History

Box 35.5 shows the procedure for assessing patients with diplopia. The following points should be clarified if the patient has not volunteered the information: Is the diplopia relieved by covering either eye? (If not, it is monocular diplopia; see Box 35.4.) Is it worse in the morning or in the evening? Is it affected by fatigue? Are the images separated horizontally, vertically, or obliquely? If obliquely, is the horizontal or vertical component more obvious? Is the distance between images constant despite the direction of gaze, or does it vary? Is the diplopia worse for near vision or for distance? Is one image tilted? Do the eyelids droop? Is the diplopia influenced by head posture? Has this condition remained stable, improved, or deteriorated? Are there any general health problems? Are there associated symptoms such as headache, dizziness, vertigo, or weakness? What medications are taken? Is there a family history of ocular, neurological, autoimmune, or endocrine disease? Has the patient had a “lazy” eye, worn a patch, or had strabismus surgery?

For example, lateral rectus muscle weakness causes diplopia that is worse at distance and worse on looking to the side of the weak muscle. Acutely, superior oblique weakness causes diplopia that is worse on looking downward to the side opposite the weak muscle and causes difficulty with tasks such as reading, watching television in bed, descending a staircase, and walking on uneven ground. Medial rectus muscle weakness causes diplopia that is worse for near than for distance vision and is worse to the contralateral side.

General Inspection

Ptosis that fatigues suggests myasthenia gravis (MG). Ptosis associated with a dilated pupil suggests an oculomotor nerve palsy. Lid lag suggests thyroid eye disease or myotonia. Lid retraction suggests thyroid eye disease, aberrant reinnervation after a third nerve palsy, a cyclical third nerve palsy, a dorsal midbrain lesion, hypokalemic periodic paralysis, or chronic corticosteroid use. Proptosis suggests an orbital lesion or, if associated with conjunctival injection and periorbital swelling, an inflammatory disorder such as orbital pseudotumor, orbital lymphoma, dural shunt fistula, or infection. Facial asymmetry suggests a superior oblique palsy that is congenital contralateral to the hemiatrophic side.

Head Posture

Because the weak extraocular muscle cannot move the eye fully, patients compensate by tilting or turning the head in the direction of action of the weak muscle (Fig. 35.9). For example, with right lateral rectus palsy, the head is slightly turned to the right; then on attempted right gaze, the patient turns the head farther to the right (see Fig. 35.9, A). With a right superior oblique palsy, the head tilts forward and to the left (see Fig. 35.9, B). The rule is as follows: The head turns or tilts in the direction of action of the weak muscle.

Fig. 35.9 A, Right lateral rectus palsy. A right esotropia is present in primary gaze; however, by turning the head to the right (in the direction of action of the weak right lateral rectus muscle), the patient can maintain both eyes on target (orthotropia), thereby achieving binocular single vision. B, Acute right superior oblique muscle palsy. Right eye extorts (excycloduction) because of the unopposed action of the right inferior oblique muscle. When the patient tilts the head to the left and forward (in the direction of action of the weak muscle), the right eye is passively intorted, while the left eye actively intorts to compensate and maintain binocular single vision. The head also tilts forward to compensate for the depressor action of the weak right superior oblique.

Sensory Visual Function

Visual acuity, stereopsis, color vision, and confrontation visual fields should be carefully and separately checked in each eye. Patients with nystagmus should have visual acuity checked binocularly as well, because it often is better than with either eye alone.

Stability of Fixation

Fixation and stability of the gaze-holding mechanism should be checked. This is done by having the patient look at a target and then observing for spontaneous eye movements such as drift, microtremor, nystagmus, opsoclonus, ocular myokymia, ocular myoclonus, or saccadic intrusions.

Versions (Pursuit, Saccades, and Ocular Muscle Overaction)

Pursuit movements are tested by asking the patient to fixate and follow (track) a moving target in all directions (Fig. 35.10, A). This test determines the range of eye movement and provides an opportunity to observe for gaze-evoked nystagmus. If spontaneous primary-position nystagmus is present, the effects of the direction of gaze and convergence on the nystagmus may be determined. Pursuit movements should be smooth and full. Cogwheel (saccadic) pursuit is a nonspecific finding and is normal in infants. When present in only one direction, however, it suggests a defect of the ipsilateral pursuit system.

Fig. 35.10 A, The nine diagnostic positions of gaze, used for testing versions (saccades and pursuit). B, Ductions are used to test the isolated action of each of the six muscles of each eye (the other five muscles are assumed to be functioning normally). Pure elevation (supraduction) and depression (infraduction) of the eyes are predominantly functions of the superior (SR) and inferior (IR) rectus muscles, respectively, with some help from the oblique muscles. That is, the eyes are rotated directly upward primarily by the SR, with some help from the inferior oblique (IO). The eyes are rotated directly downward primarily by the IR, with some help from the superior oblique (SO). LR, Lateral rectus; MR, medial rectus.

Saccades (fast eye movements) are tested by asking the patient to look rapidly from one target to another (e.g., from the examiner’s nose to a pen) while observing for a delay in initiating the movement (latency) as well as the movement’s speed, accuracy, and conjugacy. An internuclear ophthalmoplegia is best detected by this method (Video 35.1, available at www.expertconsult.com). If a specific muscle (particularly an oblique) underacts or overacts, this can be observed in eccentric gaze before testing ductions in each eye separately, as shown in Fig. 35.10, B. Assessment of disorders of conjugate (supranuclear) gaze is discussed later.

Convergence

Convergence is tested by asking patients to fixate on a target moving toward the nasion while observing the alignment of the eyes and constriction of the pupils. Miosis confirms an appropriate effort, whereas its absence suggests less than optimal effort.

Ductions

Ductions are tested monocularly by having the patient cover one eye and checking the range of movements of the other eye (see Fig. 35.10, B). If ductions are not full, the physician should check for restrictive limitation by moving the eye forcibly (see Forced Ductions, later).

Ocular Alignment and Muscle Balance

Before determining ocular alignment, first the examiner must neutralize a head tilt or turn by placing the patient in the “controlled (or forced) primary position”; otherwise, the misalignment may go undetected because of the compensating head posture. Subjective tests of ocular alignment include the red glass, Maddox rod, Lancaster red-green, and Hess screen tests.

