Chapter 7 Complex Ocular Motor Disorders in Children

Introduction cost-effective manner. A knowledgeable clinician is less likely to embark on “fishing expeditions.” A number of complex ocular motility disorders are discussed The emphasis of this chapter is on ocular motility disorders in this chapter. The diversity of these conditions reflects the of neurologic origin and their differential diagnosis. The most need for the ophthalmologist to maintain a broad working current pathophysiologic concepts of the disorders are sum- knowledge of pediatric neurologic disorders along with their marized. A section at the end of the chapter is devoted to a few ocular motor manifestations. Some clinical features of these common eyelid and pupillary abnormalities encountered in conditions (e.g., congenital ocular motor apraxia, congenital children. Some of these disorders, such as excessive blinking fibrosis syndrome) are sufficiently unique that the diagnosis in children, commonly represent benign transient tics that can be established solely on the basis of the clinical appear- receive very little attention in the ophthalmologic literature, ance. Other disorders either show overlapping manifestations but are not rare in clinical practice. These bear only superficial or effectively masquerade as other entities. Unique features resemblance to the more chronic benign essential blephar- of some conditions, such as conjugate ocular torsion in ospasm of adults although, rarely, childhood tics and adult patients with skew deviation, have been recently recognized blepharospasm show clustering in the same family, suggesting and are considered worthy of emphasis because they signifi- a possible link. Occasionally, underlying ocular surface abnor- cantly expand the differential diagnosis. Indeed, assessment malities and seizure disorders may be uncovered in children of objective torsion (and subjective torsion when possible) is with excessive blinking. Other disorders, such as hemifacial a necessary component of any comprehensive strabismo- spasm, which is more common in adults, may be the harbin- logical evaluation.323 Correction of coexisting torsion can be gers of more serious central nervous system (CNS) disorders integrated into the surgical plan, except when the torsion if encountered in very early childhood. Pediatric Horner syn- serves a compensatory function, as in patients with skew drome is treated in some detail at the end of the chapter, owing deviation. to its potentially ominous association with certain neoplasms, Although the clinical history and physical examinations especially neuroblastoma. The human immunodeficiency virus remain the “gold standard” for establishing the diagnosis, (HIV) infection has joined the ranks of other great mimickers neuroimaging has become an integral part of the diagnostic (e.g., myasthenia gravis, syphilis), with an ever-expanding list evaluation. High-resolution neuroimaging can now depict of neuro-ophthalmologic manifestations. No part of the the presence or absence of most ocular motor nerves and nervous system is spared. Even though it is not specifically the size, position, and dynamic function of the extraocular covered in this chapter, HIV-related neurological disease muscles. In patients with craniosynostosis, for example, should be included in the differential diagnosis of childhood 343 heterotopic extraocular muscles within the orbit can produce ocular motor disorders of cortical, brain stem, cerebellar, or a motility disorder indistinguishable from innervational infe- peripheral nervous system origin. rior oblique muscle overaction,736 absence of the isolated extraocular muscles can produce complex ocular motility dysfunction, and retrodisplacement of the trochlea can Strabismus in Children with Neurological produce a motility pattern indistinguishable from congenital superior oblique palsy.580 Optimal surgical treatment depends Dysfunction on accurate recognition of the specific cause of a given patient’s motility disturbance.204 Thus, a detailed know ledge Common neurologic disorders of children are frequently of clinical findings that characterize each condition is necessary associated with strabismus. These include cerebral palsy, to perform the diagnostic workup in an efficient, timely, and Down syndrome, myelomeningocele, and hydrocephalus.

M.C. Brodsky, Pediatric Neuro-Ophthalmology, 309 DOI 10.1007/978-0-387-69069-8_7, © Springer Science+Business Media, LLC 2010 310 7 Complex Ocular Motor Disorders in Children

The features of the associated strabismus are often indistin- eration. Children with neurologic disorders, who have hori- guishable from the varieties found in otherwise normal chil- zontal strabismus, have a higher prevalence of constant dren, but sufficient differences exist in a distinct minority of exotropia and primary superior oblique muscle overaction neurologically affected children to warrant separate consid- than otherwise healthy strabismic children (Fig. 7.1).334,341

Fig.7.1 (a) Bilateral superior oblique overaction in child with lumbar myelomeningocele. Note resemblance to alternating skew deviation. (b) 1MR imaging characteristically associated Chiari II malformation with pronounced peaking of tectum and herniation of cerebellar vermis into cervical spinal canal Strabismus in Children with Neurological Dysfunction 311

Cerebral palsy is perhaps one of the most common condi- esotropic children with cerebral palsy convert spontaneously tions seen in a pediatric neuro-ophthalmology practice.32 The to an exotropia over several years. For this reasons, current term cerebral palsy defines a group of chronic neurologic trends toward early surgery for infantile esotropia should not disorders resulting from damage to the immature brain. Most be loosely applied to these patients, and it is important to rule cases nowadays are due to prematurity. Care should be taken out occult neurologic disease when early strabismus surgery to distinguish the static nature of cerebral palsy from the is contemplated in seemingly normal children. inexorably progressive neurodegenerative disorders such as As children with cerebral palsy and esotropia seem to Pelizaeus–Merzbacher disease. have a strong predilection for surgical overcorrection,371 Cerebral palsy is characterized by the onset of neurologic standard surgical doses for treating esotropia should be deficits in the neonatal period and absence of progression. In reduced. In our experience, however, it is not necessary to addition to motor disorders, such as paralysis, weakness, and reduce doses for bilateral lateral rectus muscle recession in incoordination, children with cerebral palsy may display neurologic exotropia. As detailed in Chap. 1, children with sensory deficits, as exemplified by the frequent findings of cerebral palsy may have abnormalities of gaze affecting optic atrophy, deafness, and cortical visual impairment. pursuit and saccadic movements and vestibulo-ocular reflex Patients with cerebral palsy show ophthalmologic abnormal- suppression by fixation.417,618 ities with a frequency ranging from 50 to 90%. These include The craniosynostosis syndromes often present with com- optic atrophy, amblyopia, refractive errors, visual field plex forms of horizontal and vertical strabismus that are defects, congenital cataracts, corneal leukomas, retinal dys- both neurologic and anatomical in origin.144,206,280,541,558,580,646 plasia, choroiditis, macular or iris colobomas, retinopathy of Although hypertelorism is classically associated with exotro- prematurity, ptosis, spastic eyelids, abnormal head postures, pia with a V pattern, esotropia can also be seen.431 Good and ocular motility disorders.395,740 The latter include con- stereopsis is rare in the syndromic craniosynostosis and may comitant strabismus, ocular motor nerve palsy, nystagmus, sometimes be confined to certain positions of gaze.576 Some gaze palsy, and other supranuclear disturbances of ocular patients develop esotropia following craniofacial surgery, movements.489 which can disrupt stereopsis.788 Children with cerebral palsy have a markedly increased The frequent finding of overelevation of the adducting eye incidence of strabismus.489 The strabismic deviations are usu- in children with bilateral craniosynostosis was previously ally horizontal and nonparalytic. Associated vertical incomi- attributed to recession of the frontal processes, creating a tance is often seen, with A-pattern strabismus being particularly mechanical disadvantage for the superior oblique muscle. It common. In one series, 691 54% of strabismic children with now appears that excyclorotation of both orbits alters the cerebral palsy showed A pattern, and 46% showed V pattern. horizontal rectus muscle positions, positioning the lateral Variability of the magnitude and direction of the strabismus rectus muscles lower than normal and the medial rectus mus- are commonly noted in cerebral palsy.40 Some studies note a cles higher than normal (Fig. 7.2).156 This orbital excycloro- predominance of esotropia,40,489 while others have found tation is associated with marked excyclorotation of the exotropia to be more common. globes, as is evident on retinal examination.736 Although the Momentary fluctuation from esotropia to exotropia has resulting motility pattern is indistinguishable from that pro- been termed dyskinetic strabismus and is considered unique duced by primary inferior oblique muscle overaction, infe- to cerebral palsy.129 Dyskinetic strabismus is unrelated to rior oblique weakening procedures produce negligible accommodative effort or attention. In addition to the dyski- improvement. Rectus muscle transposition,172 in addition to netic strabismus of cerebral palsy, the differential diagnosis superior oblique muscle strengthening (Harado–Ito proce- of a variable strabismus shifting from exotropia to esotropia dure), is necessary to treat this condition. includes exotropia with a high AC/A ratio, as well as surgi- Other mechanisms for vertical deviations in the cranio- cally overcorrected accommodative esotropia with high synostosis include absent or anomalous superior rectus (or AC/A ratio, and exotropia with dissociated horizontal devia- other) muscles.517,576,710 Preoperative orbital imaging allows tion. Patients with oculomotor palsy with cyclic spasm may the surgeon to anticipate the multitude of orbital anatomical also appear to switch from exotropia to esotropia during a disturbances that contribute to strabismus in children with spasm phase, but the associated features are unique enough craniosynostosis.580 to obviate diagnostic confusion. Generally, the subset of children with cerebral palsy who exhibit dyskinetic strabismus are poor candidates for surgi- Visuovestibular Disorders cal correction. Children with stable deviations respond favor- ably to strabismus surgery, although their overall outcome is Some forms of esotropia and their associated ocular motility not as good as in strabismic children without cerebral signs signify benignity. From a neuro-ophthalmological 198,364 palsy. Unlike children with infantile esotropia, some perspective, horizontal strabismus can be subdivided into the 312 7 Complex Ocular Motor Disorders in Children

Fig. 7.2 Craniosynostosis. Left: Coronal orbital MR image in a girl lar muscle positions. Inferior oblique recession produced no with Crouzon’s disease and bilateral inferior oblique muscle overac- improvement. Right: Schematic diagram showing affect of extraocular tion, V-pattern, and fundus extorsion showing excyclorotated extraocu- muscle heterotopia on binocular rotations

