opsoclonus was identified clinically in 3 of 528 (0.6%) preterm infants screened for retinopathy of prematurity. On follow-up examination, the opsoclonus disappeared by the age of 6 months with no complications. Such reports of benign opsoclonus in term and preterm infants may be, at least in part, related to the insertion of an eyelid speculum.

Paraneoplastic Opsoclonus

The major diagnostic consideration for opsoclonus in the first several years of life is a neural crest tumor such as neuroblastoma. An opsoclonus-myoclonus-ataxia syndrome affects 2–3% of patients with neuroblastoma, an acute neurologic disorder characterized by involuntary chaotic jerking and ataxia.268,269,381 Conversely, neuroblastoma is found in approximately half of cases with opsoclonus in this age range.527 However, the high incidence of spontaneous regression of neuroblastoma could account for some of the remaining cases.527

Children with and without a tumor differ little in neurologic symptoms. The earliest neurological symptoms are staggering and falling. Later symptoms include body jerks, drooling, refusal to walk or sit, speech problems, decreased muscle tone, opsoclonus, rage attacks, and inability to

sleep.454,527

Patients with opsoclonus-myoclonus-ataxia and neuroblastoma have excellent survival but a high risk of neurologic sequelae.23,118,473 Musarella et al410 found a 100% 3-year survival rate in children with neuroblastoma who presented with opsoclonus, compared with 78.6% in those who presented with Horner’s syndrome and 11.2% in those with orbital metastasis. Improved survival in the subgroup with opsoclonus could not be accounted for by earlier diagnosis or a higher percentage of low-staged cases.

Late neurologic sequelae can be drastic and affect the quality of life.400 These sequelae include delays in motor function, speech, and cognition, or persisting abnormalities such as myoclonus, ataxia, dysarthria, and hypotonia.473,476 MR imaging may be normal in the acute phase,125 but children with opsoclonus-myoclonus-ataxia may show late development of cerebellar atrophy.268,269 Although the opsoclonus usually resolves, residual behavioral, language, and cognitive problems occur in most and significantly affect the quality of life.399 Some children show a clinical course suggestive of a progressive encephalopathy, rather than a timelimited single insult, as indicated by a significant negative correlation of functional status with age at testing.401

It has been hypothesized that the opsoclonus myoclonus in these children may be pathogenetically related either to a peptide produced by the tumor directly causing myoclonus and opsoclonus, or to an immunological cross-reactivity between the tumor and normal cerebellar neurons, with persistent anticerebellar antibodies being produced long after the tumor is removed.236,399,410 Increasing evidence supports

this immune hypothesis.420,473 Several forms of immunosuppressive therapy have been successful in treating opsoclo- nus-myoclonus-ataxia. Patients have had resolution of acute symptoms after treatment with steroids of adrenocorticotrophic hormone (ACTH).452 ACTH, prednisone, and intravenous immunoglobulin, and plasmapheresis are used, with ACTH associated with the best early response.527,548,597

A paraneoplastic panel should be obtained in the young child with opsoclonus, because antineuronal antibodies have been identified in several children with ­neuroblastoma.114,196,336,344 If antineuronal antibodies are found, this indicates the presence of a cancer (usually neuroblastoma). Anti-Hu antibodies have been found in a few patients with opsoclonus and neuroblastoma, but most cases have shown no detectable autoantibodies.28,53,66,344,453 Because antineuronal immune reactivity does not appear to be a long-term feature of opsoclonus in most children with neuroblastoma,268 a negative paraneoplastic panel does not rule out neuroblastoma as a diagnostic possibility. If not found, one cannot rule out the presence of a cancer because antineuronal autoantibodies have been identified in several children with neuroblastoma.114,196,336,344

Kinsbourne Encephalitis

Opsoclonus also occurs commonly as part of a “benign” encephalitis (Kinsbourne myoclonic encephalopathy, dancing eyes, and dancing feet).352,399 In affected patients, vertigo and truncal ataxia follow a prodrome of malaise and fever. Cerebellar and long-tract signs accompany shivering movements of the head and body. Along with the constantly changing, often forceful myoclonic jerking of the extremities and trunk (polymyoclonia), there are shocklike torsions of the head and neck, as well as opsoclonus.420 Spinal fluid protein may be elevated. Cerebellar and long-tract signs may also occur, but the sensorium remains clear apart from emotional lability.366 Although the illness usually resolves over weeks to months, the clinical course may be protracted and recovery incomplete.