With the red glass test, the patient views a penlight while a red filter or glass is placed, by convention, over the right eye. This allows easier identification of each image; the right eye views a red light and the left a white light. The addition of a green filter over the left eye, using red-green glasses, further simplifies the test for younger or less reliable patients. The target light is shown to the patient in the nine diagnostic positions of gaze (see Fig. 35.10, A). As the light moves into the field of action of a paretic muscle, the images separate. The patient is asked to signify where the images are most widely separated and to describe their relative positions. Interpretation of the results is summarized in Fig. 35.11.

Fig. 35.11 The red glass test. Diplopia fields for each muscle paralysis are shown. By convention, the red glass is placed over the right eye. The charts below each case are displayed as the subject, facing the examiner, indicates the position of the red (dark circle) and the white (white circle) images in the nine diagnostic positions of gaze. A, Right lateral rectus palsy. B, Right medial rectus palsy. C, Right inferior rectus palsy. D, Right superior rectus palsy. E, Right superior oblique palsy. F, Right inferior oblique palsy.

(Reprinted with permission from Cogan, D.G., 1956. Neurology of the Ocular Muscles, second edition. Charles C Thomas, Springfield, IL. Courtesy Charles C Thomas, Publisher, 1956.)

The Maddox rod test uses the same principle as for the red glass test, but the images are completely dissociated by changing the point of light seen through the rod, which is a series of half cylinders, to a straight line perpendicular to the cylinders (Fig. 35.12). This dissociation of images (a point of light and a line) breaks fusion, allowing detection of heterophorias as well as heterotropias. Cyclotorsion may be detected by asking if the image of the line is tilted (see Fig. 35.15, B). The Maddox rod can be positioned to produce a horizontal, vertical, or oblique line.

Fig. 35.12 The Maddox rod test. (Unlike in Fig. 35.11, the images are displayed as the patient perceives them.) A, By convention, the right eye is covered by the Maddox rod, which may be adjusted so the patient sees a red line, at right angles to the cylinders, in the horizontal or vertical plane, as desired (red image seen by the right eye; light source seen by the left eye). B, The Maddox rod is composed of a series of cylinders that diffract a point of light to form a line. C, Right lateral rectus palsy. D, Right medial rectus palsy. E, Right superior rectus palsy. F, Right inferior rectus palsy. G, Right superior oblique palsy. H, Right inferior oblique palsy.

A further extension of these tests includes the Lancaster red-green test and the Hess screen test, which use similar principles. Each eye views a different target (a red light through the red filter and a green light through the green filter). The relative positions of the targets are plotted on a grid screen and analyzed to determine the paretic muscle. These haploscopic tests are used mainly by ophthalmologists when quantitatively following patients with motility disorders.

The Hirschberg test, an objective method of determining ocular deviation in young or uncooperative patients, is performed by observing the point of reflection of a penlight held approximately 30 cm from the patient’s eyes (Fig. 35.13); 1 mm of decentration is equal to 7 degrees of ocular deviation. One degree is equal to approximately 2 prism diopters. One prism diopter is the power required to deviate (diffract) a ray of light by 1 cm at a distance of 1 m (Fig. 35.14).

Fig. 35.13 The Hirschberg method for estimating amount of ocular deviation. Displacement of the corneal light reflex of the deviating eye varies with the amount of ocular misalignment. One millimeter is equivalent to approximately 7 degrees of ocular deviation, and 1 degree equals approximately 2 prism diopters. A, No deviation (orthotropic). B, Left esotropia. C, Left exotropia.

Fig. 35.14 A prism with the power of 1 prism diopter (D) can diffract a ray of light 1 cm at 1 meter.

The cover-uncover test is determined for both distance (6 m) and near (33 cm) vision. The patient is asked to fixate an object held at the appropriate distance. The left eye is covered while the patient maintains fixation on the object. If the right eye is fixating, it remains on target, but if the left eye alone is fixating, the right eye moves onto the object. If the uncovered right eye moves in (adducts), the patient has a right exotropia; if it moves out (abducts), the patient has an esotropia; if it moves down, a right hypertropia; if it moves up, a right hypotropia. The physician should always observe the uncovered eye. The test should be repeated by covering the other eye. If the patient has a tropia, the physician must determine whether it is comitant or noncomitant by checking the degree of deviation in the nine diagnostic cardinal positions of gaze (see Fig. 35.10, A). With a lateral rectus palsy, the esotropia increases on looking to the side of the weak muscle and disappears on looking to the opposite side (see Fig. 35.11, A). Similarly, with a medial rectus weakness, the patient has an exotropia that increases on looking in the direction of action of that muscle (see Fig. 35.11, B). Prisms are used mainly by ophthalmologists to measure the degree of ocular deviation (see Fig. 35.14). If the diplopia is due to breakdown of a long-standing (congenital) deviation, prism measurement can detect supranormal fusional amplitudes (large fusional reserve). If no manifest deviation of the visual axes is found using the cover-uncover test, the patient is orthotropic. Then the physician may perform the cross-cover test.

During the cross-cover test (alternate-cover test), the patient is asked to fixate an object, then one eye is covered for at least 4 seconds. The examiner should observe the uncovered eye. If the patient is orthotropic, the uncovered eye does not move, but the covered eye loses fixation and assumes its position of rest—latent deviation (heterophoria or phoria). In that case, when the covered eye is uncovered, it refixates by moving back; the uncovered eye is immediately covered and loses fixation. The cross-cover test prevents binocular viewing, and thus foveal fusion, by always keeping one eye covered. Unlike the cover-uncover test, the cross-cover test detects heterophoria. Most normal persons are exophoric because of the natural alignment of the orbits.

Fixation switch diplopia occurs in patients with long-standing strabismus who partially lose visual acuity in the fixating eye, usually as a result of a cataract or refractive error. Such patients normally avoid double vision by ignoring the false image from the nonfixating eye, but a significant decrease in acuity in the “good” eye forces them to fixate with the weak eye. This causes misalignment of the previously good eye and results in diplopia. Fixation switch diplopia usually can be treated successfully with appropriate optical management.

Dissociated vertical deviation (divergence) is an asymptomatic congenital anomaly that usually is discovered during the cover test. While the patient fixates an object, one eye is covered. The covered eye loses fixation and rises; the uncovered eye maintains fixation but may turn inward. This congenital ocular motility phenomenon usually is bilateral but frequently is asymmetrical and often associated with amblyopia, esotropia, and latent nystagmus (LN). Whether the number of axons decussating in the chiasm is excessive, as suggested by evoked potential studies, remains controversial. Dissociated vertical deviation has no other clinical significance.

