Ординатура / Офтальмология / Английские материалы / The Neurology of Eye Movements_Leigh, Zee_2006

430 The Diagnosis of Disorders of EyeMovements

Most commonly, gaze-evoked nystagmus is a side effect of medications, including sedatives and anticonvulsants,616-1129'1308 or is due to intoxications with drugs, especially alcohol. Gaze-evoked nystagmus may also be caused by structural lesions that involve the gaze-holding neural network. Experimental lesions of the NPH-MVN region effectively abolish horizontal gaze-holding function230'943 and partially impair vertical gaze holding as well. Experimental inactivation of the interstitial nucleus of Cajal impairs vertical gaze holding.298 Complete loss of gazeholding function was described in a patient with lithium intoxication and lesions in the nucleus prepositus hypoglossi.295 Experimental flocculectomy greatly, but not completely, impairs horizontal gaze holding,1538 besides causing downbeat nystagmus. Disease affecting the vestibulocerebellum commonly causes gaze-evoked nystagmus, often with a downbeating component (see VIDEOS: "Gaze-evoked, rebound, and downbeat nystagmus"). Patients with cerebellar atrophy develop gaze-evoked nystagmus with lower serum concentrations of anticonvulsants than do patients with a normal cerebellum.1308 Gaze-evoked nystagmus is a feature offa-

milial episodic vertigo and ataxia type 2 (EA-2), which is a calcium channelopathy that is responsive to acetazolamide.85'90'175'1524

Rarely, cerebellar lesions cause the gazeholding mechanism to become unstable (i.e., hyperactive), so the eyes drift with increasing velocity away from central position either vertically1534 (see VIDEO: "Downbeat nystagmus") or horizontally.102

Such gaze-instability nystagmus often violates Alexander's law. Horizontal gaze nystagmus in which the quick phases of the adducting eye are slower than those of the abducting eye—a form of dissociated nys- tagmus—is characteristic of internuclear ophthalmoplegia (see VIDEOS: "Unilateral internuclear ophthalmoplegia").

DIFFERENCES BETWEEN PHYSIOLOGIC "END-POINT" NYSTAGMUS AND PATHOLOGIC GAZE-EVOKED NYSTGAMUS

Gaze-evoked nystagmus is commonly encountered in normal subjects, when it is

often called end-point nystagmus (Display 10-8).10>415>1260 Typically it occurs on look-

ing far laterally or up, and is poorly sustained. On lateral gaze, the nystagmus is primarily horizontal. It may be asymmet-

ric—for example, more prominent on looking to the right than to the left.1260

Nonetheless, in some normal individuals, the nystagmus is sustained, occurs with less than full deviations of the eye, and may be slightly dissociated or have a small torsional component. A strong downbeating component on lateral gaze, however, implies dysfunction of central vestibular connections (see VIDEOS: "Gaze-evoked, rebound, and downbeat nystagmus"). In such individuals, gaze-evoked nystagmus can usually be differentiated from nystagmus caused by disease; the gaze-evoked nystagmus has lower intensity (i.e., slower drift), and, most important, is not accompanied by other ocular motor abnormalities. Usually, pathologic gaze-evoked nystagmus is accompanied by other defects of eye movements, such as impaired smooth pursuit.220

Another form of gaze-evoked nystagmus in normal subjects is induced by sustained eccentric gaze for a minute or more

These findings probably represent the effects of fatigue and may therefore be similar to the gaze-evoked nystagmus seen with myasthenia gravis (see Fig. 9-20A),

which also increases with prolonged fixation.1228

BRUNS' NYSTAGMUS

Tumors of the cerebellopontine angle (e.g., Schwann cell tumors of the eighth nerve) may produce a combination of lowfrequency, large-amplitude horizontal nystagmus on looking ipsilaterally, due to defective gaze holding, with high-frequency, small-amplitude nystagmus on looking

contralaterally, due to vestibular imbalance.80'1004 This is called Bruns' nystag-

mus.200 Even in patients in whom an acoustic schwannoma had been resected years previously, nystagmus in darkness shows a summation of the effects of vestibular imbalance and gaze-evoked nystagmus. It has been proposed that, faced with a vestibular imbalance, the brain deliber-

ately makes the gaze-holding network leaky so that gaze-evoked nystagmus can

be used to counteract the vestibular imbalance.1159 In this way there would be at

least one position in the orbit in which the eyes would not drift.