Recent findings of small neuroblastomas or ganglioneuroblastomas in children with the chronic form of myoclonic encephalopathy have led some investigators to suggest that myoclonic encephalopathy may reflect the presence of an indolent neural crest tumor that was previously impossible to identify without high-resolution CT scanning or MR imaging.399 This theory is compatible with the finding that several neuroblastic tumors in infancy tend to regress or mature into tissue with benign neural crest cells.74 Many children fail to improve neurologically following resection of the tumor and develop a chronic ataxic syndrome that worsens with minor febrile illnesses and is associated with chronic symptoms of delayed speech and motor develop-

ment.399 The favorable response to steroid treatment suggests possible immunologic mechanisms, although an autoimmune pathogenesis has yet to be proven.497 Intravenous immunoglobulin, corticosteroids, ACTH, azathioprine, or monoclonal antibodies directed against B-lymphocytes may hasten recovery. Isolated reports suggest that clonazepam and propranolol may occasionally be effective in the treatment of this disorder.

Miscellaneous Causes

Opsoclonus has also been attributed to exposure to toxins or drugs, systemic disease, trauma, meningitis, hydrocephalus, intracranial tumors, carbohydrate-deficient glycoprotein syndrome,518 immune reconstitution,546 neuroborreliosis,560 and poststreptococcal dyskinesia.126,464 It has been suggested that girls with Turner’s syndrome may be predisposed to the development of neuroblastoma and related tumors.67

Pathophysiology

The precise anatomical localization of the abnormality underlying opsoclonus is unknown.497 Early findings of abnormal cerebellar Purkinje cells led to the supposition that opsoclonus resulted from cerebellar dysfunction.188 The clinical observation that opsoclonus regresses through phases of flutter and dysmetria lends credence to this hypothesis.479 The subsequent discovery of burst neurons (that are active immediately prior to saccades and carry information specifying the parameter of the imminent saccade) and pause neurons (that inhibit burst neurons that generate saccades) led Zee and Robinson602 to hypothesize that disorders that selectively impair pause cell function could lead to opsoclonus.

Pause cells lie in the nucleus raphe interpositus, which is located in the midline between rootlets of the abducens nerves. They discharge continuously except immediately prior to and during saccades when they pause. They pause either before eye movements in a specific direction (directional pause neurons) or before eye movements in all directions (omni-pause neurons). Their function is to inhibit saccades. However, an autopsy study of opsoclonus patients showed no abnormalities in the pontine region, where pause cells are located.468 Patients who display MR signal abnormalities in the pontine tegmental raphe (where pause cells are located) demonstrate gaze palsies or internuclear ophthalmoplegia with slowing of saccades rather than opsoclonus.88 Likewise, experimentally induced lesions of the pause cell region in monkeys have produced slow saccades rather than opsoclonus, although some areas of burst cells may have also been affected.318 It is possible that pause cell dys-

function could result from metabolic or neurotransmitter abnormalities in the absence of a discrete lesion or visible histopathological changes.468

The pathophysiology of opsoclonus is also unclear.

It has been suggested that any input driving the burst cells could also inhibit the pause cells via inhibitory burst neurons, thereby resulting in opsoclonus. One hypothesis suggests that opsoclonus results from damage to omnipause cells that are found in the nucleus raphe interpositus (rip) adjacent to the midline of the paramedian pontine reticular formation (PPRF).602 Omnipause cells inhibit saccade burst neurons in the PPRF and riMLF, preventing unwanted saccades. According to that hypothesis, saccadic oscillations occur when the pause cells fail to tonically inhibit the burst neurons. However, experimental lesions of omnipause neurons cause slowing of saccades, but not saccadic oscillations319 and patients with opsoclonus have demonstrated an absence of histopathologic changes in omnipause neurons.

However, cerebellar dysfunction has also been invoked in the pathogenesis of opsoclonus. Although injury to Purkinje cells, granule cells, and the dentate nuclei have been demonstrated, these abnormalities can also occur in individuals without opsoclonus. Furthermore, partial ablations of the cerebellar cortex440 or cerebellectomy, including the deep cerebellar nuclei in monkeys, have not been observed to produce opsoclonus. Shawkat et al497 have demonstrated overshoot dysmetria on eye movement recordings of patients with opsoclonus who had no concurrent abnormalities of smooth pursuit, optokinetic nystagmus, or vestibuloocular reflex. They suggested that these findings are compatible with a lesion affecting the cerebellar fastigial nuclei that spares the flocculus and paraflocculus.