Three-Step Test for Vertical Diplopia

Eight muscles are involved in vertical eye movements: four elevators and four depressors. The three-step test endeavors to determine whether one particular paretic muscle is responsible for vertical diplopia (Fig. 35.15). Using the cover-uncover test, which is objective, or one of the subjective tests such as the red glass test, the physician can perform the three-step test for vertical diplopia. When using one of the subjective tests, it is important to remember that the hypertropic eye views the lower image.

Fig. 35.15 Example of the three-step test in a patient with an acute right superior oblique palsy. A, In a patient with hypertropia, one of eight muscles may be responsible for vertical ocular deviation. Identifying the higher eye eliminates four muscles. Step 1: With a right hypertropia, the weak muscle is either one of the two depressors of the right eye (IR or SO) or one of the two elevators of the left eye (IO or SR) (enclosed by solid line). Step 2: If the deviation (or displacement of images) is greater on left gaze, one of the muscles acting in left gaze (enclosed by solid line) must be responsible, in this case either the depressor in the right eye (SO) or the elevator in the left eye (SR). Step 3: If the deviation is greater on right head tilt, the incyclotortors of the right eye (SR and SO) or the excyclotortors of the left eye (IR and IO) (enclosed) must be responsible, in this case, the right SO—that is, the muscle enclosed three times. If the deviation is greater on left head tilt, the left SR would be responsible. IO, Inferior oblique; IR, inferior rectus; SO, superior oblique; SR, superior rectus. B, The Maddox rod test (displayed as in Fig. 35.12, as the subject perceives the images) in a patient with a right SO palsy shows vertical separation of the images that is worse in the direction of action of the weak muscle and demonstrates subjective tilting of the image from the right eye. When the head is tilted toward the left shoulder, the separation disappears, but when the head is tilted to the right shoulder, to the side of the weak muscle, the separation is exacerbated (Bielschowsky’s third step).

Two more optional steps:

The examiner should be aware of the pitfalls of the three-step test—namely, the conditions in which the rules break down. These include restrictive ocular myopathies (Box 35.6), long-standing strabismus, skew deviation, and disorders involving more than one muscle.

The four fundamental features of the fourth cranial nerve are: (1) it has the longest intracranial course and is the thinnest of all the cranial nerves and thus very susceptible to injury; (2) it is the only cranial nerve that exits the neuraxis dorsally; (3) its nucleus of origin is on the contralateral side of the neuraxis (the oculomotor subnucleus for the superior rectus is on the opposite side also); and (4) the most common cause of isolated vertical diplopia is a fourth nerve (superior oblique) palsy.

Fatigability

Once the weak muscle is identified, the physician should determine whether it fatigues by testing its rapid (saccadic) action repetitively and its ability to sustain eccentric eye position without drift.

Forced Ductions

If the weak muscle does not fatigue, the physician should determine whether it is restricted by performing forced ductions (Video 35.2, available at www.expertconsult.com). The use of phenylephrine hydrochloride eye drops beforehand reduces the risk of subconjunctival hemorrhage. Although this test is in the realm of the ophthalmologist, it may be performed in the office using topical anesthesia and a cotton-tipped applicator, but great care must be taken to avoid injuring the cornea. The causes of restrictive myopathy are listed in Box 35.6; however, any cause of prolonged extraocular muscle paresis can result in contracture of its antagonist.

Signs Associated with Diplopia

When evaluating a patient with diplopia, the examiner should determine whether any of the signs outlined in Box 35.7 are present.

Edrophonium (Tensilon) Test

The edrophonium test is discussed in detail in Chapter 78, but a few points are emphasized here. The test must have an objective endpoint (e.g., ptosis, a tropia, limited ductions), and the physician must observe an objective change. When forced ductions are positive, indicating a restrictive myopathy, the edrophonium test will be negative and therefore is not indicated. Myasthenic ptosis may be reversed temporarily with application of an ice pack over the affected lid.

Acute Bilateral Ophthalmoplegia

The causes of acute bilateral ophthalmoplegia are outlined in Box 35.8.

Chronic Bilateral Ophthalmoplegia

The causes of chronic bilateral ophthalmoplegia are outlined in Box 35.9.

Congenital Forms of Nystagmus

The three distinct nystagmus syndromes seen in infancy were renamed by the Classification of Eye Movement Abnormalities and Strabismus (CEMAS) Working Group (2003), sponsored by the National Eye Institute. The first of these syndromes, previously known as congenital nystagmus, is now called infantile nystagmus syndrome (INS); the second, fusion maldevelopment nystagmus syndrome (FMNS), includes the latent form and manifest latent nystagmus; and the third, spasmus nutans syndrome (SNS), remains virtually unchanged from past classifications.

Infantile nystagmus syndrome usually is present from birth but may not be noticed for the first few weeks, or occasionally even years, of life. It may be accompanied by severe visual impairment but is not the result of poor vision. Disorders that, through genetic association, are responsible for poor vision in patients with INS include those designated by the mnemonic of A’s—achiasma (Jansonius et al., 2001), achromatopsia, albinism (both ocular and oculocutaneous forms), amaurotic idiocy of Leber (Leber’s congenital amaurosis), aniridia, aplasia (usually hypoplasia) of the fovea, and aplasia (usually hypoplasia) of the optic nerve—and also congenital cataracts and congenital stationary night blindness. Paradoxical pupil constriction in darkness, particularly in patients with poor vision, suggests an associated retinal or optic nerve disorder. High myopia (uncommon early in life) in infants with INS suggests congenital stationary night blindness, and high hyperopia suggests Leber congenital amaurosis; such retinal disorders can be confirmed by electroretinography. INS sometimes is associated with head titubation (head nodding). INS may be familial and is inherited in an autosomal recessive, X-linked dominant or recessive pattern. Genetic defects identified in some families include a dominant form of INS linked to chromosomal region 6p12 (Kerrison et al., 1998), an X-linked form of INS with incomplete penetrance among female carriers associated with a defect on the long arm of the X chromosome (Kerrison et al., 2001), a deletion in the OA1 gene (ocular albinism) in a family with X-linked INS associated with macular hypoplasia and ocular albinism (Preising et al., 2001), and three mutations in the OA1 gene in families with hereditary nystagmus and ocular albinism (Faugere et al., 2003). Self and Lotery (2007) recently reviewed the molecular genetics of INS.