CENTRIPETAL AND REBOUND NYSTAGMUS

If patients with gaze-evoked nystagmus sustain their attempt to look eccentrically, the nystagmus may begin to quiet down and may even reverse direction, so the eye begins to drift centrifugally ("centripetal nystagmus").824 If the eyes are then returned to the central position, a short-lived nystagmus with slow drifts in the direction of the prior eccentric gaze occurs, called rebound nystagmus (Display 10-7) (Fig. 10-9) (see VIDEOS: "Gaze-evoked, rebound, and downbeat nystagmus").155'645 Both centripetal and rebound nystagmus may reflect an attempt by brain stem or cerebellar mechanisms to correct for the centripetal drift of gaze-evoked nystagmus. Rebound nystagmus typically occurs in patients with cerebellar syndromes, but it has been re-

ported following experimental lesions of the NPH-MVN region230 and in normal

subjects who show gaze-evoked nystagmus.1260 Torsional rebound nystagmus has been described in association with vestibulocerebellar disease.1337 Extreme gaze deviation away from the side of the lesion in one patient with a lateral medullary infarction was reported to cause paroxysmal nystagmus and vertigo lasting about a minute.224 Such a phenomenon could be explained by a sustained eye position signal causing an imbalance of central vestibular mechanisms. The structures critical for rebound nystagmus remain undetermined. One patient with a tumor confined to the flocculus was reported to show gaze-

evoked nystagmus and rebound nystagmus,1504 but when the tumor spread to in-

volve the vestibular nuclei, the rebound nystagmus disappeared, even though the gaze-evoked nystagmus persisted. Thus, the vestibular nuclei or surrounding medulla may be important for generating rebound nystagmus.155'644'1504

432 The Diagnosis of Disorders of Eye Movements

Nystagmus Occurringin

Association With Disease of the

Visual System

PATHOGENESIS OF NYSTAGMUS OCCURRING WITH VISUAL SYSTEM DISORDERS

Disorders of the visual pathways are often associated with nystagmus (Display 10-9). The most obvious example is the nystagmus that invariably accompanies complete blindness (see VIDEO: "Eye movements with complete blindness").841 What is the mechanism? At least two separate effects of visual loss can be identified: (1) an inabilityto generate eye movements to correct for drifts of the eyes and (2) loss of the "error signal" that drives ocular motor adaptation and tunes eye movements to visual demands.

Visually mediated eye movements such as smooth pursuit and "fixation" stop the eyes from drifting away from a stationary object of regard (see Visual Fixation, in Chap. 4). So, for example, if normal subjects attempt to fixate on the remembered location of a target while in darkness, the eye drifts off target several times faster than if the subject actually views the target.1325 Uncorrected drifts are eventually remedied by a saccade that places the image back on the fovea. The fixation mechanism that generates smooth eye movements to correct for drifts of the eyes depends upon the motion-vision system, which is inherently slow. Thus, a response time of over 70 msec encumbers all visually mediated eye movements, including fixation, smooth pursuit, and optokinetic responses. If the response time is delayed

further by disease of the visual system, then the brain's attempts at correcting eye drifts may actually add to the retinal error rather than reducing it, leading to ocular oscillations.63 This issue is discussed further in the section on Models of Smooth Pursuit in Chap. 4. Another aspect of fix- ation—the suppression of saccades—is dealt with under Saccadic Intrusions.

In addition, vision is needed for recalibrating and optimizing all types of eye movements. This optimization depends on visual projections to the cerebellum— the "ocular motor repair-shop."1158 Thus, signals from secondary visual areas concerned with motion-vision project to the cerebellum via the pontine nuclei and middle cerebellar peduncle (Fig. 6-8); neurons in both the dorsolateral pontine nuclei and Purkinje cells in the cerebellar flocculus encode visual-motion signals.756 Visual signals for recalibration may also pass via the inferior olivary nucleus, which

sends climbing fibers to the cerebellum.683'1131 If the ocular motor system is to

be recalibrated, visual signals need to be compared with eye movement commands. One candidate for this function is the cell groups of the paramedian tracts (PMT) (see Display 6-4), which receive inputs from all premotor structures that project to ocular motoneurons and which project to the cerebellar flocculus.217 Alternatively, pathways that coordinate conjugate and vergence movements involving connections between the nucleus reticularis tegmenti pontis and cerebellar nucleus interpositus (discussed in Chap. 8) might be involved.500 Thus, lesions at any part of this visual-motor "recalibration" pathway might deprive the brain of signals that are essential to hold each of the eyes on the object of regard; the result would be drifts of the eyes away from the target, leading to nystagmus.

