head turns associated with manifest-latent nystagmus may benefit from oculinum injection into the medial rectus muscle of the fixating eye or from a recess-resect procedure of the fixating eye to simultaneously eliminate the face turn and the large esotropia.370

Nystagmus Blockage Syndrome

The nystagmus blockage syndrome is a rare variant of infantile nystagmus. It is characterized by an intermittent horizontal nystagmus accompanied by a large-angle, variable esotropia.553 The following three clinical characteristics typify the nys-

tagmus blockage syndrome:

1. The esotropia increases as the nystagmus damps and decreases as the intensity of the nystagmus increases.

2. The esotropia disappears or markedly diminishes when one eye is occluded and the fixating eye is moved into abduction.

3. The angle of esotropia increases when prisms are placed before the eyes to neutralize the deviation.

The child with nystagmus blockage syndrome invokes excessive convergence to damp an underlying infantile nystagmus or convert it to a low-amplitude manifest latent nystagmus by a purposive esotropia and improve acuity.145 During periods of convergence, pupillary constriction may or may not be observed, suggesting that some children have the ability to partially dissociate accommodation from convergence, which would predispose to nystagmus blockage syndrome by making it a visually beneficial adaptive strategy. When viewing objects of interest, children with nystagmus blockage syndrome display tonic convergence that may simulate a bilateral sixth nerve palsy. Fixation with the adducted eye necessitates a head turn toward the fixating eye to view objects that are in primary position.149An alternating head turn may signify alternating fixation during periods of esotropia. Some children with nystagmus blockage syndrome eventually develop a constant esotropia, suggesting that a progressive medial rectus contracture can develop.

The active blockage of infantile nystagmus by convergence must be distinguished from the variable esotropia that can accompany latent nystagmus.87 In the setting of infantile strabismus, monocular fixation with either eye may exert dissociated esotonus, causing an existing exotropia to decrease or an existing esotropia to increase. The resulting convergent eye movement has been misinterpreted as an active convergence blockage mechanism.233,607 Any reduction of latent nystagmus associated with dissociated esotonus is an ­epiphenomenon (because the same process occurs in patients with no latent nystagmus).146

Treatment of Nystagmus Blockage Syndrome

Nystagmus blockage syndrome has been successfully treated with strabismus surgery that consists of bilateral medial rectus posterior fixation sutures (if the eyes are straight during periods of relaxation) or bimedial recession with or without posterior fixation sutures, or unilateral recession and resection.555

Vertical Nystagmus

When the onset of vertical nystagmus is noted in the first 3 months of life, neuroimaging studies are frequently normal. In children with acquired vertical nystagmus, neuroimaging is warranted to rule out a posterior fossa lesion. In this context, upbeating and downbeating nystagmus in infancy are each associated with a distinct clinical profile and visual prognosis.

Upbeating Nystagmus in Infancy

Unlike upbeating nystagmus in adulthood, which is associated with a structural lesion involving the brainstem or cerebellum,448 upbeating nystagmus in infancy is usually associated with anterior visual pathway disease. Good et al222 found anterior pathway disease in 11 children who presented with upbeating nystagmus in infancy. The underlying diagnosis included Leber congenital amaurosis (seven cases), optic nerve hypoplasia (two cases), aniridia (one case), and ­congenital cataracts (one case). Upbeating nystagmus in infancy may be asymmetrical and may convert to a horizontal nystagmus in the first 2 years of life.222 When the optic nerves appear normal, ERG usually reveals the abnormality. Simonsz et al recently described 20 children who presented at three to six months of age with chin-up posture, high frequency, large amplitude upbeating nystagmus on attempted upgaze and who were found to have congenital stationary night blindness.504a Neuroimaging can be reserved for cases in which the results of ERG are normal.