Voluntary Nystagmus

The prevalence of voluntary nystagmus has been estimated to be 5% in a normal population of undergraduates.414 The diagnosis of voluntary “nystagmus” should be considered in any child who appears to have ocular flutter or opsoclonus. Not surprisingly, some patients with voluntary nystagmus report oscillopsia.423 Voluntary nystagmus is usually brought on by a strong convergence effort that causes the patient to display a strained facial expression, mild widening of the palpebral fissures, and occasional fluttering of the eyelids. Voluntary nystagmus appears as an extremely fineamplitude, rapid, conjugate, horizontal oscillation that resembles an ocular shiver. The strong convergence effort necessary to evoke the oscillation usually dissipates after 20–30 s, after which the facial appearance normalizes. The

Fig. 8.16  Electro-oculographic recording of voluntary “nystagmus,” demonstrating that it consists of a series of back-to-back saccades with no intersaccadic intervals. Same electro-oculographic pattern is seen in opsoclonus. Adapted, with permission, from Shults WT et al499

inability to sustain the oscillation provides a clue to the diagnosis. The ability to generate voluntary ocular tremor appears to be familial in some instances, ­suggesting an autosomal dominant inheritance, possibly with incomplete penetrance.423 A tonic imbalance in the vestibulo-optokinetic subsystem can cause infantile nystagmus but have a linear slow-phase jerk nystagmus that simulates voluntary nystagmus, as has recently been reported in a 27-month old girl.369 Rare cases of voluntary vertical nystagmus have also been reported.351

Eye movement recordings have shown that, unlike true nystagmus, voluntary “nystagmus” consists of a series of back-to-back horizontal saccades with no intersaccadic interval (Fig. 8.16), making this oscillation electro-oculographi- cally indistinguishable from opsoclonus.499

Ocular Bobbing

Ocular bobbing was defined by Fisher as intermittent, usually conjugate, rapid downward movement of the eyes followed by a slower return to the primary position.195 It is not clear which pathophysiological mechanism causes the bobbing movement. Bobbing is primarily a sign of an intrinsic pontine lesion. Vertical movements should be dependent on pontine lesions in which the vestibular nucleus and vertical tracts are protected as these movements develop on the loss of horizontal movements. Larmande et al358 suggested that ocular bobbing need not be regarded as an abnormal eye movement but as the residual movement of patients who are totally deprived of both horizontal and upward movements. Most types of bobbing develop as a result of pontine hemorrhage.322

A number of derivative terms have been coined to describe the many clinical variants of ocular bobbing.322 These include:

·· Ocular bobbing: An intermittent, usually conjugate, rapid downward movement of the eye(s) followed by a slower return to the primary position

·· Reverse bobbing: A rapid deviation of the eye(s) upward and a slow return to the primary position

·· Inverse bobbing: The eye(s) slowly moves downward then rapidly restores to its normal position

·· Converse bobbing: The eye(s) slowly moves upward and then rapidly restores to its normal position

Although reverse bobbing is usually observed in patients who are unconscious and who have significant pathology and disruption of the reticular formation, unilateral reverse ocular bobbing was recently reported in a child with tuberous sclerosis and a midpontine lesion.322

Neurological Nystagmus

The term neurological nystagmus, which has been used to describe pediatric nystagmus associated with neurodegenerative disorders, is somewhat ambiguous, because all nystagmus is fundamentally neurological in origin. As is clear from the preceding discussion, some of the rarer forms of nystagmus (spasmus nutans, monocular nystagmus, seesaw nystagmus, convergence-retraction nystagmus) should be recognized as ominous neuro-ophthalmological signs, as they often portend intracranial lesions at specific neuroanatomical sites. These forms of nystagmus are usually distinguishable from infantile nystagmus by their clinical appearance.

Neurodegenerative disease occasionally produce a horizontal nystagmus in infancy prior to the development of other neurological signs. In our experience, it is not uncommon for infants with neurodegenerative disease to be initially diagnosed as having infantile nystagmus, only to have the diagnosis amended as developmental delay, hypotonia, seizures, or other neurological problems supervene. The prevalence of children with neurodegenerative infantile nystagmus in our pediatric patient population is less than 5%. In contrast, retrospective neurological reviews that purport a high prevalence of neurodevelopmental delay in “nonhereditary infantile nystagmus” probably draw from neurological pediatric populations biased toward these disorders.