Table 7.1 Visuovestibular disorders signify benignity, although it can be argued that they consti- Dissociated vertical divergence tute a “physiologic” form of neurologic disease. Although Infantile esotropia (dissociated esotonus) they are more commonly associated with esotropia, patients Latent nystagmus with early-onset exotropia present with the same constella- Primary Inferior Oblique Overaction tion of dissociated ocular motor signs discussed in the fol- lowing lines. Brodsky and Fray117 have theorized that infantile esotropia may itself arise from a dissociated deviation. This common conditions that presumably arise from unequal occurs when unequal visual input generates dissociated eso- visual input to the two eyes and the less common conditions tonus, which leads to the gradual development of infantile associated with neurologic disease. The former conditions esotropia, and explains the preponderance of infantile esotro- constitute the visuovestibular disorders (Table 7.1), which pia over infantile exotropia in nonneurologic infants.117 may present as acquired and thereby may simulate neuro- Visuovestibular eye movements produce binocular rota- logic disease. As these conditions arise from unbalanced tions that are evoked by unequal visual input to the two eyes.110 binocular visual input to the central vestibular system, they These consist of latent nystagmus, dissociated vertical Strabismus in Children with Neurological Dysfunction 313 divergence, and primary oblique muscle overaction. These sociated vertical divergence is a visual balancing reflex that preternatural ocular rotations recapitulate the primitive eye uses weighted binocular visual input to orient eye position to movements induced by light or optokinetic stimulation in lat- the perceived vertical.105 The exaptation of a cycloversional eral-eyed animals. They are mediated by subcortical pathways movement into the human dorsal light reflex permits active extending from the optic nerves to the contralateral vestibular modulation of perceived visual tilt when the eyes are fron- nucleus and cerebellum. Although present to a small degree in tally positioned.105,108,109 normals, they develop almost exclusively when infantile strabis- Primary oblique muscle overaction consists of bilateral mus precludes the development of normal binocular cortical overelevation or overdepression of the adducting eye. Primary connections. As these visual reflexes are corrective for a central inferior oblique muscle overaction corresponds to a similar vestibular imbalance, they are not associated with dizziness, dorsal light reflex that is induced in fish when a forward or oscillopsia, or other neurologic symptoms that characterize backward shift in overhead luminance evokes an ipsidirec- vestibular disease. They are evoked by physiologic stimuli tional body pitch or torsional rotation of the eyes backward rather than by neurologic lesions. In the clinic, mechanical to reorient the body with respect to the light.107 These bin- occlusion of one eye and cortical suppression of one eye can ocular torsional rotations of the eyes constitute a physiologic both activate in the subcortical visuovestibular pathways that form of primary oblique muscle overaction that can be evoke this visuovestibular response. induced by altering binocular visual input. In humans, a for- The resurgence of visuovestibular movements in humans ward or backward rotation relative to overhead light sends with infantile strabismus shows that our eyes function not excitatory innervation to each of the elevators or each of the only as visual organs, but as balance organs. Because they depressors. Because the vestibular system segregates inner- recapitulate visual reflexes in lateral-eyed animals, the vation to its target extraocular muscles, the vertical actions of absence of early cortical binocular development is a permis- the human oblique muscles can summate in adduction with sive factor that allows them to develop, the retention of prim- those of the rectus muscles to produce the innervational itive subcortical reflexes is the proximate cause of these overelevation of the adducting eye that defines primary infe- movements.110 Infantile strabismus provides a natural experi- rior oblique muscle overaction. ment to uncover the primitive visual reflexes that lie buried The fundamental association of primary oblique muscle within us. By disrupting the development of frontal binocu- overaction with loss of binocular vision in humans suggests lar vision, infantile strabismus allows these reflexes to “bubble that the brain registers loss of binocular visual input as to the surface.” The resulting ocular motor “intrusions” corre- forward rotation of the body.107 Although primary superior spond to an imbalance of binocular visual input in three oblique muscle overaction is considered as a sign of neuro- planes of physical space. logic disease (see section on “Skew Deviation”) in the United Latent nystagmus is characterized by conjugate horizon- States and Europe, it is reported to accompany infantile tal nystagmus induced by monocular occlusion or cortical esotropia more commonly than primary inferior oblique suppression. The fast phase (in both eyes) is directed toward overaction in Argentina and South Africa,139,140,167 suggesting the side of the fixating eye. Latent nystagmus corresponds to that it may also arise from a visuovestibular imbalance.107 the optokinetic component of ocular rotation that is driven monocularly by nasal optic flow during a turning movement of the body in lateral-eyed animals.123 When infantile esotro- pia disrupts the establishment of binocular visual connec- Neurologic Esotropia tions, visual input from the fixating eye to the contralateral nucleus of the optic tract evokes a counterrotation of the eyes A variety of prenuclear neurologic diseases are characterized which corresponds to a turning movement of the body toward by an esotropic deviation of the eyes717 (Tables 7.2 and 7.3). the object of regard. The clinical expression of this visual Spielmann has suggested that organic spasm of the near reflex is also evident in the monocular nasotemporal asym- reflex, (Parinaud syndrome with convergence-retraction metry to horizontal optokinetic stimulation that characterizes nystagmus or convergence excess), and thalamic esotropia infantile strabismus.123 Dissociated vertical divergence is characterized by an Table 7.2 Complex neurologic disorders predisposing to esotropia upward drift (sometimes accompanied by a dynamic extor- Acute comitant esotropia sional movement) of a covered or cortically suppressed Congenital cranial dysinnervation syndromes 105 eye. Dissociated vertical divergence corresponds to the Convergence-retraction nystagmus dorsal light reflex that has been observed in fish and other Exercise-induced diplopia lateral-eyed animals when unequal luminance to the two Periventricular leukomalacia (with or without cerebral palsy) eyes evokes a body tilt or vertical divergence of the eyes Spasm of the near reflex toward the side with greater luminance.105 In humans, dis- Thalamic esotropia 314 7 Complex Ocular Motor Disorders in Children

Table 7.3 Exotropia as a sign of neurologic disease (two cases reported so far), Arnold–Chiari malformation, and Congenital cranial dysinnervation disorders (congenital fibrosis photosensitive epilepsy.81,195,442,566,636,694 However, isolated syndrome) spasm of accommodation can also follow neurologic injury.151 Constant exotropia (cortical visual insufficiency, congenital Several patients with intracranial tumors and spasm of the homonymous hemianopia) 178,195 Convergence insufficiency near reflex have been reported. It should be emphasized Intermittent exotropia greater at near fixation than distance fixation that most patients with spasm of the near reflex in association with other neurologic disease have other symptoms and signs that can be readily uncovered during a careful neurologic fall into a group of neurological diseases characterized by and neuro-ophthalmologic examination. convergence excess.717 Many of these disorders have been Spasm of the near reflex in infants and children should be detailed in their specific clinical context in other chapters. distinguished from nystagmus blockage syndrome and from As many neurologic patients take medications with strong convergence substitution. The latter is seen in patients with anticholinergic side effects, esotropia of neurologic origin congenital or acquired horizontal gaze paralysis (e.g., Möbius must be distinguished from anticholinergic esotropia, a sequence, multiple sclerosis), in which the patient substitutes condition in which excessive accommodative effort leads to a convergence movement for a lateral version movement accommodative esotropia. Several recent cases of esotropia when attempting to fixate an eccentric target. Spasm of the induced by systemic anticholinergic medications have near reflex can manifest in patients with significant hypero- recently been described.23,478 Anticholinergic esotropia seems pia who are unable to relax accommodation even when plus to be precipitated by increased convergence of the eyes due lenses are used.299 In this context, spasm of the near reflex to the increased accommodative effort in patients with an can mimic deteriorating accommodative esotropia.259,661 inherent tendency to develop esotropia. We examined a 12-year-old boy who had undergone left medial rectus muscle resection (4 mm) for presumed conver- gence insufficiency 4 months before. Shortly after the sur- Spasm of the Near Reflex gery, he complained of fluctuating vision and varying ocular alignment ranging from orthotropia to 80 prism diopters of Spasm of the near reflex is characterized by intermittent epi- esotropia. He was noted to have episodic, pronounced spasm sodes of miosis, convergence, and accommodation. Patients of the near reflex associated with severe spasms involving exhibit variable esotropia and varying pupillary size. Unlike the eyelids and the facial musculature (Fig. 7.3). His neuro- in other patients with intermittent esotropia, monocular logical evaluation and MR imaging of the head were totally refixation during alternate occlusion is often slow and inac- unremarkable otherwise. His symptoms continued unchanged curate. The name “spasm of the near reflex” should not be during a follow-up period of 8 months. used interchangeably with either accommodation spasm or Patients with isolated spasm of the near reflex may improve convergence spasm, each of which may present separately as with reassurance. Some patients require psychiatric coun- a distinct entity.67 seling. Current ophthalmologic treatment of spasm of the Patients with spasm of the near reflex may present with near reflex involves administering cycloplegic eye drops diplopia, blurred vision (especially for distant objects), fluc- and providing bifocal glasses for reading. Historically, some tuating vision, or nonspecific ocular discomfort. Due to its patients have shown improvement with miotic drops, placebo rarity, affected children may be misdiagnosed as having child- drops, benzodiazepines, special glasses with occlusion of the hood esotropia, and unilateral or bilateral sixth nerve palsy, inner third of each lens, monocular occlusion, or narcosug- and, less commonly, divergence insufficiency, horizontal gaze gestion during an amobarbital sodium interview. In patients palsy, ocular motor apraxia, convergence retraction nystag- with underlying organic disease, spasm of the near reflex (like mus, true myopia, or Tensilon-negative myasthenia gravis.657 essential blepharospasm) may be a type of dystonia. Like Careful attention to pupillary size, retinoscopy during other types of dystonia, some cases respond to botulinum episodes of spasm to confirm the fluctuating induced myopia, injection.525,585 In patients without organic disease, this prob- and the variable esotropia should help confirm the diagnosis. lem usually resolves spontaneously over months to years. The disorder is most commonly considered to be func- tional in nature, possibly due to underlying emotional conflict, with some patients showing signs of hysteria, malingering, Exercise-Induced Diplopia or personality disturbances.51 However, cases associated with organic disorders are occasionally reported, including Exercise-induced diplopia has rarely been reported in head trauma, stroke, pretectal lesions, neurosyphilis, labyrin- children.681,763 This condition may represent a breakdown of thine dysfunction, diphenylhydantoin intoxication, Wernicke’s an esophoria,763 but warrants neuroimaging to rule out a mid- encephalopathy, metabolic encephalopathy, Fisher’s syndrome line cerebellar tumor.681 Strabismus in Children with Neurological Dysfunction 315

Fig. 7.3 Spasm of near reflex. Twelve-year-old boy had undergone small near reflex (large esotropia, miosis, induced myopia with blurred vision) left medial rectus muscle resection for presumed convergence insufficiency. associated with severe spasms involving eyelids and facial musculature (a). Four months later, he was noted to have episodic, pronounced spasm of In between spasms, only small esotropia was variably present (b)