INS appears horizontal in most patients and may be either pendular or jerk in primary position. Pendular nystagmus often becomes jerk on lateral gaze. The horizontal oscillations may be accentuated during vertical tracking. Oculography with three-dimensional scleral search coils demonstrates that many patients with INS have a torsional component phase-locked with the horizontal component (Averbuch-Heller et al., 2002).

Patients with INS often have good vision unless an associated afferent defect is present (see earlier discussion). In INS, the nystagmus damps with convergence; latent superimposition (an increase in nystagmus amplitude occurring when one eye is covered) may be present. A null zone wherein the nystagmus intensity is minimal may be found; if this zone is to one side, the affected person turns the head to improve vision. The head often “oscillates” as well. Both features—damping of nystagmus with convergence and a null zone—can be used in therapy by changing the direction of gaze with prisms or extraocular muscle surgery to improve head posture and visual acuity. Oculographic recordings usually demonstrate either a sinusoidal (see Fig. 35.17, A) or a slow phase with an increasing exponential waveform (see Fig. 35.17, D). However, in the first few months of life, the waveform of INS may be more variable, evolving into the more classic pattern as the child gets older.

Outside the null zone, the nystagmus follows the Alexander law and increases in intensity (amplitude × frequency) on lateral gaze. Thus patients with INS or FMNS may induce an esotropia intentionally to suppress the nystagmus in the adducting eye. This strategy is called the nystagmus blockage syndrome.

Patients with INS do not experience oscillopsia (an illusory oscillation of the environment) unless a head injury, decompensated strabismus, or retinal degeneration causes a decline in vision, ocular motor function, or both. Prisms or strabismus surgery may correct such late-onset oscillopsia (Hertle et al., 2001a). Approximately 30% of patients with INS have strabismus (Leigh and Zee, 2006).

Rarely in INS, the nystagmus may be in the vertical plane or circumductory, in which the eyes move conjugately in a circular or cycloid pattern. In patients with retinal disorders such as achromatopsia, congenital cone dysfunction, or congenital stationary night blindness, INS can have an asymmetrical horizontal (albinism) or vertical waveform that varies among pendular, downbeat, and upbeat (Shawkat et al., 2000). Occasionally INS may be unilateral, occur later in the teens or adult life, or become symptomatic if changes in the internal or external environment alter foveation stability and duration, causing oscillopsia. Less common patterns of INS such as periodic alternating, upbeat, downbeat, and seesaw nystagmus (SSN) are discussed later.

Fusion maldevelopment nystagmus syndrome, as noted earlier, includes both LN and manifest latent nystagmus (MLN). LN occurs with monocular fixation, that is, when one eye is covered. The slow phase is directed toward the covered eye. The amplitude of the oscillations increases on abduction of the fixating eye. With MLN, the oscillations are present with both eyes open, but only one eye is fixating, vision in the other is ignored or suppressed as a result of strabismus or amblyopia. The nystagmus waveform has a linear (decreasing velocity) slow phase (see Fig. 35.17), which differs from that of true INS. Some patients with LN can suppress it at will.

The pathogenesis of LN may be related to impaired development of binocular vision mechanisms. Under monocular viewing conditions, rhesus monkeys deprived of binocular vision early in life have poor nasal-to-temporal optokinetic responses. The pretectal nucleus of the optic tract (NOT) is necessary for generation of slow-phase eye movements in response to horizontal full-field visual motion. In normal monkeys, the NOT on each side is driven binocularly and responds well to visual stimuli presented to either eye. In monkeys with LN, each NOT is driven mainly by the contralateral eye. Thus in the altered monkeys, when only one eye is viewing, one optic tract nucleus is stimulated, causing an imbalance between each NOT. This imbalance is believed to be responsible for LN (Kaminski and Leigh, 1997). Of interest, under monocular viewing conditions, patients with congenital esotropia have poor temporal-to-nasal pursuit, and some have LN or MLN. Indeed, in esotropic patients, LN may be unmasked in dim light or by shining a bright light at the dominant eye, as when testing pupil reflexes.

Spasmus nutans syndrome is a transient, high-frequency, low-amplitude pendular nystagmus with onset between the ages of 6 and 12 months that lasts approximately 2 years but occasionally can be as long as 5 years. The direction of the oscillations may be horizontal, vertical, or torsional; the oscillations often are dysconjugate, asymmetrical, even monocular, and variable. SNS may be associated with torticollis and head titubation, and these three features constitute the spasmus nutans triad. The titubation has a lower frequency than that of the nystagmus and thus is not compensatory. Patients can improve vision by vigorously shaking the head, presumably to stimulate the vestibulo-ocular reflex and suppress or override the ocular oscillations. Some patients may have esotropia. Clinically, spasmus nutans is distinguished from INS and FMNS by its intermittency, high frequency, vertical component, and dysconjugacy (Leigh and Zee, 2006).

Although spasmus nutans is a benign and transient disorder, it must be distinguished from acquired nystagmus caused by structural lesions involving the anterior visual pathways in approximately 2% of patients. In the latter situation, a careful ophthalmological examination reveals clinical evidence such as impaired vision, a relative afferent pupillary defect, or optic atrophy. Also, retinal disorders may masquerade as spasmus nutans; paradoxical pupil constriction in darkness is suggestive, but an electroretinogram is confirmatory. Kim and associates (2003) reported spasmus nutans in a patient with congenital ocular motor apraxia and cerebellar vermian hypoplasia.

Nystagmus Blockage Syndrome

The nystagmus blockage syndrome is a poorly understood condition in which some patients with INS, or the latent form of FMNS “purposely” induce an esotropia to suppress the nystagmus; this results in a head turn in the direction of the fixating (adducted) eye. An abducting jerk nystagmus reappears with attempted abduction of either eye. In some patients it is believed excessive convergence blocks the nystagmus, in others the waveform of INS converts to MLN (Dell’Osso and Daroff, 1999a). The differential diagnosis includes crossed fixation (the Ciancia syndrome), bilateral sixth nerve paralysis, and Duane’s syndrome. The treatment is corrective extraocular muscle surgery.