CLINICAL FEATURES OF NYSTAGMUS IN ASSOCIATION WITH VISUAL SYSTEM DISEASE

Disease affecting various parts of the visual system, from retina to cortical visual areas, and interrupting visual projections to pons and cerebellum, has been associ-

ated with nystagmus. First, we review the features of nystagmus reported with disease localized to the different sites in this pathway. Second, we discuss the features of acquired pendular nystagmus, which may be associated with disease affecting the visual system and its brain stem-cere- bellar projections.

Nystagmus Associated with Disease of the Retina and Ocular Media

Retinal disorders causing blindness, such as Leber's congenital amaurosis, lead to continuous jerk nystagmus with components in all three planes, which changes in direction over the course of seconds or minutes (Fig. 10-10A) (see VIDEO: "Eye movements with complete blindness." The drifting null point—the eye position at which nystagmus changes direc- tion—probably reflects an inability to "calibrate" the ocular motor system, and it has also been reported after experimental cerebellectomy.824'1157 Nystagmus has been

reported in association with a variety of hereditary retinal disorders; 536,712,1465,1507

some, but not all, show the increasingvelocity waveform (Fig. 10-1C) that was thought to be characteristic for congenital nystagmus. Loss of vision later in life also causes nystagmus, and seesaw nystagmus has been reported to develop in a patient who progressively lost vision due to retinitis pigmentosa

Disease Affecting the Optic Nerves and Nystagmus

Optic nerve disease is commonly associated with pendular forms of nystagmus. With unilateral disease of the optic nerve, such as tumors or trauma, nystagmus largely affects the abnormal eye (monocular nystagmus), with low-frequency, bidirectional drifts that are more prominent vertically and unidirectional drifts with

quick phases that occur horizontally (Fig. 10-10B).86'838'1111 Such nystagmus that

predominantly affects an eye with poor vision is called the Heimann-Bielschowsky phenomenon;1^ it is not confined to primary optic nerve disease, however, and also

Figure 10-10.—continued

occurs in patients with profound ambly-

opia.86'838'1111

When disease such as demyelination affects both optic nerves, the amplitude of nystagmus is often greater in the eye with poorer vision.101 Oscillations may also occur after development of a dense cataract or high myopia in childhood; when vision is restored they may disappear or they may persist, leading to oscillopsia.1108'1499 Those patients in whom nystagmus declines after restoration of vision support the contention that these ocular oscillations may be primarily caused by the lack of visual inputs required for "calibration" rather than by any primary disorder of the ocular motor system. The origin of vertical drifts that occur in a blind eye is unknown but has been attributed to disturbance of either the vertical vergence mechanism86 or a monocular visual stabilization system.838

In infants, the appearance of monocular, vertical pendular nystagmus raises the possibility of an optic nerve tumor, and imaging studies are indicated.430'530'818 However, monocular oscillations in children are sometimes due to spasmus nu-

tans,1466 which spontaneously resolves. Monocular visual impairment, such as amblyopia, also leads to horizontal nystagmus, and if present from birth, the features are those of latent nystagmus.

Disease Affecting the Optic Chiasm and Nystagmus

Parasellar lesions such as pituitary tumors have traditionally been associated with seesaw nystagmus (Display 10-6). As already discussed, seesaw nystagmus is a form of pendular nystagmus in which one half-cycle consists of elevation and intorsion of one eye and synchronous depression and extorsion of the other eye, with the vertical and torsional movements reversing during the next half cycle (see Fig. 10-8) (see VIDEO: "Seesaw nystagmus"). However, many such cases were described before the era of modern imaging, and the tumors may have compressed the midbrain. Hemi-seesaw nystagmus has been attributed to disease affecting the interstitial nucleus of Cajal or its connections.571 Congenital seesaw nystagmus, however, has been reported in a mutant strain of dogs that lacks an optic chiasm372 and in patients in whom imaging and visual evoked studies suggested a similar developmental defect.40'842 Seesaw nystagmus has also been documented to develop in a patient with progressive visual loss due to retinitis pigmentosa.915 Thus, it remains possible that visual inputs—especially crossed inputs—are important for optimizing vertical-torsional eye movements. Under natural conditions, seesaw eye movements occur when subjects view a tar-

get located off the midsagittal plane during ear-to-shoulder head roll.1253 Visual

inputs are presumably necessary to keep this response calibrated and, if removed, might lead to seesaw oscillations.56'100

Disease Affecting the Postchiasmal Visual System and Nystagmus

Horizontal nystagmus occurs in patients with unilateral disease of the cerebral hemi-

spheres, especially when the lesion is large and posterior.1270 Such patients show a con-

stant-velocity drift of the eyes toward the in-

43 The Diagnosis of Disorders of Eye Movements

tact hemisphere (i.e., quick phases directed toward the side of the lesion). The nystagmus is often low amplitude, and sometimes is only appreciated on ophthalmoscopy. Such patients usually also show asymmetry of horizontal smooth pursuit (impaired toward the side of the lesion). The asymmetry is brought out at the bedside using a handheld optokinetic drum or tape;793 the response is reduced when the stripes move toward the side of the lesion. This asymmetry of visual tracking has led to the suggestion that nystagmus in such patients is caused by an imbalance of pursuit "tone."1270 As discussed below, a congenital form of nystag- mus—latent nystagmus—has been attributed to an abnormality of such cortical motion-vision processing.