Neurologic Exotropia shown to improve proximal and tonic convergence, but not accommodative or fusional convergence.33 Convergence insufficiency is most commonly a primary The differential diagnosis of constant exotropia includes cor- condition presenting in young adults. In this setting, it is pre- tical visual insufficiency, craniofacial synostosis, and con- sumably caused by an inborn deficiency or acquired imbal- genital fibrosis syndrome. Isolated infantile exotropia is a ance of vergence eye movements that has yet to be identified.33 rare but well-recognized nonneurologic condition in which a In this setting, patients may present with sleeping on reading large-angle exotropia is associated with the same constella- or near work, tearing, heavy lids, uncomfortable eyes, asthe- tion of visuovestibular disorders that accompany infantile nopic symptoms, double vision, or blepharitis (from frequent esotropia. Some early-onset cases of intermittent exotropia rubbing of the eyes). These patients perform their near work also fall into this group.384 Some cases of infantile exotropia optimally immediately after awakening. are hereditary, showing an autosomal dominant inheritance Convergence insufficiency is also a prominent accompani- pattern.119 Nevertheless, the clinician must maintain a high ment of neurologic disease, having been reported in associa- index of suspicion for neurologic disease in the child with tion with head trauma,19,130,181,450,452,483,719 neurodegenerative infantile exotropia. disorders,75,125,631 infarction,390,593 thyroid ophthalmopathy,126 In our experience, constant exotropia is most commonly myasthenia gravis, toxic agents, medications,125,738 inflamma- seen in the setting of cortical visual insufficiency secondary tion,125,620 decompression sickness,493 whiplash injuries,134 and to hypoxic-ischemic encephalopathy.118 Associated signs attention-deficit hyperactivity disorder (ADHD).310 In the last include horizontal conjugate gaze deviation with little or no mentioned condition, it is not always clear whether conver- nystagmus and mild or sectoral pallor of the optic discs.118 gence insufficiency is the cause or effect, whether they are Because children with congenital homonymous hemianopia comorbid conditions, or whether medications used to treat the may develop a constant exotropia that serves to expand the ADHD may contribute to the convergence insufficiency. existing visual field, confrontation visual fields should be Some believe that accommodative insufficiency is the pri- checked in this setting. Signs of craniofacial disease are usu- mary source of symptoms in children diagnosed with conver- ally apparent on initial examination. As detailed below, fixed gence insufficiency,520 although this issue continues to be downgaze, associated ptosis, sparing of pupillary function, debated.680 Therefore, accommodative amplitudes and and similar findings in other family members provide clini- dynamic retinoscopy should be examined to rule out an cal clues to the diagnosis of congenital fibrosis syndrome. underlying or associated accommodative paresis.653 It is also important to check for undetected ocular torsion, which can Convergence Insufficiency secondarily impair convergence. The potential pharmaco- logical role of any medications in impairing accommodation Convergence insufficiency is a common condition charac- should always be considered.130 terized by:(1) diplopia or blurring at near, (2) decreased Convergence insufficiency should not be confused with convergence amplitudes, and (3) a recessed near point of convergence paralysis, another neurologic disorder in which accommodation.401 It seems to afflict intelligent patients and there is a constant exotropia at near. Although convergence is considered to be the one form of strabismus that is exercises are the mainstay of treatment for convergence treatable with eye exercises. Convergence training has been insufficiency,613 treatment with base in prisms has also been 316 7 Complex Ocular Motor Disorders in Children reported to be effective.721 In patients with convergence paralysis or convergence insufficiency that does not respond to these measures, bimedial resections325,360,464,786 and supe- rior transpositions of the medial rectus muscles (to induce a physiologic V pattern and allow for single binocular near vision in downgaze) (Buckley EG: verbal communication) have been used. Because convergence insufficiency repre- sents a kinetic problem rather than a static deviation, strabis- mus surgery may not provide an optimal approach. The superimposition of convergence insufficiency on a baseline exodeviation produces an exodeviation that is greater at near, which is often a soft sign of neurologic disease.616 Neurologic forms of exotropia are summarized in Table 7.3.

Skew Deviation

Skew deviation of the eyes is a prenuclear vertical strabismus that is usually associated with posterior fossa lesions, par- ticularly those affecting the brainstem tegmentum or the cer- 419 ebellum. While causative lesions are usually structural, Fig. 7.4 Ocular tilt reaction. Illustration depicts graviceptive pathways skew deviation does rarely result from elevated intracranial from the otoliths and vertical semicircular canals mediating the vestibu- pressure due to idiopathic intracranial hypertension.281 The lar reactions in the roll plane. The projections from the otoliths and the vertical semicircular canals to the ocular motor nuclei (trochlear nucleus misalignment may be comitant or incomitant, simulate a IV, oculomotor nucleus III, abducens nucleus VI), and the supranuclear paresis of an extraocular muscle, and alternate with time centers of the interstitial nucleus of Cajal (INC), and the rostral intersti- (slowly alternating skew deviation) or on lateral gaze (alter- tial nucleus of the medial longitudinal fasciculus (riMLF) are shown. nating skew on lateral gaze). As discussed below, it is usually They subserve vestibuloocular reflex (VOR) in three planes. The VOR is part of a more complex vestibular reaction that also involves vestibu- accompanied by binocular torsion and torticollis. Although lospinal connections via the medial and lateral vestibulospinal tracts for skew deviation has been historically considered to be a non- head and body posture control. Note that graviceptive vestibular path- localizing sign, simply indicating involvement of the poste- ways for the roll plane cross at the pontine level. Ocular tilt reaction is rior fossa without further reference to a specific region, our depicted schematically on the right in relation to the level of the lesion (i.e., ipsiversive with peripheral and pontomedullary lesions, and a con- understanding of its value as a clinical localizing sign has traversive with pontomesencephalic lesions). In vestibular thalamus been revised in recent years. While early studies reported the lesions, the tilts of the subjective visual vertical may be contraversive or absence of torsion in patients with skew deviation,94 this ipsiversive. With permission from Brandt et al95 myth has now been dispelled.92,93 The degree of ocular tor- sion may or may not be equal in the two eyes. reaction has been reported in patients with intra-axial brain- Skew deviation usually presents in the more general con- stem lesions (midbrain tegmentum, dorso-lateral medulla text of the ocular tilt reaction. The ocular tilt reaction is caused oblongata), unilateral vestibular neurectomy, and labyrinth- by unilateral injury to the otolithic pathways, which causes ectomy (performed in patients with severe Meniere’s disease the brain to perceive the visual world as tilted.116 The ocular or acoustic neuroma).812 The skew deviation that accompa- tilt reaction is a “righting reflex” that results from alteration nies the ocular tilt reaction may be subdivided into at least in the otolithic and/or vertical semicircular canal pathways three distinct types, each with distinct clinical features, that occurs in patients with lesions of either peripheral or ocular torsion, and localizing significance.93 central vestibular system. The ocular tilt reaction rotates the Because all three components of the ocular tilt reaction eyes and head toward the tilted visual world to restore vertical are compensatory for a subjective visual tilt, the head tilt orientation (Fig. 7.4). The result is an oculocephalic synkinesis does not serve to promote vertical fusion as it does in supe- consisting of vertical divergence of the eyes (skew deviation), rior oblique palsy.116 Consequently, prismatic or surgical head tilt in the direction of the lower eye, and ocular torsion correction of the vertical deviation does not eliminate the in the direction of head tilt.92 These compensatory roll rota- associated head tilt. Patients with the ocular tilt reaction may tions strive to realign the interpupillary axis, head, and tor- be misdiagnosed as having a superior oblique muscle palsy, sional position of the eyes, respectively, to the orientation that because the skew deviation may be incomitant, and both the patient erroneously perceives as vertical. The ocular tilt disorders can show a positive Bielschowsky Head Tilt test.284 Strabismus in Children with Neurological Dysfunction 317

The diagnosis of ocular tilt reaction should be considered analysis revealed the following: (1) The ipsilateral eye was in patients with suspected superior oblique muscle palsy who hypotropic with caudal pontomedullary lesions and higher show intorsion of the higher eye. Donahue et al217 described with rostral pontomesencephalic lesions. (2) All patients five patients with incomitant skew deviation that simulated with skew deviation showed simultaneous conjugate bilat- superior oblique muscle palsy on the Bielschowsky Three eral ocular torsion toward the hypotropic eye. Ocular torsion Step test, and intorsion of the higher eye and extorsion of the was evaluated from fundus photographs. This and other stud- lower eye. In the patient with superior oblique palsy, the ies demonstrate that skew deviation is a sensitive brainstem finding of intorsion (rather than the expected extorsion) of sign of localizing and lateralizing value.93,94 the higher eye (on both Double Maddox rod testing and indi- While the skew deviation in adults results primarily from rect ophthalmoscopy) should therefore signal the diagnosis infarction, skew deviation in children may be associated of skew deviation. In other patients, skew deviation can sim- with a wide variety of conditions, including tumors,158 ulate isolated inferior oblique palsy.217 Chiari malformation,173 autoimmune disease,632 paroxysmal Recently, Pareluker et al found that the vertical and tor- hemiparesis of childhood,214,357 and increased intracranial sional deviations associated with skew deviation resolve in pressure.52,281,530 In one case, skew deviation was diagnosed on the reclined position, a finding that provides another useful prenatal MR images in a fetus with a glioblastoma involving clue to the diagnosis.610 For reasons that are not understood, the brainstem.158 the utricles become functionally deafferented in the reclined Incomitant skew deviation may mimic a primary overac- position,113 which explains the disappearance of skew devia- tion of an oblique extraocular muscle. One type of skew tion and the disappearance of compensatory head tilt in deviation, termed alternating skew on lateral gaze or bilateral supine patients with superior oblique palsy732 (once asym- abducting hypertropia, closely resembles bilateral superior metrical utricular output can no longer be accessed to neu- oblique overaction (Fig. 7.5).332,339,341,567 Affected patients tralize the vertical deviation). typically display a right hypotropia on downgaze and to the The localizing value of skew deviation is now well estab- left and left hypotropia on downgaze and to the right. One lished.93,94 In a study of 56 adults with unilateral brainstem study of children with brainstem tumors341 showed that alter- infarctions and skew deviations, clinical and neuroimaging nating skew deviation on lateral gaze localizes to the lower

