Supranuclear and Internuclear Ocular Motility Disorders

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CHAPTER 19 Supranuclear and Internuclear Ocular Motility Disorders

David S. Zee and David Newman-Toker

OCULAR MOTOR SYNDROMES CAUSED BY LESIONS IN OCULAR MOTOR SYNDROMES CAUSED BY LESIONS OF THE MEDULLA THE SUPERIOR COLLICULUS Wallenberg’s Syndrome (Lateral Medullary Infarction) OCULAR MOTOR SYNDROMES CAUSED BY LESIONS OF Syndrome of the Anterior Inferior Cerebellar Artery THE THALAMUS Skew Deviation and the Ocular Tilt Reaction OCULAR MOTOR ABNORMALITIES AND DISEASES OF THE OCULAR MOTOR SYNDROMES CAUSED BY LESIONS IN BASAL GANGLIA THE CEREBELLUM Parkinson’s Disease Location of Lesions and Their Manifestations Huntington’s Disease Etiologies Other Diseases of Basal Ganglia OCULAR MOTOR SYNDROMES CAUSED BY LESIONS IN OCULAR MOTOR SYNDROMES CAUSED BY LESIONS IN THE PONS THE CEREBRAL HEMISPHERES Lesions of the Internuclear System: Internuclear Acute Lesions Ophthalmoplegia Persistent Deficits Caused by Large Unilateral Lesions Lesions of the Abducens Nucleus Focal Lesions Lesions of the Paramedian Pontine Reticular Formation Ocular Motor Apraxia Combined Unilateral Conjugate Gaze Palsy and Internuclear Abnormal Eye Movements and Dementia Ophthalmoplegia (One-and-a-Half Syndrome) Ocular Motor Manifestations of Seizures Slow Saccades from Pontine Lesions Eye Movements in Stupor and Coma Saccadic Oscillations from Pontine Lesions OCULAR MOTOR DYSFUNCTION AND MULTIPLE OCULAR MOTOR SYNDROMES CAUSED BY LESIONS IN SCLEROSIS THE MESENCEPHALON OCULAR MOTOR MANIFESTATIONS OF SOME METABOLIC Sites and Manifestations of Lesions DISORDERS Neurologic Disorders that Primarily Affect the Mesencephalon EFFECTS OF DRUGS ON EYE MOVEMENTS

In this chapter, we survey clinicopathologic correlations proach, although we also discuss certain metabolic, infec- for supranuclear ocular motor disorders. The presentation tious, degenerative, and inflammatory diseases in which su- follows the schema of the 1999 text by Leigh and Zee (1), pranuclear and internuclear disorders of eye movements are and the material in this chapter is intended to complement prominent. Details about these conditions can be found in that of Chapters 17 and 23. We emphasize an anatomic ap- the appropriate chapters in other volumes of this text.

OCULAR MOTOR SYNDROMES CAUSED BY LESIONS IN THE MEDULLA Many structures within the medulla are important in the intercalatus nucleus, and ventrally the nucleus of Roller. control of eye movements: the vestibular nuclei, perihypog- These nuclei are interconnected with other ocular motor lossal nuclei, and inferior olive and its outflow pathway structures in the brain stem and cerebellum. The NPH and through the inferior cerebellar peduncle. The perihypoglos- the adjacent medial vestibular nuclei (MVN) are critical for sal nuclei consist of the nucleus prepositus hypoglossi holding horizontal positions of gaze (the neural integrator) (NPH), which lies in the floor of the fourth ventricle, the (2). These structures also participate in vertical gaze-hold- 907 908 CLINICAL NEURO-OPHTHALMOLOGY ing, although more rostral structures, especially the intersti- neurons and their dendrites contain increased acetylcholines- tial nucleus of Cajal (INC), also contribute. With lesions in terase reaction product (14). Guillain and Mollaret (15) sug- the paramedian structures of the medulla, nystagmus—com- gested that disruption of connections between the dentate monly upbeat—is the most common finding (3). Upbeat and the contralateral olivary nucleus (which run via the red nystagmus may also reflect involvement of a ventral tegmen- nucleus and central tegmental tract) causes this syndrome. tal pathway for the upward vestibulo-ocular reflex (VOR) Another hypothesis is that the ocular oscillations are caused producing a downward vestibular bias and a consequent up- by instability in circuits that include the projection from the beat nystagmus (4). Wernicke’s disease commonly affects inferior olive to the flocculus, which is thought to be impor- the region of NPH and MVN, which may account for the tant in the adaptive control of the VOR (10). horizontal gaze-evoked nystagmus and spontaneous vertical Occasionally, lesions are restricted to the vestibular nu- nystagmus and loss of vestibular responses that occur with clei. For example, vertigo may be the sole symptom of an this disease. exacerbation of multiple sclerosis (MS) (16,17) and of brain Lesions of the inferior olivary nucleus or its connections stem ischemia (18–21). Nystagmus caused by lesions in the may produce the oculopalatal myoclonus (oculopalatal vestibular nuclei may be purely horizontal, vertical, or tor- tremor) syndrome (5,6). This condition usually develops sional, or mixed. Moreover, nystagmus from a central vestib- weeks to months after a brain stem or cerebellar infarction, ular lesion can mimic that caused by peripheral vestibular although it may also occur with degenerative conditions disease (22,23). Dolichoectasia of the basilar artery may pro- (7,8). The term myoclonus is misleading because the move- duce a variety of combinations of central and peripheral ves- ments of affected muscles are to and fro and are approxi- tibular syndromes (24,25). Microvascular compression of mately synchronized, typically at a rate of 2–4 cycles/sec. the vestibulocochlear nerve may produce paroxysmal ver- Ocular palatal tremor is the better term (6). The abnormal tigo (26,27). Brandt and Dieterich (28), Bu¨ttner et al. (29), ocular movements consist of pendular oscillations that are and Dieterich (30) provide useful topographic schemes for often vertical but may have a horizontal or torsional compo- localizing central vestibular syndromes and central vestibu- nent. Predominantly vertical oscillations are usually associ- lar nystagmus within the brain stem and cerebellum. ated with symmetric bilateral palatal tremor. Mixed vertical and torsional movements, sometimes disconjugate and with WALLENBERG’S SYNDROME (LATERAL a seesaw quality, are associated with unilateral or asymmet- MEDULLARY INFARCTION) ric palatal tremor (9,10). Occasionally, patients develop the eye oscillations without movements of the palate. Closing Lesions of the vestibular nuclei commonly affect neigh- the eyes may bring out the vertical ocular oscillations (11). boring structures, in particular the cerebellar peduncles and The nystagmus sometimes disappears with sleep, but the perihypoglossal nuclei. The best-recognized syndrome in- palatal movements usually persist. Occasionally, the oscilla- volving the vestibular nuclei is caused by a lateral medullary tions resolve spontaneously. Gabapentin may partially ame- infarction (Wallenberg’s syndrome) (Fig. 19.2). The typical liorate the eye oscillations (12). findings of Wallenberg’s syndrome are impairment of sensa- The main pathologic finding with palatal tremor is hyper- tion of pain and temperature over the ipsilateral face, ipsi- trophy of the inferior olivary nucleus, which is often seen on lateral Horner’s syndrome and limb ataxia, and dysarthria magnetic resonance (MR) imaging (13). The olivary nucleus and dysphagia. Sensation of pain and temperature are im- contains enlarged, vacuolated neurons with expanded den- paired over the contralateral trunk and limbs. The ipsilateral drites and enlarged astrocytes (Fig. 19.1). The hypertrophic facial nerve may also be affected if the infarct extends more

Figure 19.1. Pathology of palato-ocular myoclonus. A section through the cerebellum and medulla shows marked demyelination of the right dentate nucleus and restiform body (double arrows). The left inferior olive is hypertrophic and shows mild demyelination (arrow). (From Nathanson M. Palatal myoclonus: further clinical and pathophysiological observations. Arch Neurol Psychiatry 1956;75Ϻ285–296.) SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 909

and unusual sensations of body and environmental tilt, often so bizarre as to suggest a psychogenic origin (35,36). Pa- tients may report that the whole room appears tilted on its side or even upside down; with their eyes closed, they may feel themselves to be tilted. Such symptoms are occasionally reported in patients without signs of lateral medullary infarction and may be caused by transient brain stem or cerebellar ischemia (37–40) and occasionally with lesions in the thalamus (41), cerebral hemispheres (42), or peripheral vestibular apparatus (43). Lateropulsion, a compelling sensation of being pulled toward the side of the lesion, is often a prominent symptom in patients with Wallenberg’s syndrome and is also reflected Figure 19.2. Wallenberg’s syndrome. Transverse section through the me- in the ocular motor system (44–46). If the patient is asked dulla oblongata showing a unilateral infarction in its dorsolateral region. to fix straight ahead and then gently close the lids, the eyes (From Ongerboer de Visser BW, Kuypers HGJM. Late blink reflex changes deviate conjugately toward the side of the lesion. This is in lateral medullary lesions: an electrophysiological and neuroanatomical reflected in the corrective saccades that the patient must study of Wallenberg’s syndrome. Brain 1978;101Ϻ285–294.) make on eye opening to reacquire the target. Lateropulsion may appear with a blink. Saccadic eye movements are also affected by lateropul- rostrally (Fig. 19.3). Wallenberg’s syndrome is most com- sion (Fig. 19.5) (44,46–49). Horizontal saccades directed monly caused by occlusion of the ipsilateral vertebral artery; toward the side of the lesion usually overshoot the target, occasionally, the posterior inferior cerebellar artery is selec- and saccades directed away from the side of the lesion under- tively involved (31,32) (Fig. 19.4). Dissection of the verte- shoot the target; this is referred to as ipsipulsion of saccades bral artery (either spontaneous or traumatic, such as follow- and should be differentiated from the contrapulsion of sac- ing chiropractic manipulation) may cause Wallenberg’s cades that occurs with lesions in the superior cerebellar pe- syndrome (33). Rarely, demyelinating disease is the cause duncle due, for example, to superior cerebellar artery occlu- (34). sions (discussed later). Quick phases of nystagmus are The symptoms of Wallenberg’s syndrome include vertigo similarly affected in Wallenberg’s syndrome, so that sac-

Figure 19.3. Medulla oblongata showing the specific neural structures (shaded area) that are commonly damaged in Wallen- berg’s syndrome. 910 CLINICAL NEURO-OPHTHALMOLOGY

phases) can also occur (54). The ocular tilt reaction (discussed later) commonly occurs in Wallenberg’s syndrome (55), including a skew deviation with an ipsilateral hypotropia. The eyes counter-roll with the top poles rotated toward the side of the lesion, but unequally, so that there is also a cyclodeviation. The lower eye is usually more ex- torted. Some patients show ipsilateral head tilt (56). The skew deviation and head tilt arise from imbalance in pathways mediating otolith responses. The subjective sensations of tilt or inversion of the world probably also reflect involvement of central projections from the graviceptors—the utricle and saccule. Smooth pursuit is usually impaired in Wallenberg’s syndrome, particularly for tracking targets moving away from the side of the lesion (46). Caloric testing usually shows intact horizontal canal function. During both rotational and caloric testing, there is a directional preponderance of slow phases, usually toward the side of the lesion (45,46,57). Head nystagmus also occurs in some patients (44). Many of the findings in Wallenberg’s syndrome, including the bizarre visual disturbances and the skew deviation, may reflect imbalance of otolith influences caused by direct damage to the caudal aspects of the vestibular nuclei. Dam- age to the restiform body, which carries olivocerebellar projections, may also account for some of the ocular motor findings, especially the steady-state deviation of the eyes toward the side of the lesion and the ipsipulsion of saccades (47–49,58,59). Ipsipulsion of saccades, with deviation of the eyes to the side of the lesion, can be reproduced experimen- Figure 19.4. Neuroimaging of Wallenberg’s syndrome. T2-weighted magnetic resonance image, axial view, in a 51-year-old man with Wallen- tally by lesions of the fastigial nucleus (60). This finding berg’s syndrome characterized in part by lateropulsion of saccades toward supports the hypothesis that in Wallenberg’s syndrome, the the right side, a skew deviation with the right eye being hypotropic, and interruption of climbing fiber input to the dorsal cerebellar the ocular tilt reaction, shows a hyperintense area (arrowhead) consistent vermis releases Purkinje cell inhibition upon the underlying with an infarct on the right side of the medulla. fastigial nucleus, thus leading to the equivalent of a lesion in the fastigial nucleus (58). An analogous increase in Pur- kinje cell inhibition from the flocculus to the vestibular nu- cades directed away from the side of the lesion are smaller cleus may also play a role in the nystagmus (slow phase than those toward the lesion. On attempting a purely vertical toward the side of the lesion) seen in these patients. refixation, an oblique saccade directed toward the side of the lesion is produced. Corrective saccades then bring the SYNDROME OF THE ANTERIOR INFERIOR eyes back to the target (50). Saccades made in total darkness CEREBELLAR ARTERY also show lateropulsion, although in one report the patient The anterior inferior cerebellar artery (AICA) supplies was still able to make corrective saccades to the remembered portions of the vestibular nuclei and the adjacent dorsolateral location of a previously seen target (51). This finding im- brain stem, and the inferior lateral cerebellum. The AICA plied that the central nervous system ‘‘knew’’ actual eye is also the origin of the labyrinthine artery in most persons position. With time, vertical saccades may become more and also sends a twig to the cerebellar flocculus in the cerebe- bizarre; S-shaped saccadic trajectories can appear a week or llopontine angle. Consequently, ischemia in the distribution more after the onset of the illness and may reflect an adaptive of the AICA may cause vertigo, vomiting, hearing loss, fa- strategy to correct the saccadic abnormality. Torsipulsion, cial palsy, and ipsilateral limb ataxia, along with deficits in inappropriate torsional saccades during attempted horizontal gaze-holding and pursuit as well as vestibular nystagmus or vertical saccades, also may occur, sometimes in associa- (61–63) (Fig. 19.6). The ocular motor signs reflect a combi- tion with torsional nystagmus (52,53). nation of involvement of the labyrinth, vestibular nuclei, and Spontaneous nystagmus in Wallenberg’s syndrome, when flocculus (discussed later) . present, is usually horizontal or mixed horizontal and torsional with a small vertical component (52). In primary posi- SKEW DEVIATIONANDTHE OCULAR TILT tion, the slow phase is directed toward the side of the lesion, REACTION although it may reverse direction in eccentric positions, suggesting that the gaze-holding mechanism is also impaired. Skew deviation is a vertical misalignment of the visual Lid nystagmus (synkinetic lid twitches with horizontal quick axes caused by a disturbance of prenuclear vestibular inputs SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 911

Figure 19.5. Lateropulsion of saccades in a patient with a left Wallenberg’s syndrome. A, On attempted leftward gaze, the patient overshoots the target and must make a corrective saccade. B, On attempted rightward gaze, the patient makes a series of hypometric saccades. C and D, On attempted upward and downward gaze, the eyes move obliquely to the left and must make several refixation movements back to center. (Redrawn from Kommerell G, Hoyt WF. Lateropulsion of saccadic eye movements: electro-oculographic studies in a patient with Wallenberg’s syndrome. Arch Neurol 1973;28Ϻ313–318.) to the oculomotor nuclei. Torsional and horizontal devia- In many patients, skew deviation is associated with ocular tions may be associated findings. The hypertropia may be torsion and head tilt, the pathologic ocular tilt reaction the same (comitant) in all positions of gaze, or it may vary (OTR), which may be tonic (sustained) (56) or paroxysmal and even alternate (typically with an alternating abducting (70,71). Such patients also show a deviation of the subjective hypertropia—i.e., right hypertropia on right gaze, left hyper- vertical (72,73). The ocular torsion may be dissociated, pro- tropia on left gaze) (64–67). When skew deviation is incomi- ducing a cyclodeviation (74). The OTR is usually attributed tant, it may mimic an isolated superior (68) or inferior (69) to an imbalance in otolith-ocular and otolith-collic reflexes oblique palsy by the Bielschowsky three-step test. In such that are part of a phylogenetically old righting response to cases, however, it appears that the addition of a fourth step, a lateral tilt of the head (75). In patients with more rostral assessment of ocular torsion in both eyes, may be able to lesions, interruption of descending pathways involved with distinguish skew deviation from isolated oblique weakness: controlling head posture may also contribute to the head tilt with skew mimicking superior oblique palsy, the hypertropic of the OTR (75,76). eye is incyclotorted (rather than excyclotorted, as one would Skew deviation occurs with a variety of abnormalities in expect if the hypertropia were the result of superior oblique the vestibular periphery, brain stem, or cerebellum weakness) (68). By analogy, when skew mimics inferior (66,77–83) and with raised intracranial pressure from supra- oblique palsy, the hypotropic eye is excyclotorted (rather tentorial tumors or pseudotumor cerebri (84,85). In infants, than incyclotorted, as one would expect if the hypotropia a skew deviation may be the harbinger of a subsequent hori- were the result of inferior oblique weakness) (69). It remains zontal strabismus (86). to be seen, however, whether the addition of this fourth step Why does skew deviation occur with lesions at so many will reliably distinguish between superior oblique palsy and sites within the posterior fossa? An imbalance in otolith path- all forms of skew deviation, or whether some cases will ways is the most likely cause (77). An imbalance of posterior simply be indistinguishable at the bedside. semicircular canal inputs may also play a role (56,87), al- 912 CLINICAL NEURO-OPHTHALMOLOGY

Figure 19.6. Neuroimaging of infarct in territory of the left anterior inferior cerebellar artery (AICA). A, T2-weighted axial magnetic resonance (MR) scan shows hyperintense area in the region of the left middle cerebellar peduncle (arrowhead). B, T1-weighted axial MR scan after intravenous injection of paramagnetic contrast material shows diffuse enhancement in the distal distribution of the AICA involving the left cerebellar hemisphere. The 69-year-old patient had, among other manifestations, left-beating gaze-evoked nystagmus.

though if that is the case nystagmus should also be present compensatory response to the perceived tilt of the subjective (88). visual vertical, although it may also reflect direct involve- To understand skew deviation, it is helpful to consider ment of descending projections from the vestibular nuclei physiologic aspects of otolith-ocular reflexes (75). In lateral- or the INC to cervical motoneurons (76). eyed animals, tilting the head laterally around the longitudi- Lesions of the vestibular organ or its nerve can cause both nal (anterior-posterior) axis causes a disjunctive, vertical skew deviation and the OTR by producing an imbalance in (skew) deviation (i.e., one eye goes up, the other down) that utricle inputs (80,93). The ocular tilt reaction may also occur acts to hold the visual axis of each eye close to the horizontal. as a component of Tullio phenomenon, which is character- In human subjects, who are frontal-eyed, a static head tilt ized by sound-induced vestibular symptoms (94–96). It oc- (ear to shoulder) causes sustained, largely conjugate counter- curs in patients with perilymph fistula either at the oval or rolling of the eyes (ocular torsion) that is about 10% of the round window, with other abnormal communications be- head roll (89–91), although the actual amount may be related tween the membranous labyrinth and the perilymph space, to various factors, including the angle of vergence. Thus, or with abnormalities of the ossicular chain and its connec- the static ocular response does not compensate for the head tion with the membranous labyrinth. Dehiscence of the roof tilt and is thought to be vestigial. There may also be a small of the superior semicircular canal is another recently identi- amount of skewing in normal subjects during rotation of the fied cause (96–98). The OTR is consistent with the effects head around its roll (anterior-posterior) axis (92). In contrast, of experimental stimulation of the otoliths (100) and the peripheral or central lesions that disrupt otolith inputs often utricular nerve (101), which cause ipsilateral hypertropia and cause large amounts of skew deviation (e.g., 7Њ) and ocular conjugate ocular counter-rolling (i.e., top pole of the eyes torsion (e.g., 25Њ). Usually, any pathologic head tilt (ear to toward the contralateral ear). shoulder) is contralateral to the hypertropic eye, and the ocu- The utricle projects predominantly to the ipsilateral lateral lar torsion is such that the upper poles of the eyes rotate vestibular nucleus, whereas the saccule projects to the y- toward the lower ear. The contralateral head tilt may be a group of vestibular nuclei (101,102). Thus, lesions of the SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 913 vestibular nuclei (e.g., as part of Wallenberg’s lateral medul- the mesencephalon, in or around the INC, thus may cause lary syndrome) may also cause skew deviation with hypo- skew deviation (78,108,109) and the OTR (56,110). When tropia on the side of the lesion (55). In addition, some pa- the head tilt is sustained (tonic), it is contralateral to the side tients show an ipsilateral head tilt and disconjugate ocular of the lesion; in addition, there is usually a hypertropia that torsion. The latter is an excylotropia, with excyclodeviation is ipsilateral to the lesion and a conjugate cyclotorsion that of the ipsilateral, lower eye, but small or absent incyclodevi- is characterized by intorsion of the ipsilateral eye and extor- ation of the contralateral, higher eye (52,103). sion of the contralateral eye (i.e., ocular counter-rolling away Skew deviation is encountered in patients with cerebellar from the side of the mesencephalic lesion). Defects of verti- lesions (66,67,104–106). Some of these patients show an cal eye movements and oculomotor or trochlear nerve func- alternating skew deviation that is characterized by a hyperde- tion are also common in this setting. Combined prenuclear viation of the abducting eye. This abnormality also may be and fascicular or nuclear lesions in the midbrain may create analogous to a phylogenetically old, otolith-mediated, right- torsion of one eye and the OTR (111,112). ing reflex present in lateral-eyed animals, which in this case In patients with meso-diencephalic lesions, spontaneous is related to the ocular motor response that compensates for ocular oscillations may also be present that suggest involve- fore-and-aft motion (as opposed to lateral roll) of the head. ment of otolith inputs to the oculomotor system, such as Although the brain stem is likely also involved in some of seesaw nystagmus (113) or, more rarely, slowly alternating these patients, skew deviation can occur in some patients skew deviation (114–116). In the latter case, skew deviation who appear to have pure cerebellar disease. This suggests slowly alternates or varies cyclically in magnitude over the that just as the cerebellum governs the semicircular canal- course of a few minutes. The periodicity of the phenomenon ocular reflex, it also influences the otolith-ocular reflexes. (with each eye typically being hypertropic for about 30 sec- Indeed, downbeat nystagmus, which is sometimes attribut- onds to a minute) is reminiscent of periodic alternating nys- able to disease of the flocculus (discussed later), commonly tagmus, and the two phenomena can coexist (117). coexists with this pattern of skew deviation that alternates In some patients, the skew deviation (with or without a with lateral gaze. head tilt) is not sustained but paroxysmal (70,71). In one Utricular projections from the vestibular nuclei probably patient with a clearly defined lesion close to the right INC, cross the midline and ascend in the medial longitudinal fasciculus (MLF). Therefore, unilateral internuclear ophthal- episodes of contralateral hypertropia and ipsilateral head tilt moplegia (INO) is often associated with a skew deviation, occurred, suggesting an irritative mechanism (71). This in- presumably because lesions of one MLF cause an imbalance terpretation of the findings in paroxysmal skew deviation is of ascending otolith inputs. The INO is usually on the side supported by the results of electric stimulation near the INC of the hypertropic eye, likely reflecting that utricular projec- in the monkey. This produces an ocular tilt reaction that tions are generally damaged in the MLF after crossing at consists of depression and extorsion of the ipsilateral eye the level of the mid-pons (i.e., a right MLF lesion damages and elevation and intorsion of the contralateral eye (118). utricular inputs from the left ear, leading to a right hyper- With the head free to move, an ipsilateral head tilt also occurs tropia similar conceptually to that seen with a left lateral (119). In human patients, stimulation in the region of the INC medullary syndrome or right rostral midbrain syndrome) causes an ipsilateral OTR (120). Microvascular compression (107). may also cause a paroxysmal skew deviation with torsional In the midbrain, otolith projections contact the oculomotor nystagmus (121). Skew deviation has also been reported as and trochlear nerve nuclei as well as the INC. Lesions in an epileptic phenomenon (122).