If ERG is also negative, the diagnosis of hereditary vertical nystagmus should be considered (discussed later).323,379,509 The positive family history and good visual acuity in patients with familial upbeating nystagmus readily distinguishes it from infantile upbeating nystagmus associated with anterior visual pathway disease.222

Congenital Downbeat Nystagmus

Congenital downbeat nystagmus is rare. Little is known about its pathogenesis, but an accumulating body of evidence suggests that it is usually hereditary and rarely associated with a structural CNS lesion.80 It differs fundamentally from the horizontal and upbeating forms of infantile nystagmus in its tendency to resolve spontaneously in the first few years of life. The infant with a downbeat nystagmus and negative neuroimaging is likely to have a benign form of downbeat nystagmus characterized by (1) a chindown position; (2) some degree of ataxia and imbalance when learning to walk; (3) resolution of nystagmus and anomalous head posture by 2 years of age; and (4) a firstdegree relative with a history of a chin-down position in infancy that resolved (Fig. 8.15).64

A parent may also show subtle evidence of central vestibular imbalance (gaze-evoked nystagmus, subtle, downbeating nystagmus on oblique gaze downward).64 Unlike acquired hereditary forms of downbeat nystagmus that may have their onset in childhood and may be harbingers of spinocerebellar degeneration, congenital hereditary downbeating nystagmus seems to impart a benign neurological prognosis. Eye movement recordings have demonstrated a linear slow-wave configuration, unlike the increasing exponential waveform considered classic for infantile nystagmus. In contradistinction to the anterior visual pathway disease that frequently underlies upbeating nystagmus, patients with transient familial downbeating nystagmus of infancy have good vision once the nystagmus resolves.

Phenomenologically, tonic upgaze and downbeat nystagmus are closely related conditions, differing only in the

presence or absence of rhythmical downward saccades. It is likely that benign hereditary downbeat nystagmus and the syndrome of benign tonic upward deviation of the eyes with ataxia are variants of the same disorder. In several affected children, tonic upgaze has evolved into downbeating nystagmus.

In benign tonic upward deviation of the eyes, the conjugate upward deviation usually improves following sleep and becomes worse with fatigue or stress.19,175,185,214 Several children have improved following treatment with levodopa.94 Prismatic therapy may be a useful therapeutic adjunct in the treatment of this condition while awaiting resolution.573 Both conditions probably result from an imbalance in central vestibular tone that is gradually compensated.94 In a child with acquired downbeat nystagmus, MR imaging should therefore be obtained to rule out an underlying CNS malformation at the level of the craniocervical junction, such as Arnold–Chiari malformation, basilar impression, platybasia, syringobulbia, and Klippel–Feil anomaly.482 In many of these conditions, the downbeat nystagmus results from compression of the herniated cerebellum against the caudal brainstem rather than an intrinsic abnormality of the ocular motor pathways, as demonstrated by the clinical improvement that often follows surgical decompression.47,482

Hereditary conditions such as episodic ataxia type 2 can present with downbeat nystagmus with recurrent attacks of ataxia that are provoked by physical exertion, emotional stress, or alcohol.521 Migraine headaches occur in more than half of cases.312 Cerebellar atrophy, especially of the anterior vermis, can be detected on MR imaging.550 Episodic ataxia type 2 usually begins in early childhood, most often before age 20.521 Between spells, more that 90% of patients exhibit central ocular motor disturbances such as gaze-holding

­deficits,saccadicsmoothpursuit,impairedvisual­suppression of the VOR (especially downbeat nystagmus) or, rarely, bilateral internuclear ophthalmoplegia. Episodic ataxia 2 is allelic with familial hemiplegic migraine type 1, which is almost exclusively caused by gain-of-function mutations, resulting in an increase of calcium flow through the CACNA1A channel.439

As discussed in the section on skew deviation, downbeat nystagmus (a pitch movement) may be a bilateral form of the ocular tilt reaction (a roll movement) at least in some patients.76 Brandt and Dieterich73 suggested that overlapping pathways modulate roll and pitch function of the VOR, making efficient use of the vestibular network. According to their hypothesis, a unilateral skew deviation reflects a central graviceptive imbalance in the roll plane while bilateral paramedian lesions or bilateral dysfunction of the cerebellar flocculus produces a tone imbalance in the pitch plane. The principle behind this operation resembles the guidance system of airplanes, wherein unilateral activation of a brake flap causes the plane to roll, while bilateral activation results in downward pitch. In a bilateral ocular tilt reaction, the vertical components summate to produce the slow-phase vertical drift of both eyes while the torsional components cancel each other out. Thus, a roll imbalance manifests as an ocular tilt reaction, while bilateral otolithic imbalance produces upbeat or downbeat nystagmus in conjunction with an alternating skew deviation on lateral gaze.73