Fig. 7.5 Alternating skew on lateral gaze: Patient presented with new (b) but displayed left hypotropia on gaze down and to right (a) and right onset of downbeat nystagmus and oscillopsia. He was diagnosed with hypotropia on gaze down and to left (c). Note similarity to bilateral spinocerebellar degeneration. He was orthotropic in primary position overaction of superior oblique muscles 318 7 Complex Ocular Motor Disorders in Children brainstem or cerebellum. Given the similar localization of While most primary oblique muscle overaction is inner- neuroanatomic lesions in patients with myelomeningocele vational in origin, heterotopia of the extraocular muscles and (most whom have Chiari II malformation) and the observa- their surrounding connective tissues has been recognized as tion that these patients show a predilection for superior an anatomical cause of apparent primary oblique muscle oblique overaction (Fig. 7.1), Hamed et al have argued that overaction.169,203,204 Other conditions causing overdepression primary superior oblique overaction and skew deviation are of the adducting eye (mimicking primary superior oblique phenomenologically indistinguishable.334,339,341 This hypoth- muscle overaction) include inferior rectus muscle palsy, esis is further supported by the observation that strabismic apparent overaction of the oblique muscles in exotropia, children who have superior oblique overaction show a higher downshoot of the eye in Duane syndrome, physiologic “over- frequency of associated neurologic disorders compared with action” of the oblique muscles in eccentric gaze, and other a control population consisting of strabismic children with- restrictive or paretic conditions.334 Overelevation or overde- out superior oblique overaction.339 Superior oblique overac- pression in adduction is therefore an ocular sign that may tion is commonly seen in conjunction with more generalized reflect a variety of conditions. It is now possible to con- neurological disease such as cerebral palsy, myelomeningo- ceptualize oblique muscle overaction as comprising a cele, and hydrocephalus. visuovestibular type (primary inferior oblique muscle over- Brandt and Dieterich96 later suggested that overlapping action), a bilateral vestibular injury (primary superior oblique pathways modulate roll and pitch function of the vestibulo- muscle overaction), a leash-effect type (Duane syndrome), ocular reflex, making efficient use of the vestibular network. and a muscle heterotopia type. 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 Gaze Palsies, Gaze Deviations, the cerebellar flocculus produces a tone imbalance in the pitch plane. The principle behind this operation resembles and Ophthalmoplegia the guidance system of airplanes, wherein unilateral activa- tion of a brake flap causes the plane to roll, while bilateral This section discusses conditions causing ophthalmoplegia activation results in downward pitch. (i.e., mixed vertical and horizontal ocular paresis), or gaze In a bilateral ocular tilt reaction, the vertical components palsies (horizontal or vertical). Gaze palsy may reflect abnor- summate to produce the slow phase vertical drift of both eyes malities of saccadic eye movements, as may result from while the torsional components cancel each other out. Thus, frontal lobe or frontomesencephalic saccadic pathway a roll imbalance manifests as an ocular tilt reaction, while damage, pursuit eye movements, as may result from occip- bilateral otolithic imbalance produces upbeat or downbeat ito-parieto-mesencephalic damage, or both, as may result nystagmus in conjunction with an alternating skew deviation from damage to the brainstem gaze center. It is sometimes on lateral gaze.96 Zee835 presented an interesting model in difficult to distinguish a horizontal gaze palsy from a unilat- lateral-eyed animals to demonstrate how a pitch disturbance eral oculomotor or abducens nerve paresis with a compensa- (forward or backward) would generate the patterns of verti- tory head turn.63 An infant or toddler with an abducens nerve cal deviation in lateral gaze that are seen in humans with palsy may appear to have a gaze palsy when he or she adopts bilateral alternating skew deviation. a compensatory head position to achieve binocularity and Thus, while unilateral skew deviation corresponds to resists any gaze shift out of the zone of binocularity. In such central graviceptive dysfunction of otolithic pathways in cases, one must place a patch on the suspected paretic eye, the roll (tilt) plane, lateral alternating skew deviation which leads to resolution of the head turn in ocular motor corresponds to a central graviceptive dysfunction of oto- nerve paresis, but not in gaze palsy. Complete resolution lithic pathways in the pitch plane.107 By viewing a pencil of such a head turn may occasionally require several days of slanted forward or backward in the pitch plane, then clos- patching.63 ing one eye and then the other, the reader can see that each image appears tilted in opposite directions when viewed monocularly.109 Guyton and Weingarten323 hypothesized that primary Horizontal Gaze Palsy in Children oblique muscle overaction and A- and V-pattern strabismus are a result of sensory torsion that arises when fusion is The causes of horizontal gaze palsy in children are shown in absent. However, it now appears that true oblique muscle Table 7.4. Generally speaking, inability to conjugately move overaction, caused by premotor disinhibition in the presence the eyes horizontally to one side is caused by a lesion in the of early binocular visual loss, is the cause, rather than the contralateral frontal eye field or the ipsilateral paramedian effect, of primary oblique muscle overaction.107 pontine reticular formation (PPRF) or abducens nucleus. Gaze Palsies, Gaze Deviations, and Ophthalmoplegia 319

Table 7.4 Causes of horizontal gaze palsy in children Congenital Ocular Motor Apraxia Brainstem arteriovenous malformation Bilateral Duane syndrome Congenital horizontal gaze palsy and scoliosis Apraxia (Greek: inaction) literally denotes the inability to Congenital horizontal gaze paralysis and ear dysplasia perform volitional, purposeful motor activity despite the Familial, congenital paralysis of horizontal gaze absence of paralysis. In the context of eye movements, the Leigh syndrome term apraxia should be limited to describe conditions in Möbius sequence which volitional saccades are defective, but reflex and random Neuronopathic Gaucher disease movements are preserved (i.e., the quick phases of vestibular Pontine glioma Wildervanck syndrome or optokinetic nystagmus), underscoring the presence of intact lower motor neuron pathways. This apraxic defect becomes more readily understandable by noting the presence Such a lesion may be distinguishable with reflex maneuvers of at least two major classes of cerebrally triggered saccades, (e.g., caloric stimulation, Doll’s head maneuver) that would namely, intrinsically triggered (volitional) saccades and extrin- drive the eyes into the paretic gaze if the PPRF and abducens sically triggered (reflexive) saccades. Children with true nucleus are intact. Neuronopathic Gaucher disease with hepa- saccadic apraxia show a defect in the first class of saccades, 695 tosplenomegaly can be associated with isolated horizontal gaze but not in the second. palsy. Children with type 2 Gaucher disease may also show a COMA is characterized by the selective absence of hori- 174 “fixed” esotropia, while those with type 3 may be accompanied zontal saccades with preservation of vertical saccades. by head thrusts suggestive of COMA.611 Causes of horizontal COMA was so named because it was thought to fulfill the gaze palsy that are now classified as congenital cranial dysin- strict definition of apraxia outlined above, namely, the reflex nervation syndromes (such as congenital horizontal gaze palsy and random eye movements as well as the fast phases of with scoliosis) are detailed later in this chapter. optokinetic nystagmus are preserved. However, there is no Congenital bilateral paralysis of horizontal gaze has been clear evidence for a cortical etiology and it is now recog- reported in association with facial paralysis, most likely rep- nized that the quick reflexive fast phases are also defective in 354 354 resenting a form of Möbius sequence (facial diplegia and these patients. For these reasons, Harris et al advocate sixth nerve palsy). It has also been described without facial use of the term intermittent saccadic failure. paralysis. In the latter cases, the most typical findings are Ocular motor apraxia is divided into congenital and total absence of conjugate horizontal gaze, both volitionally acquired varieties. The acquired form is usually encountered and after stimulation of optokinetic and vestibular systems; in adults, following bilateral basal ganglia or cerebral hemi- 623 preserved convergence with substitution of convergence spheric lesions, although some acquired cases have been movements for conjugate eye movements upon attempting reported in children. For example, two children developed 829 horizontal lateral gaze; cross-fixation; and apparently normal isolated ocular motor apraxia following cardiac surgery. In vertical eye movements.61 These cases, which show overlap children, the idiopathic form of COMA must be differenti- with the Wildervanck syndrome, have occurred either as an ated from the forms seen in Gaucher disease, ataxia telangi- isolated abnormality or in association with other findings ectasia, and Leigh disease (discussed later). Acquired ocular that included kyphoscoliosis, facial contracture and myo- motor apraxia seldom fulfills the strict definition of an kymia, and the Klippel–Feil syndrome (fusion of cervical apraxic disorder.695 Most acquired cases more closely reflect and upper thoracic vertebrae) in one patient.311 The precise a global saccadic dysfunction rather than an apraxic disorder cause of these cases is unknown, but the underlying defect and may be better designated as horizontal saccadic palsies has been speculated to represent selective maldevelopment or gaze palsies, depending on whether or not smooth pursuit affecting either the horizontal gaze center in the PPRF or the is also affected.354 The natural history is one of gradual reso- motor neurons and interneurons in the abducens nuclei. Yee lution over several years (with persisting subclinical defects), et al824 reviewed the evidence and concluded that a develop- which may reflect the normal maturation process or the mental anomaly affecting the abducens nucleus, but not the development of blink-induced saccades.354 horizontal gaze center in the PPRF, is most consistent with A prominent feature of this syndrome is large-amplitude the clinical findings in this syndrome. They further specu- horizontal head thrusting to achieve visual fixation.268 lated that the involvement of the facial musculature associ- However, head thrusting need not always be present. The ated with some cases may result from a similar developmental quick phases of induced vestibular nystagmus and optoki- anomaly of the facial nucleus. Some cases of bilateral hori- netic nystagmus are intermittently or completely absent, zontal gaze paralysis are familial.824 In children with pontine causing the eyes to deviate and “lock up” at the mechanical gliomas, involvement of the abducens nuclei and/or the limit of gaze at the end of the slow phase.354 The classical PPRF may lead to horizontal gaze palsy (Fig. 7.6). explanation of the head thrusts is that they are compensatory, 320 7 Complex Ocular Motor Disorders in Children

Fig. 7.6 Horizontal gaze palsy. Child with pontine glioma shows paralysis of (a) right gaze and (b) left gaze but intact (c) upgaze and (d) downgaze. (e) MR imaging shows diffuse enlargement of pons from glioma which explains why the head is thrust in the direction of an The concept that head thrusts are always compensatory eccentric target, and the eyes rotate conjugately in the oppo- has been challenged by evidence suggesting that a thrust- site direction under the influence of the resulting vestibulo- saccade synkinesis is the explanation for head thrusts; in ocular reflex. The head excursion must then overshoot the that, the thrusts may actually facilitate the initiation of sac- intended target to allow the controversively rotated eyes to cades in a subgroup of patients.837 Eustace et al255 questioned fixate the desired target. Once fixation is achieved, the head whether, rather than being compensatory, the head thrusts in slowly reassumes its neutral position to allow a direct, COMA may be a defect that reflects an inability to unlock or straight gaze. The child is usually noted to blink at the onset cancel the effects of the vestibulo-ocular reflex. Interestingly, of head thrusts. some children with COMA display occasional head thrusts Gaze Palsies, Gaze Deviations, and Ophthalmoplegia 321 or a low-amplitude horizontal head nodding, even when development. One mother of a 3-year-old girl stated, “Her fixating a stable target. speech has been good in terms of word acquisition, but she The head thrusts so characteristic of COMA appear when has an odd linking of phrases – lots of backwards phrases.” the baby acquires head and neck control (usually at 6 months). These studies indicate that COMA is the salient feature of Therefore, although congenital, the disorder is rarely diag- a more generalized neurological disorder,312 and that nosed until late infancy. At an earlier age, blindness may be “isolated” cases are at risk for mild-to-moderate educational suspected due to failure to follow objects. This failure to visu- difficulties. ally pursue objects is understandable given the defective sac- The association of COMA with CNS lesions has long been cadic system, because infants “follow” with a series of recognized.232,268,599 Neuroimaging often discloses vermian hypometric saccades. In this context, failure to pursue may be hypoplasia and dilatation of the fourth ventricle at the upper misconstrued as a visual deficit. Evaluation of the vestibulo- brainstem level.448 Sargent et al674 found hypoplasia of the ocular response in such infants by spinning them elicits a slow cerebellar vermis in approximately 50% of patients with but not a fast component, which helps establish the diagnosis. COMA, with preferential involvement of the inferior portion. Although isolated COMA is usually sporadic, familial Additional involvement of the superior portion correlated cases have been documented.84,175,293,320,628,775 Phillips et al615 with more severe feeding difficulties, speech apraxia, or more described COMA in four children of an affected father, indi- severe generalized motor problems. Kim et al437 reported cating probable autosomal dominant transmission. COMA COMA with spasmus nutans in a child with cerebellar verm- has been associated with a wide variety of conditions rang- ian hypoplasia. They speculated that hypoplasia of the vermal ing from the relatively benign to the rapidly progressive cortex could disinhibit the caudal fastigial nucleus, leading to neurometabolic degenerations. COMA may be congenital or an abnormally increased activity in the fixation region of the acquired.519 It may also be idiopathic or associated with superior colliculus and results in the inhibition of saccadic structural brain abnormalities (e.g., cerebellar hypoplasia, generation. On the other hand, Harris et al found vermian agenesis of the corpus callosum), neurodegenerative disor- hypoplasia in only one of two siblings with COMA, suggest- ders (e.g., ataxia telangectasia, Gaucher disease), perinatal ing that this defect may not be causative, but a marker of some problems (e.g., hypoxia, cerebral palsy, hydrocephalus), or other underlying pathology.369 Shawkat et al found abnormal acquired disease (e.g., herpes encephalitis, posterior fossa scans in 61% of patients with saccadic initiation failure.697 tumors, ischemia) (Table 7.5).354,519 These disorders should Most abnormalities involved the brainstem and cerebellar be suspected when vertical saccades are affected or when vermis, although other abnormalities of the cerebral cortex saccades are slow.354 and basal ganglia were also detected. While affected children are often judged to be otherwise Other neuroimaging abnormalities have been reported less healthy, most have associated deficits in other motor spheres, frequently, including porencephalic cyst, agenesis or hyp- resulting in problems in oral-motor planning affecting speech oplasia of the corpus callosum,84 posterior fossa tumors such output (speech apraxia), as well as truncal ataxia, hypotonia, as medulloblastoma or lipoma, and gray matter heteroto- developmental delay, or perceptual visual-spatial diffi- pias.27,505,725,731,833 Recently, a subgroup of autosomal recessive culties.312,396,519,635,674,725,726 In a recent study,519 11 of 14 patients cerebellar ataxias was identified.473 It includes four distinct with no structural abnormality on neuroimaging showed subtypes: ataxia-telangectasia, ataxia-telangectasia-like dis- abnormal neurodevelopment, although it has been stated that order, and ataxia with ocular motor ataxia types 1 and 2. The speech delay in ocular motor apraxia is expressive and due to phenotypes share similarities, and the responsible genes verbal apraxia.396,635 These included delayed speech and read- ATM, MRE11, APTX, and SETX, respectively, are all impli- ing, and abnormalities of language development involving cated in DNA break repair. As in many other DNA repair both receptive (comprehension) and expressive (language) deficiencies, neurodegeneration is a hallmark of these dis- eases.473 The first two conditions are detailed in Chap. 10. The third, ataxia with ocular motor apraxia type 1 (AOA type 1) is Table 7.5 Neurometabolic causes of congenital ocular motor apraxia a recently described autosomal-recessive condition of child- 354 (Adapted from Harris et al ) hood onset that is caused by mutations in the APTX gene, Ataxia telangectasia which encodes the protein aprataxin.826 Onset is usually 2–10 Gaucher disease years (mean, 6.8 years), with gait and limb ataxia, dysarthria, Joubert syndrome Krabbe disease ocular motor apraxia, mild peripheral neuropathy, and pro- 473,481 Niemann–Pick–syndrome gression of neurological deficits. MR imaging may show Cockayne syndrome cortical and cerebellar atrophy that is most prominent in the Pelizeus–Merzbacher disease mid-vermis.267 Aprataxin mutations are associated with low Recessive ataxia with ocular apraxia coenzyme Q10 levels in muscle, which is not associated with Spinocerebellar ataxia type 2 duration, severity, or progression of the disease.473 322 7 Complex Ocular Motor Disorders in Children