Sometimes, intermittent nystagmus is due to seizure activity affecting cortical areas responsible for generating smoothpursuit movements;721 this is discussed below in the section Eye Movements During Epileptic Seizures.

ACQUIRED PENDULAR

NYSTAGMUS AND ITS

RELATIONSHIP TO DISEASEOF

THE VISUALPATHWAYS

Acquired pendular nystagmus (Fig. 10-11) is one of the more common types of nystagmus and is often associated with distressing visual symptoms (see VIDEOS: "Acquired nys-

tagmus impairing vision"). Its pathogenesis remains unclear, and more than one mechanism may be responsible. It is encountered in a variety of conditions (Table 10-6), including several disorders of myelin, the syndrome of oculopalatal tremor, and in association with Whipple's disease. We will first describe the common features of the nystagmus and then discuss characteristics peculiar to the three major types separately.

Clinical Characteristics of Acquired Pendular Nystagmus

Acquired pendular nystagmus usually has horizontal, vertical, and torsional components, although one may predominate (Display 10-10). (In congenital pendular nystagmus, usually the oscillation is predominantly horizontal, with small torsional and negligible vertical components.) The horizontal, vertical, and torsional components of each eye's oscillations usually have the same frequency. If the horizontal and vertical oscillatory components are in phase, the trajectory of the nystagmus is oblique. If the horizontal and vertical oscillatory components are out of phase, the trajectory will be elliptical (Fig. 10-11). A special case is a phase difference of 90° and equal amplitude of the horizontal and vertical components, when the trajectory is circular. When the oscillations of each eye are compared, the

Table 10-6. Etiology of

Pendular Nystagmus

Visual Loss (including unilateral disease of the optic nerve)430'838

Disorders of Central Myelin Multiple sclerosis63'101-879 Pelizaeus-Merzbacher disease1393 Cockayne's syndrome280'925 Peroxisomal disorders790 Toluene abuse891

Syndrome of Oculopalatal "Myoclonus" or Tremor, developing after brain stem

stroke63'993 or as a degenerative1311 or familial disorder658

Acute Brain Stem Stroke747 Whipple's Disease1248 Spinocerebellar Degenerations62'534 Hypoxic Encephalopathy62 Congenital Nystagmus356

nystagmus may be conjugate, but often the trajectories are dissimilar (i.e., disconjugate), and the size of oscillations is different (i.e., dissociated). Sometimes the nystagmus appears monocular, and there may be an asynchrony of timing (phase shift), which may reach 180°, in which case the oscillations may be regarded as a form of convergent-divergent nystagmus.64

The waveform of acquired pendular nystagmus may approximate a sine wave, but often it is more complex.64 The frequency of oscillations of acquired pendular nystagmus

ranges from 1 to 8 Hz, with a typical value of 3.5 Hz;555 for any particular patient, the

frequency tends to remain fairly constant. Only rarely is the frequency of oscillations different in the two eyes." In some patients, the nystagmus stops momentarily after a saccade (postsaccadic suppression).48 The nystagmus may be suppressed or brought out by eyelid closure.485'691 In some patients, smooth pursuit may be intact, so despite the oscillations, tracking eye movements occur with nystagmus superimposed.555

Acquired Pendular Nystagmus With

Demyelinative Disease

Acquired pendular nystagmus is a common feature of a variety of disorders of

central myelin, including multiple sclerosis (MS), congenital disorders such Pelizaeus-Merzbacher disease (see VIDEOS: "Pelizaeus-Merzbacher disease"),1393 and toluene abuse.891 Since concurrent optic neuritis often coexists in patients with MS who have pendular nystagmus, prolonged response time of the visual processing might be responsible for the ocular oscillations. Evidence to support this notion comes from the observation that oscillations are larger in the eye with evidence of more severe optic nerve demyelination.101 However, the nystagmus often remains unchanged in darkness (when visual inputs have no influence on eye movements). As discussed in the section on Models of Smooth Pursuit, in Chap. 4, spontaneous ocular oscillations can be induced in normal subjects by experimentally delaying the latency of visual feedback during fixation (see Fig. 4-10); however, the frequency of these induced oscillations is less than 2.5 Hz, which is lower than in most patients with pendular nystagmus.63 Furthermore, when this experimental technique was applied to patients with acquired pendular nystagmus, it did not change the characteristics of the nystagmus but instead superimposed lower-frequency oscillations similar to those induced in normal subjects. Thus, disturbance of visual fixation due to visual delays cannot account for the high-frequency oscillations that often characterize acquired pendular nystagmus.