OCULAR MOTOR SYNDROMES CAUSED BY LESIONS IN THE CEREBELLUM Clinicians are appropriately cautious in attributing eye features of each of these syndromes are summarized in Table movement abnormalities specifically to cerebellar dysfunc- 19.1. tion, because the brain stem is so frequently damaged in patients with lesions of the cerebellum. Likewise, brain stem LOCATION OF LESIONS AND THEIR lesions can produce a ‘‘functional’’ cerebellar lesion and MANIFESTATIONS corresponding cerebellar eye signs by virtue of a change in the climbing fiber activity projecting to cerebellar Purkinje Experimental lesions of the dorsal vermis (lobules VI and cells, as occurs in Wallenberg’s syndrome (discussed previ- VII) and of the underlying fastigial nuclei (called the fastigial ously). Holmes (123) and Cogan (77), however, recognized oculomotor region) cause saccadic dysmetria, typically hy- specific cerebellar eye signs, and Daroff (124) listed more pometria if the vermis alone is involved and hypermetria if than 30 ‘‘cerebellar eye signs’’ in a compendium published the deep nuclei are affected (127). Pursuit, especially the in 1982. Recent clinical and experimental studies provide initial acceleration of the eyes during tracking, is also af- additional evidence that cerebellar lesions alone can cause fected by dorsal vermis lesions (128). Lesions of the deep specific ocular motor abnormalities (104,125,126). In es- nuclei can lead to macrosaccadic oscillations, an extreme sence, three principal syndromes can be identified: the syn- degree of hypermetria. Lesions restricted to the dorsal ver- drome of the dorsal vermis and underlying posterior fastigial mis produce not only saccadic dysmetria but also impaired nuclei, the syndrome of the flocculus and paraflocculus, and initiation of pursuit with a decrease in the acceleration of the syndrome of the nodulus and ventral uvula. The main the eyes during tracking, and disturbances of eye alignment 914 CLINICAL NEURO-OPHTHALMOLOGY

Table 19.1 Localization of Cerebellar Eye Movement Abnormalities

Structure Function Disorder

Flocculus and paraflocculus Retinal-image stabilization (smooth tracking Impaired smooth pursuit, VOR cancellation and fixation with head still or free suppression of suppression of caloric nystagmus; gaze-evoked, inappropriate vestibular nystagmus, holding rebound, centripetal and downbeat nystagmus; positions of gaze, adaptive control of the VOR postsaccadic drift; inappropriate amplitude or direction and pulse-step match) of the VOR Nodulus and ventral uvula Control of low-frequency response of the VOR Periodic alternating nystagmus, impaired tilt suppression of postrotatory nystagmus, positional nystagmus, impaired habituation of the VOR, increased duration of vestibular responses. Dorsal vermis and posterior fastigial Saccade accuracy, smooth-pursuit eye alignment Saccadic dysmetria, impaired pursuit, esodeviations nucleus

VOR, vestibulo-ocular reflex. (Zee DS, Walker MF. Cerebellar control of eye movements. In: Chalupa LM, Werner JS, eds. The Visual Neurosciences. Cambridge, MA: MIT Press, 2003:1485Ð1498.) including the development of an esodeviation. The pattern phases of nystagmus during sustained rotations, a failure of saccadic dysmetria that occurs in cerebellar disease, as of tilt suppression of postrotatory nystagmus (145), loss of well as whether corrective saccades occur, may also vary habituation (146) and positional nystagmus (147). with the type of visual stimulus. Saccades to remembered Syndromes of the dorsal vermis and fastigial nucleus, targets are more dysmetric (129–131). In some cerebellar flocculus and paraflocculus, and nodulus are frequently en- patients, only corrective saccades are dysmetric (132). Sac- countered in patients with degenerative disorders that pre- cadic dysmetria may be present for externally triggered sumably affect only the cerebellum. In some instances, movements to a visual target but not for internally triggered pathologic examination confirms disease restricted to the saccades during scanning of a visual scene (133). Deficits cerebellum (148). Similar findings occur in patients with of pursuit may also be produced by lesions of the dorsal focal structural lesions of the cerebellum. vermis (130), as can defects in motion perception (134). FitzGibbon et al. (149) attributed another ocular motor Bilateral symmetric lesions of the deep nuclei do not lead to sign to a focal cerebellar lesion. Patients with cavernous pursuit deficits during sustained tracking, although unilateral angiomas in the middle cerebellar peduncle show torsional lesions lead to a contralateral deficit (135,136), probably nystagmus during vertical pursuit. The direction of the tor- because of an imbalance in eye acceleration signals. sional nystagmus changes with the direction of the pursuit, Experimental lesions of the flocculus and paraflocculus with the eye velocity of the slow phase of the torsional nys- cause gaze-evoked nystagmus, rebound nystagmus, and tagmus being directly proportional to the eye velocity of the downbeat nystagmus. Such lesions also cause impaired slow phase of pursuit. This finding probably relates to the smooth tracking (either with head still [smooth pursuit] or fact that smooth pursuit is organized in, and superimposed with head moving), postsaccadic drift, and loss of some on, a phylogenetically old vertical ‘‘labyrinthine-optoki- adaptive capabilities, such as the ability to adjust the ampli- netic’’ coordinate system. Thus, for a pure vertical pursuit tude and direction of the VOR or the pulse-step (phasic- movement to occur, opposite torsional components must tonic) match for saccades. Unilateral lesions produce ipsi- cancel (as is the case for pure vertical vestibular nystagmus). lateral deficits in pursuit and gaze-holding (47,137,140). In The middle cerebellar peduncle probably carries information patients with cerebellar disease, pursuit defects with the head to and from the cerebellum (perhaps between the flocculus still, defects in combined eye and head tracking, and gaze- and the nucleus reticularis tegmenti pontis in the pons) and holding deficits frequently occur together, reflecting their contains vertical pursuit signals encoded with a torsional common substrate in the flocculus and vestibular nuclei component (150). (139). Quantitatively, however, pursuit with the head still is Other signs that occur in patients with lesions restricted sometimes relatively more impaired (140,141). Patients with to the cerebellum cannot always be attributed to dysfunction cerebellar disease may show timing errors during tracking of a particular part of the cerebellum. They include square- of periodic targets (141), but there is some preservation of wave jerks (151,152), alternating skew deviation (67,104), predictive capability (142). The ability to generate anticipa- cross-coupled VOR responses (inappropriately directed slow tory smooth eye movements of high speed at the onset of phases) (147,153,154), disconjugate (poorly yoked) sac- tracking is also impaired in some cerebellar patients (143). cades with disconjugate gaze-evoked nystagmus (104,126) Experimental lesions of the nodulus lead to an increase and divergent nystagmus (155), centripetal nystagmus (156), in the duration of vestibular responses that predisposes the primary position upbeating nystagmus (157), positional nys- animal to the development of periodic alternating nystagmus tagmus (158), increased responsiveness of the cervico-ocular (144). Other abnormalities of the ‘‘velocity-storage mecha- reflex (159), and impaired responses to linear translation (L- nism’’ also are present, including abnormally directed slow VOR) (154,160,161). SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 915

The cerebellum is also important in long-term adaptive Table 19.2 functions that keep eye movements appropriate to the visual Eye Signs in the Arnold-Chiari Malformation stimulus (162). Experimentally, it has been shown that control of VOR amplitude and direction, saccade amplitude, Downbeat nystagmus (occasionally with a torsional component), worse on pursuit initiation, and phoria adaptation are all under cerebel- lateral gaze Sidebeat nystagmus (primary position, unidirectional, horizontal nystagmus) lar control. For example, adaptation of the gain of the VOR Periodic alternating nystagmus is impaired in patients with cerebellar lesions (163). This Divergent nystagmus adaptive or ‘‘repair shop’’ function of the cerebellum proba- Esotropia bly accounts for both the enduring nature of the ocular motor Gaze-evoked nystagmus deficits that accompany diffuse cerebellar lesions and, per- Rebound nystagmus including torsional rebound haps, the somewhat variable effects of cerebellar lesions. Impaired pursuit (and VOR cancellation) Thus, inherent, idiosyncratic abnormalities in brain stem or Impaired OKN with slow build-up of eye velocity in response to a constant peripheral ocular motor mechanisms that are normally ‘‘re- velocity stimulus paired’’ by the cerebellum may reappear after cerebellar le- Convergence nystagmus sions. For example, some patients with cerebellar disease Divergence paralysis Skew deviation accentuated or alternating on lateral gaze may not be able to adapt to a phoria induced by wearing Saccadic dysmetria prisms (164,165), and the same is true for monkeys with Internuclear ophthalmoplegia cerebellar vermis lesions (126). Children with cerebellar le- Increased VOR gain sions often make better recoveries than adults (166). If cere- Shortened VOR time constant bellar ablation is performed in neonatal monkeys, almost- Positional nystagmus complete recovery occurs, provided the deep cerebellar nuclei are left intact; if they are not, gaze-holding and smooth OKN, optokinetic nystagmus; VOR, vestibulo-ocular reflex. pursuit never fully recover (167).

ETIOLOGIES with other lesions located at the craniocervical junction (172). The positional nystagmus of posterior fossa lesions There are many conditions that produce cerebellar eye (173–175) must be differentiated from the more common signs. These include developmental anomalies, degenerative benign paroxysmal positional nystagmus of the labyrinth diseases, vascular diseases, and tumors. (147,158,176–181). The Dandy-Walker syndrome consists of a malformation Developmental Anomalies of the Hindbrain of the cerebellar vermis, a membranous cyst of the fourth The Arnold-Chiari malformation is an abnormality of the hindbrain involving the caudal cerebellum (including the vestibulocerebellum, flocculus, paraflocculus [tonsils], uvula, and nodulus) and the caudal medulla (168,169). In the type I malformation, the cerebellar tonsils are displaced caudally into the foramen magnum and the medulla is elon- gated. A meningomyelocele usually is not present. Such patients often develop symptoms in adult life. In the type II malformation, both the fourth ventricle and the inferior vermis extend below the foramen magnum; the brain stem and spinal cord are thin; and a lumbar meningomyelocele is usually present. Patients with type II malformation usually present in childhood, but in milder cases, the onset of symptoms is delayed until adulthood. Presenting symptoms of the Ar- nold-Chiari malformation include oscillopsia that is brought on or exacerbated by head movements, and dizziness, vertigo, cervical pain, and headaches, all of which can be brought on by Valsalva maneuvers. A variety of ocular motor abnormalities, and especially downbeat nystagmus (both spontaneous and positional), occur in patients with the Arnold-Chiari malformation (Table 19.2). Many of these signs are reproducible by vestibulocerebellar lesions in monkeys (170). Diagnosis is by MR imaging, with sagittal views of the craniocervical junction (Fig. 19.7). Patients often im- Figure 19.7. Neuroimaging of an Arnold-Chiari malformation. T1- prove after suboccipital decompression, although it may take weighted sagittal magnetic resonance image shows herniation of cerebellar months for the eye movement abnormalities to diminish tonsils below the foramen magnum (arrowhead). Note flattening of the (171). A similar ocular motor syndrome can occur in patients brain stem in this region. 916 CLINICAL NEURO-OPHTHALMOLOGY ventricle, and malformations of the cerebellar cortex and cerebellar eye signs, including downbeat nystagmus, and deep cerebellar nuclei. Patients with this condition often many are mapped to the same area of chromosome 19 in show a mild saccadic dysmetria, although some patients which hemiplegic migraine and SCA6 are mapped have normal eye movements (182). Ocular motor abnormali- (200–202). Such syndromes may be associated with mi- ties, including nystagmus and strabismus, also occur in pa- graine, essential tremor, or myokymia; many are channel- tients with agenesis of the vermis (183) or hypoplasia of the opathies (203,204). entire cerebellum (184). Other rare syndromes associated with anomalous cerebellar development include Coffin-Siris Vascular Diseases syndrome (developmental delay, hypotonia, cutaneous The cerebellum is supplied by three branches of the verte- changes, and abnormalities of the roof of the fourth ventri- brobasilar circulation: the posterior inferior cerebellar artery cle) (185) and Joubert’s syndrome (a variable combination (PICA), the AICA, and the superior cerebellar artery (SCA). of episodic tachypnea, psychomotor retardation, retinal dys- Occlusion of one or more of these vessels often produces trophy, torsional nystagmus, skew deviation, ocular motor brain stem infarction too, making precise clinicopathologic apraxia, agenesis of the cerebellar vermis, and fibrosis of correlation difficult. Infarction in the distribution of the dis- the extraocular muscles) (186–188). tal PICA may cause acute vertigo and nystagmus that often simulates an acute peripheral vestibular lesion (205). These Degenerative Diseases symptoms probably reflect a central imbalance in horizontal VOR pathways created by asymmetric infarction of the ves- Many degenerative processes can affect the cerebellum tibulocerebellum. The vestibulocerebellum also influences or its connections and produce cerebellar eye signs. The the gaze-holding networks within the vestibular nuclei, and hereditary ataxias show considerable variability in pheno- patients with lesions in the vestibulocerebellum may have typic expression. As a result, there have been difficulties prominent gaze-evoked nystagmus that helps differentiate with classification, a problem that is being partially resolved this cerebellar lesion from an acute peripheral vestibu- with the discovery of genetic markers and the realization lopathy. that phenotype is influenced by both primary and modifier genes (189–195). Moreover, many of these conditions also affect brain stem structures. Thus, other, presumably nonce- rebellar, ocular motor signs may be present (e.g., slow saccades, prolonged saccadic latencies, decreased or absent vestibulo-ocular responses, and ophthalmoplegia). It remains to be proved whether eye movement abnormalities can be used to reliably detect extracerebellar involvement or early signs of disease in persons at risk for developing hereditary ataxias In general, patients with Friedreich’s ataxia show a decrease of vestibulo-ocular responses and prominent square-wave jerks. Slow saccades point to brain stem involvement, as occurs with SCA2. In one form of a recessively inherited cerebellar degeneration with peripheral neuropathy and prominent square-wave jerks (saccadic intrusions) and saccadic dysmetria, the speed of large saccades was actually too fast (196). In general, the gross amount of atrophy of different parts of the cerebellum as shown by MR imaging does not correlate well with the severity of ocular motor dysfunction (197), although more sensitive imaging analysis techniques of individual lobules will likely reveal better clinical-anatomic correlations. Paraneoplastic cerebellar degeneration is a rare remote effect of cancer, usually occurring with breast, ovarian, or small-cell lung cancer (198,199). The onset of symptoms is usually acute or subacute, with severe midline and appendic- ular ataxia, dysarthria, and downbeat nystagmus. Autopsies show a total loss of Purkinje cells. Such patients have lost the output from the cerebellar cortex, and the common finding of primary position downbeat nystagmus is compatible with Figure 19.8. Neuroimaging of infarct in the territory of the superior cere- the hypothesis that a preponderance of inhibitory projections bellar artery (SCA) in a 69-year-old man with hypertension. Computed of the cerebellum to the central connections of the superior tomographic scan shows a large hypodense area in the left cerebellar hemi- semicircular canals can cause this nystagmus. sphere corresponding to the distribution of the left SCA. The patient had The episodic vertigo and ataxia syndromes, often respon- a left horizontal gaze palsy from compression of the left side of the brain sive to acetazolamide, may be associated with prominent stem. SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 917

Infarction in the territory of the AICA, the branches of compression is upward or directly forward, respectively. The which often supply the flocculus, may cause vertigo, vomit- oculomotor, trochlear, and abducens nerves may also be af- ing, hearing loss, facial palsy, and ipsilateral limb ataxia, fected. Ocular motor dysfunction may also be caused by along with gaze-holding and pursuit deficits as well as ves- secondary obstructive hydrocephalus and increased intracra- tibular nystagmus (61–63,206) (Fig. 19.6). The ocular motor nial pressure. signs reflect a combination of involvement of the labyrinth, Medulloblastomas arising in the posterior medullary vestibular nuclei, and flocculus. velum frequently produce or are associated with positional Infarction in the territory of the SCA causes ataxia, limb nystagmus. Involvement of the nodulus and uvula is presum- dysmetria, and vertigo (206,207) (Fig. 19.8). A characteristic ably responsible for this finding (213) and may also account abnormality is saccadic contrapulsion. Contralateral sac- for the inability to suppress postrotational nystagmus by tilt- cades overshoot and ipsilateral saccades undershoot the tar- ing the head (145,146). Tumors within the fourth ventricle get. Attempted vertical saccades are oblique, with a horizon- may affect the cerebellar nuclei, vestibulocerebellum, and tal component away from the side of the lesion (208–210). dorsal medulla. Upbeating nystagmus may occur in such Thus, this saccadic disorder is the opposite of the saccadic cases. ipsipulsion seen in Wallenberg’s syndrome (discussed previ- Vestibular schwannomas may compress the cerebellar ously) and probably reflects interruption of outputs from the flocculus (which lies in the cerebellopontine angle) and pro- fastigial nucleus running in the uncinate fasciculus next to duce eye signs of vestibulocerebellar lesions (214), including the superior cerebellar peduncle (121,211). Infarction re- Brun’s nystagmus, in which there is a coarse nystagmus stricted to the posterior-inferior vermis can selectively im- beating to the side of the lesion (reflecting a gaze-holding pair pursuit and optokinetic eye movements (212). deficit) and a fine nystagmus beating away from the side of the lesion (reflecting a vestibular imbalance). Head-shaking Mass Lesions nystagmus may be present (215). MR imaging after intrave- Cerebellar hemorrhage, tumors, infarcts, abscesses, cysts, nous injection of contrast is the most sensitive and specific and extra-axial hematomas may all cause cerebellar eye method used to detect small lesions in this region. Acute signs by direct damage to the cerebellar parenchyma. Cere- cerebellar hemorrhage frequently causes nystagmus, gaze bellar lesions, however, may also compress the brain stem palsy (usually toward the side of the lesion), abducens nerve and produce additional signs. Vertical or horizontal gaze palsy, and skew deviation (216–218). These signs are, in disorders can occur, depending on whether the direction of part, caused by compression of the brain stem.

OCULAR MOTOR SYNDROMES CAUSED BY LESIONS OF THE PONS LESIONS OF THE INTERNUCLEAR SYSTEM: speed (determined by the high-frequency ‘‘pulse’’ of inner- INTERNUCLEAR OPHTHALMOPLEGIA vation) is diminished out of proportion to the limitation in range of adduction (determined by the low-frequency Among the fibers that make up the MLF, many carry a ‘‘step’’ of innervation). An adduction lag is brought out clin- conjugate horizontal eye movement command from abdu- ically by asking the patient to make large-amplitude (which cens internuclear neurons in the pons to the medial rectus subdivision of the contralateral oculomotor nuclear complex in the midbrain. Other fibers in the MLF carry signals for holding vertical eye position, for vertical smooth pursuit, and for the vertical VOR.

Manifestations Lesions of the MLF produce INO (219,220) (Fig. 19.9). When the lesion is unilateral, the INO is characterized by weakness of adduction ipsilateral to the side of the lesion (Fig. 19.10). This weakness may vary from a complete loss of adduction beyond the midline to a mild decrease in the velocity or acceleration of adduction without any limitation in range of motion (Fig. 19.11). The fibers subserving horizontal gaze in the MLF each carry commands for all types of conjugate eye movements. Hence, vestibular slow phases, pursuit and optokinetic following, and saccades and quick phases of nystagmus are all affected by the MLF lesion. The weakness of adduction, however, may be more obvious for Figure 19.9. Neuroimaging in a patient with a left internuclear ophthal- saccades because damaged axons, especially those that are moplegia. T2-weighted magnetic resonance image, axial view, shows a tiny demyelinated, show a greater defect for carrying high- rather area of hyperintensity consistent with an infarct in the region corresponding than low-frequency impulses. This dissociation is reflected to the location of the left medial longitudinal fasciculus (arrowhead). The in a ‘‘pulse-step mismatch’’ that occurs because saccade patient also had a skew deviation. 918 CLINICAL NEURO-OPHTHALMOLOGY

Figure 19.10. Unilateral, right internuclear ophthalmoplegia in a 32-year-old man with multiple sclerosis. Note complete lack of adduction in the right eye on attempted left horizontal gaze. require the highest speeds) horizontal saccades back and parity that occurs when a unilateral INO is associated with forth across the midline or by using an ‘‘optokinetic’’ tape a skew deviation also may interfere with convergence effort. or drum with repetitive symbols to produce nystagmus that In some patients with an INO, abducting saccades in the allows easy comparison of the movements of the two eyes affected eye may also be slow or ‘‘fractionated’’ (226,227). (221). Quantitative recordings of eye movements in patients This phenomenon may reflect impaired inhibition of the af- with MS show that the most sensitive sign of adduction fected medial rectus, although Kommerell (228) was unable weakness in INO is a decreased ratio either of peak eye to find any evidence of impaired medial rectus inhibition in velocity (222) or of peak acceleration (223) of the adducting one patient with a unilateral INO in whom he performed saccades of the eye on the side of the lesion to the abducting electromyography. Slowing of abducting saccades tends to saccades of the other eye (224). be more prominent in bilateral INO, probably because of When patients with INO are able to converge, despite damage to extra-MLF pathways running through the pontine absence of voluntary adduction, the lesion is located cau- tegmentum (229,230). dally with preservation of the medial rectus subdivision of The second cardinal sign of an INO is nystagmus in the the oculomotor nuclear complex (225). Patients with INO contralateral eye when it is abducted. This nystagmus con- and intact convergence were said to have a posterior INO sists of a centripetal (inward) drift, followed by a corrective by Cogan (77). Although the presence of intact convergence saccade that may be hypermetric, hypometric, or orthomet- is important in such cases, the absence of convergence in ric. It is present in nearly all patients with INO (231). A the setting of an INO (the ‘‘anterior’’ INO of Cogan) does number of mechanisms could account for the abduction nys- not necessarily imply a rostral lesion involving the medial tagmus of INO (220) and may not be mutually exclusive. rectus nuclear subdivision. Some patients simply are not able They include (a) an increase in convergence tone; (b) im- to produce a strong convergence effort, and the vertical dis- paired inhibition of the medial rectus contralateral to the