Ataxia with ocular motor apraxia type 2 (AOA type 2) is an autosomal recessive disorder associated with mutations in the Senataxin (SETX) gene.189,506,559 The age of onset is later (11–20 years), with sensory motor neuropathy, primary ovar- ian failure, chorea, and ocular motor apraxia in about half of affected patients. An elevated level of serum alpha-fetoprotein is a consistent finding.481 Ocular motor apraxia can also be a clinical manifestation of other well-known neurologic or systemic diseases. The association of COMA and a “molar tooth sign” should sug- gest the diagnosis of Joubert syndrome and Related Disorders (JRSD). First described in 1969, Joubert syndrome is charac- terized by the variable combination of episodic neonatal tachpynea and apnea, rhythmic protrusion of the tongue, ataxia, hypotonia, and a variable degree of psychomotor retar- dation.405 The episodic tachpynea presents in the neonatal period and alternates with periods of apnea, resembling the panting of a dog, and usually resolves or improves over time. Typical facial features include high rounded eyebrows, broad nasal bridge, anteverted nostrils, and low-set ears.89,513,609 The associated congenital retinal dystrophy was at first labeled as a variant of Leber congenital amaurosis but subse- quently considered different because the visual loss is not as profound (20/60 to 20/200) in JRSD, compared with counting Fig. 7.7 Axial T1-weighted MR image in patient with Joubert disease fingers or worse in Leber congenital amaurosis. In addition, showing “molar tooth” sign the visual evoked potentials (VEPs) are relatively spared (mild-to-moderate reduction in amplitudes, compared with absent or highly attenuated signals). Both conditions show maloriented superior cerebellar peduncles, and an abnormally flat or highly attenuated electroretinograms (ERGs).516 Other deep interpeduncular fossa. As first described by Maria, ophthalmologic findings include ptosis, congenital ocular axial MR imaging at the pontomesencephalic level has fibrosis, and colobomas.468 Systemic manifestations have shown that this malformation produces a peculiar appearance been infrequently reported, including meningoencephalocele, resembling a molar tooth (Fig. 7.7).456,515,516,651 The pathological microcephaly, polydactyly, kidney abnormalities, soft tissue findings include vermian hypoplasia or dysplasia, elonga- tumors of the tongue, liver disease, and duodenal atresia.513 tion of the caudal midbrain tegmentum, and marked dysplasia Ocular motor disorders described in JSRD include slow, of the caudal medulla. hypometric saccades, ocular motor apraxia, strabismus, The molar tooth sign (and the absence of associated periodic alternating gaze deviation, pendular torsional hydrocephalus) distinguishes Joubert syndrome from the nystagmus, seesaw nystagmus, skew deviation, and defec- vermian agenesis that occurs with the Dandy–Walker variant, tive smooth pursuit, as well as optokinetic and vestibular but 10% of patients with a Dandy–Walker-like cyst have the responses.468,515,797a The ocular motor apraxia in JRSD differs molar tooth sign and are clinically similar to classic Joubert from COMA in that both volitional saccades and quick syndrome patients. Such patients were referred to as “Dandy– phases of nystagmus are impaired in both the horizontal and Walker Plus” by Maria et al514 Importantly, the molar tooth vertical directions, and the problem does not resolve with sign is not seen in isolated vermian hypoplasia because the time.757 The most common ocular motor abnormalities are cerebellar peduncles and interpeduncular fossa can be nor- saccadic dysfunction with head thrusts and primary position mal in several vermian hypoplasia syndromes. The deep nystagmus (typically, seesaw nystagmus).432 interpeduncular fossa and decreased anteroposterior diame- Joubert syndrome is characterized by hypoplasia of the ter of the brainstem isthmus in the molar tooth sign can best cerebellar vermis and a particular midbrain–hindbrain be explained by nondecussation of the ascending superior “molar tooth” sign, a finding shared by a group of Joubert cerebellar peduncles. The coincident finding of asymmetri- syndrome-related disorders with a wide phenotypic vari- cal VEPs in some patients with seesaw nystagmus suggests ability. 432 The molar tooth sign is a complex malformation failure of chiasmal decussation.432 This finding, together with of the hindbrain–midbrain junction (brainstem isthmus) the absence of decussation in both the superior cerebellar characterized by cerebellar vermis hypoplasia, thick and peduncles and the corticospinal tracts at the medullary pyramids, Gaze Palsies, Gaze Deviations, and Ophthalmoplegia 323 suggests that patients with Joubert syndrome have a defect of Although ataxia telangiectasia is said to be associated with axon guidance in the motor circuits.265,432,626,715 slow saccades, eye movement recordings in patients with Although the molar tooth sign is still considered essential ataxia telangiectasia have showed saccadic velocities to be to the diagnosis of Joubert syndrome, there are a number of faster than normal, but followed by slow eye movements that Joubert syndrome-related disorders such as COACH, Arima, were not clearly saccadic in origin.492 Debakan, and Senior-Løken that are much more rare and A syndrome mimicking ataxia telangiectasia with slowly which may also show a molar tooth sign on MR imaging. In progressive ataxia, choreoathetosis, and ocular motor apraxia these conditions, there are numerous other abnormalities in in the horizontal and vertical plane has been described.12 addition to the neurological features of the Joubert syndrome; Although the neurological findings are indistinguishable involvement of other organs such as eye, kidney, and liver, from those of ataxia telangiectasia, the onset tends to be later have been described.673,675 The Arima syndrome exhibits and patients have not shown evidence of multisystem involve- pigmentary degeneration suggestive of Leber congenital ment. Ocular motor apraxia is often found in patients with amaurosis, severe psychomotor retardation, hypotonia, char- Gaucher disease,253 a lysosomal storage disorder, and may acteristic facies, polycystic kidneys, and absent cerebellar even be the presenting feature of the disease.316 Other chil- vermis. Joubert and Arima syndromes may be distinguished dren with Gaucher disease show a supranuclear horizontal by such clinical features as neonatal tachypnea, which is gaze palsy.611 one of the cardinal features of Joubert syndrome. In most patients with COMA, the ability to generate The identification of mutations in seven different cilium saccades improves over the first decade, with better eye genes in up to 20% of patients with Joubert syndrome suggests movements and less noticeable head thrusts.177 This sponta- that a certain percentage of Joubert syndrome is a celiopathy neous improvement led Cogan to favor a delayed maturation that can affect various organ systems, including the connect- of the ocular motor pathways rather than congenitally absent ing cilium of photoreceptors.432,609 Although patients with the initiation pathway for horizontal saccades as the underlying NPHP1 deletion often have juvenile nephronophthisis and cause. While the ocular motor abnormalities tend to improve rarely have retinal dystrophy, patients with AH1 mutations with age, most affected children show some degree of delayed seem less likely to develop retinal dystrophy.609,767 Mutations motor, speech, or cognitive development.726 Notwithstanding in the AHI1 gene can also be associated with other CNS the benign course in most cases, it is advisable to obtain MR malformations (in non-Joubert patients) such as corpus callosal imaging to rule out intracranial pathology (tumor, congenital abnormalities, polymicrogyria, hydrocephalus, and encepha- structural malformations), the occurrence of which has been lomeningocele.292 Patients with the CEP290 mutation seem to well documented in a minority of children. Treatment of have both nephronophthisis and retinal dystrophy.91,679,772 Other underlying pathology may ameliorate or cure the apraxia in phenotypes have included nonspecific renal cortical cysts, some cases,833 but not in all.731 For instance, Zaret et al833 ocular colobomas, and encephaloceles.91,432,679,772 described a case of COMA that showed rapid improvement Joubert syndrome may be sporadic or familial, with familial after surgical evacuation of a large cystic tumor in the rostral cases inherited in an autosomal recessive pattern. Recent brainstem, while complete resection of a posterior fossa genetic analyses have suggested at least three loci, JBTS1 lipoma in a 10-month-old girl had no effect on the apraxia. (9q34.3), JBTS2 (11.2-q12.3), and JBTS3 (6q23).770 Only Although typical COMA involves a bilateral palsy of the JBTS3 gene, AHI1, encoding Jouberin, has been cloned. volitional horizontal saccades and unilateral cases,146,434 cases JBTS1 and 3 primarily show features restricted to the CNS, involving only vertical saccades have been described.383,645 with JBTS1 showing largely pure cerebellar and midbrain– hindbrain junction involvement, and JBTS3 displaying cerebellar, midbrain–hindbrain junction, and cerebral cortical features, most notably polymicrogyria. Conversely, JBTS2 is Vertical Gaze Palsies in Children associated with multiorgan involvement of kidney, retina, and liver, in addition to the CNS features, and results in Vertical gaze disturbances are generally less common than extreme phenotypic variability.771 horizontal ones and, among vertical disorders, upgaze palsy Occasionally, COMA is one of the manifestations of a and combined upgaze and downgaze paralysis are more degenerative disorder such as ataxia telangiectasia.53,727 Some common than downgaze palsy (Fig. 7.8). Most vertical gaze children with ataxia telangiectasia may pose a diagnostic palsies are supranuclear and conjugate (i.e., upgaze palsy, quandary by showing no overt immune dysfunction, incon- downgaze palsy, and vertical gaze palsy). Supranuclear spicuous oculocutaneous telangiectasia, and an atypical disconjugate vertical gaze syndromes are rare, and their neurological presentation with dystonia predominating over topographic correlation is less precisely determined. They cerebellar ataxia.166 Vertical saccades are usually involved to include skew deviation and variants (e.g., slowly alternating some degree when COMA is associated with systemic disease. skew deviation), seesaw nystagmus, monocular upgaze palsy, 324 7 Complex Ocular Motor Disorders in Children