The clinical overlap between infantile nystagmus and the horizontal pendular nystagmus associated with neurological disease should not be misconstrued as an indication for neuroimaging in infants with paradigmatic infantile nystagmus, because neuroimaging is rarely helpful early in the course of

a neurodegenerative disorder if no other neurological signs are apparent. In other neurologic conditions, awareness that the nystagmus is neurologic may alter its treatment. In children with hydrocephalus, for example, neurosurgical treatment such as shunting may alter abnormal head positions associated with neurologic nystagmus. Strabismus surgery to change the null position should be performed after any effects of neurosurgical treatment can be evaluated.220 The neurodegenerative disorders discussed below are particularly prone to cause nystagmus.

Leigh Subacute Necrotizing

Encephalomyelopathy

Leigh disease is an autosomal recessive mitochondrial disorder leading to progressive neurological degeneration in infancy or childhood. Its onset is usually heralded by the insidious development of psychomotor retardation and brainstem and cerebellar dysfunction resulting in ataxia, dystonia, and nystagmus. Limb weakness and optic atrophy are often noted. T2-weighted MR imaging in Leigh disease shows characteristic symmetrical hyperintense lesions involving the basal ganglia and brainstem, with predominant involvement of the putamen.387 Patients with Leigh disease usually have metabolic acidosis, with elevated lactate and pyruvate concentrations in the blood and CSF, suggesting that a disorder of pyruvate metabolism may be the primary biochemical defect. Specific mitochondrial enzyme deficiencies associated with Leigh disease have been reported to include pyruvate carboxylase deficiency, pyruvate dehydrogenase complex defects, and cytochrome c oxidase deficiency.317,398 Current evidence suggests that a nuclear DNA-encoded factor is responsible for the mitochondrial enzyme deficiencies in most patients with Leigh disease.243,460 Nystagmus, ophthalmoplegia, and optic atrophy are the predominant neuroophthalmologic findings in Leigh’s disease. In addition to nystagmus of virtually any type, children with Leigh disease can manifest with a variety of brainstem ocular motility deficits, including dorsal midbrain syndrome,450 internuclear ophthalmoplegia, and horizontal gaze palsy. Leigh disease can also produce nystagmus and head nodding, thereby mimicking spasmus nutans.488

Pelizaeus-Merzbacher Disease

Pelizaeus-Merzbacher disease is an X-linked recessive leukodystrophy with a fairly characteristic clinical picture.18 It often presents in infancy with abnormal tremu-

lous movements of the eyes and intermittent shaking movements of the head that may simulate spasmus nutans.18,41,376 Electro-oculography shows a distinctive combination of elliptical pendular and upbeat nystagmus that has not been described in other neurodegenerative diseases.537 These early findings are followed by loss of developmental milestones, choreiform and athetoid movements, severe cerebellar signs, and difficulty initiating saccades. Seizures, pyramidal signs, and spasticity appear later. Standing and talking are not possible, and some infants do not even develop head control.18 In contrast, intellectual function is often preserved until the terminal stages of the disease. Children may also display ocular motor apraxia and cerebellar eye signs, including saccadic dysmetria.366,427,537 MR imaging shows lack of myelination without frank evidence of white matter destruction.48 The presumptive clinical diagnosis is confirmed on postmortem examination that shows a diffuse, patchy, “tiger-stripe” demyelination throughout the brain.

Pelizeus-Merzbacher disease affects primarily the white matter of the CNS and is caused by mutations of the proteolipid protein 1 gene, which codes for proteolipid protein (PLP), one of the major structural proteins of myelin.298a Most affected patients have duplications of the PLP gene, which has been mapped to Xq21.1.298a These mutations probably result in the accumulation of PLP in the oligodendrocytes, with resultant impaired cell function and early oligodendrocyte death, resulting in impaired myelin formation.298a

Joubert Syndrome

Joubert syndrome comprises the triad of congenital retinal dystrophy, episodic panting tachypnea, and variable absence of the cerebellar vermis.332 Affected infants also exhibit profound developmental delay and hypotonia.355 The congenital retinal dystrophy in Joubert syndrome was initially classified as Leber congenital amaurosis.406 Unlike Leber congenital amaurosis, however, Joubert syndrome is associated with good visual acuity (visual acuity may be as high as 20/60) and relatively preserved VEPs.355

The nystagmus in Joubert syndrome may consist of a torsional pendular nystagmus or a seesaw nystagmus.355 Alternating hyperdeviation of the eyes, tonic deviation of the eyes laterally, periodic alternating gaze deviation,257 and abnormal saccadic movements (decreased velocity, hypometria, increased latency) have also been described.355,406 Children may have congenital ocular motor apraxia and use head thrusts to view objects of interest in the lateral visual field.355,406 The important role