Figure 19.11. Ocular motor recording of a patient with a mild right internuclear ophthalmoplegia. On attempted left horizontal gaze, the velocity of the adducting right eye is less than the velocity of the abducting left eye, which overshoots the target and shows mild abducting nystagmus. SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 919 lesion (232); (c) interruption of descending internuclear fibers that project to the abducens nucleus (233); (d) a superimposed gaze-evoked nystagmus; and (e) adaptation to the contralateral medial rectus weakness (234–236). Because abduction nystagmus is not observed in acute experimental INO induced by injection of lidocaine into the MLF of monkeys (237), the cause of abduction nystagmus must relate either to lesions outside the MLF or to an adaptive response to the initial adduction weakness. Patching experiments in patients with INO show that in many cases the abducting nystagmus diminishes if the patient is required to habitually view with the nonparetic eye (235,236). In these patients, the abducting nystagmus relates, at least in part, to a conjugate (because of Hering’s law of equal innervation to the two eyes) adaptive change in innervation that acts to improve adduction of the paretic eye, but at the expense of a disturbance in abducting saccades of the contralateral eye. Abducting saccades overshoot the target and are followed by a centripetal drift (‘‘pulse-step mismatch’’), giving the appearance of an abducting nystagmus. Such nystagmus usually dies out after a beat or two, and the postsaccadic drift is brief. It would bring the eye to a stable eccentric position if it were not interrupted by corrective eccentric saccades. Figure 19.12. Skew deviation in a patient following an operation on the The other common mechanism for abduction nystagmus posterior fossa for a superiorly placed vermis tumor. The deviation persisted is a dissociated gaze-evoked nystagmus that appears more for 3 weeks. prominent in the abducting eye because the adducting eye is weak. In contrast to the abducting nystagmus produced by adaptation, such gaze-evoked abduction nystagmus is more sustained, and the postsaccadic drift would bring the eye to patients with bilateral INO cannot fix steadily. In such pa- the primary position if it were not interrupted by corrective tients, sporadic bursts of monocular abducting saccades may eccentric saccades. Interruption of the paramedian tracts that occur in each eye (243). run near the MLF and carry fibers to and from the flocculus Patients with bilateral INO have bilateral adduction weak- may be responsible for the gaze-evoked nystagmus that is ness and abducting nystagmus (Figs. 19.13 and 19.14). Such associated with INO (238). patients also have impaired vertical vestibular and pursuit Skew deviation commonly occurs with unilateral INO but eye movements and impaired vertical gaze-holding with rarely with bilateral INO. When skew deviation is associated gaze-evoked nystagmus on looking up or down (244–247). with INO, the higher eye is usually on the side of the lesion Many patients with an INO have no visual symptoms, (Fig. 19.12). It is usually easy to differentiate skew deviation particularly when there is no limitation of adduction (231). of an INO from trochlear nerve palsy because of the ad- In other cases, the presence of either limitation of adduction ducting weakness and abducting nystagmus, but at times or skew deviation may cause diplopia that is horizontal, ver- skew deviation and trochlear nerve palsy may be hard to tical, or oblique. Patients with INO occasionally complain separate (68). Skew deviation may reflect imbalance of oto- of oscillopsia (248). Horizontal oscillopsia usually occurs lith inputs that cross in the medulla and ascend in the MLF from either the adduction lag or the abduction nystagmus, (discussed previously). whereas vertical oscillopsia occurs during head movements Dissociated vertical nystagmus (downbeat in the ipsi- and is caused by a deficient vertical VOR (249). In many lateral eye, torsional in the contralateral eye) may occur with patients, visual symptoms become less bothersome or re- an INO (239). This pattern of dissociated nystagmus reflects solve completely, either because of recovery of function of the fact that posterior semicircular canal pathways mediating MLF axons or because of more central adaptive mecha- excitation pass through the MLF, but some anterior semicir- nisms. cular canal pathways do not (240). Experimental INO pro- Lesions that damage the MLF may also damage the abdu- duced by lidocaine blockade causes ipsilateral hypertropia cens nucleus, fascicle, or both on either side of the brain and unilateral downbeating nystagmus (237). Patients with stem. Lesions that damage the MLF on one side and the a unilateral INO may also have an ipsiversive torsional nys- ipsilateral abducens nucleus produce the one-and-a-half syn- tagmus (top poles of the eyes cyclorotate so as to beat toward drome (discussed later), whereas lesions that damage the the side of the lesion) (241,242). The torsional nystagmus ipsilateral abducens fascicle produce horizontal ophthal- is sometimes dissociated and is usually but not always asso- moplegia in the ipsilateral eye from the combination of an ciated with a skew deviation. It may relate to interruption of INO and an abducens nerve palsy. Lesions that damage the pathways between the vestibular nuclei and the INC. Some MLF on one side and the paramedian pontine reticular for- 920 CLINICAL NEURO-OPHTHALMOLOGY

Figure 19.13. Bilateral internuclear ophthalmoplegia in a young woman with multiple sclerosis. The pupils have been dilated with mydriatics.

mation (PPRF) or abducens nucleus on the opposite side Etiologies produce a horizontal gaze palsy toward the side of the damaged PPRF or abducens nucleus. In such cases, the INO Table 19.3 summarizes some causes of INO. In general, cannot be diagnosed because of the overriding horizontal a unilateral INO is most commonly caused by ischemia, gaze palsy. Damage to the MLF on one side and to the although there is often subtle involvement of the other side contralateral abducens nerve fascicle will produce abduction (Fig. 19.15). Bilateral INO is commonly caused by demyelination associated with MS, but even in MS, the INO may be weakness of the contralateral eye combined with adduction quite asymmetric (250) (Fig. 19.16). Although MR imaging weakness of the ipsilateral eye. In this setting, there will be frequently shows a lesion in the MLF in patients with INO a ‘‘pseudo-horizontal gaze palsy’’ on attempted horizontal (250a) (Fig. 19.9), there are many exceptions (251,252). gaze away from the side of the MLF lesion. The diagnosis Thin cuts and sagittal T2-weighted imaging are sometimes may be suspected in a patient who appears to have a horizon- required. tal gaze palsy that is asymmetric, with one eye (usually the adducting eye) being more limited than the other. Posterior INO of Lutz As with patients having conjugate gaze palsy from damage to the abducens nucleus, patients with the one-and-a- In 1923, Lutz (253) described a condition in which abduc- half syndrome often have an associated facial nerve paraly- tion (not adduction) was impaired with respect to saccades sis. This paralysis is ipsilateral to the horizontal gaze palsy and pursuit but not with respect to vestibular stimulation. and occurs from damage to the fascicle of the facial nerve As noted above, Cogan (77) described an INO as one in as it loops around the abducens nucleus (discussed later). which there was slowed or limited adduction of one eye,

Figure 19.14. Ocular motor recording showing the saccadic velocities of a patient with bilateral internuclear ophthalmoplegia. On attempted right horizontal gaze, the velocity of the adducting left eye is less than the velocity of the abducting right eye. The right eye overshoots the target and shows abducting nystagmus. On attempted left horizontal gaze, the velocity of the adducting right eye is less than the velocity of the abducting left eye. The left eye overshoots the target and shows abducting nystagmus. SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 921

Figure 19.15. Pathology of unilateral internuclear ophthalmoplegia. A, Section through the pons in a patient with a left internuclear ophthalmoplegia shows a small infarction in the region of the left medial longitudinal fasciculus (arrows). Sections are numbered from rostral to caudal. B, Area from the infarct indicated by the arrow in A and the surrounding region. The large arrowhead points to the infarct involving the left medial longitudinal fasciculus. The small arrowhead points to a small infarct just lateral to the right medial longitudinal fasciculus. C, Section through the rostral pons in a patient with a left internuclear ophthalmoplegia. There is a septic infarction involving the left medial longitudinal fasciculus (arrowheads). Many axons of the left medial longitudinal fasciculus have been destroyed, but the right medial longitudinal fasciculus is entirely normal. (A and B, From Cogan DG, Kubik CS, Smith JL. Internuclear ophthalmoplegia: a review of 58 cases. Arch Ophthalmol 1950;44Ϻ783–796. C, From Ross AT, DeMyer WE. Isolated syndrome of the medial longitudinal fasciculus in man. Arch Neurol 1966;15Ϻ203–205.)

associated with overshoot of the abducting eye. Because this to understand because the abducens nucleus contains neu- condition appeared to be the opposite of the INO that Lutz rons that innervate both lateral and medial rectus muscles for (253) had described, some authors began to refer to the eye all conjugate eye movements (219,257,258). Patients with movement abnormality observed by Lutz as the ‘‘posterior abducens palsy thus may show nystagmus in the contralat- INO of Lutz’’ and the eye movement abnormality observed eral adducting eye, if the weak abducting eye is used prefer- by Cogan (77) as the ‘‘anterior INO of Cogan.’’ This resulted entially for fixation (256). This nystagmus could reflect the in confusing terminology because Cogan (77) had his own same type of mechanisms (an adaptive response or a disso- anterior and posterior types of INO that were based on ciated nystagmus) that accounts for the abducting nystagmus whether convergence was present. In any event, the INO that develops in patients with typical INO. described by Cogan (77) is quite common, whereas the pos- C¸ elebisoy and Akyu¨rekli (259) described a patient in terior INO of Lutz is rare (254–256). whom a posterior INO of Lutz was mimicked by a rostral The pathogenesis of the posterior INO of Lutz is difficult brain stem infarction that caused a horizontal gaze paresis 922 CLINICAL NEURO-OPHTHALMOLOGY

Table 19.3 to one side and a pseudo-abducens paresis on attempted gaze Etiology of Internuclear Ophthalmoplegia to the other side. The patient also had bilateral vertical gaze palsy and other evidence of midbrain dysfunction. The Multiple sclerosis (commonly bilateral [223]); postirradiation demyelination mechanisms of posterior INO using examples with more Brain stem infarction (commonly unilateral), including complication of rostral brain stem lesions have been discussed (227). In other arteriography and hemorrhage (250) Brain stem and fourth ventricular tumors cases an infranuclear cause has been suggested (260). Arnold-Chiari malformation, and associated hydrocephalus and syringobulbia Infection: bacterial, viral, and other forms of meningoencephalitis LESIONS OF THE ABDUCENS NUCLEUS Hydrocephalus, subdural hematoma, supratentorial arteriovenous mal- Lesions of the abducens nucleus cause an ipsilateral palsy formation of horizontal conjugate gaze because the abducens nucleus Nutritional disorders: Wernicke’s encephalopathy and pernicious anemia (864) contains two groups of neurons: abducens motoneurons that Metabolic disorders: hepatic encephalopathy innervate the ipsilateral lateral rectus muscle, and abducens Drug intoxication: phenothiazines, tricyclic antidepressants, narcotics, internuclear neurons that innervate the contralateral medial propranolol, lithium, barbiturates, D-penicillamine, toluene rectus motor neurons via the MLF. Vergence movements of Cancer: due to carcinomatous infiltration or remote effect the eyes are spared, however, so that adduction is possible Head trauma, and cervical hyperextension or manipulation with a near stimulus. Such a localized lesion can be produced Degenerative conditions: progressive supranuclear palsy experimentally (261), but it occurs rarely in humans Syphilis (262–264) except in Mo¨bius syndrome, a congenital brain Pseudo-internuclear ophthalmoplegia of myasthenia gravis and Fisher’s stem anomaly with horizontal gaze disturbances, often with syndrome an associated facial palsy (265). This condition occurs in at least some cases from aplasia or hypoplasia of both abducens nuclei. More often, however, the abducens nucleus is affected in association with adjacent tegmental structures, particularly the genu of the facial nerve, the MLF, and the PPRF (229,266). Lesions restricted to the abducens nucleus can often be distinguished from those in the adjacent caudal PPRF (see also below), because only in the latter may pursuit and vestibular movements be spared, and only in the former may ipsilateral saccades in the contralateral field be spared by virtue of intact inhibition upon the contralateral abducens nucleus. Gaze-evoked nystagmus on contralateral gaze also occurs in patients with presumed abducens nucleus lesions (263). Possible mechanisms for the gaze-evoked nystagmus include damage to adjacent vestibular or NPH pathways that are involved in neural integration for gaze-holding, or damage to the paramedian cells and tracts that lie in part in the rostral abducens nucleus and have reciprocal connections with the cerebellar flocculus, a structure also involved in gaze-holding (238).

LESIONS OF THE PARAMEDIAN PONTINE RETICULAR FORMATION(PPRF) The PPRF, which corresponds principally to medial portions of the nucleus reticularis pontis caudalis, contains burst neurons that are important in the generation of saccades, and the paramedian nucleus raphe interpositus contains pause neurons that inhibit burst neurons at all times except during saccades. Destructive lesions of the PPRF, such as infarction and hemorrhage, tend to affect all cell groups, along with fibers of passage that convey pursuit and vestibular signals to the Figure 19.16. Brain stem pathology in a patient with a bilateral in- ipsilateral abducens nucleus. Unilateral destructive lesions ternuclear ophthalmoplegia and severe cerebrovascular and cardiovascular cause an ipsilateral, conjugate, horizontal, gaze palsy disease. Section at pontomesencephalic junction shows paramedian necrosis with areas of coalescing cavitation in the regions normally occupied (233,267,268). With acute lesions, the eyes may be deviated by both medial longitudinal fasciculi. This lesion involves both sides contralaterally. Nystagmus occurs when gaze is directed into of the midline. (From Gonyea EF. Bilateral internuclear ophthalmoplegia: the intact contralateral field of movement with quick phases association with occlusive cerebrovascular disease. Arch Neurol 1974; directed away from the lesioned side; this is usually accentu- 31Ϻ168–173.) ated in darkness. Ipsilaterally directed saccades and quick SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 923 phases are small and slow and do not carry the eye past the tal eye movements, but, particularly with chronic lesions midline. The degree of slowing of saccades directed toward such as tumors, reflexive eye movements may be spared. the lesioned side, when made in the intact field of gaze, Bilateral pontine lesions may impair vertical eye move- probably depends on whether projections to inhibitory burst ments (284–286). Signals for vertical vestibular and smooth neurons, which project to the contralateral abducens nucleus, pursuit eye movements ascend in the MLF and other path- are damaged. Recall that excitatory saccadic inputs reach ways through the pons; consequently, vestibular and pursuit the abducens nucleus from the ipsilateral population of exci- eye movements can be impaired with pontine lesions. Ab- tatory burst cells in the PPRF, whereas inhibitory saccadic normal (usually slow) vertical saccades occur in patients inputs originate from contralateral inhibitory burst cells in with discrete, bilateral pontine lesions (278,287–289) and the medulla. If the lesion is restricted to the ipsilateral abdu- in monkeys with bilateral neurotoxic lesions of the PPRF cens nucleus, saccades from the opposite field of gaze to the (280,290). Pause cells project rostrally to vertical burst neu- midline may be relatively rapid, because inhibition of the rons located in the midbrain. Pontine lesions, therefore, may antagonist is intact. If the PPRF is extensively damaged, lead to desynchronization of vertical (and horizontal) burst particularly in its more caudal part, inhibition is also affected neuron discharge and consequently to slow vertical (and hor- so that saccades beginning from the field of gaze opposite izontal) saccades. Ocular flutter has been reported with a to the lesioned side and moving to the midline are extremely PPRF lesion (291). slow. Rapid eye movements directed to the side opposite the lesion appear normal. Vertical saccades may be slightly COMBINED UNILATERAL CONJUGATE GAZE slow, and an inappropriate horizontal component, directed PALSY AND INTERNUCLEAR OPHTHALMOPLEGIA away from the side of the lesion, may occur during attempted (ONE-AND-A-HALF SYNDROME) vertical saccades (269). Smooth-pursuit movements and slow phases of optoki- Combined lesions of the abducens nucleus or PPRF and netic nystagmus may be preserved in both directions within adjacent MLF on one side of the brain stem cause an ipsi- the intact field of movement of a patient with a lesion of the lateral horizontal gaze palsy and INO, so that the only pre- PPRF, but they usually cannot bring the eyes across the served horizontal eye movement is abduction of the contra- midline. Sometimes horizontal pursuit is asymmetrically im- lateral eye; hence the name one-and-a-half syndrome (Figs. paired, more so for contralateral target motion (270). This 19.17–19.19) (18,229,282,292,293). Such patients may is in contrast to the effects of more basal lesions in the pons show an exotropia when attempting to look straight ahead; that impair ipsilateral or bilateral pursuit (271–273). Be- the eye opposite the side of the lesion is deviated outward. cause of the confluence of pursuit pathways in the brain This misalignment of the eyes is thought to be caused by stem and its cerebellar connections, the direction of a pursuit the unopposed drives of the intact pontine gaze center to deficit with a brain stem lesion is not reliable for determining the spared abducens nucleus and is called paralytic pontine the side of the lesion (274). In some patients with PPRF exotropia lesions, vestibular stimuli drive the eyes past the midline. (294). Many patients, however, have an esotropia Presumably, in such individuals, either the ipsilateral abdu- or no deviation in primary position (as with many cases of cens nucleus or its direct vestibular input is intact, or the INO), though it may be always present when fixation is PPRF lesion is more rostral (269,275). With more restricted eliminated (295). The spared abduction saccades of the con- lesions, usually hemorrhages, both smooth pursuit and the tralateral eye are followed by centripetal drift, so that a nys- VOR may be preserved, whereas saccades are absent or slow tagmus similar to that of the abducting eye in INO is present. (276). Occasionally in such patients, vestibular stimuli can Occasionally, the ipsilateral horizontal vestibular responses drive only the contralateral adducting eye and not the ipsi- are preserved when voluntary gaze is abolished (275, lateral abducting eye into the ipsilateral field. This finding 282,293), suggesting that the pontine lesion is more rostral implies a lesion of one PPRF and the ipsilateral abducens in the PPRF or more discrete in the caudal PPRF (296), thus nerve but sparing the abducens nucleus (277). sparing the vestibular projections to the abducens nucleus. Bilateral lesions restricted to the PPRF are uncommon. Although attempts at conjugate movements elicit no adduc- Discrete infarction (278) or tumor (279) can cause a selective tion, vergence movements may be preserved. Ocular bob- loss of saccades, leaving smooth pursuit and the VOR rela- bing may accompany the one-and-a-half syndrome (297). tively preserved. Such a selective deficit implies loss or dys- The one-and-a-half syndrome may result from brain stem function of saccadic burst neurons but sparing of fibers of ischemia (298–302), MS (292), tumor (303,304), hemor- passage conveying smooth pursuit and the VOR. Experimen- rhage (305), trauma (306), and other miscellaneous causes, tal lesions of the PPRF in monkeys, using neurotoxins that including HIV infection with tuberculosis, (302). Bilateral spare fibers of passage, may cause a similar deficit (280). INO with associated abducens nerve palsy also may mimic Patients with horizontal gaze palsies may substitute conver- the one-and-a-half syndrome, as can myasthenia gravis gence for impaired conjugate adduction and then cross-fixate (299). A ‘‘one-and-a-half syndrome’’ has been described in to extend their range of view (281). Furthermore, during which only adduction in one eye was spared (307). The pa- the recovery phase from bilateral gaze palsies from vascular tient had mucormycosis that caused an abducens nerve palsy lesions, involuntary synkinetic divergence and convergence from cavernous sinus infiltration on one side and a contralat- movements may appear with horizontal or vertical gaze eral horizontal gaze palsy from simultaneous carotid artery (282,283). Bilateral pontine lesions may abolish all horizon- occlusion. 924 CLINICAL NEURO-OPHTHALMOLOGY

Figure 19.17. One-and-a-half syndrome in a 23-year-old man with multiple sclerosis. Arrows indicate direction of attempted gaze. All ocular motor signs cleared within 3 months after onset.

Figure 19.18. Location of lesions producing the one-and-a-half syndrome. A, The important structures involved in the produc- tion of horizontal gaze. MLF, medial longitudinal fasciculus; PPRF, paramedian pontine reticular formation. Neurons project from the PPRF to the abducens nucleus and neurons in the abducens nucleus are both motoneurons whose axons represent the abducens nerve and internuclear neurons whose axons ascend in the contralateral MLF. B, The areas that may be involved when a one-and-a-half syndrome is present. Involvement of either the abducens nucleus or the PPRF can cause the horizontal gaze palsy. Damage to the ipsilateral medial longitudinal fasciculus produces the internuclear ophthalmoplegia. (Modified from Sharpe JA, Rosenberg MA, Hoyt WF, et al. Paralytic pontine exotropia: a sign of acute unilateral pontine gaze palsy and internuclear ophthalmoplegia. Neurology 1974;24Ϻ1076–1081.) SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 925

Figure 19.19. Brain stem findings in a 48- year-old hypertensive man with a recent myo- cardial infarction who developed a complete right horizontal gaze palsy and a complete B right internuclear ophthalmoplegia (one-and- a-half syndrome). Sections through the pons demonstrate an extensive area of hemorrhage. The drawings on the right illustrate the relationship of the hemorrhage to the fourth ventricle, superior cerebellar peduncles, medial longitudinal fasciculi, medial tectospinal tracts, medial lemnisci, dentate nuclei (all outlined in heavy black lines), and the abducens nuclei (black). A, Rostral pons. B, Mid- pons. C, Caudal pons. (From Pierrot-Deseil- ligny C, Chain F, Serdaru M, et al. The ‘‘one- and-a-half’’ syndrome: electro-oculographic analyses of five cases with deductions about the physiological mechanisms of lateral gaze. C Brain 1981;104Ϻ665–699.)

SLOW SACCADES FROM PONTINE LESIONS tients is not established. Conversely, if the saccades are so slow that they cannot bring the eye to the moving target, Slow saccades are characteristic of many degenerative and metabolic diseases (Table 19.4). Horizontal saccades may then even if pursuit is intact, it may not appear so because be slowed in patients with spinocerebellar degenerations; the eye seems to lag the target. Vestibular stimulation elicits vertical saccades are often relatively less affected in such normal compensatory slow phases, but quick phases of nys- patients. In diseases that principally affect the midbrain, such tagmus are slow and show approximately the same abnormal as progressive supranuclear palsy, vertical saccades are the relationship between amplitude and peak velocity, as do vol- first to become slow. In some patients with slow saccades, untary saccades. Patients with SCA2 usually make saccades blinks of the eyelids may actually speed up the movements of normal amplitude despite their low velocity. Progressive (308). The explanation for this phenomenon is uncertain, supranuclear palsy, however, causes both slow and small but it probably reflects the effects of blinks upon pause and horizontal saccades (discussed later). Patients with slow sac- burst neurons rather than a momentary deprivation of vision. cades may use a variety of strategies of combining eye and Some patients with slow saccades can generate smooth-pur- head movements to move their gaze more quickly to the suit movements of up to about 20Њ/sec. It is difficult to distin- target. guish a considerably slowed saccade from pursuit, however, Slow horizontal saccades may be caused by disease of so that whether pursuit function is truly intact in such pa- saccadic burst cells in the PPRF. Autopsy examinations of 926 CLINICAL NEURO-OPHTHALMOLOGY

Table 19.4 the brains of patients with SCA2 with slow saccades demon- Etiology of Slow Saccades strate a marked loss of neurons from the nucleus reticularis pontis caudalis and the adjacent raphe nuclei (309). Alterna- Olivopontocerebellar atrophy and related spinocerebellar degenerations tively, slowing of saccades may reflect abnormal inputs to Huntington’s disease the paramedian reticular formation from the cerebral hemi- Progressive supranuclear palsy Parkinson’s (advanced cases) and related diseases; Lytico-Bodig and spheres, the superior colliculus, or the cerebellum. Lesions Caribbean Parkinson’s in the pause cell region also may produce slow saccades Whipple’s disease (290). Lipid storage diseases Wilson’s disease SACCADIC OSCILLATIONS FROM PONTINE Drug intoxication: anticonvulsants, benzodiazepines LESIONS Tetanus In dementia: Alzheimer’s disease (stimulus-dependent) and in association Saccadic oscillations that lack an intersaccadic interval, with AIDS such as opsoclonus and ocular flutter, probably result from Lesions of the paramedian pontine reticular formation pontine lesions in the pause cell region (310). A number Internuclear ophthalmoplegia of other mechanisms are possible, however. Macrosaccadic Peripheral nerve palsy, diseases affecting the neuromuscular junction and oscillations (an extreme form of saccadic dysmetria) also extraocular muscle, restrictive ophthalmopathy Paraneoplastic syndromes occur with pontine lesions (311), as can ocular flutter (291) (see Chapter 23).