Fig. 7.8 Supranuclear vertical gaze palsy. Five-year-old boy with cerebral palsy shows total paralysis of (a) upgaze and (b) downgaze. (c) Right gaze and (d) left gaze are intact. (e) Elevation of eye with Bell’s phenomenon indicates that upgaze paralysis is supranuclear ocular tilt reaction, vertical one-and-a-half syndrome, and reported a case of purely vertical ocular motor apraxia in a V-pattern pseudobobbing. Some of these disorders are not 4-year-old boy whose MR imaging demonstrated bilateral only location-specific, but also point to a specific mechanism subthalamic lesions.231 Rare cases of isolated vertical COMA of injury (e.g., acute downgaze palsy suggests bilateral have also been associated with birth asphyxia.27,383,645 The infarction of the posterior thalamo-subthalamic paramedian association of this disorder with perinatal hypoxic encephal- territory). Occasionally, cases involving complete vertical opathy implicates injury to the frontal eye fields and posterior ophthalmoplegia are described that remain unexplained parietal cortex or their descending projections through the despite thorough evaluation. Nightingale and Barton578 internal capsule and basal ganglia to the rostral interstitial described a 6-year-old girl who had episodes of severe ataxia nucleus of the medial longitudinal fasciculus (riMLF). and vertical supranuclear ophthalmoplegia. Horizontal eye movements were not affected, and the patient was normal in between attacks. Downgaze Palsy in Children Congenital vertical ocular motor apraxia may occur as a benign nonprogressive condition similar to the horizontal Isolated downgaze palsy usually results from a bilateral lesion variety or may signal the presence of intracranial tumors, (usually infarction) involving the midbrain reticular forma- especially if other neurological signs are present.231 Ebner tion and affecting the lateral parts of the riMLF bilaterally. Gaze Palsies, Gaze Deviations, and Ophthalmoplegia 325

In general, an acquired isolated downgaze paralysis requires the contralateral superior rectus subnucleus and ipsilateral bilateral lesions at the level of the upper midbrain tegmen- inferior oblique subnucleus. This disorder should be distin- tum, while a unilateral lesion may be sufficient to produce an guished from a different condition, also termed a one-and- upgaze palsy or a combined upgaze and downgaze palsy.79 one-half syndrome, consisting of bilateral upgaze palsy and Green et al311 reported a 9-year-old girl with selective down- monocular depression deficit due to thalamomesencephalic gaze paralysis following pneumococcal meningitis. MR infarction ipsilateral to the downgaze paresis.80 imaging showed bilateral lesions in the riMLF. In the setting of a bilateral midbrain lesion, the examiner can often use horizontal eye movements to assess which side of the midbrain Upgaze Palsy in Children is more severely affected. If the right side of the midbrain is more severely affected, the patient will have a saccadic deficit The most common causes of upgaze palsy in children include to the left and a pursuit deficit to the right, because saccadic hydrocephalus (congenital and acquired) and various condi- innervation from the hemispheres is crossed and pursuit inner- tions associated with the dorsal midbrain syndrome, such as vation is uncrossed. a tumor in the pineal region, arteriovenous malformations, In adults, downgaze paresis is most commonly an early encephalitis, and third ventricular tumors.421 Midbrain infarc- sign of progressive supranuclear palsy. Kumagai et al455 tion, multiple sclerosis, and syphilis are rare causes in described a patient with selective downgaze paresis who had children. The eye signs of hydrocephalus are detailed in the a pineal germinoma with bilateral involvement of the thal- chapter on neuro-ophthalmologic signs of intracranial dis- amo-mesencephalic junction. Rhythmic vergence eye move- ease. Ocular motility disorders reported in hydrocephalus are ments (alternating convergence and divergence) were listed in Table 7.6. observed at a rate of 3 Hz during eyelid closure. Upgaze paresis is the hallmark of the dorsal midbrain Downgaze palsy in children is a well-known feature of syndrome.326 Mild cases involve only upward saccades, but DAF (downgaze palsy, ataxia or athetosis, and foam cells in severe cases show paralysis of all upward movements. the bone marrow) syndrome, a neurovisceral storage disease Attempts to produce upward saccades, best elicited by fixat- considered to be a variant of Niemann–Pick disease type C. ing a downward rotating optokinetic nystagmus drum, evoke It is characterized by supranuclear gaze palsy in the vertical convergence-retraction nystagmus. The pupils are usually plane (typically downgaze palsy), hepatosplenomegaly, mid-dilated and show light-near dissociation. The upper eye- slowly progressive ataxia, mental deterioration, and other lid shows pathologic lid retraction (Collier’s sign) and lid CNS disorders. Foamy cells or sea-blue histiocytes in the lag, due to disruption of inhibitory fibers from the posterior bone marrow as well as accumulation of sphingomyelin, commissure to the central caudal nucleus.182 The setting sun cholesterol, and other glycosphingolipids are characteristic sign is unique to children and is suggestive of congenital histopathologic findings. The acronym DAF was coined by hydrocephalus. It is not clear why a similar sign is not seen Cogan to denote this triad of findings.176 Rarely, patients in adults with acquired hydrocephalus. The setting sun sign show predominantly horizontal supranuclear gaze palsy.373 may be thought of as a combination of Collier’s sign and An autosomal recessive inheritance pattern is suspected.42 tonic downgaze, which has been reported in some children with The age of onset of neurologic symptoms is between 5 and hydrocephalus, with or without associated intraventricular 15 years. In addition to abnormalities indicated by the acro- hemorrhage.735 nym, affected patients have hepatosplenomegaly, dementia, and widespread CNS dysfunction. Other neurological symp- toms and signs include poor coordination, slurred speech, dysphagia, seizures, cerebellar dysfunction, hyperreflexia, Table 7.6 Ocular motility disorders in hydrocephalus59,167 and involuntary movements (dystonia, chorea, or atheto- A-pattern esotropia with superior oblique muscle overaction sis).100 The DAF variant of Niemann–Pick disease should be Convergence insufficiency suspected when evaluating school-aged children who have Convergence-retraction nystagmus suffered a recent decline in intelligence or school perfor- Convergence spasm mance and who show progressive neurologic disease and Fixation instability vertical supranuclear ophthalmoplegia. Lid retraction Mydriasis with light-near dissociation An acquired condition of bilateral downgaze palsy with Pseudo-abducens palsy monocular elevation palsy, termed the vertical one-and-one- Setting sun sign (in infants) half syndrome, has been reported in a patient with bilateral Skew deviation infarction in the mesodiencephalic region.201 The authors Superior oblique palsy (unilateral or bilateral) speculated that the lesions may have affected the efferent Upgaze paralysis (affecting saccades more than pursuit) fibers of the riMLF bilaterally and the supranuclear fibers to V-pattern pseudobobbing (with shunt failure) 326 7 Complex Ocular Motor Disorders in Children