Humans have a physiological upward velocity bias because the gain of all upward slow eye movements is greater than that of downward slow eye movements in normal human subjects and in monkeys.68 Because gravity influences the vestibular system, it is hypothesized that the excitatory superior vestibular nucleus and ventral tegmental tract pathways, along with their specific floccular inhibition, have incorporated an upward drift bias to counteract the gravity pull.448 In adults, 4-aminopyridine and 3,4 aminopyridine have recently been used to successfully treat downbeat nystagmus with minimal side effects, presumably by intensifying the excitability of Purkinje cells and their inhibitory cerebellar input on vestibular nuclei neurons.

Hereditary Vertical Nystagmus

Several families have been described with vertical pendular (or occasionally upbeating) nystagmus, cerebellar ataxia, and negative neuroimaging studies.323,379 In one report,323 the cerebellar findings were progressive, suggesting that these patients had a hereditary, cerebellar degeneration. Hereditary vertical nystagmus does rarely occur as an intermittent phenomenon.509

Periodic Alternating Nystagmus

Up to 17% of the infantile nystagmus population (with or without sensory visual deficits) has a periodicity to their nystagmus.177,279,494 These patients are found on prolonged observation to have a reversal in the direction of their nystagmus at approximately 2-min intervals. As the nystagmus finishes one half-cycle (e.g., right-beating nystagmus), there is a brief transition period in which upbeating nystagmus, downbeating nystagmus, or square wave jerks may be seen before the next half-cycle (e.g., left-beating nystagmus) commences.365 Careful examination usually shows that the nystagmus is actually aperiodic, in that one phase generally predominates. It is also ­common for the duration of each phase of the cycle to vary from one cycle to the next. It is important (and often difficult) to distinguish periodic alternating nystagmus from infantile nystagmus with “double torticollis,” in which two separate horizontal null points exist and the patient randomly uses one or the other. In some families, periodic alternating nystagmus is inherited as an isolated X-linked condition.285 Structural CNS lesions are rarely seen in congenital periodic alternating nystagmus and the underlying pathophysiology remains elusive.

Congenital periodic alternating nystagmus is associated with a high incidence of albinism. Therefore, pupillary light reflexes should be examined for a positive angle kappa, and slit lamp examination should be carefully performed to look for iris transillumination. Those with albinism tend not to have compensatory head positions, perhaps because of poor vision which does not improve sufficiently to warrant this adaptation.494 Those who do have anomalous head turns may show a unidirectional head turn despite the fact that the nystagmus reverses direction.494 In some cases, the cycles have been found to be as long as 5 min.234 Gradstein et al234 have found that a four muscle recession works best in the treatment of head turns associated with periodic alternating nystagmus. Acquired periodic alternating nystagmus is usually seen in older children or adults but may present in early childhood. Causes of acquired periodic alternating nystagmus include multiple sclerosis, posterior fossa lesions, encephalitis, otitis media, syphilis, aqueductal stenosis, and Arnold–Chiari malformation.257 Unlike congenital periodic alternating nystagmus, acquired periodic alternating nystagmus is usually associated with structural lesions involving the cerebellum or its central connections. Kalyanaranman317 reported three siblings who had periodic alternating nystagmus with associated head nodding as part of cerebrocerebellar degeneration. Reports of acquired periodic alternating nystagmus following visual loss (e.g., vitreous hemorrhage or cataract) and its disappearance with restoration of vision provide an important clue to the underlying pathophysiology.309

Animal experiments combined with additional data in humans suggest that acquired periodic alternating nystagmus probably requires concurrent CNS dysfunction at two separate levels. The nodulus and uvula of the cerebellum are believed to control post-rotational nystagmus, which is prolonged following ablation. Periodic alternating nystagmus can be produced in animals following ablation of these structures if visual deprivation is superimposed.