OCULAR MOTOR SYNDROMES CAUSED BY LESIONS IN THE MESENCEPHALON SITES AND MANIFESTATIONS OF LESIONS tion is known by a variety of names: Parinaud’s syndrome, Koerber-Salus-Elschnig syndrome, pretectal syndrome, dor- Disturbances of vertical eye movements from midbrain sal midbrain syndrome, and the sylvian aqueduct syndrome lesions are usually caused by damage to one or more of (313,314). Unilateral midbrain lesions can also create the three main structures: the posterior commissure, the rostral same ocular motor syndrome, possibly by interrupting the interstitial nucleus of the medial longitudinal fasciculus, or afferent and efferent connections of the posterior commis- the INC (312). sure, or possibly by disturbing supranuclear inputs from the Posterior Commissure nucleus of the posterior commissure directly to the midbrain oculomotor nuclei (discussed later). Although paralysis of Lesions of the posterior commissure cause a syndrome upward gaze in this syndrome has, in the past, been ascribed characterized by loss of upward gaze and other associated to destruction of the superior colliculi, this is not the case. findings (Table 19.5 and Figs. 19.20 and 19.21). The condi- Experimental lesions restricted to the superior colliculus in nonhuman primates produce no limitation of upward gaze (315). Furthermore, the selective upgaze paralysis seen in Table 19.5 this syndrome cannot be explained on the basis of different Features of the Syndrome of the Posterior Commissure (aka Dorsal crossing patterns of premotor burst neurons originating in Midbrain Syndrome) the riMLF (downward premotor neurons are uncrossed to the Limitation of upward eye movements (Parinaud’s syndrome) third and fourth cranial nerve nuclei, while upward premotor Saccades neurons are both uncrossed and crossed), since none of these Smooth pursuit neurons appear to cross via the posterior commissure Vestibulo-ocular reflex (312,316). Although sparse data are available, damage to Bell’s phenomenon premotor neurons in the nucleus of the posterior commissure Lid retraction (Collier’s sign); occasionally ptosis that selectively subserve upward eye movements (or their Disturbances of downward eye movements axons, which appear to traverse the posterior commissure to Downward gaze preference (“setting sun” sign) arrive at their oculomotor targets) may be involved in the Downbeating nystagmus genesis of the selective loss of upward eye movements in Downward saccades and smooth pursuit may be impaired, but vestibular movements are relatively preserved. the syndrome of the posterior commissure (317). Disturbances of vergence eye movements The vertical gaze deficit caused by lesions of the posterior Convergence-retraction nystagmus (Koerber-Salus-Elschnig syndrome) commissure usually affects all types of eye movements, al- Paralysis of convergence though the VOR and Bell’s phenomenon are sometimes Spasm of convergence spared. Below the horizontal meridian, vertical saccades can Paralysis of divergence be made but are usually slow. Acutely, the eyes may be “A” or “V” pattern exotropia tonically deviated downward (setting-sun sign); this finding Pseudo-abducens palsy is prominent in premature infants with intraventricular hem- Fixation instability (square-wave jerks) orrhage (318). Transient downward deviation of the eyes Skew deviation Pupillary abnormalities (light–near dissociation) occasionally occurs in healthy neonates, but in such cases, the eyes can be easily driven above the horizontal meridian SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 927

Figure 19.20. Appearance of a patient with Parinaud’s dorsal midbrain syndrome. Above left, The eyes are straight in primary position. Note bilateral upper eyelid retraction. Above right, Downward gaze is normal. Below center, There is marked limitation of upward gaze bilaterally, worse on the left, producing a right hypertropia. (From Bajandas FJ, Aptman M, Stevens S. The sylvian aqueduct syndrome as a sign of thalamic vascular malformation. In: Smith JL, ed. Neuro-Ophthalmology Focus 1980. New York: Masson, 1979Ϻ401–406.) by the vertical doll’s head maneuver (86). Tonic upward The dorsal midbrain syndrome is also characterized by deviation of the eyes occurs in some patients with midbrain disturbances of horizontal eye movements. In some patients lesions (319). Oculogyric crises may also occur in patients convergence is paralyzed, whereas in others it is excessive with midbrain lesions and are discussed below. Episodic and causes convergence spasm. During horizontal saccades, (paroxysmal) tonic up-gaze may also occur in otherwise nor- the abducting eye may move more slowly than its adducting mal infants, in patients with other neurologic deficits, includ- fellow. This finding is called pseudo-abducens palsy (313) ing ataxia, as a familial dominantly inherited disorder, and, and may reflect an excess of convergence tone (328). It may occasionally, with structural lesions in the midbrain be responsible for an early symptom of evolving posterior (320–327). commissure lesions—reading difficulty caused by a transient inability to find, and to focus both eyes on, the beginning of the next line when a horizontal saccade is made. Convergence-retraction nystagmus is another sign often evident in patients with disease affecting the dorsal midbrain (329,330) (Fig. 19.22). Experimental lesions suggest that this eye movement disturbance results from damage to the posterior commissure (331). Originally thought to be a saccadic disorder consisting of asynchronous, opposed saccades, recent quantitative measures suggest that the adducting movements are abnormal convergence movements (332). Abnormalities of the eyelids occur in patients with dorsal midbrain lesions. The most common is eyelid retraction (Collier’s tucked lid sign), but ptosis occasionally occurs. In some patients, the abnormalities of the lids may be more prominent than those of the eye movements (333,334). Pupillary reactions are also commonly affected in patients Figure 19.21. Dorsal midbrain syndrome. A, Gaze straight ahead. B,On with lesions in the region of the posterior commissure. The attempted upward gaze, the patient develops convergence-retraction nys- pupils are usually large and react better to an accommodative tagmus. stimulus than to light (i.e., light-near dissociation). 928 CLINICAL NEURO-OPHTHALMOLOGY

Figure 19.22. Dorsal midbrain syndrome. A, Position of eyes in primary position. B, Retraction on attempted upward gaze. C, Lateral view of right eye when the patient is looking straight ahead. D, On attempted upward gaze, obvious retraction of the globe occurs. (From Lyle DJ, Mayfield FH. Retraction nystagmus: a case report. Am J Ophthalmol 1954;37Ϻ177–182.)

Many disease processes can affect the region of the poste- duce this syndrome by enlarging the aqueduct and third ven- rior commissure (Table 19.6 and Figs. 19.23–19.25). Pineal tricle or the suprapineal recess, thus stretching or compress- tumors (335,336) produce the dorsal midbrain syndrome ing the posterior commissure (337,338). Shunt dysfunction either by direct pressure on the posterior commissure or by may produce Parinaud’s syndrome before dilation of the causing obstructive hydrocephalus. Hydrocephalus may pro- ventricles is apparent on neuroimaging or measures of intra-

Table 19.6 Etiology of Disorders of Vertical Gaze

Tumor: Classically, pineal germinoma or teratoma in an adolescent male; also pineocytoma, pineoblastoma, glioma, metastasis Hydrocephalus: Usually aqueductal stenosis leading to dilatation of the third ventricle and aqueduct or enlargement of the suprapineal recess with pressure on the posterior commissure Vascular: Midbrain or thalamic hemorrhage or infarction Metabolic: Lipid storage disease: Niemann-Pick variants Drug-induced Degenerative: Progressive supranuclear palsy, cortical basal degeneration, Lytico-Bodig diffuse Lewy body disease; miscellaneous degenerations Miscellaneous: Multiple sclerosis, Whipple’s disease, hypoxia, encephalitis, Figure 19.23. Pathology of dorsal midbrain syndrome. Contusion hemor- syphilis, aneurysm, neurosurgical procedure, mesencephalic clefts, rhages are present in the region of the oculomotor nucleus and posterior tuberculoma, trauma, benign transient form of childhood commissure after a fall that resulted in an impact to the right side of the vertex. (Courtesy of Dr. Richard Lindenberg.) SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 929

Figure 19.24. Metastatic malignant melanoma causing a dorsal mid-brain syndrome. Horizontal section through the inferior third ventricle (V) shows replacement of posterior commissure (PC) by metastatic melanoma. CC, corpus callosum. (From Keane JR, Davis RL. Pretectal syndrome with metastatic melanoma to the posterior commissure. Am J Ophthalmol 1976;82Ϻ910–914.)

Figure 19.25. Locations of lesions producing isolated paralysis of upward gaze. Left, Four lesions giving rise to upward gaze paralysis have been superimposed on a sagittal section of the human brain stem. The enlargement of the lesions on the right shows that the common areas involved (stippled regions) include the interstitial nucleus of Cajal (iC), the nucleus of Darkschewitsch (nD), and fibers of the posterior commissure (PC). IC, inferior colliculus; MT, mammillothalamic tract; riMLF, rostral interstitial nucleus of the medial longitudinal fasciculus; RN, red nucleus; SC, superior colliculus; T, thalamus; TR, tractus retroflexus; III, oculomotor nerve. (Redrawn from Bu¨ttner-En- never JA, Bu¨ttner U, Cohen B, et al. Vertical gaze paralysis and the rostral interstitial nucleus of the medial longitudinal fasciculus. Brain 1982;105Ϻ125– 149.) 930 CLINICAL NEURO-OPHTHALMOLOGY cranial pressure are consistently high (339). An intermittent by individual burst neurons within the left riMLF nucleus Parinaud’s syndrome dependent on head position was de- only). scribed in a patient with a posterior fossa subdural hematoma Because infranuclear fibers innervating the superior (340). oblique (fourth) and superior rectus (third) muscles are crossed projections, each riMLF burst neuron for downward Rostral Interstitial Nucleus of the Medial Longitudinal saccades can control the movement of both eyes without Fasciculus sending axon collaterals across the midline. Thus, unilateral midbrain lesions in the riMLF can produce selective loss of The rostral interstitial nucleus of the medial longitudinal downward saccades. fasciculus (riMLF), which lies in the prerubral fields of the The same burst neurons that lack right–left asymmetry mesencephalon, contains the burst neurons that generate ver- with respect to vertical saccades are ‘‘lateralized’’ with re- tical and torsional saccades (analogous to the PPRF in the spect to ‘‘directionality’’ of torsional saccades; that is to say, pons for horizontal saccades). The riMLF lies dorsomedial all of the right riMLF vertical-torsional burst neurons drive to the rostral half of the red nucleus, medial to the fields of saccades toward the right shoulder (top pole rotating to the Forel, lateral to the periventricular gray and the nucleus of right), and all of the left riMLF vertical-torsional burst neu- Darkschewitsch, and immediately rostral to the INC. The rons drive saccades toward the left shoulder. Thus, unilateral riMLF projects to ipsilateral more than contralateral third midbrain lesions in the riMLF can also produce selective loss and fourth nerve nuclei, the INC (important for vertical gaze- of ipsilesional torsional saccades. The associated left–right holding [discussed later]), and caudal targets, including the asymmetry in tonic firing rates between the two riMLF nu- cell groups of paramedian tract, that relay ocular motor sig- clei may explain both the contralesional-beating torsional nals to the cerebellum. Although the right and left riMLF nystagmus (a sign of vertical VOR imbalance), and the tonic nuclei are interconnected, the projections are now believed ocular torsion toward the contralesional side (a sign of oto- to course ventral to the cerebral aqueduct rather than via the lith ocular imbalance). posterior commissure, as thought previously (312,316). Clinically, bilateral lesions of the riMLF are more com- Given this information, it is not unexpected that bilateral mon than unilateral lesions. They generally cause either loss experimental lesions of the riMLF abolish all vertical and of downward saccades or loss of all vertical saccades (345) torsional saccadic movements (341,342). However, unilat- (Figs. 19.26–19.28). Lesions of the riMLF are usually in- eral experimental lesions of the riMLF produce slowed farcts in the distribution of a small perforating vessel (the downward saccades, loss of ipsilesional torsional quick posterior thalamo-subthalamic paramedian artery) that arises phases of the VOR, contralesional beating torsional nystag- between the bifurcation of the basilar artery and the origin of mus, and tonic contralesional ocular torsion (343). An ana- the posterior communicating artery (Fig. 19.28). This vessel tomic explanation for these findings follows. may be paired or single (346,347); it supplies structures that Burst neurons within the riMLF have mixed vertical and include the riMLF, the rostromedial red nucleus, the adjacent torsional vectors rather than subpopulations of neurons with subthalamus, the posterior inferior portion of the dorsome- either vertical or torsional vectors, echoing the anatomic dial nucleus, and the parafascicular nucleus of the thalamus. structure of the vertical semicircular canals (presumably Some investigators think that paralysis of downward sac- since the vestibulo-ocular system is the phylogenetically- cades results from lateral lesions of both riMLFs, whereas older substrate underlying the saccadic system (344)). The medial bilateral lesions cause a total palsy of vertical sac- net vector sum of various burst neurons firing may, however, cades (Figs. 19.28–19.32) (348). Others (349), however, lead to purely vertical or purely torsional saccadic eye move- have observed that downward gaze paresis is more often ments. Burst neurons within the riMLF subserving upward- associated with medial lesions than with lateral ones. Al- torsional saccades appear to be redundant (i.e., project to though vertical smooth pursuit and the VOR may be affected both ipsilateral and contralateral third and fourth nerve nu- with lesions in this area, this probably reflects damage to clei), while those subserving downward-torsional saccades nearby structures, such as the MLF and INC (350). Deleu are not (i.e., project to the ipsilateral third and fourth nerve et al. (351) reported a patient with a vertical one-and-a-half nuclei only (312,316)). Each vertical-torsional saccade burst syndrome. The patient had loss of all downward movements neuron sends axon collaterals to yoke muscle pairs that sub- and selective loss of upward movements in one eye. A verti- serve the same pulling direction in each eye; specifically, cal one-and-a-half syndrome in which there was impairment these pairings are as follows: (a) right superior rectus and of all upward eye movements and a selective deficit of down- left inferior oblique (serving upward-leftward torsional sac- ward saccades in the eye on the side of the lesion has also cades, innervated by individual burst neurons within each been reported (352,353,354). Unilateral lesions of the mid- riMLF nucleus); (b) left superior rectus and right inferior brain can also produce combined complete up-gaze and oblique (serving upward-rightward torsional saccades, in- down-gaze palsy, isolated up-gaze palsy, or monocular ele- nervated by individual burst neurons within each riMLF nu- vator palsy (353). cleus); (c) right inferior rectus and left superior oblique Clinically, unilateral lesions of the riMLF generally pro- (serving downward-rightward torsional saccades, innervated duce a down-gaze palsy, mainly affecting saccades or, more by individual burst neurons within the right riMLF nucleus rarely, a complete vertical gaze palsy for all eye movement only); and (d) left inferior rectus and right superior oblique types (268,348,355,356). As seen with experimental lesions, (serving downward-leftward torsional saccades, innervated unilateral lesions of the riMLF also produce a contralaterally SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 931

Figure 19.27. Isolated paralysis of downward gaze in a 42-year-old alco- holic man. Above, Upward gaze is normal. Below, The patient cannot make voluntary downward eye movements. Bilateral simultaneous caloric stimulation with warm water induced downward nystagmus, but the excursion of the fast phases was truncated at the level of direct forward gaze. (From Jacobs L, Anderson PJ, Bender MB. The lesions producing paralysis of downward but not upward gaze. Arch Neurol 1973;28Ϻ319–323.)

Interstitial Nucleus of Cajal The INC, which lies adjacent and caudal to the riMLF in the midbrain reticular formation, contains premotor neurons that subserve vertical gaze-holding (analogous to the perihy- Figure 19.26. Neuroimaging of a lesion in a patient with bilateral conju- poglossal nucleus in the medulla for horizontal gaze) (312). gate vertical saccadic gaze palsy and cognitive dysfunction. T2-weighted The INC projects to contralateral (more than ipsilateral) third axial magnetic resonance image shows a hyperintense midline lesion (arrowhead) affecting the region of the rostral interstitial nucleus of the medial and fourth nerve nuclei, the riMLF (important for vertical longitudinal fasciculus. and torsional saccades [discussed previously]), and caudal targets, including the cell groups of paramedian tract, which relay ocular motor signals to the cerebellum, as well as the ipsilateral vestibular and perihypoglossal nuclei (subserving beating torsional nystagmus, a tonic torsional deviation to horizontal gaze-holding), and the ipsilateral C1-C2 ventral the contralateral side, and a deficit in generating ipsilaterally horns (involved in eye–head coordination), among others directed torsional quick phases (i.e., top pole rolling toward (312,316,360). The right and left INC are interconnected via the side of the lesion) (357,358). As pointed out above, the the posterior commissure. selective impairment of downward saccades with unilateral Given this information, it is not surprising that bilateral riMLF lesions appears to result from a lack of redundancy experimental lesions of the INC severely impair both vertical in the premotor pathways for down-gaze—burst neurons and torsional gaze-holding and disrupt normal vertical and subserving downward(-torsional) saccades project only to torsional VOR responses (361). Unilateral experimental le- the ipsilateral third and fourth nerve nuclei, while those sub- sions of the INC produce similar (though less profound) serving upward(-torsional) saccades project both ipsi- vertical and torsional gaze-holding deficits (vertical gaze- laterally and contralaterally (312,316). These apparent facts evoked nystagmus, and spontaneous, ipsilesional beating notwithstanding, Ranalli et al. (359) described a patient with torsional nystagmus), along with tonic contralesional ocular a unilateral lesion of the riMLF (which partially involved torsion (362). the adjacent INC) that led to a loss of saccades above the Lesions restricted to the INC are not well studied in hu- primary position and slow and limited saccades below. mans, apparently because isolated lesions of INC are rare Smooth pursuit and the VOR were also affected in the verti- (due to frequent involvement of riMLF). Nevertheless, avail- cal plane, being restricted in range and reduced in gain. The able evidence suggests that such lesions produce a clinical anatomic underpinnings of this clinical picture remain uncer- syndrome characterized by vertical gaze-evoked nystagmus, tain. impaired vertical smooth pursuit, tonic torsional deviation 932 CLINICAL NEURO-OPHTHALMOLOGY

Figure 19.28. Pathology of isolated paralysis of downward gaze. A, In a 58-year-old man who died of septic shock and was noted to have selective paralysis of downward gaze, the cut surface of the rostral mesencephalon reveals bilateral cavitary infarcts (arrows). The posterior commissure (PC) is intact. B and C, In a 42-year-old man who suffered an infarction of the brain stem and was noted to have selective paralysis of downward gaze, sections through the rostral mesencephalon show zones of bilateral infarction and necrosis involving portions of the tractus retroflexus and red nuclei on both sides. Zones of necrosis also involve portions of the intralaminar, dorsomedial, lateral, and posteromedial thalamic nuclei. D, Section through the mesencephalon at the level of the posterior commissure shows bilateral zones of infarction (arrows) in the periaqueductal gray matter. The posterior commissure itself and other portions of the pretectal region of the mesencephalon are normal. (A, From Trojanowski JQ, Wray SH. Vertical gaze ophthalmoplegia: selective paralysis of downgaze. Neurology 1980;30Ϻ605–610. B–D, From Jacobs L, Anderson PJ, Bender MB. The lesions producing paralysis of downward but not upward gaze. Arch Neurol 1973;28Ϻ319–323.) to the contralateral side, and torsional nystagmus tion of the INC in a human produced torsional nystagmus (110,358,363). The torsional nystagmus has been variably and the OTR (120). reported as contralesional beating or ipsilesional beating (110,358). Recent studies suggest that the apparent confu- Periaqueductal Gray Matter and Mesencephalic sion may stem from the comorbid presence of riMLF damage Reticular Formation in those cases where contralesional-beating nystagmus is present (358). A jerk seesaw nystagmus may also occur in The effects of lesions localized to mesencephalic struc- patients with lesions that damage the INC (364), although tures other than the posterior commissure, INC, and the seesaw nystagmus has not been reproduced in the monkey riMLF are less clear. The periaqueductal gray matter of the with INC lesions (365). The INC may also contribute to mesencephalon contains neurons that stop discharging dur- dynamic properties of the VOR, especially its low-frequency ing saccades. A patient with bilateral lesions of the periaque- behavior, by virtue of the effect on the vestibular velocity ductal gray matter, caudal to the posterior commissure and storage mechanism (366). Lesions in the midbrain produce ventral to the superior colliculus, showed a selective defect a change in the phase of the VOR (367), and electric stimula- of down-gaze, with tonic upward deviation of the eyes (368). SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 933

Figure 19.29. Locations of lesions producing isolated paralysis of downward gaze. Left, Sagittal section through the human brain stem on which the bilaterally destroyed areas in the six autopsied cases of isolated downward gaze paralysis are superimposed. Right, An enlargement of the lesions shows that the common area destroyed in these cases (stippled region) lies dorsal to the red nucleus at the level of the tractus retroflexus (TR)—that is, around the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) and the nucleus of Darkschewitsch (nD). iC, interstitial nucleus of Cajal; IC, inferior colliculus; MT, mammillothalamic tract; PC, posterior commissure; RN, red nucleus; SC, superior colliculus; T, thalamus; III, oculomotor nerve; nIII, oculomotor nucleus. (Redrawn from Bu¨ttner-Ennever JA, Bu¨ttner U, Cohen B, et al. Vertical gaze paralysis and the rostral interstitial nucleus of the medial longitudinal fasciculus. Brain 1982;105Ϻ125– 149.)

Figure 19.30. Smallest area critical for the selective mediation of downgaze (stippled area). Left, Sagittal view of the brain stem as seen from the midline. Right, Coro- nal view of the critical region as seen from a rostral approach. The involved region is rostral to the posterior commissure (PC) in a region that has been designated as the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). iC, interstitial nucleus of Cajal; MLF, medial longitudinal fasciculus; MT, mammillothalamic tract; nD, nucleus of Darkschewitsch; nIII, oculomotor nucleus; RN, red nucleus; SC, superior colliculus; T, thalamus; TR, tractus retroflexus; V, third ventricle. (Redrawn from Pierrot-Deseilligny C, Chain F, Gray F, et al. Parinaud’s syndrome: electro-oculographic analysis of six cases with deductions about vertical gaze organization in the premotor structures. Brain 1982;105Ϻ667– 696.) 934 CLINICAL NEURO-OPHTHALMOLOGY

Figure 19.31. Locations of brain stem lesions that produce paralysis of both upward and downward gaze. Left, Five unilateral or bilateral lesions producing upward and downward gaze paralysis are superimposed on a sagittal section of the human brain. The enlargement on the right shows the common area involved (stippled region). This area includes parts of the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), the interstitial nucleus of Cajal (iC), and the nucleus of Darkschewitsch (nD). IC, inferior colliculus; MT, mammillothalamic tract; PC, posterior commissure; RN, red nucleus; SC, superior colliculus; T, thalamus; TR, tractus retroflexus; III, oculomotor nerve; nIII, oculomotor nucleus. (Redrawn from Bu¨ttner- Ennever JA, Bu¨ttner U, Cohen B, et al. Vertical gaze paralysis and the rostral interstitial nucleus of the medial longitudinal fasciculus. Brain 1982; 105Ϻ125–149.)