A more likely possibility is that visual projections to the cerebellum are impaired, leading to instability in the reciprocal connections between brain stem nuclei and cerebellum that are important for recalibration. Thus, it may be relevant that internuclear ophthalmoplegia is common in these patients, suggesting involvement of brain stem regions close to the cell

groups of the paramedian tracts (PMT) (see Display 6-4).217'221 In patients in

whom the oscillations are predominantly convergent-divergent, it is possible that instability arises in connections between the nucleus reticularis tegmenti pontis and the cerebellar nucleus interpositus,

which both contribute to vergence movements.64'500

Oculopalatal Tremor (Myoclonus)

Acquired pendular nystagmus may be one component of the syndrome of oculopalatal (pharyngolaryngodiaphragmatic) tremor (see VIDEO: "Oculopalatal tremor").561'993 This condition usually develops several months after brain stem or cerebellar infarction (Fig. 10-12), though it may not be recognized until years after

the stroke. Oculopalatal tremor also occurs with degenerative conditions.64'1311

The term tremor is more accurate than myoclonus, since the movements of affected muscles are to and fro and are approximately synchronized, typically at a rate of about 2 cycles per second. The palate is most often affected, but the eyes, facial muscles, pharynx, tongue, larynx, diaphragm, mouth of the eustachian tube, neck, trunk, and extremities may also move, in synchrony. Essential rhythmic palatal myoclonus is an idiopathic disorder in which ocular oscillations do not accompany palatal movements, unlike the symptomatic variety, but in which auditory clicking is common.381 Pendular vertical oscillations of the eyes may occur acutely with pontine infarctions that cause horizontal gaze palsy;747 associated palatal movements usually do not develop for several months.

The ocular movements, present in most cases, consist of pendular oscillations that are often vertical but may have a horizontal or torsional component. If the palatal tremor is unilateral, the pendular oscillations consist of a mixed vertical-torsional movement, with the eye on the side of the palatal tremor intorting as it rises and extorting as it falls. The opposite eye extorts as it rises and intorts as it falls. The movements may be disconjugate, with some orbital position dependency,555'993 and some patients may show cyclovergence (torsional vergence) oscillations.64 Occasionally, following brain stem infarction, patients develop the eye oscillationswithout movements of the palate. Eyelid closure may bring out the vertical ocular oscillations.691 The nystagmus sometimes disappears with sleep, but the palatal movements usually persist. Once established, the condition is usually intractable, and spontaneous remission is uncommon.693

The main pathologic finding with palatal tremor is hypertrophy of the inferior

olivary nucleus; this may be evident by MRI.1311 There may also be destruction of

the contralateral dentate nucleus.561 Histologically, the olivary nucleus has enlarged, vacuolated neurons with enlarged astrocytes. The hypertrophic neurons and their dendrites contain increased acetylcholine esterase reaction products.777 Functional scanning has demonstrated increased glucose metabolism.407 Guillain and Mollaret proposed that disruption of connections between the dentate nucleus and the contralateral inferior olivary nucleus, which run via the red nucleus and

central tegmental tract, is responsible for the syndrome.561 However, the red nu-

cleus is not known to have a role in the control of eye movements. It has also been postulated that the nystagmus is due to an instability in the projections from the inferior olive to the flocculus,which is thought to be important in the adaptive control of the vestibulo-ocular reflex.993 It is also possible that projections from the PMT cell groups (see Display 6-4), which feed back ocular motor signals to the cerebellum,217 are impaired or delayed, leading to oscillations.63

Convergent-Divergent Forms

of Nystagmus

Convergent forms of nystagmus are often small in amplitude and may be missed without reliable records to document the phase relationship between each eye. Comparatively few reports exist of convergent or divergent forms, and not much is known about their pathogenesis. More than one mechanism is likely, and an oscillation that emanates from the vergence mechanism itself is probably rare. Here, we discuss disjunctive forms of pendular nystagmus, vertical jerk nystagmus that has disjunctive horizontal components, and convergence-retraction nystagmus, which is properly classified as a disorder of saccades.

Convergence-divergence forms of nystagmus should be differentiated from conjugate nystagmus that is evoked or