Pendular Nystagmus

Pendular nystagmus (see Fig. 35.17, A) has a sinusoidal waveform and usually is horizontal. It may be either congenital or acquired. Large-amplitude (“searching”) pendular nystagmus usually is associated with poor vision as a result of afferent disorders such as optic neuropathy, which can be unilateral, and retinal disorders (see INS). Acquired pendular nystagmus (APN) typically has horizontal, vertical, and torsional components, although one may be dominant. The oscillations of each eye may be so different that the nystagmus may appear monocular clinically (Leigh and Zee, 2006). The most common cause of APN is multiple sclerosis (MS), followed by brainstem vascular disease; MS patients frequently have optic neuropathy that usually is worse in the eye with the larger oscillations. Other disorders of myelin, including Cockayne syndrome, Pelizaeus-Merzbacher disease, peroxisomal disorders, disorders associated with toluene abuse, as well as spinocerebellar disease, hypoxic encephalopathy, and Whipple disease, can cause pendular nystagmus.

Pendular nystagmus probably results from disruption of normal feedback from cerebellar nuclei to the NI (Das et al., 2000). This is in keeping with the predominance of paramedian pontine lesions on magnetic resonance imaging (MRI) in patients with horizontal pendular nystagmus (Lopez et al., 1995, 1996) and with the predominance of medullary lesions in those with torsional pendular nystagmus. The rhythmic pendular oscillations may be the result of deafferentation of the inferior olive by lesions involving the central tegmental tracts, medial vestibular nuclei, or paramedian tracts, causing instability in the system. Disruption of prenuclear ocular motor pathways necessary for orthotropia (and conjugacy) may be a factor as well. A similar mechanism may be responsible for oculopalatal myoclonus (discussed later in this section).

Pendular vergence nystagmus, previously called convergent-divergent nystagmus, a rare variant of acquired pendular nystagmus, is dysconjugate and occurs in patients with MS, brainstem stroke, Chiari malformations, cerebral Whipple disease (see Oculomasticatory Myorhythmia), occasionally palated myoclonus, and progressive ataxia (Averbuch-Heller et al., 1995). The eyes oscillate, mainly horizontally, in opposite directions simultaneously, although they sometimes form circular, elliptical, or oblique trajectories, depending on the phase relationship of the horizontal, vertical, and torsional vectors responsible for the oscillations.

Cyclovergent nystagmus (i.e., dysconjugate torsional nystagmus in which the upper poles of the eyes oscillate in opposite directions) was detected by scleral search coil oculography in a patient with progressive ataxia and palatal myoclonus (Averbuch-Heller et al., 1995). On rare occasions, cyclovergent nystagmus may be observed clinically.

Vertical pendular nystagmus closely resembles the vertical ocular oscillation associated with palatal myoclonus (the oculopalatal syndrome) (Dell’Osso and Daroff, 1999a) and may be a form of the same disorder, which also results from lesions of the deep cerebellar nuclei and their connections.

Elliptical pendular nystagmus, with a larger vertical component and superimposed or interposed upbeat nystagmus, is characteristic of Pelizaeus-Merzbacher disease. This nystagmus can be difficult to discern with the naked eye. It is seen more easily with an ophthalmoscope, but oculography using scleral search coils may be necessary to detect it (Dell’Osso and Daroff, 1999b).

Oculomasticatory Myorhythmia

Oculomasticatory myorhythmia, described in patients with Whipple disease and, to date, pathognomonic of that disorder, consists of continuous rhythmic jaw contractions synchronous with dissociated pendular vergence oscillations. It may be associated with supranuclear vertical gaze palsy, altered mentation, somnolence, mild uveitis, or retinopathy (Knox et al., 1995). Myorhythmia of the face and arms is described in Hashimoto encephalopathy (Erickson et al., 2002).

Gaze-Paretic Nystagmus

Gaze-paretic nystagmus, the most common type of nystagmus, usually is symmetrical and evoked by eccentric gaze to either side but is absent in the primary position. Frequently it is present on eccentric vertical gaze, with upward-beating nystagmus on upgaze and downward-beating nystagmus on downgaze. It may be asymmetrical with asymmetrical central nervous system (CNS) disease or with disorders such as myasthenia. It has a jerk waveform, with the fast phase in the direction of gaze. Oculographic recordings show a decreasing exponential slow phase (see Fig. 35.17, C). Gaze-paretic nystagmus results from dysfunction of the NI and commonly is caused by alcohol or drug intoxication (by anticonvulsants and tranquilizers). When it is caused by structural disease, it tends to be asymmetrical.

Vestibular Nystagmus

Vestibular nystagmus results from damage to the labyrinth, vestibular nerve, vestibular nuclei, or their connections in the brainstem or cerebellum. Vestibular nystagmus may be divided into central and peripheral forms on the basis of the associated features outlined in Chapter 37. Peripheral vestibular nystagmus, caused by dysfunction of the vestibular end organ or nerve, has a linear slow phase (see Fig. 35.17, B), whereas with central lesions, the slow phase may be variable. Usually, peripheral vestibular nystagmus is associated with severe vegetative symptoms and signs including nausea, vomiting, perspiration, and diarrhea; it also may be associated with hearing loss and tinnitus. With central vestibular nystagmus, vegetative symptoms are less severe, but other neurological features may be present, such as headache, ataxia, dysconjugate gaze, and pyramidal tract signs (see Chapter 19).

Caloric-Induced Nystagmus

Caloric-induced nystagmus is discussed in Chapter 37.

Physiological Nystagmus

Physiological (endpoint) nystagmus is a jerk nystagmus observed on extreme lateral or upward gaze. If the bridge of the nose obstructs the view of the adducting eye, physiological nystagmus may be dysconjugate because the amplitude is greater in the abducting eye. A torsional component is sometimes seen. Physiological nystagmus is distinguished from pathological nystagmus by its symmetry on right and left gaze and by the absence of other neurological features. It is not present when the angle of gaze is less than 30 degrees from primary position. Oculographic recordings primarily demonstrate a linear slow phase (see Fig. 35.17, B) and may detect transient small-amplitude rebound nystagmus.

Dysconjugate Nystagmus

Dysconjugate (dissociated) nystagmus occurs when the ocular oscillations are out of phase (in different directions). It is seen with internuclear ophthalmoplegia, other brainstem lesions (see earlier discussion of pendular vergence nystagmus under Pendular Nystagmus), and spasmus nutans. Monocular nystagmus also is dysconjugate and may be associated with amblyopia and other forms of vision loss (Box 35.11).