It is believed that normal vestibular repair mechanisms act to reverse the direction of the nystagmus. Under normal circumstances, the oscillations of periodic alternating nystagmus would be blocked by visual fixation, smooth pursuit, and optokinetic mechanisms. When these visual stabilization systems are held in abeyance (in the setting of visual deprivation with concurrent disease of the cerebellar flocculus), removal of Purkinje cell inhibition on the vestibular nuclei allows the central velocity storage mechanism to become unstable,362,366 and the acquired form of periodic alternating nystagmus develops. It is therefore likely that patients who acquire periodic alternating nystagmus following loss of vision may harbor a congenital lesion of cerebellum that is clinically silent until there is a reduction in retinal input.252

Pharmacological evidence suggests that the nodulus and uvula maintain inhibitory control on the vestibular rotational responses via the inhibitory neurotransmitter GABA.99 Halmagyi et al255 documented successful treatment of the acquired form of periodic alternating nystagmus with the GABA-ergic drug baclofen. The finding that acquired periodic alternating nystagmus is abolished by baclofen, both in humans and in animals following ablation of the nodulus and uvula, further supports the accepted pathogenetic mechanism for acquired periodic alternating nystagmus. Although congenital periodic alternating nystagmus is reportedly refractory to baclofen, patients occasionally improve with treatment.99,113

Seesaw nystagmus characteristically increases in bright light and dampens with accommodation or convergence.604

Although it is accepted that seesaw nystagmus can be an ominous neuro-ophthalmologic sign and that it often correlates with the presence of a suprasellar mass lesion, the precise neuroanatomical site of injury remains speculative. The two major theories of causation center on abnormal ocular motor output and anomalous visual sensory input. The motor theory states that large parasellar lesions compress the adjacent diencephalon and compress, injure, or disrupt the adjacent interstitial nucleus of Cajal. Discrete lesions involving the interstitial nucleus of Cajal at the junction of the rostral midbrain and diencephalon have been described in two patients with seesaw nystagmus.320,462 Stimulation of the interstitial nucleus of Cajal in the monkey produces an ocular tilt reaction consisting of extorsion and depression of the eye on the stimulated side and intorsion and elevation of the other eye, which is similar to a half cycle of seesaw nystagmus.577

The sensory hypothesis of Nakada and Kwee415 purports that chiasmal lesions disrupt subcortical pathways that carry signals from the inferior olive and cerebellar flocculus, which may normally be used for adaptive control of vestibular responses. According to this hypothesis, associated bitemporal hemianopia alters retinal error signals that reach the inferiorolivarynucleusthroughtwodiscretepathways,independent of the geniculocortical projections.524 Retinal error signals in the inferior olivary nucleus and their connections with Purkinje cells in the cerebellum are utilized for VOR adaptation, which renders the visuovestibular control system unstable,415 while the pursuit system is unaffected. Nakada and Kwee415 speculated that integrity of the inferior-olivary nodulus connections in seesaw nystagmus could explain the 180-degree phase difference that distinguishes it from the midline form of oculopalatal myoclonus, where these connections are disrupted.

Seesaw Nystagmus

Seesaw nystagmus is an uncommon form of pendular nystagmus characterized by simultaneous elevation and intorsion of one eye, with depression and extorsion of the other eye, followed by a reversal of the cycle.128,365 Seesaw nystagmus usually occurs in patients with large suprasellar tumors involving the optic chiasm and extending into the third ventricle. These children usually have a bitemporal hemianopia.128 However, it is now recognized to accompany infantile nystagmus in patients with achiasmia.140 Most patients with idiopathic infantile nystagmus also display a subtle seesaw nystagmus on eye movement recordings.169 Less commonly, focal lesions confined to the rostral mesencephalon produce seesaw nystagmus in conjunction with other brainstem ocular motility disorders. Mild seesaw nystagmus is easily misinterpreted as torsional nystagmus if the vertical component of the nystagmus is overlooked.

Congenital versus Acquired Seesaw Nystagmus

In congenital seesaw nystagmus, neuroimaging must be obtained to look for achiasmia (discussed above). Congenital seesaw nystagmus is rarely seen in infants with albinism and other sensory visual disorders who later convert to a horizontal nystagmus.297,600 It has been noted that congenital forms of seesaw nystagmus may lack the torsional components or even show the opposite pattern (i.e., extorsion with elevation and intorsion with depression).128,481 Zell and Biglan604 have stressed that the direction of cyclodeviation of the globes on vertical excursion cannot be relied on to clinically differentiate the congenital from the acquired form of seesaw nystagmus.

Acquired seesaw nystagmus in children is most commonly caused by craniopharyngioma and other parasellar tumors but