The upgaze palsy of congenital hydrocephalus usually Table 7.7 Diffuse ophthalmoplegia in children improves dramatically and quickly after shunt placement. Bickerstaff brainstem encephalitis Incomplete, delayed improvement over months to years Botulism suggests damage to the upgaze pathway either as a result of Chronic progressive external ophthalmoplegia thalamic hemorrhage and infarction or by the hydrocephalus Intrinsic brain stem tumors 735 Kearns–Sayre syndrome itself. Maple syrup urine disease Children with severe, congenital visual loss may have Medications (e.g., toxic doses of phenytoin, amitriptylene) difficulty moving their eyes volitionally. In this context, Miller Fisher syndrome upward gaze is the most severely affected.393 Jan et al393 theo- Mitochondrial encephalopathy (CPEO, MELAS, MERRF, MNGIE, rized that a selective upgaze deficit exists because children MDS, Pearson syndrome) with marked visual impairment rarely look up, because they Myasthenia gravis Olivopontocerebellar degeneration see much more with their limited vision when viewing closer Tick fever objects sideways or downward. Toxicity of chemotherapeutic agents (e.g., vincristine) Isolated paralysis of upgaze may be the presenting sign of the Miller Fisher syndrome.423 It may also result from vita- 671 present with acute ophthalmoplegia, including Fisher syn- min B1 or B12 deficiency. Isolated bilateral elevation defi- ciency may be due to congenital restriction of the inferior drome, botulinum, and tick fever, can cause usually have rectus muscles in the congenital fibrosis syndrome.759 telltale historical clues. Each disorder has a characteristic, if Diagnostic confusion arises because congenital fibrosis syn- overlapping, clinical profile, making it possible for the diag- drome can produce convergent movements of the eyes in nosis to be established on clinical grounds in most cases. attempted upgaze, which simulates convergence retraction nystagmus. The distinguishing clinical feature is that patients with congenital fibrosis syndrome display ptosis rather than Chronic Progressive External lid retraction. As discussed below, these restrictive phenom- ena can also be differentiated from the dorsal midbrain Ophthalmoplegia syndrome by the positive family history, positive forced ductions, and the finding of hypoplasia of the intracranial Chronic progressive external ophthalmoplegia (CPEO) is an nerves and extraocular muscles in the congenital fibrosis umbrella term that includes a number of diverse conditions syndrome, but not in dorsal midbrain syndrome. having in common insidious onset of slowly progressive, In adult patients, upgaze palsy is usually less disabling typically symmetric, multidirectional external ophthalmople- than downgaze palsy, because the superior visual space is gia. The various conditions encompassing CPEO range from comparatively less important. This is in contrast to down- disorders limited to the eyelids and extraocular muscles to gaze palsies, which cause significant visual deficits due to ones that include systemic and encephalopathic features. the importance of downgaze for such tasks as reading, walk- Extraocular muscles have smaller motor unit sizes, higher ing, and eating. However, the visual significance of upgaze motor neuron discharge rates, higher blood flow, and higher palsy is much more profound in children who, by virtue of mitochondrial volume fractions than skeletal muscles.688 their short stature, spend a considerable amount of their time These differences suggest that the energy demands and there- looking up. fore the susceptibility to mitochondrial dysfunction are greater in extraocular muscle. Because of the often gradual and symmetric involvement of the extraocular muscles, patients with CPEO generally do Diffuse Ophthalmoplegia in Children not experience diplopia.59,614,639,713 Ptosis and ophthalmople- gia generally occur together, but each can occur alone, and The numerous manifestations of diffuse ophthalmoplegia in the ptosis can be asymmetrical. When strabismus does occur, children can usually be differentiated by clinical history and the most common deviation is exotropia, with or without a associated findings (Table 7.7).305 Mitochondrial disorders vertical deviation.639,700 Confirmation of the diagnosis usually and the spinocerebellar ataxias (SCAs) should be considered requires fresh muscle biopsy for histopathological examina- when the onset is gradual and the eye signs are progressive, tion (using cytochrome oxidase stain with electron micros- and when myasthenia gravis has been ruled out. Ocular copy to look for “parking lot” inclusions) and Southern blot myasthenia gravis is associated with variability and fatiga- analysis to look for deletions. Polymerase chain reaction bility, with or without muscle systemic weakness. Congenital (PCR) has recently been used to detect the mutation in cranial dysinnervation disorders, such as congenital fibrosis swabbed buccal cells.386 syndrome, are usually present at birth and often associated Mitochondrial encephalopathy is divided into several with ptosis and fixed downgaze. Many other conditions that clinical phenotypes, including Kearns–Sayre syndrome; the Diffuse Ophthalmoplegia in Children 327 syndrome of mitochondrial encephalopathy, lactic acidosis, inheritance is characterized by accumulation of multiple dele- and stroke (MELAS); mitochondrial neurointestinal enceph- tions of mtDNA in the patient’s tissues. Most single deletions alopathy (MNGIE); and the syndrome of myoclonus, epi- are not inherited, but occur spontaneously after fertilization lepsy, and ragged red fibers (MERRF).688 The later syndrome of the oocyte. Individuals with multiple different deletions is not generally associated with external ophthalmoplegia. likely come from pedigrees in which there is a nuclear muta- Kearns–Sayre syndrome is characterized by the triad of tion in a gene encoding a protein that regulates mitochondrial progressive external ophthalmoplegia, pigmentary degenera- DNA replication and therefore is inherited mendelianly (usu- tion of the retina, and heart block. Most cases are sporadic. ally autosomal dominant or autosomal recessive).59,74,315,838 No The onset of the disorder occurs before age 20. Affected clinical difference between hereditary and sporadic CPEO patients have short stature, other neurologic disorders, and can be demonstrated.59,838 Many patients without structural an elevated protein concentration (>100 mg/dL) in the cere- abnormalities of mitochondrial DNA have point mutations at brospinal fluid (CSF). Other findings may include hearing many different nucleotide positions, which are inherited loss, cerebellar signs, mental retardation, delayed puberty, maternally.386 Point mutations causing CPEO are often vestibular abnormalities, and “ragged red fibers” on muscle homoplasmic. Large-scale deletions resulting in CPEO are biopsy,688 mental deterioration, pyramidal signs, and diabe- almost always heteroplasmic; the more tissue with the dele- tes.59,212,424,472,705,838 In addition to complete heart block, car- tions (i.e., the greater the degree of heteroplasmy), the more diac conduction abnormalities include bundle branch block, likely the phenotype will be severe (i.e., more toward Kearns– bifascicular disease, and intraventricular conduction defects Sayre syndrome phenotype rather than the simple CPEO phe- and are thought to result from an associated cardiomyopathy. notype).47,783 While mitochondrial disorders that have both The heart block generally occurs years after onset of the ocu- dominant and recessive modes of inheritance are usually lar signs and may cause sudden death. The retinal pigmen- caused by mutations at different loci, both can be caused by tary degeneration progresses slowly and may be too subtle mutations in the polymerase gamma (POLG) gene.184,267a early on to detect ophthalmoscopically. The associated ptosis The risk of developing a severe phenotype (i.e., addi- may become visually significant, but surgical correction tional CNS symptoms with neurological manifestations) is should be approached with caution because the limited eye higher when the age of onset is before age 9 and lower when movements and the absence of Bell’s phenomenon render the onset is after age 20.47 While mitochondrial disorders patients prone to exposure keratopathy. associated with ophthalmoplegia tend to affect adults, early Orbital neuroimaging is probably of little value in CPEO. symptoms are often experienced in childhood. MELAS is One study found marked atrophy of the extraocular mus- the mitochondrial disease that is most consistently associ- cles,608 while another showed little or no reduction in extraoc- ated with retrochiasmal visual loss. MELAS is character- ular muscle volume.601 Furthermore, myasthenia gravis may ized by recurrent abrupt attacks of headache, vomiting, focal also show atrophic extraocular muscles late in the course of and generalized seizures, and focal neurologic symptoms the disease, making it difficult to distinguish from CPEO.595 and signs lasting hours to days.74 There is a posterior cere- It has been suggested that the myopathic process that results bral predilection for damage, and visual disturbances have in chronic progressive external ophthalmoplegia renders rec- been reported in more than half of patients. It is not uncom- tus muscle recessions less effective than resections for cor- mon for patients with MELAS to have CPEO, pigmentary recting the associated strabismus that occasionally develops retinopathy, optic atrophy, or homonymous hemianopia. in these patients.507,713 Postoperative prisms are occasionally Patients may present with stroke-like episodes, seizures, necessary to fine-tune single binocular vision.791 headaches, progressive dementia, and exercise intoler- CPEO may be sporadic, show Mendelian inheritance, ance.539 Classically, the brain MRI of patients with MELAS or show maternal inheritance.386 Almost half of CPEO demonstrates lesions that may mimic ischemia, except that cases are sporadic and associated with single deletions of they usually do not respect vascular territories and are often mtDNA.74,314,315,476,617 In sporadic cases of CPEO and Kearns– restricted to the cortex with relative sparing of deep white Sayre syndrome, all the mutant mtDNAs in an individual matter.366 However, lesions spanning both gray and white have the same deletion. Because Kearns–Sayre syndrome is matter have been reported.554 an artificial construct of the most severe cases of the CPEO The diagnosis of MELAS is established made from the syndromes, it is always more likely to have deletions (90%) characteristic neuroimaging findings, elevated lactic acid lev- than CPEO in general, and it is more likely to be sporadic. els, ragged red fibers on muscle biopsy, or genetic sequencing. However, some members of severe autosomal dominant MELAS is often maternally inherited, with 80% of patients CPEO pedigrees have had a high deletion load express the harboring the A3243G transition within the mitochondrial full-blown Kearns–Sayre syndrome phenotype, while other genome, although many other mutations have also been family members do not.74 reported.162 Patients with MERRF syndrome present with Autosomal dominant or recessive inheritance is noted in combinations of myoclonic epilepsy, ataxia, spasticity, gener- about 15% of patients with CPEO. Autosomal dominant alized seizures, optic atrophy, and/or dementia.315 They may 328 7 Complex Ocular Motor Disorders in Children also have muscle weakness, myopathy, neuropathy, ophthal- in the tonic fibers. The more constant activity also makes moplegia, ptosis, headache, foot deformity, cervical lipoma, or the orbital extraocular muscle fibers more susceptible to sensorineural hearing loss. Myoclonus is usually the present- fatigue.408–411,481 It has also been suggested that antibodies ing symptom and is often precipitated by noise, photic stimu- directed against the fetal form of the acetylcholine receptor, lation, or action. Myopathy is generally subclinical or mild. which may be found at synapses on extraocular but not skel- Biochemical aberrations may include elevations of serum etal muscles, may be an important factor that predisposes the pyruvate, or pyruvate and lactate, and reduced activities of extraocular muscles to involvement by myasthenia.407 Nearly complexes I and IV. The most common mutation, accounting 90% of patients with myasthenia develop ocular involvement for 80% of MERRF cases, is at np 8344 within the tRNA.346 at some point during their illness. Most patients with ocular Other mutations in the same tRNA gene, t8356C and G8363C, myasthenia who develop systemic symptoms and signs do so are also found in association with this phenotype.606 within 2 years of onset.69,459 Mitochondrial Neurogastrointestinal Encephalomyopathy Three distinct myasthenic syndromes may be encountered (MNGIE) syndrome is an autosomal recessive syndrome in the pediatric age group: transient neonatal, congenital, characterized by chronic progressive external ophthlmople- and juvenile. This classification is not based on age at gia intestinal hypomotility, and neuropathy.795 Clinical pre- presentation but on pathophysiology. Both congenital myas- sentation is usually in childhood, although gastrointestinal thenia and juvenile myasthenia may present any time between symptoms may be problematic long before other features of infancy and adulthood, but are distinguished primarily by the the disease appear. Some patients have diabetes mellitus, fact that congenital myasthenia is not immune-mediated. heart block, or cardiomyopathy. Long-term prognosis is However, this distinguishing feature is not absolute because poor, with most patients dying in early-to-mid adulthood juvenile- and adult-onset myasthenia may also be antibody- from weight loss and other gastrointestinal complications.795 negative. Also, the defect in acquired myasthenia is post- MR imaging may show an unsuspected leukoencephalopa- synaptic, while the defect in congenital myasthenia may be thy of the brain.184,365,542,581 Most patients have mutations in either at the presynaptic or postsynaptic level. the nuclear-encoded thymidine phosphorylase gene.795 In the child with progressive external ophthalmoplegia, a history of marrow failure with transfusion-dependent sidero- Transient Neonatal Myasthenia blastic anemia, and exocrine pancreatic dysfunction causing malabsorption or diarrhea should raise suspicion for the Pearson Transient neonatal myasthenia gravis is due to transfer of syndrome. This disorder is characterized by a progressive pig- antibody from the mother, tends to spare eye movements.285 mentary retinopathy that initially spares the posterior pole. Approximately 12% of newborn infants of myasthenic Older patients may develop symptoms of Kearn Sayre syn- mothers develop transient myasthenic symptoms, presum- drome. It is caused by deletions in mitochondrial DNA.659a ably due to passive transplacental transfer of anti-AChR IgGs. Serum AChR antibody titers of affected neonates fol- low the same pattern as their mothers. Neonatal disease does not appear to correlate with the severity of maternal symp- Myasthenia Gravis toms; affected mothers commonly have active myasthenia, but they may be in remission or, rarely, have undiagnosed Myasthenia gravis was the first recognized autoimmune subclinical disease. The onset of transient neonatal myas- neurologic disease. Myasthenia gravis is a disorder of neuro- thenia occurs within a few hours after birth in two-thirds of muscular transmission characterized by fatiguability and patients, and within the first 3 days in all of them. Affected fluctuating muscular weakness, with a predilection for the infants present with temporary skeletal muscle weakness extraocular muscles.48 In severe cases, acute respiratory fail- producing hypotonia, a feeble cry, difficulty sucking and ure and death may occur. About half of all patients with swallowing, facial diparesis, and mild respiratory distress. myasthenia present with ophthalmologic symptoms. These Occasionally, they may suffer respiratory depression that include ptosis, strabismus, and limited ocular ductions, all requires mechanical ventilation. Transient neonatal myas- with a tendency to be highly variable. No pupillary involve- thenia tends to spare eye movements.285 Ocular involvement, ment is clinically discerned in myasthenia, and the presence including ptosis, limited eye movements, and orbicularis of pupillary signs effectively excludes the diagnosis. weakness, affects 15% of infants. Myasthenia gravis has a well-known predilection for An atypical, more severe form of transient neonatal myas- extraocular muscle involvement. Factors that may predispose thenia includes the above-mentioned manifestations in addi- the extraocular muscles to preferential involvement in myas- tion to multiple joint contractures and occasional prenatal thenia gravis include their higher discharge rates, differences difficulties such as polyhydramnios or decreased fetal move- in complement inhibitor proteins, and lack of action potentials ment. Unlike the typical variety, response to oral or parenteral Diffuse Ophthalmoplegia in Children 329 anticholinesterase agents is poor. Severe cases may rarely seronegative myasthenia gravis. Congenital myasthenic require assisted mechanical ventilation for up to 1 year. syndromes occur in infants born to nonmyasthenic mothers The pathogenesis of the disorder is increasingly under- and that are associated with hypotonia and weakness.60,239,240 stood. It is controversial and uncertain whether the maternal Congenital myasthenic syndromes should be suspected in and neonatal antibodies are similar and passively transferred, patients with seronegative myasthenia gravis, in infants with or different, with the neonate synthesizing their own antibod- hypotonia and poor development of motor milestones, and in ies, or whether both mechanisms are in play.479,760 Transient patients with a childhood history of neuromuscular difficul- neonatal myasthenia is not fully explained by passive trans- ties affecting cranial, respiratory, truncal, or limb muscles.351 placental IgG transfer because these antibodies are also In some patients, however, symptoms may not appear until found in the serum of many newborns who are asymptom- later childhood or even adulthood. Forty-two percent of the atic. Other infants are symptomatic without detectable cases present before the age of 2 years, and over 60% before antibodies in their maternal serum. Also, high IgG levels 20 years.574 In contradistinction to juvenile and adult-onset have been found in a few asymptomatic infants. There is now myasthenia, which have an autoimmune basis and are attrib- a report of transient neonatal myasthenia in an infant with utable to antibodies that bind to the acetylcholine receptor anti-MuSK antibodies.579 and cause increased turnover and destruction of the receptor, Clinical symptoms usually last 2 or 3 weeks,560 but may congenital myasthenia is not immune-mediated.351 resolve in 1 week or linger on for 2 months before complete The congenital myasthenia syndromes are caused by struc- recovery. Response to oral (e.g., pyridostigmine bromide) or tural or functional alterations at the myoneural junction.246,550,699 parenteral anticholinesterase agents is very good, and these Most cases present in the neonatal period or shortly thereafter agents should be administered until spontaneous resolution with poor feeding, failure to thrive, and weakness. Three con- occurs. No permanent neuromuscular sequelae are detect- genital myasthenia syndromes (slow-channel syndrome, pro- able after resolution. If this condition is not recognized and longed channel open time syndrome, and limb girdle promptly treated, some affected infants may deteriorate from myasthenia) may present later in childhood or adolescence respiratory depression to respiratory arrest and death. and represent a specific, rare group of potential differential The characteristic clinical features and the history of diagnoses.351 A distinction between congenital and acquired maternal myasthenia should be enough to confirm the diag- myasthenia cannot be made with certainty on the basis of the nosis, but the diagnosis may be delayed if the mother’s dis- age of onset because both types may manifest during the ease has not been previously detected. Further verification of neonatal period, infancy, or childhood, and acquired myasthe- the diagnosis may be derived from a favorable response to nia may also be antibody-negative.288 Congenital myasthenia is neostigmine methylsulfate, with improvement of symptoms usually characterized by ocular musculature with ophthalmo- 10–15 min after intramuscular injection of 0.15 mg/kg of paresis, orbicularis weakness, and ptosis. body weight. Alternatively, intramuscular edrophonium We described a unique child who had a congenital oculo- chloride (Tensilon) may be administered intramuscularly or motor nerve palsy with aberrant regeneration and fatigable subcutaneously (0.15 mg/kg) or intravenously (0.10 mg/kg). ptosis associated with congental myasthenia gravis. During Sufficient differences exist between transient neonatal periods of levator fatigability, gaze activation of the ipsilat- myasthenia and the congenital myasthenic syndromes (see eral superior or medial rectus muscles produced instanta- below) to render diagnostic confusion rare. Congenital myas- neous levator retraction with no fatigability (Fig. 7.9). The thenia does not occur in infants born to mothers with acquired ability of this child’s synkinetic neuromuscular connections myasthenia. The other condition affecting neuromuscular to override her myasthenia suggested that there was selective transmission in this age group, infant botulism, is readily sensitivity of the myasthenic levator muscle to the misdi- ruled out because it occurs after the second week of life, 5 rected oculomotor axons, which presumably provided fresh days after the infant ingests food contaminated with synaptic reserve of acetylcholine to their target fibers.111 Clostridium botulinum, whereas the onset of transient neona- Congenital myasthenic syndromes can arise from presyn- tal myasthenia is within the first 3 days of life only. aptic, synaptic, or postsynaptic defects.244 The major syn- dromes in which the defect is presynaptic are related to defects in Ach synthesis, mobilization, or release.351 Presynaptic Congenital Myasthenic Syndromes congenital myasthenic syndromes were previously called “familial infantile myasthenia.”355,647 Congenital myasthenia constitutes a heterogeneous group of Postsynaptic syndromes are mainly caused by endplate genetic disorders affecting neuromuscular transmission that acetylcholinesterase deficiency and Ach receptor kinetics, presents in the first year of life, producing mainly ptosis, and including the fast- and slow-channel syndromes.785 The array usually has a benign course.239,240,242–246,351 Although rare, of disorders and involved genes identified has increased congenital myasthenic syndromes are an important cause of significantly.351 While genes have been identified for many 330 7 Complex Ocular Motor Disorders in Children