Another reported lesion of the periaqueductal gray matter of both elevator muscles (the superior rectus and inferior caused persistent up-gaze palsy (369). Thus, it seems that oblique muscles) of one eye. This double elevator palsy is lesions of the periaqueductal gray matter of the midbrain thought to be supranuclear in origin, because in the primary may cause an imbalance of the vertical gaze-holding mecha- position, the eyes are nearly straight, and only on looking nism. Areas of the mesencephalic reticular formation outside upward does a vertical disconjugacy become evident (376). of the riMLF and INC have also been implicated in control of This condition occurs in patients with midbrain infarction saccades. Lesions there affect horizontal and vertical saccade and tumor; the lesion may be ipsilateral or contralateral accuracy; the pattern depends on the exact location within (353,377,378). Rarely, it is congenital (379,380). Because the mesencephalic reticular formation (370,371). the superior rectus is a stronger elevator than the inferior oblique, it is not always possible to be sure of inferior oblique Other Sites and Manifestations weakness. If, however, the inferior oblique is weak in addi- Unilateral, paramedian midbrain lesions sometimes cause tion to the superior rectus, then a nuclear lesion is unlikely, impairment of ipsilateral, horizontal smooth pursuit by af- because these two muscles are supplied by the ipsilateral fecting the descending smooth-pursuit pathway; contralat- and contralateral oculomotor subnuclei, respectively. More eral saccades may also be affected (372), but the horizontal likely, prenuclear inputs to the oculomotor nuclei are im- VOR tends to be spared (Roth-Bielschowsky phenomenon) paired in such patients. The VOR is variably affected. Mono- (313). Paramedian midbrain lesions often damage the oculo- cular elevator palsy may be associated with a contralateral motor nerve nucleus, thereby producing a combination of down-gaze palsy (381). Occasionally monocular elevator nuclear and prenuclear deficits (372,373). Lesions that dam- palsy is caused by a lesion selectively involving the inferior age the oculomotor nucleus are characterized by bilateral oblique and superior rectus muscle fascicles of the oculomo- elevator and eyelid weakness, because the superior rectus tor nerve as it exits the brain stem (382). In most instances, subnucleus is located contralaterally, and the levator sub- however, a monocular paresis of elevation results from nucleus is located in the midline. Abnormal pupils are com- causes other than midbrain disease, such as thyroid ophthal- mon in patients with such lesions. Occasionally, large mid- mopathy, blowout fracture of the orbit, myasthenia gravis, brain lesions also cause complete loss of horizontal eye or restrictive ophthalmopathies. MR scanning of the orbit movements (374,375). may be helpful in differentiating restrictive eye muscle dis- Rarely, midbrain lesions selectively impair the function eases causing a similar clinical picture (383). SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 935

Figure 19.32. Supranuclear vertical ophthalmoplegia in a patient with a metabolic storage disease (DAF syndrome). Top, In primary position, the patient’s eyes are straight. She is also able to make normal voluntary horizontal eye movements. Center, The patient cannot make voluntary upward or downward vertical eye movements. Bottom, On oculocephalic testing, full vertical ocular excur- sions are elicited. (From von Noorden GK, Mau- menee AE. Atlas of Strabismus, 2nd ed. St Louis: CV Mosby, 1973Ϻ161.)

NEUROLOGIC DISORDERS THAT PRIMARILY of PSP occur and appear to be inherited in an autosomal- AFFECT THE MESENCEPHALON dominant fashion (392,393), the disease is usually sporadic. The initial ocular motor deficit of PSP is usually impair- Two neurologic disorders produce profound disturbances ment of vertical saccades and quick phases, either down or of ocular motility, primarily because of their effects on cells up (245). The saccades are at first slow and later also small, in the mesencephalon: progressive supranuclear palsy and with eventual complete loss of voluntary vertical refixations. Whipple’s disease. Vertical smooth pursuit is usually relatively preserved, and the VOR is intact until later in the disease, although a charac- Progressive Supranuclear Palsy teristic nuchal rigidity may make the vertical doll’s head maneuver difficult to perform. A large-field visual stimulus Progressive supranuclear palsy (PSP) is a degenerative often elicits much better visual tracking than does a small disease of later life characterized by disturbances of tone target (394). Bell’s phenomenon is usually absent. There and posture leading to falls, difficulties with swallowing and are many types of eyelid abnormalities in PSP, including speech, and mental slowing (384–389). PSP is one of the blepharospasm, apraxia of eyelid closing or opening, lid re- tauopathies (385,390). Abnormal eye movements are usually traction, and lid lag (395). present early in the course of the disease, but occasionally Horizontal eye movements also show characteristic ab- they are noted late or not at all (391). Although familial cases normalities in patients with PSP, including impaired fixation 936 CLINICAL NEURO-OPHTHALMOLOGY with square-wave jerks, impaired pursuit, impaired vestibu- The differential diagnosis of PSP includes a similar syn- lar cancellation, and saccades and quick phases that are small drome caused by multiple infarcts that affect the basal gan- and eventually slow (396–398). In some patients, the abnor- glia, internal capsule, and midbrain (418–420). Hydrocepha- mality of voluntary horizontal eye movements resembles an lus may also mimic PSP (421), as can Whipple’s disease INO; however, vestibular stimulation may overcome the lim- (422) and a delayed syndrome following aortic valve re- itation of adduction in such cases (399). Convergence eye placement (423). At the bedside, slowing of vertical sac- movements are commonly impaired in patients with PSP, cades, the inability to suppress blinks to a bright light (a and many patients have severe convergence insufficiency visual ‘‘glabellar sign’’), the ‘‘applause sign’’ (persistent (400). Late in the disease, the ocular motor deficit may clapping after instructed to clap just three times), and tonic progress to a complete ophthalmoplegia. deviation of the eyes and head following sustained rotation Studies of eye movements in patients with PSP may also of the body in a vestibular chair are helpful diagnostic find- reflect the disturbances of attention that occur in this disor- ings (424). der. The latency (reaction time) of horizontal saccades in PSP should be differentiated from cortical-basal gangli- PSP is prolonged in some patients, but in others, saccadic onic degeneration, which may affect vertical and horizontal latency (using a gap paradigm in which the fixation target gaze but which also causes focal dystonia, ideomotor goes out before the new peripheral target appears) is reduced apraxia, alien hand syndrome, myoclonus, and an asymmet- so that patients show short-latency or express saccades ric akinetic-rigid syndrome with late onset of gait or balance (401–403). Patients with PSP also make errors with an antis- disturbances (402,403,425–429). A syndrome similar to PSP accade task in which they are required to look away from a has been reported from Guadeloupe and has been attributed presented target. Both the express saccades and errors on to exposure to mitochondrial complex 1 inhibitors such as the antisaccade task suggest defects in frontal lobe function quinolones, acetogenins, and rotenoids (430). It also is a tauopathy. The Parkinson-dementia complex of Guam (Lyt- (401) and, although neuropathologic changes in the frontal ico-Bodig variant) also resembles PSP (431,432). PSP lobe are mild in patients with PSP, positron emission tomo- should also be differentiated from Parkinson’s disease (dis- graphic (PET) scanning indicates profound frontal hypome- cussed later). Although upward gaze may be limited in PSP tabolism in such patients (404). Defects of visual attention and in Parkinson’s disease, impaired downward gaze, slow are more prominent in the vertical than in the horizontal vertical saccades, abnormal horizontal saccades, and square- plane (405), and poor performance on visual search tasks wave jerks are much more characteristic of PSP. Diffuse may be related in part to loss of voluntary saccades and Lewy body disease may present a problem in differential disruption of steady fixation by square-wave jerks (406). diagnosis and mimic PSP (433) or Parkinson’s disease (434). PSP is a diffuse brain stem disorder, although cortical Other basal ganglia disorders that may mimic PSP include involvement also occurs (407). Both computed tomographic idiopathic striopallidodentate calcification (435), autosomal- (CT) scanning and MR imaging show atrophy of the mid- dominant parkinsonism and dementia with pallidopontoni- brain and dilation of the quadrigeminal cisterns, cerebral gral degeneration (436), multisystem atrophy, and olivopon- aqueduct, and third and fourth ventricles (408). There is a tocerebellar atrophy (398). Some of the neurologic deficits characteristic ‘‘hummingbird sign’’ due to the midbrain atro- of PSP, but generally not the eye movements, have been phy (409). Histologically, neuronal loss, neurofibrillary tan- reported to improve modestly with methysergide therapy gles, and gliosis principally affect the brain stem reticular (437), tricyclic antidepressants (438), or dopamine agonists formation and the ocular motor nuclei (384,410). The mid- such as bromocriptine (388,439,440). brain may bear the brunt of the early pathology, accounting for the relative vulnerability of vertical saccades (411). Thus, Whipple’s Disease the slowing of vertical saccades probably results from dysfunction of burst neurons in the riMLF, whereas the neck Whipple’s disease is a rare multisystem disorder charac- stiffness, often with dorsiflexion, may be caused by damage terized by weight loss, diarrhea, arthritis, lymphadenopathy, to the INC, which contributes to the control of head move- and fever that may involve and even be confined to the cen- ments (412). Abnormalities are also present in the nucleus tral nervous system (441,442). This disease can cause a de- raphe interpositus in the pons in which omnipause neurons, fect of ocular motility that may mimic PSP (443). Initially, important for control of velocity and amplitude of both hori- vertical saccades and quick phases are abnormal (444); zontal and vertical saccades, are located (413). Recent stud- eventually, all eye movements may be lost (445). A highly ies suggest that PSP likely causes the abnormal saccade ve- characteristic finding is pendular vergence oscillations and locity by virtue of its direct effect on premotor saccade burst concurrent contractions of the masticatory muscles: oculo- neurons within the midbrain (414,415). Pathology within masticatory myorhythmia (446–448). The pendular ver- the substantia nigra pars reticulata may also play a role gence oscillations are always associated with vertical sac- (416). Pursuit abnormalities may reflect damage to the cade palsy. Rhythmic palatal tremor may also be present deep pontine nuclei (417). The pedunculopontine nucleus (449). Rajput and Mchattie (450) described ophthalmoplegia is also specifically affected and may be associated with with myorhythmia of the leg, but not of the eyes or jaw. secondary damage to a number of other cortical and sub- Whipple’s disease can be diagnosed using molecular analy- cortical structures (407). sis and can be treated with antibiotics (442). SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 937

OCULAR MOTOR SYNDROMES CAUSED BY LESIONS OF THE SUPERIOR COLLICULUS Lesions restricted to the superior colliculi are rare in hu- normal latency but were hypometric. These findings are sim- mans. One patient (297) underwent removal of a cavernous ilar to those seen after experimental ablation of the superior angioma from the right superior colliculus. Following sur- colliculi in monkeys (451). Pierrot-Deseilligny et al. (452) gery, he had persistently impaired upward gaze, implying reported a patient who had a hematoma largely restricted to pretectal damage, but a full range of horizontal eye move- the right superior colliculus. The patient showed defects in ments. Systematic testing of horizontal saccades demon- latency and accuracy for contralateral saccades and in- strated a paucity of spontaneous refixations contralateral to creased numbers of inappropriate saccades during the anti- the side of the lesion. Saccades to the left occurred after a saccade task.

OCULAR MOTOR SYNDROMES CAUSED BY LESIONS OF THE THALAMUS Thalamic lesions are characterized by disturbances of both ward deviation of the eyes may represent either an irritant horizontal and vertical gaze (453). Conjugate deviation of effect of the hemorrhage on structures responsible for down- the eyes contralateral to the side of the lesion (also called ward gaze or an imbalance created by an acute up-gaze palsy. wrong-way deviation) may occur with hemorrhage affecting Resolution of the downward deviation occurs after treatment the medial thalamus (Fig. 19.33) (18,454). The reason for of raised intracranial pressure; thus, traction on mesence- this contraversive deviation is unclear. The descending path- phalic structures or hydrocephalus may cause this condition. ways from the frontal eye fields to the pons have not yet Esotropia, sometimes quite marked, occurs in patients crossed at this level, although the notion of a precise ocular with caudal thalamic lesions. Although it is usually associ- motor decussation is less certain now than in the past. Dam- ated with downward gaze deviation, it may occur as an iso- age to the descending pathway for smooth pursuit might lated finding (458,459). The esotropia that occurs with thala- lead to a paretic, contraversive deviation of the eyes (305). mic lesions may reflect a disturbance of inputs to premotor Nevertheless, a patient with a defect of smooth pursuit divergence neurons in the midbrain (328). Combined lesions rected toward the side of a small hemorrhage in the posterior of the thalamus and midbrain may cause paresis of conver- thalamus and adjacent internal capsule still showed an ipsi- gence (460). versive gaze preference (455). Another possibility is that Patients with posterolateral thalamic infarctions may have wrong-way deviation may be an irritative phenomenon, be- disturbances of the subjective visual vertical (either ipsi- cause neurophysiologic studies show that saccade-related lateral or contralateral) (72). The ocular tilt reaction is not neurons in the intralaminar thalamic nuclei mainly discharge present, however, unless the rostral midbrain is also dam- for contralateral saccades. aged. Forced downward deviation of the eyes, with convergence Infarction of the caudal thalamus caused by occlusion of and miosis, is another common feature of thalamic hemor- the proximal portion of the posterior cerebral artery or its rhage; affected patients appear to peer at their noses perforator branch, the posterior thalamosubthalamic par- (456,547). In autopsied cases, the hemorrhage usually ex- amedian artery, is reported to cause paralysis of downgaze. tends into or compresses the midbrain. Hence, forced down- In fact, this deficit is probably caused not by damage to

Figure 19.33. Contralateral (‘‘wrong-side’’) gaze deviation with supratentorial, thalamic-basal ganglia hemorrhage. A, top, The patient’s eyes are deviated to the right. Bottom, Coronal section immediately posterior to the mammillary bodies shows a left intracerebral hemorrhage involving the thalamus, internal capsule, and basal ganglia. B, top, In another patient, the eyes are deviated down and left. Bottom, Horizontal section through the mid-diencephalon reveals a right intracerebral hemorrhage involving the pretectum, thalamus, posterior limb of the internal capsule, globus pallidus, and putamen. In both patients, the hemorrhage also involved the lateral midbrain tegmentum. (From Keane JR. Contralateral gaze deviation with supratentorial hemorrhage: three pathologically verified cases. Arch Neurol 1975;32Ϻ119–122.) 938 CLINICAL NEURO-OPHTHALMOLOGY the thalamus but by damage to the adjacent riMLF or its grammed using extraretinal information about eye position immediate premotor inputs (461,462). Some patients have must pass through the thalamus and possibly the internal impairment of horizontal gaze, perhaps from interruption of medullary lamina (471). Lesions in the posterior parietal descending pathways (463,464). Associated disturbances of cortex and in the supplementary eye field in the frontal lobes arousal and short-term memory occur in some patients with create similar deficits in the double-step paradigm. Patients thalamic lesions and may be caused by damage to specific with thalamic lesions also show defects in saccade adapta- thalamic nuclei (465,466). Experimentally, combined le- tion, likely reflecting interruption in pathways that carry information to and from the cerebellum (472). sions of the superior colliculus and caudal thalamus in mon- Patients with lesions of the pulvinar develop difficulties keys produce an enduring saccadic hypometria without corin shifting attention and gaze into the contralateral hemifield, rective saccades (467), implying a role for these structures manifested by a paucity and prolonged latency of visually in generating efference copy signals (468–470). guided saccades (473,474). These results are consistent with Patients with central thalamic lesions show defects in dou- some reported effects of pharmacologic and destructive le- ble-step saccade paradigms (making successive accurate sac- sions of the pulvinar in the monkey and indicate the impor- cades after a target has quickly jumped twice to different tance of this thalamic nucleus in directing visual attention locations), suggesting that information for saccades pro- (475,476).

OCULAR MOTOR ABNORMALITIES AND DISEASES OF THE BASAL GANGLIA PARKINSON’S DISEASE disease, implicating the basal ganglia in ocular motor learning (506). Patients with Parkinson’s disease may show a number of Pallidotomy causes no improvement in ocular motor per- ocular motor findings (477). Steady fixation is often dis- formance and may actually cause mild deficits in internally rupted by square-wave jerks (478). Upward gaze is often generated saccades and square-wave jerks (507,508). In con- moderately restricted (479), although this abnormality frequently is observed in normal, elderly persons (480). Con- trast, stimulation of the subthalamic nucleus has been re- vergence insufficiency is a common and often symptomatic ported to improve saccade performance in Parkinson’s pa- disturbance (481,481a). tients (403). Saccades made reflexively to novel visual stimuli in Par- Clinically, the saccadic initiation defect to command or kinson’s disease are usually of relatively normal amplitude to continuously visible targets appears to be more marked (426,428,482). In contrast, saccades in Parkinson’s disease in the vertical plane. Upward saccades especially may be become hypometric in more complicated tasks such as when hypometric. In contrast, vertical saccades to randomly ap- patients are asked to perform rapid, self-paced refixations pearing visual targets are normal (496). If downward sac- between two stationary targets (478,482–486). During such cades are abnormal, or the velocity of vertical saccades in a test, which relies on an internally generated, predictive either direction is decreased, PSP is a more likely diagnosis strategy, intersaccadic intervals increase above values dur- than Parkinson’s. ing unpredictable tracking to suddenly appearing targets Combined movements of the eye and head may be abnor- (482,483). This effect is not, however, related simply to the mal in Parkinson’s disease. Affected patients tend not to persistence of the target light, because saccades made in move their heads unless instructed to do so (509–511). Dur- anticipation of the appearance of a target light or to a remem- ing rapid eye-head gaze shifts, in response to either predict- bered target location are also hypometric (482,487–491), able or unpredictable step displacements of the target, pa- and patients with Parkinson’s disease have difficulty in gen- tients show increased latency and slowing of head or eye erating sequences of memory-guided saccades to all types movements (510). of stimuli (492,493). Despite this hypometria, patients can Smooth-pursuit movements are usually impaired, al- still shift their gaze, using a series of saccades, to the location though minimally so in mildly affected patients (497). Dur- of a target that is briefly flashed, indicating a retained ability ing tracking of a target moving in a predictable, sinusoidal to encode the location of objects in extrapersonal space pattern, pursuit gain (eye velocity/target velocity) is de- (478,494). Saccadic latencies during nonpredictive tracking creased, leading to catch-up saccades (512). Because the may be normal or mildly increased (478,485,495,496). Pa- catch-up saccades are hypometric, however, the cumulative tients with Parkinson’s disease often show defects in gener- tracking eye movement is less than that of the target, and ating predictive saccades (495,497). Saccadic velocity may this may be one mechanism for defective smooth tracking be normal or, particularly in advanced cases, mildly reduced (497,513). Despite the impairment of smooth-pursuit gain, (478,498). Patients with mild disease perform normally on the phase relationship between eye and target movement the antisaccade task (499,500), but with advanced disease, during tracking of a periodic target is normal (495); this errors increase, especially when patients are also taking anti- implies a normal predictive smooth tracking strategy (484). cholinergic drugs (501,502) Patients with Parkinson’s dis- Cancellation of the VOR, by fixing upon an object moving ease have also been shown to be impaired in saccade search with the head, is abnormal, however, so that during com- strategies that require use of ‘‘working memory’’ (503,504) bined, active eye-head tracking, gain (gaze velocity/target although this may depend upon the difficulty of the task velocity) is reduced (510). (505). Saccade adaptation may be affected in Parkinson’s Both caloric and low-frequency rotational vestibular re- SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 939 sponses, in darkness, may be hypoactive in patients with to an obsessive fixation of a thought. The eyes typically Parkinson’s disease (514,515). At higher frequencies of head deviate upward and sometimes laterally (Fig. 19.34); they rotation, however, and particularly during visual fixation, rarely deviate downward. During the period of upward de- the gain of the VOR is close to 1.0, which accounts for the viation, the movements of the eyes in the upper field of gaze lack of complaint of oscillopsia in such patients (515). appear nearly normal. Affected patients have great difficulty Patients with the syndrome of amyotrophic lateral scle- looking down, except when they combine a blink and down- rosis plus parkinsonism plus dementia (Lytico-Bodig syn- ward saccade. Thus, the ocular disorder may reflect an im- drome), who live on the islands of the South Pacific Ocean, balance of the vertical gaze-holding mechanism. Anticholin- including Guam, may show more severe deficits than pa- ergic drugs promptly terminate both the thought disorder tients with idiopathic Parkinson’s, including limitation of and the ocular deviation, a finding that suggests that the vertical gaze (432). Patients with diffuse Lewy body disease, disorders of thought and eye movements are linked by a Creutzfeldt-Jakob disease, multisystem atrophy (516), corti- pharmacologic imbalance common to both (521). Ocu- cal-basal ganglion degeneration, Guadeloupean parkinson- logyric crises are distinct from the brief upward ocular devia- ism, and PSP must also be distinguished from those with tions that occur in Tourette’s syndrome (discussed later), in idiopathic Parkinson’s (402,424,426,428,430,433,517,518). Rett’s syndrome (523), and in most patients with tardive Antisaccade testing is abnormal in cortical-basal ganglion dyskinesia (524). In some patients with tardive dyskinesias, degeneration (519) and in PSP (discussed previously). MR however, the upward eye deviations are longer-lasting and imaging may help in the differential diagnosis between Par- also are associated with the characteristic neuropsychologi- kinson’s and similar disorders (408,520). cal features of oculogyric crises (525), thus making the dif- Oculogyric crises, once encountered mainly in patients ferentiation between the two entities difficult. Delayed ocu- with postencephalitic parkinsonism, now occur primarily as logyric crises occurred in one patient after a focal a side effect of drugs, especially neuroleptic agents (521), striatocapsular infarction (526) and in another with bilateral although they may occur in other conditions such as reversi- lentiform lesions (527). Episodic brief spells of tonic up- ble posterior leukoencephalopathy (522). A typical attack gaze occurred after bilateral lentiform lesions in a patient begins with feelings of fear or depression, which give rise (528).