Monocular Nystagmus

Monocular nystagmus may be pendular or jerk and also may be horizontal, vertical, or oblique. Oculographic recordings may reveal small-amplitude oscillations in the fellow eye. Monocular nystagmus may occur in patients with alternating hemiplegia of childhood (Egan, 2002), amblyopia, strabismus, monocular blindness, spasmus nutans, internuclear ophthalmoplegia, MS, or (rarely) seizures (Grant et al., 2002), and of course when the other eye is completely ophthalmoplegic or absent.

The Heimann-Bielschowsky phenomenon is a rare form of monocular vertical pendular oscillation, with a frequency of 1 to 5 Hz, that occurs in an amblyopic eye or after acquired monocular vision loss, such as with cataract. In the latter situation, it may be reversible after successful treatment of the underlying condition or with gabapentin (Rahman et al., 2006).

Superior oblique myokymia may be mistaken for a monocular torsional or vertical nystagmus (see Box 35.11).

Upbeat Nystagmus

Upbeat nystagmus is a spontaneous jerk nystagmus with the fast phase upward while the eyes are in primary position (Hirose et al., 1998). It is attributed to interruption of the anterior semicircular canal projections, which are responsible for the upward vestibulo-ocular reflex, causing downward drift of the eyes with corrective upward saccades. The amplitude and intensity of the nystagmus usually increase on upgaze. This finding strongly suggests bilateral paramedian lesions of the brainstem, usually at the pontomedullary or pontomesencephalic junction, the paramedian tract neurons in the lower medulla, or midline cerebellum (vermis). Rarely, upbeat nystagmus may be congenital, or it may result from Wernicke encephalopathy or intoxication with anticonvulsants, organophosphates, lithium, nicotine, or thallium (author’s personal observation). In infants, upbeat nystagmus may be a sign of anterior visual pathway disease, such as Leber congenital amaurosis (see Chapter 36), optic nerve hypoplasia, aniridia, or cataracts. Small-amplitude upbeat nystagmus may be seen in persons who are carriers of blue-cone monochromatism, whereas affected patients may have intermittent pendular oblique nystagmus. If the intensity of upbeat nystagmus diminishes in downgaze, base-up prisms over both eyes may improve the oscillopsia; gabapentin also may be helpful (Table 35.4). For an extensive list of causes of upbeat nystagmus, see Leigh and Zee’s textbook (2006).

Table 35.4 Treatment of Nystagmus and Non-Nystagmus Oscillations*

ACTH, Adrenocorticotropic hormone; AEDs, antiepileptic drugs; 5-HT, 5-hydroxytryptamine; APN, acquired pendular nystagmus; PAN, periodic alternating nystagmus; SSN, seesaw nystagmus.

* Treat underlying cause when possible.

† Memantine is reported to exacerbate MS (Villoslada el al., 2009).

Downbeat Nystagmus

Downbeat nystagmus is a spontaneous downward-beating jerk nystagmus present in primary position and is attributed to either (1) interruption of the posterior semicircular canal projections, which are responsible for the downward vestibulo-ocular reflex (VOR), causing upward drift of the eyes with corrective downward saccades, or (2) impaired cerebellar inhibition of the vestibular circuits for upward eye movements, resulting in uninhibited upward drifting of the eyes, with corrective downward saccades. The amplitude of the oscillations increases when the eyes are deviated laterally and slightly downward (the Daroff sign).

Downbeat nystagmus may be apparent only with changes in posture (positional downbeat nystagmus), particularly the head-hanging position. Downbeat nystagmus results from either damage to the commissural fibers between the vestibular nuclei in the floor of the fourth ventricle or bilateral damage to the flocculus that disinhibits the VOR in pitch; frequently it occurs with structural lesions at the craniocervical junction (Box 35.12). A thorough investigation for such should be made. MRI of the foramen magnum region (in the sagittal plane) is the investigation of choice. Olson and Jacobson suggested that in some cases of unexplained downbeat nystagmus, the cause is a radiographically occult infarction (2001); however, lesions that cause downbeat nystagmus are bilateral (Brandt and Dietrich, 1995). Causes of downbeat nystagmus are listed in Box 35.12.

Box 35.12 Causes of Downbeat Nystagmus

Congenital (rare)

Transiently in normal neonates

Craniocervical junction abnormalities:

Basilar invagination (e.g., Paget disease)

Chiari malformations

Dolichoectasia of the vertebrobasilar arterial system

Foramen magnum tumors

Syringobulbia

Cerebellar disorders:

Alcoholic cerebellar degeneration (chronic usage)

Anoxic cerebellar degeneration

Anti–glutamic acid decarboxylase antibodies (anti-GAD65 antibodies)

Familial spinocerebellar degeneration, particularly SCA-6, and with multiple system atrophy (Leigh and Zee, 2006)

Episodic ataxia

Cerebellar degeneration following human T-lymphotropic virus types I and II (Castillo et al., 2000)

Paraneoplastic cerebellar degeneration

Heat stroke–induced cerebellar degeneration

Metabolic disorders (drugs, toxins, and deficiencies):

Alcohol intoxication

Amiodarone

Anticonvulsants

Lithium

Opioids (Rottach et al., 2002)

Toluene abuse

Magnesium depletion

Wernicke encephalopathy

Vitamin B₁₂ deficiency

Other:

Benign paroxysmal positional vertigo: positional downbeat nystagmus with anterior canal lesion

Brainstem encephalitis

Cardiogenic vertigo (Choi et al., 2011)

Carriers of blue-cone monochromatism may have small-amplitude downbeat nystagmus.

Cephalic tetanus (Orwitz et al., 1997)

Hydrocephalus

Leukodystrophy

Multiple sclerosis

Syncope

Vertebrobasilar ischemia

The treatment of downbeat nystagmus involves correction of the underlying cause when possible. When downbeat nystagmus damps on convergence, it may be treated successfully with base-out prisms, reducing the oscillopsia and improving the visual acuity. Baclofen, clonazepam, or 4-aminopyridine may also help (see Table 35.4); 4-aminopyridine is more effective in downbeat nystagmus associated with cerebellar atrophy rather than structural lesions (Huppert et al., 2011).

Both upbeat and downbeat nystagmus may be altered in amplitude and direction by a variety of maneuvers (e.g., convergence, head tilting, changes in posture) and by 3,4-diaminopyridine (Leigh and Zee, 2006).

