing pupil). Episodes of mydriasis, which are more common in women, last for minutes to days and may recur at random intervals. Oculomotor palsies and ptosis are notably lacking, but sometimes the pupil is distorted during the attack. Some patients complain of blurred vision and head pain on the side of the mydriasis, suggesting an atypical ophthalmoplegic migraine. In children, following a minor or major seizure, one pupil may remain dilated for a protracted period of time. The main consideration in an awake patient is that the cornea has inadvertently (or purposefully) been exposed to mydriatic solutions, among them vasopressor agents used in cardiac resuscitation.

Differential Diagnosis of Anisocoria (Figure 14-11)

In regard to pupillary disorders, there are two main issues with which the neurologist has to contend. One is the problem of unequal pupils (anisocoria), and determining whether this abnormality is derived from sympathetic or parasympathetic denervation. The second problem is the relative afferent pupillary defect, and how to recognize it; this was discussed earlier.

In dealing with anisocoria, 20 percent of normal persons show an inequality of 0.3 to 0.5 mm or more in pupillary diameter. This is "simple," or physiologic, anisocoria, and it may be a source of confusion in patients with small pupils. Its main characteristic is that the same degree of asymmetry in size is maintained in low, ambient, and bright light conditions. It is also variable from day to day and even from hour to hour, and often will have disappeared at the time of a second examination (Loewenfeld; Lam et al).

The first step in the analysis of pupillary asymmetry is to determine which of the pupils is abnormal. An abnormal larger pupil can be identified by a reduced direct and consensual light reaction. If the smaller pupil is causing asymmetry, it will fail to enlarge in response to shading both eyes or reducing ambient light. More simply stated, light exaggerates the anisocoria caused by a third-nerve lesion, and darkness accentuates the anisocoria in the case of a Horner syndrome.

A persistently small pupil always raises the question of a Horner syndrome, a diagnosis that may be difficult if the ptosis is slight. In darkness, the Horner pupil dilates more slowly and to a lesser degree than the normal one because it lacks the pull of the dilator muscle (dilation lag). The diagnosis in the past had been confirmed by placing 1 or 2 drops of 2 to 10 percent cocaine in each eye; the Horner pupil dilates not at all or much less than the normal one. A more recently introduced approach that is more dependable and obviates the difficulties in obtaining cocaine is to apply the alpha-agonist apraclonidine to both eyes and observe the reversal of miosis on the affected side of Horner syndrome (the opposite effect to cocaine). Such responses to either drug will occur with a lesion at any point along the sympathetic pathway because lesions of the first- or second-order sympathetic neurons eventually deplete norepinephrine at the synapses with third-order neurons. The reduction of neurotransmitter at the nerve endings in the ciliary dilator muscle greatly reduces the reuptake blocking effects of cocaine. If the subsequent (24 h after cocaine) application of the adrenergic mydriatic hydroxyamphetamine (1 percent) has no effect, the lesion can be localized to the postganglionic portion of the pathway as this drug releases any norepinephrine that may remain in the third-order neuron. Localization of the lesion to the central or preganglionic parts of the sympathetic pathway depends upon the associated symptoms and signs (see Chap. 26).

A variety of lesions, some of them purely ocular, such as uveitis, may also give rise to a dilated pupil.

Drug-induced iridoplegia is another cause of anisocoria. Not infrequently, particularly among nurses and pharmacists, a mydriatic fixed pupil is the result of accidental or deliberate application of an atropinic or sympathomimetic drug. We have observed this in house officers after they had participated in resuscitation from a cardiac arrest and been inadvertently sprayed with a sympathomimetic drug. Failure of 1 percent pilocarpine drops to contract the pupil provides proof that the iris sphincter has been blocked by atropine or some other anticholinergic agent. This is particularly the case when only one eye is affected.

As a rule, bilateral smallness of pupils does not pose a difficult diagnostic problem. The clinical associations, acute and chronic, have already been discussed. Long-standing bilateral Adie pupils tend to be small and show tonic near responses. They can be readily distinguished from Argyll Robertson pupils, which constrict quickly to near (accommodation) and redilate quickly on release from the near stimulus.

Figure 14-11 is a useful schematic, devised by Thompson and Pilley, for sorting out the various types of anisocoria.