Figure 19.34. Oculogyric crisis in patients with postencephalitic parkinsonism. A, In a young man. Note hyperextension of neck, opening of the mouth, and conjugate deviation of the eyes up and to the right. B, In a middle-aged man. Again, the eyes are conjugately deviated up and to the right. (From Kyrieleis W. Die Augenvera¨nderungen bei entzu¨ndlichen Erkrankungen des Zentralnervensystems. III. Die nichteitrigen entzu¨ndlichen Erkrankungen des Zentralnervensystems. A. Die nichteitrige epidemische Encephalitis [Encephalitis epidemica, lethargica]. In: Schieck F, Bru¨ckner A, eds. Kurzes Handbuch der Ophthalmo- logie, vol 6. Berlin: Julius Springer, 1931Ϻ712–738.) 940 CLINICAL NEURO-OPHTHALMOLOGY

In general, treatment of Parkinson’s disease with L-dopa holding and the VOR are preserved, though there may be a does not seem to improve the ocular motor deficits (479), deficit in VOR adaptive capability (550). Late in the disease, except for saccadic accuracy (i.e., saccades become larger) rotational stimulation causes the eyes to tonically deviate (498,529). Occasionally, reversal of saccadic slowing occurs with few or no quick phases. with treatment (530), and newly diagnosed patients with id- Fixation is abnormal in some patients with Huntington’s iopathic disease may experience improved smooth pursuit disease because of saccadic intrusions (541,551). This defect after institution of dopaminergic therapy (529). In patients of steady fixation is particularly evident when the patient with parkinsonism caused by methyl-4-phenyl-1,2,3,6-tetra- views a textured background (89). The paradoxical findings hydropyridine (MPTP) toxicity, saccadic latency is short- of difficulty in initiating voluntary saccades but with an ex- ened and saccadic accuracy improved by dopaminergic cess of extraneous saccades during attempted fixation can agents (531). In addition, reflex blepharospasm is improved be further elucidated using novel test stimuli. Such studies in these patients with treatment. These findings are similar reveal an excessive distractibility in, for example, an antisac- to those in monkeys. When these animals are given MPTP, cade task (542). A second finding is that saccades to visual they develop increased latency and duration of saccades, stimuli are made at normal latency, whereas those made to decreased rate of spontaneous saccades, and inappropriate command are delayed. These findings may be related to the saccades, all of which are reversed by dopaminergic therapy parallel pathways that control the various types of saccadic (532,533). In patients with idiopathic disease who show pro- responses. On the one hand, disease affecting either the fron- nounced drug-related fluctuations, there is disagreement as tal lobes or the caudate nucleus, which inhibits the pars reti- to whether smooth pursuit shows increase in gain during culata of the substantia nigra, may lead to difficulties in ‘‘on’’ periods (498,534,535). Although patients who are re- initiating voluntary saccades in tasks that require learned or ceiving L-dopa and who show dyskinetic movements of other predictive behavior (537,538). On the other hand, Hunting- body parts (536) are said to have unsteady gaze, particularly ton’s also affects the pars reticulata of the substantia nigra in darkness, this phenomenon usually is not evident clini- (552). Because the pars reticulata of the substantia nigra cally. inhibits the superior colliculus and therefore suppresses re- The dopaminergic pars compacta of the substantia nigra flexive saccades to visual stimuli, one might expect exces- does not appear to contain neurons related to eye movement, sive distractibility during attempted fixation. The slowing whereas the pars reticulata does (537,538). In monkeys with of saccades may reflect damage to saccadic burst neurons MPTP-induced parkinsonism, the cerebral metabolic rate (553), but at least some pathologic evidence (554) suggests was reduced in the frontal eye field and paralamellar medio- that disturbance of prenuclear inputs, such as the superior dorsal thalamus (539). It is possible that these metabolic colliculus or frontal eye field, is responsible. changes are related to loss of projections from the dopamine- Despite the nearly ubiquitous finding of abnormal eye depleted substantia nigra. movements in patients with Huntington’s, some persons with the disease who are evaluated before they become HUNTINGTON’S DISEASE symptomatic show normal eye movements (89,555). Thus, routine testing of eye movements is not a reliable method Huntington’s disease produces disturbances of voluntary for determining which offspring of affected patients will go gaze, particularly saccades (540–543). It is caused by a ge- on to develop the disease. Reveley et al. (556) reported some netic defect of the IT15 gene (the ‘‘Huntington’’ gene) on improvement in the eye movement abnormalities in patients chromosome 4, producing a CAG triplet repeat (544). Initia- with Huntington’s who were treated with sulpiride. tion of saccades in patients with Huntington’s disease may Neuroacanthocytosis (557) must be distinguished from be difficult. Such patients show prolonged latencies, espe- Huntington’s disease (and PSP), but eye movement abnor- cially when the saccade is to be made on command, in antici- malities do not seem to be an important feature of this disor- pation of a target moving in a predictable fashion, or in a der. Dentatorubropallidoluysian atrophy (558), also called self-paced fashion. An obligatory blink or head turn may be the Haw River syndrome (559), is another CAG triplet repeat used to start the eye moving (545). Saccades may be slow disease (B37, chromosome 12) that must be distinguished in the horizontal or vertical plane; this deficit can often be from Huntington’s, although myoclonus and ataxia are more detected early in the disease if eye movements are measured common in dentatorubropallidoluysian atrophy than in Hun- (89), but it may not be evident clinically until late in the tington’s. course (541). Saccades may be slower in patients who become symptomatic at an earlier age, and such persons are OTHER DISEASES OF BASAL GANGLIA more likely to have inherited the disease from their father (546). The slowing of vertical saccades in Huntington’s dis- A number of conditions other than Parkinson’s and Hun- ease probably does not occur in patients with chorea from tington’s that affect the basal ganglia cause abnormal eye nondegenerative conditions or tardive dyskinesia (547). movements. Hepatolenticular degeneration (Wilson’s dis- Longitudinal studies of saccades can be used to quantify the ease) and juvenile dystonic lipidosis (Niemann-Pick type progression of the disease (540,548). 2s) are discussed below. Other conditions include caudate Smooth pursuit may also be impaired with decreased gain hemorrhage, which has been associated with ipsilateral gaze in patients with Huntington’s disease, but it often is rela- preference (560) and, rarely, Sydenham’s chorea. Vermersch tively spared compared with saccades. By contrast, gaze- et al. (561) recorded saccadic eye movements in patients SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 941 with bilateral lesions in the lentiform nucleus and found tasks, though there is considerable disagreement among prominent abnormalities in saccades that required an internal these studies as to the exact deficits (568–573). A confound- representation of the target (remembered saccades, saccades ing factor in these studies is the presence or absence of asso- to sequences, predictive saccades) but normal responses for ciated attention-deficit/hyperactivity disorder (ADHD) visually guided saccades, including antisaccades (which are (572,574,575). nonetheless triggered by a visual target). Lekwuwa et al. Routine ocular motor functions are normal in most pa- (562) suggested that defects in control of predictive pursuit tients with essential blepharospasm (576). In some studies, eye movements are a feature of striatal damage. however, abnormal saccade latencies are seen for both vis- Patients with Tourette’s syndrome may show a variety of ually guided and memory-guided saccades (577,578), sug- ocular abnormalities, including blepharospasm and eye tics gesting a possible basal ganglia localization. Patients with that include involuntary gaze deviations (563,564), but sac- spasmodic torticollis may show abnormalities in vestibular cades, fixation, and pursuit, when tested in conventional lab- function, including the torsional VOR (88,579). Patients oratory testing paradigms, show no abnormalities (565). The with tardive dyskinesia may show increased saccade distrac- gaze deviations must be distinguished from benign eye tibility (580). Severely affected patients with Lesch-Nyhan movement tics, which children often outgrow (566,567). syndrome (hypoxanthine-guanine phosphoribosyltransfer- Quantitative testing of patients with Tourette’s syndrome ase [HPRT] deficiency) show excessive distractibility, diffi- have shown various saccade abnormalities in ‘‘higher- culty initiating saccades, and an oculomotor apraxia-like level’’ tasks such as the antisaccade task and ‘‘go/no-go’’ condition (581).

OCULAR MOTOR SYNDROMES CAUSED BY LESIONS IN THE CEREBRAL HEMISPHERES Extensive reviews of the effects of cerebral hemisphere lesions on eye movements were done by Pierrot-Deseilligny (582) and Leigh and Kennard (583). One particular issue that must be considered in assessing abnormalities of eye movements in patients with lesions in the cerebral hemispheres is the sometimes confounding role of defects in directing visual attention and the associated neglect (584–587).

ACUTE LESIONS Following an acute lesion of one cerebral hemisphere, the eyes usually deviate conjugately toward the side of the lesion (Prevost’s or Vulpian’s sign) (588) (Fig. 19.35). Gaze deviations are more common after large strokes involving predominantly the right postrolandic cortex (589,590) (Fig. 19.36). Visual hemineglect often accompanies such gaze deviations (590,591). Gaze deviation that occurs after a stroke usually resolves within a few days to a week; if gaze deviation persists, there may be a previous lesion in the contralateral frontal lobe (592). In general, for comparably sized lesions, ocular motor defects—both pursuit and saccades—are more profound when the lesion is in the nondominant hemisphere (593). In the acute phase, patients may not voluntarily direct their eyes toward the side of the intact hemisphere, in part because of neglect. Shortly thereafter, however, vestibular stimulation usually produces a full range of horizontal movement (with the slow phase), in contrast to most gaze palsies associated with pontine lesions (313). When quick phases of caloric nystagmus directed away from the side of the Figure 19.35. Persistent hemispheral (supranuclear) horizontal gaze palsy lesion are absent, consciousness is usually impaired. Some- following severe frontal head trauma. Five weeks before this photograph was taken, the patient sustained a severe blow to the head, causing a de- times, in addition to ipsiversive deviation of the eyes, there pressed right frontal skull fracture. Operation disclosed extensive contusion is a small-amplitude nystagmus with ipsilateral quick and necrosis of the right frontal lobe (arrows indicate the site of the surgical phases. A similar finding occurs acutely after hemidecortica- incision). The patient had akinetic mutism and was hemiplegic on the right tion in the monkey (594). The slow phases of this nystagmus side. His eyes remained in right conjugate gaze at all times, but he could may reflect unopposed pursuit drives directed away from follow a very slowly moving target to the left. 942 CLINICAL NEURO-OPHTHALMOLOGY

Figure 19.36. Neuroimaging of an acute infarct in the territory of the left anterior cerebral and middle cerebral arteries. A, T2-weighted axial magnetic resonance image shows diffuse hyperintensity in the distribution of the left anterior cerebral artery (large arrowheads). Note the small area of hyperintensity in the right frontal region, consistent with an old infarct (small arrowhead). B, T2-weighted magnetic resonance image at a lower plane reveals an area of hyperintensity in the region of the left middle cerebral artery (arrowhead). The patient had a supranuclear conjugate gaze paresis to the left side and right hemineglect. He also had difficulty generating rightward saccades. The ocular motor signs were transient, as expected from a left-sided cerebral lesion. the side of the lesion. Vertical saccades may be abnormal; right hemisphere lesions. In the right hemisphere, the lesions they are dysmetric with an inappropriate horizontal compo- are located predominantly in the subcortical frontoparietal nent toward the side of the lesion (595). Because both hemi- region and the internal capsule. In the left hemisphere, the spheres usually must be activated to elicit a purely vertical lesions are usually larger, covering the entire frontotemporo- saccade, the loss of one hemisphere may cause such oblique parietal area. The larger the lesion, the more persistent the saccades. conjugate deviation. Quantitative recordings in such patients Following intracarotid injection of barbiturate (Wada test show that both the pursuit and the saccade deficits associated to determine cerebral dominance), a transient gaze prefer- with conjugate deviation of the eyes are predominantly con- ence may occur in association with hemiparesis; such a de- tralateral, but as the conjugate deviation resolves, an ipsi- viation occurs more commonly with right-sided injections, lateral pursuit defect becomes more apparent (599). Cranio- providing further evidence for the dominance of the right topic defects in saccades and especially pursuit may outlast hemisphere in directing attention (596). During the period the conjugate deviation, however, being greater in the field of hemiparesis of the Wada test, contralateral and ipsilateral contralateral to the lesion (600). The initial conjugate devia- saccades are still possible, with relatively minor slowing of tion may reflect the effect on eye movements of cerebral the former. This persistence of voluntary saccades is proba- hemisphere asymmetries in attention mechanisms (596), bly related to the influence of posterior cerebral areas, which whereas the more enduring eye movement defects after the receive blood supply from the vertebrobasilar system and conjugate deviation resolves may reflect more specific de- which project to the superior colliculus, independently of fects in motor control mechanisms mediated by the hemi- the frontal eye fields (597). spheres. Conjugate eye deviation is occasionally ‘‘wrong- As noted above, acute cerebral hemisphere lesions are way’’ (i.e., contralateral to the side of the lesion) (601). The frequently associated with a conjugate deviation of the eyes lesions are almost always hemorrhagic, most commonly in (598) (Fig. 19.35). The deviation is usually ipsilateral to the the thalamus. Affected patients usually have signs of rostral side of the affected hemisphere and is more common with brain stem dysfunction and a shift of midline structures. Epi- SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 943 leptic phenomena, impairment of ipsilateral pursuit pathways, and more caudal damage to descending pathways near the brain stem are evoked as explanations. In most cases, the last cause seems most plausible. Acute hemisphere lesions may cause epileptic seizures with contralateral deviation of the eyes or nystagmus, often with an associated head turn. The ocular motor manifestations of epilepsy are discussed below. Unilateral or bilateral ptosis may also occur with acute lesions in the cerebral hemispheres, usually in Figure 19.37. Conjugate lateral deviation of the eyes on forced closure of the eyelids in a patient with a tuberculoma of the left occipitoparietal the nondominant hemisphere (311,602). region. (From Cogan DG. Neurologic significance of lateral conjugate de- PERSISTENT DEFICITS CAUSED BY LARGE viation of the eyes on forced closure of the lids. Arch Ophthalmol 1948; 39;37–42.) UNILATERAL LESIONS Persistent ocular motor deficits caused by lesions such as hemidecortication for intractable seizures are summarized in Table 19.7. Although there may be no resting deviation movements may be too fast (pursuit gain more than 1); for of the eyes, forced eyelid closure may cause a contralateral higher target velocities, pursuit gain toward the intact side spastic conjugate eye movement, the mechanism of which is normal (605,606). This disturbance of smooth pursuit is not understood (Fig. 19.37) (603,604). This tonic deviation probably reflects loss of both posterior (occipital-parietal- (Cogan’s sign) differs from the tonic deviation associated temporal) and frontal influences. with Wallenberg’s syndrome, because in the former, active A convenient way to demonstrate the asymmetry of or attempted eyelid closure is necessary to cause the eyes smooth pursuit that occurs with large hemisphere lesions is to deviate, whereas in the latter, the deviation occurs even with a hand-held optokinetic tape or drum (607). The re- with eyes open in darkness. Cogan’s sign occurs most fre- sponse is decreased when the stripes are moved or the drum quently with parietotemporal lesions. is rotated toward the side of the lesion. At the bedside, this In primary position, a small-amplitude nystagmus may optokinetic response is usually judged by the frequency and be present that is best seen during ophthalmoscopy. It is amplitude of quick phases, but because these quick-phase characterized by slow phases directed toward the side of the variables also depend on slow-phase velocity, a decreased intact hemisphere and may represent an imbalance in response may reflect impaired slow-phase generation, im- smooth-pursuit tone (605). Horizontal pursuit gain (eye ve- paired quick-phase generation, or a combination of the two. locity/target velocity) is low for tracking of targets moving Hemidecortication causes abnormalities of both contralat- toward the side of the lesion for all stimulus velocities. For eral and ipsilateral horizontal saccades (605,608). Saccades targets moving slowly toward the intact hemisphere, the eye are usually slower than normal for refixations into and sometimes out of the hemianopic field. Saccadic latency is also prolonged in both directions (605). For small refixations, Table 19.7 contralaterally directed saccades have greater latencies than Persistent Effects of Large Unilateral Lesions of the Cerebral ipsilateral saccades. Prolonged saccadic reaction time may Hemispheres on Ocular Motor Function reflect (a) defects in visual detection because of the hemianopia, (b) defects in directing visual attention, and (c) abnor- Fixation: In darkness, eyes usually drift away from the side of the lesion. This may also be evident during fixation (on ophthalmoscopic exam) as mal motor programming. Saccadic accuracy is impaired nystagmus with quick phases toward the side of the lesion. Square-wave asymmetrically: most contralaterally directed saccades do jerks. not put the eye on target (608). Saccades: Slower saccades to both sides, especially contralaterally; latency The horizontal VOR may be mildly asymmetric in hemi- longer for small saccades directed contralateral to the side of the lesion; decorticate patients, with the gain (eye velocity/head veloc- inaccurate (hypometric and hypermetric) saccades into the “blind” ity) being greater for compensatory eye movements directed hemifield. away from the side of the lesion (609,610). More asymmetry Smooth pursuit: Reduced pursuit gain toward the side of the lesion; smooth- appears when visual fixation and vestibular stimulation are pursuit gain away from the side of the lesion may be increased for low- velocity targets. combined (during rotation while fixating a stationary ob- Optokinetic: Reduced gain for stimuli directed toward the side of the lesion; ject), probably reflecting the ipsilateral smooth-pursuit defi- impaired optokinetic after-nystagmus; may be relatively preserved cit. The asymmetry is still present during head rotation if compared with pursuit, with prolonged build-up of slow-phase velocity. the patient imagines a stationary object (610). Vestibular: During sinusoidal rotation, VOR gain in darkness may be slightly asymmetric (greater for eye movements away from the side of the lesion); with attempted fixation of an imagined or real stationary target, FOCAL LESIONS the asymmetry is increased. Forced eyelid closure: Eyes usually deviate conjugately away from the side Ocular motor disturbances that occur from focal lesions of the lesion (“spasticity of conjugate gaze”). of the cerebral hemispheres depend on a variety of factors, including the location and size of the lesion and whether the VOR, vestibulo-ocular reflex. lesion is unilateral or bilateral. 944 CLINICAL NEURO-OPHTHALMOLOGY