Periodic Alternating Nystagmus

Periodic alternating nystagmus (PAN) is a horizontal jerk nystagmus in which the fast phase beats in one direction and then damps or stops for a few seconds before changing direction to the opposite side every 30 to 180 seconds. During the short transition period, vertical nystagmus or square wave jerks may occur. PAN has the same clinical significance as downbeat nystagmus, and the two entities sometimes coexist. Attention should be focused at the craniocervical junction. PAN also may occur in Creutzfeldt-Jakob disease.

When PAN is congenital, it may be associated with albinism. In one series of patients with congenital PAN, none had pure vertical oscillations, even during the transition period (Gradstein et al., 1997). Although not all patients with acquired PAN have vertical nystagmus during the transition period, its presence may distinguish acquired from congenital PAN (personal observation); this finding does not obviate further evaluation when appropriate. Transient episodes of PAN were provoked by attacks of Ménière disease in a patient with a hypoplastic cerebellum and an enlarged cisterna magna (Chiu and Hain, 2002). Episodic PAN can be a manifestation of a seizure (see later discussion of ictal nystagmus). An atypical form of paroxysmal alternating skew deviation and nystagmus has followed partial destruction of the inferior uvula and adjacent pyramis during biopsy of a suspected brainstem glioma (Radtke et al., 2001).

Lesions of the cerebellar nodulus cause loss of γ-aminobutyric acid (GABA)-mediated inhibition from the Purkinje cells to the vestibular nuclei, impairing the velocity storage mechanism. It is likely that overcompensation in feedback loops causes cyclical firing between reciprocally connected inhibitory neurons and generates the unusual oscillations of acquired PAN. Affected patients have hyperactive vestibular responses and poor vestibular fixation suppression, attributed to involvement of the nodulus and uvula (Leigh and Zee, 2006).

Treatment of PAN should be directed at correcting the cause, such as a Chiari malformation, when possible. Baclofen, a GABA-b agonist, replaces the missing inhibition and usually is effective in the acquired form of the disease and occasionally in the congenital form. Dextroamphetamine resulted in clinical improvement in a patient with PAN who also had rod-cone dystrophy and strabismus (Hertle et al., 2001b).

Rebound Nystagmus

Rebound nystagmus is a horizontal gaze–evoked nystagmus in which the direction of the fast phase reverses with sustained lateral gaze or beats transiently in the opposite direction when the eyes return to primary position (Video 35.3, available at www.expertconsult.com). The latter is occasionally a physiological finding and caused by dysfunction of the cerebellum or the perihypoglossal nuclei in the medulla. Occasionally, rebound nystagmus may be torsional.

Centripetal Nystagmus

Cerebellar dysfunction can cause a form of gaze-evoked nystagmus in which the fast phase beats toward primary position (i.e., centripetally) and the slow phase drifts peripherally toward an eccentric target. Centripetal nystagmus is similar to rebound nystagmus and may result from overcompensation by the cerebellar nodulus and uvula to adjust for a directional bias by temporarily moving the null zone during eccentric gaze. Centripetal nystagmus in both the horizontal and vertical planes may be associated with Creutzfeldt-Jakob disease.

Convergence-Evoked Nystagmus

Convergence-evoked nystagmus is an unusual ocular oscillation, usually pendular, induced by voluntary convergence (see earlier discussion of pendular vergence nystagmus under Pendular Nystagmus). The movements may be conjugate or dissociated. This condition may be congenital or acquired, such as in patients with MS. A jerk form occurs with Chiari type I malformations. Convergence-evoked vertical nystagmus (upbeat more common than downbeat) also occurs. Convergence-evoked nystagmus should be distinguished from voluntary nystagmus and from convergence retraction nystagmus (see Saccadic Intrusions and Other Non-Nystagmus Ocular Oscillations, later).

Seesaw Nystagmus

Seesaw nystagmus is a spectacular ocular oscillation in which one eye rises and intorts as the other eye falls and extorts. The waveform appears pendular. The oscillations usually become faster and smaller on upgaze but slower and larger on downgaze; they may cease in darkness. Disordered control of the normal ocular counter-rolling reflex may be responsible. Bitemporal hemianopia, caused by acquired chiasmal defects or impaired central vision, plays a significant role in generating SSN. Disruption of retinal error signals necessary for VOR adaptation, which normally are conveyed to the inferior olive by the chiasmal crossing fibers, results in an unstable visuovestibular environment. Fixation and pursuit feedback accentuate this instability, causing synchronous oscillations of floccular Purkinje cells, which relay to the nodulus, resulting in SSN. This mechanism also may be the basis for the ocular oscillations of oculopalatal myoclonus. The observations of SSN and INS in achiasmatic humans and achiasmatic Belgian sheepdogs support this hypothesis (Dell’Osso and Daroff, 1998). Significantly, the onset of both SSN and oculopalatal myoclonus may be delayed after CNS lesions.

SSN occurs with lesions in the region of the mesodiencephalic junction, particularly the zona incerta and the interstitial nucleus of Cajal. Congenital SSN may be associated with a superimposed horizontal pendular nystagmus; some patients with congenital SSN may be achiasmatic or have septo-optic dysplasia. Acquired SSN may be associated with suprasellar tumors, Joubert syndrome, and Leigh disease, particularly the jerk form described later. Acquired pendular SSN may be accompanied by a bitemporal hemianopia from trauma or an expanding lesion in the third ventricular region, or by severe loss of central vision due to disorders such as choroiditis, cone-rod dystrophy, whole-brain radiation and intrathecal methotrexate, and vitreous hemorrhage (Dell’Osso and Daroff, 1998). Transient (latent) SSN may occur for a few seconds after a blink, perhaps because of loss of fixation, in patients with chiasmal region lesions. If SSN damps with convergence, base-out prisms may be helpful. Baclofen also may be beneficial in SSN.

Reverse congenital seesaw nystagmus is a rare condition in which the rising eye extorts as the falling eye intorts.

A jerk waveform hemi-SSN occurs with unilateral mesodiencephalic lesions, presumably as a result of selective unilateral inactivation of the torsional eye-velocity integrator in the interstitial nucleus of Cajal. During the fast (jerk) phases, the upper poles of the eyes rotate toward the side of the lesion. In hemi-jerk SSN caused by lateral medullary lesions, the fast phases jerk away from the side of the lesion. In both situations, the torsional component is always conjugate. With mesodiencephalic lesions, the vertical component is always disjunctive (the eyes oscillate in opposite directions, with the intorting eye rising and the extorting eye falling), but with medullary lesions it may be either conjugate (usually upward) or disjunctive. Other features of brainstem dysfunction may be necessary to localize the lesion.