Occipital Lobe Lesions paired (627). Such a behavior deficit occurs in patients with lesions affecting the temporoparieto-occipital cortex A unilateral lesion of either occipital lobe causes a contra- (625,628–631). lateral visual field defect and an ocular motor deficit (sac- Lesions of adjacent cortex (including Brodmann areas 19 cadic dysmetria) that reflects the patient’s homonymous and 39), which probably correspond to the medial superior hemianopia. Saccades into the hemianopic visual field are temporal (MST) visual area and underlying white matter, dysmetric, usually hypometric, and similar patterns of sac- lead to a directional defect in smooth pursuit that is charac- cades are seen with acoustic targets, implying some degree terized by impaired tracking (reduced gain) for targets mov- of common motor programming, perhaps influenced by as- ing toward the side of the lesion, irrespective of the visual sociated defects in directing spatial attention (611). Charac- hemifield in which the target lies (628,632,633). Barton et teristic patterns also occur in patients who have hemianopic al. (630) did not find a direct correlation between pursuit and dyslexia (612). Patients with hemianopia usually show a va- motion detection deficits. Either could be present without the riety of compensatory strategies to increase saccadic accu- other, although unavoidable differences in the paradigms for racy (613), unless hemineglect is also present (614). These eye movement and for motion perception precluded a strict strategies include (a) a staircase of search saccades with one-to-one correspondence. Lawden et al. (634) showed that backward, glissadic drifts; (b) a deliberate overshooting sac- pursuit is also influenced by the presence of a stationary- cade to bring the target into the intact hemifield of vision; structure background in patients with cerebral lesions. Le- and (c) with predictable targets, saccades using memory of sions in the inferior parietal cortex (area 40) and in white previous attempts. Such findings have been used to develop matter containing frontoparietal connections were associated simple clinical tests for distinguishing homonymous hemia- with a significant degradation in pursuit capability when pa- nopias with and without neglect (615). Rapid gaze shifts tients had to track a small target moving on a structured achieved by combined movements of eye and head also show background rather than a small target moving in darkness. increased latency of head movements and development of In some patients, pursuit gain away from the side of the compensatory strategies when looking to the hemianopic parietal lobe lesion is also somewhat reduced, especially side (616). Smooth pursuit remains intact with unilateral when the eyes move into the contralateral field of gaze. This lesions of the striate cortex, as long as the moving stimulus phenomenon probably results from contralateral neglect is presented to the intact hemifield (617). Optokinetic nys- (600,635) and may be associated with a paucity of explora- tagmus elicited at the bedside is usually symmetric, unless tory eye movements in the contralateral field (636). In other subcortical pathways involved in smooth tracking are also patients, contralateral pursuit gain is increased (628,637). affected (618; discussed later). Subcortical, thalamic, and brain stem lesions may cause an Bilateral occipital lesions cause cortical blindness. A pa- ipsilateral defect from damage to involvement of the de- tient with bilateral, congenital occipital lesions and little re- scending pathway for smooth pursuit (623,638,639). Full- sidual vision was reported to be able to make voluntary sac- field optokinetic stimulation is also impaired with experi- cades but not smooth pursuit (619). Optokinetic responses mental lesions of MST in monkeys (627). In human patients are present in monkeys following bilateral occipital lobec- with parietal lesions, optokinetic nystagmus (OKN) is often tomy (620), but this may not be the case in humans (621). impaired in response to stimuli moving toward the side of Focal occipital seizures may cause either contralateral or the lesion, although it may be relatively spared compared ipsilateral deviation of the eyes and nystagmus (discussed with foveal tracking (624,640). Optokinetic after-nystagmus later). (OKAN) and circularvection (the sensation of self-rotation) Parietal Lobe Lesions may also be impaired (625). In monkeys, acute lesions of the parietal lobe cause asymmetries of the VOR (641), but Unilateral lesions of the parietal lobes, especially those comparable studies in humans are lacking. involving the inferior parietal lobule and underlying deep Unilateral lesions of the parietal lobe may affect saccadic white matter, cause abnormalities of ocular tracking of mov- initiation, causing an increase in saccadic latencies, either ing targets, including an asymmetry of smooth pursuit and bilaterally (642) or only for saccades to contralateral targets of optokinetic nystagmus as tested at the bedside with hand- (643,644). These changes are independent of any visual field held drums or tapes (607,622–625). Lesions at the temporo- defect. The latency defects are enhanced when the fixation parieto-occipital junction probably affect secondary visual target remains on and a new target appears in the periphery areas that are important for motion processing and for pro- (the ‘‘overlap’’ task) and are diminished when the fixation gramming of smooth-pursuit eye movements (626). One target is extinguished before the presentation of the new such area is likely to be the human homologue of what in target in the periphery (the ‘‘gap’’ task). Other deficits re- monkeys is called the middle temporal (MT) visual area. ported with unilateral parietal lesions include inaccuracy and Lesions of MT in monkeys impair the ability to estimate hypometria of contralaterally directed visually guided sac- the speed of a moving target that is within the affected visual cades (645), mild saccadic slowing (646), and disturbances field, although stationary objects can be seen and accurately of predictive saccadic tracking (647). Memory-guided sac- localized. The ocular motor consequences of this scotoma cades are especially impaired, being both delayed and inac- for motion or retinotopic defect are that saccades made to curate (648,649). These changes in saccades are more promi- targets moving in the affected, contralateral hemifield are nent with right hemisphere lesions. The saccade defects inaccurate and that the initiation of smooth pursuit is im- associated with parietal lesions may be caused in part by SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 945 difficulties in shifting attention from one position to another feeling of dizziness is common with a variety of seizure in extrapersonal space (650), but there are no strict correla- types, a true sensation of rotation—tornado epilepsy—is tions between attention and the ocular motor deficits a rare but well-described epileptic phenomenon (664, (651–653). In a double-step paradigm in which subjects had 673–679). to be able to use nonretinal, corollary discharge information about the saccade to the first target to compute the size and Frontal Lobe Lesions direction of the second saccade, patients with parietal lesions were not able to make the appropriate computation about Lesions of the frontal lobe, in both monkeys and humans, the size and direction of the saccade (i.e., their spatial com- may produce an ipsilateral conjugate deviation of the eyes putation was impaired, implying a defect in using extrareti- that resolves with time (313,680). Rarely, contralateral de- nal signals of eye position) (645,654,655). In general, pari- viation occurs with acute frontal lesions (305), which may etal lesions have relatively little effect on generation of more include just the frontal eye fields (681) or frontoparietal le- volitional internally guided saccades (i.e., when the target sions (682). Enduring deficits after frontal lobe lesions in- position is memorized or known) or on reflexive saccade clude abnormalities of saccades and smooth pursuit (651). inhibition (as in the antisaccade task) but seem more in- Three areas within the frontal lobes that play an important volved with triggering the superior colliculus directly to ini- role in the control of eye movements are (a) the frontal eye tiate reflexive saccades to the unexpected appearance of fields; (b) the supplementary eye fields in the supplementary novel targets in the visual environment (656). Patients with motor area; and (c) the prefrontal cortex, especially the dor- parietal lesions also show defects in visual search tasks, solateral portion (683). though they may involve both the ipsilateral and contralat- Unilateral frontal eye field lesions lead to a slight increase eral visual fields (587,649,657,658). Selection of targets of in saccade latency to reflexively triggered saccades with a interest among competing visual stimuli is also affected by predominantly contralateral hypometria (684–687). Laten- experimental parietal lesions (659), and this finding may be cies are greatest in the overlap task (when the initial fixation related to parietal patients who show simultagnosia. target remains on, even after the peripheral target appears), Bilateral parietal lobe lesions may cause acquired ocular suggesting a role for the frontal eye fields in disengagement motor apraxia, particularly if the lesions are large (discussed from central fixation. Saccades may show a prolonged la- later). When smooth pursuit is possible, it is particularly tency to predictable target jumps, particularly in patients limited with higher-acceleration target motion (660). with right-sided frontal lesions (684,688). There is also a bilateral deficit in latency and accuracy for saccades to a Temporal Lobe Lesions remembered visual target but not for remembered saccades after a vestibular (rotation) input (671). With attempted ver- The effects of temporal lobe lesions on eye movements tical saccades, a horizontal component directed toward the are less well studied. In patients with posterior temporal side of the lesion often causes an oblique movement (595). lesions, fixation-suppression of caloric-induced nystagmus Mild slowing of contralateral saccades occurs in some pa- is said to be impaired when slow phases are directed away tients (684). Deep, unilateral frontal lobe lesions cause in- from the side of the lesion (661). This abnormality may creased latency for contralateral saccades (642). This deficit reflect impairment of visual-motion or smooth-pursuit path- is probably caused by damage of efferent and afferent con- ways rather than any effect on vestibular nystagmus per se. nections of the frontal eye fields. Patients with homonymous hemianopia and lesions affecting Patients with unilateral frontal lesions show defects in the temporal lobes may lack the sensation of self-rotation the antisaccade task. This requires the subject to suppress a (circularvection) that normally occurs during full-field op- reflexive glance toward a peripheral visual target and, in- tokinetic stimulation, compared with patients who have a stead, look toward its mirror location in the contralateral homonymous hemianopia from occipital lesions and who do visual field (689). Patients with unilateral frontal lobe lesions experience circularvection (662). These findings support the that involve the dorsolateral portion of the frontal cortex localization of the vestibular cortex to the superior temporal have difficulty in suppressing the reflexive glance, especially gyrus and, perhaps, the adjacent parietal cortex (663–670). if the visual stimulus appears in the visual hemifield contra- Patients with parietoinsular lesions may have tilts of the sub- lateral to the side of the lesion (690). Patients with lesions jective visual vertical, usually contraversive (107). This is in the frontal eye fields alone do not have this problem, not associated with a skew deviation, although occasionally though they do have difficulty in generating the antisaccade there is some monocular torsion. Patients with lesions in the when the target lies in the visual hemifield ipsilateral to the same area may also have a defect in generating memory- lesion (689,691). After lesions in the dorsolateral portion of guided saccades after a vestibular (rotational) stimulus (671). the frontal cortex, there is also a deficit in both vestibular Finally, patients with lesions in the medial temporal (rotation) and visually guided memory saccades (692) as lobe—the hippocampus—show marked impairment of gen- well as deficits in generating predictive saccades (693) and erating sequences of saccades, whereas their spatial memory in visual search (587,694). Taken together, the results of is intact (672). lesion studies suggest that the dorsolateral portion of the Seizures emanating in the temporal lobes may cause a frontal cortex has an overall role in decisional processes variety of vestibular sensations, although lesions in the fron- related to suppressing unwanted saccades and facilitating tal lobes may produce similar phenomenon. Although a mild saccades to known upcoming target locations. Lesion studies 946 CLINICAL NEURO-OPHTHALMOLOGY also suggest that the anterior cingulate cortex may also play drome, the lesions are usually bilateral and located in the a role in suppressing unwanted saccades (695). Lesions af- parietal or occipital lobes. The anatomic basis for this dis- fecting the supplementary eye fields, especially in the left turbance is not known, although it has been attributed to hemisphere, impair the ability of patients to make a remem- defects in the inhibitory control of the superior colliculus by bered sequence of saccades (696,697). Likewise, patients the substantia nigra, pars reticulata (712). Spasm of fixation with such lesions cannot make a memory-guided saccade to refers to a rare defect in generating voluntary eye movements a visual target, but they can do so after a body rotation when a fixation target is continuously present; it is alleviated (692,698). Patients with lesions of the supplementary eye when the central fixation target is removed (712). fields may also show abnormalities in changing the direction of saccades from a previously learned sequence (699). OCULAR MOTOR APRAXIA Patients with unilateral frontal lobe lesions also show pur- Ocular motor apraxia is characterized by an impaired abil- suit deficits (562,593,625,687,700,701). The frontal and ity to generate saccades on command (Fig. 19.38). Congeni- supplementary eye fields and perhaps the dorsolateral por- tal ocular motor apraxia was first described by Cogan in tion of the prefrontal cortex play a role in this abnormality. 1965. An abnormality in eye movements may be recognized Defects are in both initiation and maintenance (more so at shortly after birth, when the child does not appear to fixate higher target speeds and frequencies). If lesions are in the upon objects normally and may appear blind (713). Some supplementary eye field, defects are ipsilateral; if lesions are children with congenital ocular motor apraxia are said to in the frontal eye field, defects are bilateral but usually have a transient head and limb tremor in the first few days greater for ipsilateral tracking. Patients with lesions of the of life. Between ages 4 and 6 months, characteristic thrusting supplementary eye field may have delayed reversal with pe- horizontal head movements develop, sometimes with promi- riodic constant-velocity stimuli, implying impaired anticipa- nent blinking or even rubbing of the eyelids, when the child tion of the target trajectory. Saccades to moving targets are attempts to change fixation. In children with poor head con- also inaccurate in some of these patients. Patients with le- trol, development of head thrusting may be delayed or ab- sions affecting the frontal eye fields may also show cranio- sent. Almost all patients also show a defect in generating topic as well as directional (ipsilateral) defects in pursuit quick phases of nystagmus, which can usually be appreciated (600). Tracking in the field contralateral to the lesion is at the bedside by manual spinning of the patient, either when worse than in the ipsilateral field. Visual exploration deficits holding the child out at arm’s length or by rotating the child may also play a role in some of the eye movement deficits on a swivel chair (if necessary sitting in an adult’s lap). seen with frontal lesions (702). Despite difficulties in shifting horizontal gaze, vertical vol- Acute bilateral frontal or frontoparietal lesions may pro- untary eye movements are normal. duce a striking disturbance of ocular motility that is called Measurements of eye and head movements have further acquired ocular motor apraxia. It is characterized by loss characterized congenital ocular motor apraxia (714–716). of voluntary control of eye movements, both saccades and With the head immobilized, patients show both impaired pursuit, with preservation of reflex movements, including initiation (increased latency) and decreased amplitude (hy- the VOR and quick phases of nystagmus. There is also rela- pometria) of voluntary saccades in response to either a sim- tive preservation of saccades made to visual targets, com- ple verbal command to look left or right or in tracking a step pared with internally guided saccades made on command, displacement of a target. Saccades are also delayed during and preservation of saccades made with blinking or with attempted refixations between auditory targets in complete head movements (703,704). Voluntary movements of the darkness. Thus, abnormal visual-fixation reflexes cannot ex- eyes are limited in the horizontal and usually also in the vertical plane. The defect of voluntary eye movements probably reflects disruption of descending pathways from both the frontal eye fields and the parietal cortex so that the superior colliculus and brain stem reticular formation are bereft of their supranuclear inputs. The behavior deficit is similar to that produced by combined, experimental lesions of the frontal eye fields and superior colliculus (705). When a similar disorder of ocular motility, called ‘‘psychic paralysis of gaze,’’ is associated with optic ataxia and disturbance of visual attention (simultanagnosia), the eponym Ba´lint’s syndrome is used (703–706) (see Chapter 13). The main abnormalities are a defect in the visual guidance of saccades (increased latency and decreased accuracy) Figure 19.38. Congenital ocular motor apraxia. The patient was looking and inaccurate searching saccades. Voluntary saccades may to the right (left) when he was told to glance at the camera. His head rapidly moved to the left, while the eyes remained deviated toward the right. As be made with greater ease than those in response to visual a result, the patient’s head had to turn further to the left in order to permit targets, the converse of what one usually finds with more fixation ahead (center). Once the patient was able to fixate on the camera, frontal lesions (707–709). Spontaneous blinking may be lost his head turned slowly back to the right until it was straight (right). (From (710). In one patient, the visual scene faded during fixation Urrets-Zavalia A, Remonda C. Congenital ocular motor apraxia. Ophthal- and intentional blinking restored it (711). In Ba´lint’s syn- mologica 1957;134Ϻ157–167.) SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 947 plain the difficulty initiating saccades. Saccadic velocities quick phases (both horizontal and vertical) are typically af- are normal, however, and saccades or quick phases of nys- fected, and because saccades may be slow. In the early stages tagmus of large amplitude can occasionally be generated. of these diseases, however, the ocular motor apraxia may These findings indicate that in these patients, the premotor be indistinguishable from congenital ocular motor apraxia. brain stem burst neurons that generate saccadic eye move- Thus, patients with ataxia-telangiectasia (Louis-Bar syn- ments are intact. In younger patients, however, the timing drome, 11q22-23) and its variants (ataxia-oculomotor and amplitude (but not velocity) of quick phases of vestibular apraxia syndrome of Aicardi, types 1 and 2), Gaucher’s dis- and optokinetic nystagmus may be impaired (i.e., the eyes ease (types 2 and 3,1q21-31), Niemann-Pick disease type intermittently deviate tonically in the direction of the slow 2s, Pelizaeus-Merzbacher disease, Cockayne’s syndrome, phase because of a defect in the initiation of quick phases). Huntington’s disease, hepatolenticular degeneration, vita- Sometimes the saccade defects and head thrusts are asym- min E deficiency, some of the peroxisome disorders, Whip- metric (717). Pursuit eye movements may also be of low ple’s disease, and many other storage diseases and amino- gain, but the corrective saccades are usually promptly gener- acidurias may appear to have ocular motor apraxia ated. The defects in congenital ocular motor apraxia are usu- (723,724,727–735) (Fig. 19.32). ally restricted to the horizontal plane, an important differen- A few features that can be used to distinguish some of tial diagnostic point because most acquired cases of ocular these disorders from congenital ocular motor apraxia include motor apraxia also cause defects in the vertical plane. the following: The head thrusts made by patients with congenital ocular motor apraxia probably reflect one of several adaptive strate- 1. In Pelizaeus-Merzbacher disease, pendular, elliptical gies to facilitate changes in gaze (714,718). Younger patients nystagmus, upbeat nystagmus, saccade dysmetria, and appear to use their intact VOR, which drives their eyes into other cerebellar signs (especially truncal titubation) are an extreme contraversive position in the orbit. As the head often present. continues to move past the target, the eyes are dragged along 2. Patients with Niemann-Pick disease characteristically in space until they become aligned with the target. The head show a vertical and especially downgaze disturbance then rotates backward and the eyes maintain fixation as they along with dysarthria, ataxia, cognitive dysfunction, and are brought back to the primary position in the orbit by the emotional changes. Such patients have so-called foam VOR. In contrast, older patients appear to use the head cells in the bone marrow. Rarely, a horizontal gaze dis- movement alone to trigger the generation of a saccadic eye turbance dominates the picture. The typical vertical pat- movement that cannot normally be made with the head still. tern of gaze disturbance in Niemann-Pick must be dis- This strategy may reflect the use of a phylogenetically old tinguished from the vertical gaze palsies associated with linkage between head and saccadic eye movements that oc- kernicterus, in which athetosis and hearing loss are com- curs reflexively in afoveate animals such as the rabbit when monly associated. they desire to redirect their center of visual attention. 3. In Gaucher’s disease, vertical gaze may be affected, but The cause of congenital ocular motor apraxia is unknown. horizontal gaze disturbances are more common. Cogan (719) suggested a delay in the normal development 4. Tay-Sachs disease impairs vertical and, subsequently, of the mechanisms by which we assume voluntary control horizontal eye movements. over eye movements. Delayed psychomotor development 5. Late-onset hexosaminidase deficiency also preferen- (especially in learning to read and in speech), infantile hypo- tially affects vertical gaze. tonia, strabismus, incoordination, torsional nystagmus, and 6. In Whipple’s disease, supranuclear and especially verti- clumsiness occur in some patients (720). Associated anoma- cal gaze palsy is frequent and may be associated with lies, especially agenesis of the corpus callosum and cerebel- the convergence oscillations of ‘‘oculomasticatory myo- lar dysplasia and hypoplasia (e.g., as part of Joubert’s syn- rhythmia.’’ drome), are found in a number of patients with congenital 7. In Joubert’s syndrome, patients commonly have skew ocular motor apraxia (721–724). Most likely, however, such deviations that change with lateral gaze and also sponta- anomalies are markers of abnormal development rather than neously alternate as to which eye is higher, along with being directly responsible for the eye movement disorder. seesaw and pendular nystagmus. Patients with Joubert’s Congenital ocular motor apraxia is occasionally familial and syndrome may also have pigmentary degeneration of has been reported in monozygotic twins (725,726). Patients the retina as well as breathing disturbances early in life. usually improve with age, with the head movements becom- 8. In vitamin E deficiency (e.g., abetalipoproteinemia), a ing less prominent as the patients are better able to direct slow but full range of abduction and limited range but their eyes voluntarily. normal speed of adduction are characteristic. A variety of disorders that directly involve the brain stem 9. Patients with ataxia-telangiectasia have other cerebellar mechanisms for generating saccades, including structural or eye signs and elevated levels of alpha-fetoprotein. degenerative processes within the pontine and mesence- 10. In childhood Huntington’s disease, slowing of saccades phalic reticular formations, are characterized by the develop- is prominent, and rigidity may be more apparent than ment of a strategy of head thrusting or blinking to shift gaze chorea. that superficially resembles congenital ocular motor apraxia. These disorders usually can be differentiated from congeni- The role of blinking in facilitating eye movements in pa- tal ocular motor apraxia because all types of saccades and tients with congenital ocular motor apraxia may be related 948 CLINICAL NEURO-OPHTHALMOLOGY to a natural synkinesis of blinking and saccade-generating OCULAR MOTOR MANIFESTATIONS OF SEIZURES or in some cases to lesions in the posterior fossa. Zee et al. (308) studied two patients who could make saccades of nor- Eye and head movements are common manifestations of mal velocity and amplitude only in association with a simul- epileptic seizures, and the wide representation of oculomotor taneous blink. In one patient, the initiation of saccades was and vestibular control within the cerebral cortex leads to a also facilitated by blinks, much like patients with typical number of possible ways that seizures can affect eye move- congenital ocular motor apraxia; however, both patients had ments themselves and visual or vestibular perceptions (670). other signs of cerebellar or brain stem dysfunction, suggest- A variety of eye movements can occur with seizures, in- ing a posterior fossa localization for blink facilitation of sac- cluding horizontal or vertical gaze deviation, skew deviation, cadic velocity and amplitude. and spontaneous, retractory, periodic alternating or monocular nystagmus (122,766–776). Epileptic convergence nystagmus may occur with periodic lateralizing epileptiform ABNORMAL EYE MOVEMENTS AND DEMENTIA discharges (777) and with burst-suppression patterns Patients with various dementing processes have abnormal (778,779). The seizure focus may arise from any lobe, al- eye movements, reflecting either disturbances in cerebral though the lesions usually are more posterior. Epileptic nys- cortical structures or in other subcortical structures that may tagmus can occur with typical absence seizures (780) and with infantile spasms (781). also be affected by that particular disease. Excessive errors Patients with epileptic foci affecting the temporoparieto- on the antisaccade test (736–739), particularly when associ- occipital cortex may show either ipsiversive or contraversive ated with a ‘‘visual grasp reflex’’ (741), are a useful indicator eye deviation and nystagmus (766,782–784). Seizures are of an organic process when pseudodementia is a diagnostic usually accompanied by relatively fast cortical activity. Ip- consideration in a patient with a possible cognitive decline. siversive gaze deviation may be caused by a smooth-pursuit Patients with Alzheimer’s disease have excessive numbers movement, with the quick phases of nystagmus being trig- of square-wave jerks and defects in saccade latency and, gered by the eccentric eye position and ipsilateral drift of occasionally, accuracy and velocity (737,739,740). Alzhei- the eyes. Contraversive deviation may be initiated by sac- mer’s patients show longer mean fixation durations and a cades and the subsequent nystagmus from an impaired gaze- reduced number of exploring saccades when viewing simple holding mechanism (deficient neural integrator). Furman et but not complex scenes, perhaps reflecting a motivation defi- al. (678) described a patient with a temporoparietal seizure cit. Impaired predictive tracking and excessive number of focus who showed no gaze deviation before the onset of anticipatory saccades are a feature of Alzheimer’s disease nystagmus. Her attacks were accompanied by vertigo, sug- (737), as is difficulty generating saccades during reading gesting involvement of the ‘‘vestibular cortex’’ of the supe- (738). Eye movements may be used to monitor higher-level rior temporal sulcus. processes, such as ‘‘curiosity,’’ by looking at exploratory Overall, contraversive deviation of the eyes is more com- behavior (visual search and scan paths) while a subject views mon than ipsiversive deviation during seizures. In cases with novel visual stimuli (587). This capability too appears to posterior foci (temporal, parietal, or occipital lobes), experi- be diminished in Alzheimer’s patients (742). Impairment of mental studies suggest that eye movements may be mediated spatially directed attention may also be reflected in eye by projections via either the superior colliculus or the frontal movement abnormalities (743), and a Ba´lint-like syndrome eye fields (785). Thus, saccades may be generated by more may develop (744). Pursuit abnormalities also occur in Alz- than one of the descending parallel pathways. Frontal lobe heimer’s patients (745,746). foci are also reported to cause contraversive deviations un- Patients with Creutzfeldt-Jakob disease may show limita- less they are bilateral, in which case vertical deviations also tion of vertical gaze and slow vertical saccades (747,748) may occur (786). These results are consistent with stimula- as well as two rare forms of nystagmus: periodic alternating tion studies in monkeys, in which unilateral stimulation of nystagmus (748) and centripetal nystagmus (749). Over- the frontal eye fields typically causes oblique saccades with doses of lithium or bismuth may lead to syndromes that a contralateral horizontal component; the direction of the mimic Creutzfeldt-Jakob disease (750,751). Cerebellar eye vertical saccade depends upon a cortical map (787). Purely signs are typically found in another prion disorder: Gerst- vertical movements require bilateral stimulation of the fron- mann-Stru¨ssler-Scheinker disease (752,753). tal eye fields. Because there are also neurons in the frontal Patients infected with the human immunodeficiency virus eye fields that contribute to smooth pursuit, it is theoretically (HIV) show a number of ocular motor abnormalities that possible that frontal lobe foci could lead to an ipsiversive usually reflect the effects of an opportunistic infection or deviation. coexistent neoplasia (754–758). However, HIV encephalop- Head turning is a common accompaniment of epileptic athy itself can cause disturbed ocular motility (759), includ- gaze deviation. In patients who are conscious during the ing errors on the antisaccade task, increased fixation instabil- seizure, a frontal focus is likely, and the initial direction of ity, increased latencies of horizontal and, especially, vertical head turning is usually, but not invariably, contralateral to saccades (760), acquired ocular motor apraxia (761), cere- the seizure focus (788–790). A contralateral focus is also bellar and brain stem signs, including gaze-evoked and dis- likely in a patient who shows marked, sustained, and unnatu- sociated nystagmus (762,763), slow saccades (764), and de- ral lateral positioning of the head and eyes (789,790). In creased but especially asymmetric pursuit gain (760,765). patients who are unconscious during the seizure, the focus SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 949 may arise from any lobe, and head turning may be toward or of the lids (eyes-open coma) may also occur in unconscious away from the side of the lesion (788,791,792). As discussed patients and may be related to pontomesencephalic dysfunc- above, seizures emanating in the superior temporal lobes tion (803). may cause a variety of vestibular sensations (670), and oc- Deviations of the visual axes in coma may be caused by cipital lobe seizures may produce oscillopsia (793). Rarely, skew deviation, by a phoria that is normally compensated for seizures are precipitated by movements of the eyes, such as by fusional mechanisms, or by paralysis of the oculomotor, convergence (794) or sustained lateral deviation (795). trochlear, or abducens nerves. Restrictive ophthalmopathy, particularly blowout fracture of the orbit, may be an addi- EYE MOVEMENTS IN STUPOR AND COMA tional mechanism in patients who have suffered facial trauma. The diagnosis of the cause of the deviation depends The ocular motor examination is especially useful for upon determining whether the range of movement of the evaluating the unconscious patient, because both arousal and eyes induced by head rotation or caloric stimulation (dis- eye movements are controlled by neurons in the brain stem cussed later) is reduced in a pattern corresponding to specific reticular formation. Comatose patients do not make eye muscle weakness. In addition, assessment of the pupils and movements that depend upon cortical visual processing. Vol- other brain stem reflexes may help. Complete oculomotor untary saccades and smooth pursuit are in abeyance, and nerve palsy causes pupillary dilation, ipsilateral ptosis, and quick phases of nystagmus also may be absent. The ocular deviation of the eye down and out. Pupillary involvement motor examination of the unconscious patient, therefore, is an early sign of uncal herniation (797), and disturbances consists of observing the resting position of the eyes, looking of eye movements usually follow (804). Vertical misalign- for any spontaneous movements, and reflexively inducing ment of the eyes is usually caused by skew deviation or eye movements (796–798). trochlear nerve palsy, the latter being particularly common Gaze Deviations following head trauma. Bilateral abducens palsy occurs when increased intracranial pressure compromises the Conjugate, horizontal deviation of the eyes is common in nerves as they bend over the petroclinoid ligament. Occa- coma. When this is caused by lesions above the brain stem sionally, skew deviation and INO occur in patients with met- ocular motor decussation between the midbrain and pons, abolic encephalopathy or drug intoxication. the eyes are usually directed toward the side of the lesion and away from the hemiparesis. A vestibular stimulus, however, Spontaneous Eye Movements usually drives the eyes across the midline. If the conjugate deviation is caused by a lesion below the ocular motor decus- Spontaneous eye movements that occur in unconscious sation, the eyes will be directed away from the side of the patients may help establish the etiology of the coma. Slow lesion and toward the hemiparesis. The latter is typically conjugate or disconjugate roving eye movements are similar seen with pontine lesions, but also in some patients with to the eye movements of light sleep but slower than the rapid thalamic (18) and rarely hemispheric disease above the thala- eye movements (REM) of paradoxic or REM sleep. If a mus (so-called wrong-way deviations) (305,682). complete range can be shown, their presence indicates that Intermittent deviations of the eyes and head are usually brain stem gaze mechanisms are intact (796). caused by seizure activity. At the onset of each attack, gaze Other types of spontaneous eye movements consist of var- is usually deviated contralateral to the side of the seizure ious forms of vertical to-and-fro movements, often called focus and may be followed by nystagmus with contralat- ‘‘bobbing.’’ Typical ocular bobbing consists of intermittent, erally directed quick phases. Toward the end of the seizure, usually conjugate, rapid downward movement of the eyes gaze drifts to an ipsilateral (paretic) position. followed by a slower return to the primary position Tonic downward deviation of the eyes, often accompanied (805,806). Reflex horizontal eye movements are usually ab- by convergence, occurs in patients with thalamic hemor- sent. Ocular bobbing is a classic sign of intrinsic pontine rhage (453,456) and with lesions affecting the dorsal mid- lesions, usually hemorrhage, but it also occurs in patients brain. It may be induced by unilateral caloric stimulation, with cerebellar lesions that compress the pons and in meta- after the initial horizontal deviation subsides, in patients with bolic or toxic encephalopathy. Inverse bobbing also occurs coma induced by sedative drugs (799). Forced downward in this setting. This eye movement abnormality, which is also deviation of the eyes can also be seen in patients with nonor- called ocular dipping, is characterized by a slow downward ganic (feigned) coma or seizures (800). movement, followed by a rapid return to midposition. Re- Tonic upward deviation of the eyes is uncommon in coma, verse bobbing consists of rapid deviation of the eyes upward but it may be seen after an hypoxic-ischemic insult, even and a slow return to the horizontal, whereas converse bob- when no pathologic lesions are found in the midbrain (801). bing (also called reverse dipping) is characterized by a slow Patients who survive after manifesting this ocular motor dis- upward drift of the eyes that is followed by a rapid return turbance typically develop downbeating nystagmus, the up- to primary position. These variants of ocular bobbing are ward drift of which is thought to be caused by loss of inhibi- less reliable for localization than is straightforward ocular tion on the upward vertical VOR (802). Upward deviation bobbing. Nevertheless, the occurrence in some patients of of the eyes also occurs as a component of oculogyric crisis, several different types of ocular bobbing during their illness which usually occurs as a side effect of certain drugs, espe- suggests a common underlying pathophysiology (807–810). cially neuroleptic agents (521). Tonic uninhibited elevation Because the pathways that mediate upward and downward 950 CLINICAL NEURO-OPHTHALMOLOGY eye movements differ anatomically and probably pharmaco- jects, this is unlikely to be the case in unconscious patients. logically, it seems likely that these movements represent a Therefore, eye rotations induced by head rotation in uncon- varying imbalance of mechanisms for vertical gaze. Rarely, scious individuals principally result from the effects of the large-amplitude pendular vertical oscillations occur in the semicircular canals and their central connections (i.e., the acute phase of a brain stem stroke (804). VOR). The head should not be rotated in unconscious pa- Repetitive vertical eye movements, including variants of tients unless there is certainty that no neck injury or abnor- ocular bobbing, may contain convergent-divergent compo- mality is present. Conventionally, high-frequency (1–2 Hz) nents. Such movements are usually caused by disease affect- quasi-sinusoidal rotations or position-step stimuli are ap- ing the dorsal midbrain (109,808,812). plied; the latter consists of a sudden head turn to a new Monocular bobbing movements may occur as a synkinesis position. Both horizontal and vertical rotations should be with jaw movement. Such movements are similar to those performed. If small-amplitude head rotations are performed, seen in the congenital condition called the Marcus Gunn the adequacy of the VOR can be estimated by observing the jaw-winking phenomenon and primarily involve the neural optic disc of one eye with an ophthalmoscope (344). pathways to the inferior rectus muscle (813). Caloric irrigation of the external auditory meatus causes Ping-pong gaze consists of slow, horizontal, conjugate convection currents of the vestibular endolymph that dis- deviations of the eyes that alternate every few seconds. In place the cupula of a semicircular canal; thus, this procedure more alert patients, ping-pong gaze has been shown to be a also tests the VOR. The canal stimulated depends on the series of small saccades that take the eyes back and forth orientation of the head (e.g., with the head elevated 30Њ from from one extreme orbital position to the other (814,815). the supine position, the horizontal canals are principally Although ping-pong gaze can occur in patients with posterior stimulated). Before caloric stimulation, the physician should fossa hemorrhage (816), it is usually a sign of bilateral in- always check that the tympanic membrane is intact. Usually farction of the cerebral hemispheres. In one reported case, only about 5 cc of ice water need be introduced into the no cerebral hemispheric lesions were noted, but bilateral external auditory meatus, but large quantities (100 cc or lesions of the cerebral peduncles were present (817). Some- more) may be necessary to induce a response in some coma- times oscillations with a periodicity similar to that of ping- tose patients. pong gaze can be induced transiently by a rapid head rotation Caloric stimulation with ice water is sometimes a more in patients with bilateral hemisphere disease (818). effective stimulus than head rotation, in part because of the Rapid, small-amplitude, vertical eye movements may be sustained nature of the stimulus and in part because of the the only manifestation of epileptic seizures in patients with arousing effect of the cold water. Combined cold caloric coexistent brain stem injury (819). Rapid, monocular eye stimulation and head rotation may be the most effective stimulus in the deeply unconscious patient (796). This usually movements with horizontal, vertical, or torsional compo- produces tonic deviation of the eyes toward the irrigated ear nents that occur in patients with coma may also indicate in patients with intact vestibular function. brain stem dysfunction. In testing reflex eye movements in unresponsive patients, Identification of patients who are conscious but quadri- it is important to note (a) the magnitude of the response; (b) plegic, the locked-in syndrome or de-efferented state, de- whether the ocular deviation is conjugate; (c) the dynamic pends on identifying preserved voluntary vertical eye move- response to position-step head rotations; and (d) the occur- ments (797,820). The syndrome is typically caused by rence of any quick phases of nystagmus, particularly during pontine infarction and is characterized in part by a variable caloric stimulation. Impaired abduction suggests abducens loss of voluntary and reflex horizontal movements, such that nerve palsy. Impaired adduction usually indicates either INO eyelid or vertical eye movements may be the only means or oculomotor nerve palsy, although occasionally impaired of communication during the acute illness. The locked-in adduction to vestibular stimulation is observed in patients syndrome also occurs with midbrain lesions, in which case with metabolic coma or drug intoxication. Vertical responses ptosis and ophthalmoplegia may be present (821). may be impaired with disease of the midbrain (822) or bilat- Reflex Eye Movements eral lesions of the MLF. Pontine lesions may abolish the reflex eye movements in the horizontal plane but spare the Reflex eye movements may be elicited in unconscious vertical responses. When reflex eye movements are present patients either by head rotation (the doll’s head or oculoce- in an unresponsive patient, the brain stem is likely to be phalic maneuver) or by caloric stimulation (798). Head rota- structurally intact. When reflex eye movements are abnormal tion, with the patient supine, stimulates the labyrinthine or absent, the cause may be structural disease, profound met- semicircular canals, the otoliths, and neck muscle proprio- abolic coma, or drug intoxication (823). Intoxication with a ceptors. However, unless there has been prior loss of vestibu- variety of medications may lead to partial or total loss of lar function (e.g., from aminoglycoside toxicity), the contri- reflexive eye movements. Metabolic disturbances can cause bution made by neck muscle proprioceptors to generating restriction of reflex eye movements, but usually only with reflex eye movements (the cervico-ocular reflex) is insignifi- profound coma (824). When used in combination with other cant (818). Furthermore, the otolith contribution is probably clinical signs, reflex eye movements are useful in evaluating small compared with that of the labyrinthine semicircular the prognosis of comatose patients (825,826). canals. Finally, although visually mediated eye movements, If reflex eye movements are intact in an unconscious pa- such as fixation and smooth pursuit, can influence the eye tient, the eyes are carried into a corner of the orbit when the movements produced by head rotation in normal, awake sub- head is rapidly rotated horizontally to a new position (posi- SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 951 tion step stimulus). If the head is held stationary in its new Singh and Strobos (827) induced retraction nystagmus with position, the eyes may slowly drift back to the midline. This caloric stimulation. Patients who survive coma but who are implies that the gaze-holding mechanism (neural integrator) left in a persistent vegetative state, with severe damage of is not functioning normally. Patients with more rapid centri- the cerebral hemispheres but preservation of the brain stem petal drift may have more severe brain injury (818). (828), regain nystagmus with caloric or rotational stimula- Quick phases of nystagmus are usually absent in acutely tion (818). Caloric nystagmus was present in patients with unconscious patients. Their presence, without a tonic devia- neocortical death and an isoelectric electroencephalogram tion of the eyes, should raise the possibility of nonorganic (829). (i.e., feigned) coma. In patients who are stuporous but un- Normal subjects have been studied during syncope (830). cooperative, caloric nystagmus may be a useful way of in- Subjects developed downbeat nystagmus and tonic upward ducing eye movements that cannot be initiated voluntarily. deviation of the eyes. There was also an increased amplitude For example, in a patient with a pineal tumor but no overt of the VOR in most of the subjects. These findings are most abnormalities during testing of voluntary eye movements, compatible with cerebellar hypoperfusion.