Torsional (Rotary) Nystagmus

In torsional nystagmus (TN), the eye oscillates in a pure rotary or plane. TN may be present in primary position or with either head positioning or gaze deviation. Usually it results from lesions in the central vestibular pathways. Pure TN occurs only with central vestibular dysfunction, whereas mixed torsional-linear nystagmus may occur with peripheral vestibular disease. When the waveform of TN is pendular (i.e., torsional pendular nystagmus), the lesion usually is in the medulla (Lopez et al., 1995). Skew deviation frequently coexists with TN.

In patients with lesions of the middle cerebellar peduncle, TN with a jerk waveform—similar to jerk SSN—may be evoked by vertical pursuit eye movement and during fixation suppression of the vertical VOR. The direction of the fast phase changes with pursuit direction; it usually is toward the side of the lesion on downward pursuit and away from the side of the lesion on upward pursuit (FitzGibbon et al., 1996).

Ictal Nystagmus

Ictal nystagmus often accompanies adversive seizures and beats to the side opposite the focus. Ictal nystagmus may be associated with transient pupillary dilation of either the abducting or adducting eye (Masjuan et al., 1997). Pupillary oscillations synchronous with the nystagmus may occur rarely. Ictal nystagmus associated with unformed visual hallucinations, homonymous hemianopia, and unusual MRI findings occurs in patients with non-ketotic hyperglycemia (Lavin 2005). Nystagmus as the only motor manifestation of a seizure is rare; however, there are reports of isolated ictal nystagmus, such as occurs in patients with vivid ictal visual hallucinations. Monocular nystagmus associated with ipsilateral hemianopic visual hallucinations in a binocular patient can occur as the only manifestation of a partial seizure caused by a focal discharge in the contralateral medial occipital lobe (Grant et al., 2002). It is difficult to draw any conclusion clinically regarding the location of the seizure discharge in these patients, because seizure foci were found in occipital, parietal, temporal, and frontal areas. Usually the nystagmus is horizontal, but vertical nystagmus, mainly in comatose patients, was reported on occasion. In comatose patients, periodic eye movements should alert the physician to the possibility of status epilepticus; indeed, PAN associated with periodic alternating gaze deviation and periodic alternating head rotation may be a manifestation of a seizure (Moster and Schnayder, 1998). The monocular abducting nystagmus seen in alternating hemiplegia of childhood is likely ictal in origin.

Brun Nystagmus

Brun nystagmus occurs in patients with large cerebellopontine angle tumors. The nystagmus is bilateral but asymmetrical, with a jerk waveform. It is characterized by large-amplitude, low-frequency fast phases on gaze toward the side of the lesion but small-amplitude, high-frequency fast phases on gaze to the other side. The ipsilateral large-amplitude (coarse) nystagmus has an exponentially decreasing velocity slow phase attributed to compression of the brainstem NI, which includes the ipsilateral medial vestibular nucleus. The contralateral small-amplitude, high-frequency nystagmus has a linear slow phase attributed to ipsilateral vestibular dysfunction (see Fig. 35.17). Occasionally an anterior inferior cerebellar artery territory stroke can cause Brun nystagmus (personal observation).

Episodic Nystagmus (Periodic Nystagmus)

Episodic nystagmus is associated with disorders in which the patient has paroxysmal episodes of vertigo, ataxia, and nystagmus lasting up to 24 hours. The nystagmus may be torsional, vertical, or dissociated. The frequency of attacks varies, ranging from once a day to only a few times per year. Such periodic ataxias occur in patients with hereditary inborn errors of metabolism, in an autosomal dominant form without any detectable metabolic defect (channelopathy), in some forms of spinocerebellar degeneration, in basilar migraine, and in MS. Acetazolamide or 4-aminopyridine may alleviate or prevent attacks in the familial form (see Chapter 72).

Perverted Nystagmus

Perverted vestibular nystagmus occurs in a plane different from that of the applied vestibular stimulus and is caused by lesions involving central vestibular connections. For example, horizontal head shaking in a patient with MS caused transient downbeat nystagmus (Minagar et al., 2001).

Lid Nystagmus

Lid nystagmus, characterized by rhythmic jerking movements of the upper eyelids, occurs in the following situations: (1) synchronous with vertical ocular nystagmus, (2) synchronous with the fast phase of gaze-evoked horizontal nystagmus in some patients with the lateral medullary syndrome, (3) evoked by horizontal gaze in some patients with midbrain tumors that injure the M-group of neurons adjacent to the riMLF, and (4) during voluntary convergence (the Pick sign) in some patients with medullary or cerebellar disease (Dell’Osso and Daroff, 1999a; Leigh and Zee, 2006).

Optokinetic Nystagmus

True optokinetic nystagmus (OKN) is a rhythmic involuntary conjugate ocular oscillation provoked by a compelling full visual field stimulus, such as that produced by rotating an image of the environment around the patient or by turning the patient in a revolving chair. The oscillations are biphasic, and the nystagmus consists of initial slow phases provoked by and in the direction of the stimulus, followed by corrective fast phases. Elicitation of OKN in response to a pocket tape is a useful bedside test but only evaluates foveal pursuit and refixation saccades, which is helpful in several circumstances including: (1) detection of a subtle internuclear ophthalmoplegia; (2) provocation of convergence-retraction nystagmus, wherein the tape is moved downward in an attempt to induce upward saccades; (3) congenital nystagmus, wherein the direction of the fast phase may be paradoxical—that is, in the direction of the slowly moving tape or drum; (4) psychogenic blindness or ophthalmoplegia; (5) homonymous hemianopia caused by a large, deep-seated parietotemporo-occipital lesion, in which the OKN response is depressed or absent as the tape moves toward the side of the lesion.

A large mirror may be used to induce true optokinetic movements in patients with psychogenic ophthalmoplegia or psychogenic blindness. The examiner holds the mirror in front of the patient, whose eyes are open. The mirror is gently rocked so that the reflected environment (full visual fields) move. This compelling optokinetic stimulus forces reflex slow eye movements. The patient may close the eyes, look away, or exhibit convergence in an attempt to avoid the reflex response. Care must be taken in diagnosing psychogenic disorders with this test in patients with supranuclear gaze palsies, ocular motor apraxia, or poor vision; even those with “count-fingers” vision may still have an OKN response.