OCULAR MOTOR DYSFUNCTION AND MULTIPLE SCLEROSIS MS causes a variety of ocular motor deficits; bilateral (610,843,844), and impaired cancellation of the horizontal INO, cerebellar eye signs (including gaze-evoked nystag- VOR may be present (610). Abnormalities of vertical gaze- mus), and acquired pendular nystagmus are the most com- holding, smooth pursuit, and eye-head tracking occur in pa- mon (224,250,831–835) (see Chapter 60). Pendular or ellip- tients with an INO (359). Other abnormalities in patients tical nystagmus is a frequent disabling manifestation of the with MS include horizontal and vertical gaze palsies (845), disease (836,837). Measurement of eye movements may gaze-evoked blepharoclonus (846), vertical nystagmus, sac- help establish the diagnosis of MS during early stages of cadic pulsion (847), various vestibular abnormalities (832), the disease. Saccadic abnormalities may be more readily and superior oblique myokymia. detected when targets are presented randomly so that neither Diagnosis of early MS depends on the demonstration of their time of onset nor their location can be predicted. Large lesions disseminated throughout the nervous system. Subtle saccades (20Њ or more) are more likely to show changes deficits of ocular motility can provide a sensitive method in velocity than are small saccades (838). Because normal for identifying subclinical lesions, but there is a need for subjects show differences in the peak velocity of abducting caution because these tests are not specific for MS (848). and adducting saccades, it is worth developing a normative The clinician must compare the results of ocular motor stud- database for each of these. With these provisos, most patients ies with other clinical or laboratory findings before making with MS show saccadic abnormalities that include prolonged a diagnosis (849). latency, inaccuracy, and decreased velocity. In particular, A number of drugs, including gabapentin and memantine minor slowing of adducting saccades may indicate an INO (an agent with NMDA blocking, AMPA receptor modula- that may not be evident with clinical testing (839). tion, and dopaminergic action) may ameliorate the visually Some patients with MS show saccadic oscillations disabling pendular nystagmus commonly observed in MS (243,840–842). Smooth-pursuit gain may be decreased (12,850).

OCULAR MOTOR MANIFESTATIONS OF SOME METABOLIC DISORDERS Some babies who ultimately develop normally show tran- idase deficiency also preferentially affects vertical gaze sient ocular motor disturbances, including upward or down- (855). Variants of Niemann-Pick disease that begin after the ward deviation of the eyes (but with a full range of reflex first year of life (e.g., the sea-blue histiocyte syndrome or vertical movement), intermittent opsoclonus, and skew de- juvenile dystonic lipidosis) are characterized by deficits of viation (86,320,851,852). The last may be associated with voluntary vertical eye movements, particularly saccades and the eventual development of horizontal strabismus. In addi- smooth pursuit; vertical vestibular and horizontal eye move- tion, premature babies may show reduced excursion of the ments are relatively preserved (856–859) (Fig. 19.32). adducting eye with caloric stimulation, suggesting an INO. Gaucher’s disease is associated with a prominent deficit of In such infants, full deviation of both eyes usually occurs horizontal gaze, and slow saccades may be a prominent find- with rotational stimuli (853), although quick phases of nys- ing in adults with this condition (860). tagmus may be absent (854). The time constant of the VOR Wernicke’s encephalopathy is characterized by the triad (as reflected in the duration of nystagmus to a sustained of ophthalmoplegia, mental confusion, and gait ataxia. It is constant velocity stimulus) in newborns is low (typically 6 caused by thiamine deficiency and is most commonly en- seconds) and does not attain adult values until the infant is countered in alcoholics. The ocular motor findings include about 2 months old (854). Thus, normal infants may have weakness of abduction, gaze-evoked nystagmus and primary abnormal eye movements. position vertical nystagmus, impaired vestibular responses The lipid storage diseases are often characterized by gaze to caloric and rotational stimulation, INO, the one-and-a- palsies. Tay-Sachs disease impairs vertical and, subse- half syndrome, and horizontal and vertical gaze palsies that quently, horizontal eye movements. Adult-onset hexosamin- may progress to total ophthalmoplegia (861–866). The oph- 952 CLINICAL NEURO-OPHTHALMOLOGY thalmoplegia is bilateral but may be asymmetric. Experi- (113) reported seesaw nystagmus and the OTR in a patient mental thiamine deficiency in monkeys causes an orderly with Leigh’s disease. progression of ophthalmoplegia associated with well-cir- Pelizaeus-Merzbacher disease is an X-linked recessive cumscribed histopathologic changes (867). These changes leukodystrophy (877) with severe cerebellar signs, including consist of neuronal loss and gliosis in the oculomotor, troch- saccadic dysmetria. Some patients also show difficulty initi- lear, abducens, and vestibular nuclei. In humans, demyelinating saccades and pendular nystagmus (730,878). ation, vascular changes, and hemorrhage also may occur. In Deficiency of vitamin E may cause a progressive neuro- addition to the sites listed above, lesions are found in the logic condition characterized by areflexia, cerebellar ataxia, paraventricular regions of the thalamus, hypothalamus, peri- and loss of joint position sense. Ocular motor involvement aqueductal gray matter, superior vermis of the cerebellum, includes progressive gaze restriction, sometimes with stra- and dorsal motor nucleus of the vagus. Thus, gaze-evoked bismus. Vitamin E deficiency is more common in children, nystagmus and the impaired caloric responses can be attrib- in whom it may be caused by abetalipoproteinemia (Bassen- uted to vestibular nucleus involvement. The abduction weak- Kornzweig disease). It is also reported in adults who have ness and INO may reflect damage to the abducens nerve and bowel or liver diseases that interfere with fat absorption or the MLF, respectively, whereas paralysis of horizontal gaze as an inherited ataxia on chromosome 8q13, the site of the may be caused by damage to the PPRF or abducens nucleus. ␣-tocopherol transfer protein gene (879). Vitamin E defi- The one-and-a-half syndrome indicates dysfunction of the ciency is characterized by a dissociated ophthalmoplegia and MLF and either the abducens nucleus or the PPRF, and total by nystagmus in which adduction is fast but with a limited ophthalmoplegia may be caused by damage to all of the range and abduction is slow but with a full range (880). A ocular motor nerve nuclei. Most likely, affected areas of the posterior INO of Lutz (discussed previously) occurs in some brain contain neurons that use high amounts of glucose and, patients (254,255). The combination of ocular motor find- therefore, are particularly dependent upon thiamine, an im- ings in patients with vitamin E deficiency probably reflects portant coenzyme in glucose metabolism (868). Administra- a mixture of central and peripheral pathology. tion of thiamine usually causes rapid improvement of the Wilson’s disease, hepatolenticular degeneration, is an in- ocular motor signs, although complete recovery may take herited disorder of copper metabolism that is transmitted in several weeks. Coexistent magnesium deficiency should also an autosomal-recessive fashion. The defect is in a copper- be treated. In patients with Wernicke’s disease who go on transporting adenosine triphosphatase (ATPase) gene at to develop Korsakoff’s syndrome, which is primarily charac- q14.3 on chromosome 13. CT scanning in patients with this terized by a severe and enduring memory loss, ocular motor condition shows hypodense areas, and PET scanning indi- abnormalities may persist (869,870). The ocular motor ab- cates a decreased rate of glucose metabolism in the globus normalities include slow and inaccurate saccades, impaired pallidus and putamen (881). The classic clinical picture is smooth pursuit, and gaze-evoked nystagmus. MR imaging a prominent dysarthria, abnormal movements, psychiatric shows a distinctive pattern of abnormality in Wernicke’s symptoms, and liver disease. Ocular motor disorders in hepa- disease, with T2 intensity in structures around the third and tolenticular degeneration include a distractibility of gaze, fourth ventricles and the aqueduct (871). with inability to voluntarily fix upon an object unless other Leigh’s syndrome is a fatal subacute necrotizing encepha- competing visual stimuli are removed (e.g., fixation of a lopathy of infancy or childhood characterized by psychomo- solitary light in an otherwise dark room) (882). Slow sac- tor retardation, seizures, and brain stem abnormalities, in- cades were reported in one patient with this condition (883), cluding eye movements. It is an inherited disorder caused and apraxia of eyelid opening can also occur (884). either by abnormalities of mitochondrial deoxyribonucleic Amyotrophic lateral sclerosis is associated with various acid (DNA), in which case it is maternally inherited, or by eye-movement disorders, including nystagmus (885), sac- a chromosomal abnormality, in which case it is transmitted cade disturbances that suggest a frontal lobe disturbance as an autosomal-recessive disorder. Some cases show an un- (886–888), and impaired pursuit (889). Occasionally slow derlying defect of pyruvate dehydrogenase (872); others re- saccades are a feature (886). However, the existence of mul- flect a mitochondrial cytopathy (873,874). Both the distur- tisystem diseases in which motor neuron degeneration is just bances of ocular motility and the pathologic findings one neurologic feature makes specific clinical diagnoses dif- resemble those caused by experimental thiamine deficiency ficult (890,891). Ocular motor abnormalities were reported or Wernicke’s encephalopathy (875,876). Halmagyi et al. in a single patient with Kugelberg-Welander disease (892).

EFFECTS OF DRUGS ON EYE MOVEMENTS Many substances affect eye movements (Table 19.8). In Patients with drug-induced abnormalities of eye move- some cases, the drug induces abnormalities of eye movements most often complain of diplopia, caused by ocular ments at therapeutic concentrations (e.g., anticonvulsants) misalignment, or oscillopsia, caused by spontaneous nystag- (893). In other cases, abnormalities of eye movements de- mus or an inappropriate VOR (894). Many drugs have their velop only when concentrations of the drug in the central effect on central vestibular and cerebellar connections and nervous system are inappropriately elevated. In still other cause ataxia and gaze-evoked nystagmus (895). cases, the eye-movement abnormalities are caused by sub- Although all classes of eye movements may be affected by stances not meant for internal use. therapeutic doses of various drugs, smooth pursuit, eccentric SUPRANUCLEAR AND INTERNUCLEAR OCULAR MOTILITY DISORDERS 953

Table 19.8 ties, including fixation instability and downbeat nystagmus Effect of Drugs on Eye Movements (908). In one patient who showed marked impairment of all types of horizontal eye movements and downbeat nystagmus Benzodiazepines: Reduced velocity and increased duration of saccades, prior to death, neuronal loss was mainly confined to the NPH impaired smooth pursuit, decreased gain and increased time constant of and adjacent MVN(909). Thus, the pathophysiology was VOR, divergence paralysis Tricyclic antidepressants: Internuclear ophthalmoplegia, partial or total similar to that produced by experimental lesions of these gaze paresis, opsoclonus nuclei in monkeys (910); that is, the neural integrator (gaze- Phenytoin: Impaired smooth pursuit and VOR suppression, gaze-evoked holding network) was disrupted. The propensity of lithium nystagmus, downbeat nystagmus, periodic alternating nystagmus, total to damage this area of the medulla is related to its proximity gaze paresis, convergence spasm to the choroid plexus of the fourth ventricle and thus to Carbamazepine: Decreased velocity of saccades, impaired smooth pursuit, elevated local concentrations of lithium (909). Cerebellar gaze-evoked nystagmus, oculogyric crisis, downbeat nystagmus, total damage may also occur after lithium intoxication (911). gaze paresis Amiodarone can cause prominent cerebellar eye signs, in- Phenobarbital and other barbiturates: Reduced peak saccadic velocity, cluding downbeat nystagmus (912). gaze-evoked nystagmus, impaired smooth pursuit, impaired vergence, In addition to drugs, certain toxins can cause abnormal eye decreased VOR gain, perverted caloric responses, vertical nystagmus, partial or total gaze paresis movements. Some, such as chlordecone (913) and thallium Phenothiazines: Oculogyric crisis, internuclear ophthalmoplegia (914), cause saccadic oscillations. Intoxication with hydro- Lithium carbonate: Saccadic dysmetria, impaired smooth pursuit, gaze- carbons can cause a vestibulopathy (915,916), and exposure evoked nystagmus, downbeat nystagmus, oculogyric crisis, internuclear to trichloroethylene and other solvents may affect pursuit, ophthalmoplegia, total gaze paresis, opsoclonus suppression of the VOR, and saccades (917,918). Prolonged Amphetamines: Reduced saccade latency, increased accommodative exposure to toluene, especially in glue-sniffing addiction, convergence/accommodation ratio may lead to a variety of ocular motor disturbances, including Ethyl alcohol: Reduced peak velocity, increased latency, and hypometria of pendular (919) and downbeat (920) nystagmus, saccadic os- saccades, impaired smooth pursuit and VOR suppression, gaze-evoked cillations (921–923), and INO (924). Tobacco has a num- nystagmus, positionally induced nystagmus, normal static VOR ber of ocular motor effects. It causes upbeat nystagmus compensation, reversed compensation of vestibular lesions (925,926), impaired pursuit (926), decreased saccade latency Nicotine: Upbeat nystagmus, in darkness: Square-wave jerks, impaired horizontal and vertical pursuit (927), and increased square-wave jerks during pursuit (928), Methadone: Saccadic hypometria, impaired smooth pursuit although performance is normal on the antisaccade test Baclofen: Reduced VOR time constant, total gaze paresis (898,929,930). Cocaine can affect eye movements, with op- ␤-Blockers: Diplopia, internuclear ophthalmoplegia soclonus being the most dramatic abnormality (931). Chloral hydrate: Impaired smooth pursuit Ototoxicity, especially that associated with administration Nitrous oxide: Reduced saccadic peak velocity, impaired smooth pursuit of aminoglycosides, is an important cause of VOR loss (934). Intravenous gentamicin is most often responsible. Its VOR, vestibulo-ocular reflex. toxicity may be insidious, occurring without hearing symptoms and even with normal blood levels and relatively short periods of administration (935). Some patients who develop gaze holding, and convergence are particularly susceptible. ototoxicity may be genetically predisposed to its toxic side For example, diazepam, methadone, phenytoin, barbiturates, effects (936,937). Topical (intratympanic) gentamicin is chloral hydrate, and alcohol all impair smooth-pursuit track- used to purposefully ablate labyrinthine function as part of ing. Some drugs have specific effects on ocular motility and the treatment of intractable Me´nie`re’s syndrome but occa- thus provide insights into both the function of the ocular sionally leads to unwanted labyrinthine loss when used to motor system and the mode of drug action. For example, treat external ear infections (938). 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