Fig. 7.9 Myasthenic ptosis in a child with congenital left oculomotor weakness. Lower panel: Primary and secondary positions of gaze shing nerve palsy. Upper panel: Facial photographs depict the clinical vari- retraction of the left upper eyelid in adduction and supraduction due to ability of the left upper lid ptosis and the compensatory head turn before oculomotor synkinesis. Even with prolonged fixation, fatigable ptosis treatment. This child’s congenital myasthenia was worse on the day of could not be elicitied in these positions of gaze. With permission from the right photograph, as evidenced by the increased ptosis and left facial Brodsky111 forms of congenital myasthenic syndromes, mutation analy- limiting enzyme in the synthesis of acetylcholine, cause the sis is not yet available on a commercial basis.60,239,240 Some congenital myasthenic syndrome associated with episodic cases may be familial, with other siblings affected, support- apnea (previously known as “familial infantile myasthe- ing a genetic basis for the disorder.733 nia”).591 Recently, a unique congenital myasthenic syndrome Most commonly, congenital myasthenic syndromes are caused by mutations of a perijunctional skeletal muscle caused by mutations that reduce the expression or alter the sodium channel has been discovered.521 kinetics of the acetylecholine receptor.245 Reduced receptor Congenital myasthenia is not immune-mediated, in contra- expression is also caused by mutations in rapsyn, a molecule distinction to juvenile- and adult-onset acquired myasthenia, that is produced by muscle and is important for acetylcholine which have an autoimmune basis and are attributed to antibodies receptor aggregation on the postsynaptic membrane.245 that bind to the acetylcholine receptor and cause increased The second most common congenital myasthenic syn- turnover and destruction of the receptor.26 Serum antiacetyl- drome is caused by mutations of the acetylcholinesterase choline receptor antibodies and other autoantibodies are absent. molecule.242 Mutations of choline acetyltransferase, the rate- Congenital myasthenia is not associated with any autoimmune Diffuse Ophthalmoplegia in Children 331

Table 7.8 Classification of congenital myasthenic syndromes (based while a syndrome characterized by impaired ACh release on 271 index cases evaluated at Mayo Clinic) shows few, if any, of these features. Presynaptic defects (7%) The developmental milestones, progression or regression Choline acetyltransferase (ChAT) deficiency of symptoms and signs during infancy and childhood, response Paucity of synaptic vesicles to any therapeutic modalities, and a complete family pedigree Congenital Lambert–Eaton-like syndrome Other unclassified presynaptic defects should be recorded. In some congenital myasthenia syn- Synaptic defect (basal lamina) (14%) dromes, a specific diagnosis can be made by simple histologi- Endplate AChE deficiency cal or EMG studies while, in others, a complex panel of in vitro Postsynaptic defects (79%) electrophysiological, ultrastructural, and immunocytochenical Reduced AChR expression (with or without minor AChR kinetic investigations are needed for accurate diagnosis.244 abnormality) Because the congenital myasthenic syndromes are not s !#H2MUTATIONSISOLATEDORWITHPLECTINDElCIENCY – Rapsyn mutations immune-mediated, neither plasmapheresis nor immunosup- – MuSK mutations pression has any beneficial effect. Thymectomy usually pro- – DOK-7 mutations (formerly “Limb-Girdle” myasthenia) duces negligible benefits, although a transient improvement s !#H2KINETICABNORMALITYSOMEWITHMILDREDUCED!#H2 has been reported in two patients, one of whom had an abnor- expression) mal thymus.170,803 Because of the diversity of the underlying – Slow-channel syndrome abnormalities, no specific conclusion can be drawn regarding – Fast-channel syndrome the efficacy of the anticholinesterase preparations. Some types s3ODIUMCHANNELMUTATIONS AChE acetylcholinesterase; AChR acetylcholine receptor; ChAT cho- of congenital myasthenia (e.g., congenital acetylcholine recep- line acetyl-transferase; MuSK muscle specific kinase tor deficiency) respond favorably to anticholinesterase prepa- rations, while other types (e.g., acetylcholinesterase deficiency, slow-channel syndrome) are refractory to such treatment and may even be made worse by it. Therefore, an effort to differ- disease or any particular human leukocyte antigen genotype, entiate juvenile myasthenia from congenital myasthenia and and cytohistochemical studies fail to reveal immune com- to specifically identify the type of congenital myasthenic syn- plexes at the myoneural junction. The condition is generally drome has important therapeutic implications. On the basis of nonremitting. Once thought to be a single disorder, it is now the identified pathophysiology of the congenital myasthenic known to represent a group of diverse disorders distinguishable syndrome, a number of other pharmacologic interventions are by the specific site of dysfunction at the myoneural junction tried in individual children, including fluoxetine, ephedrine, (Table 7.8). Multiple inherited defects of neuromuscular albuterol, and 3,4-diaminopyridine. transmission at presynaptic or postsynaptic levels are known, but some defects have not yet been characterized. The putative inheritance of most of these defects is autosomal recessive, Juvenile Myasthenia with the exception of the slow-channel syndrome, which is autosomal dominant. Juvenile myasthenia is said to be similar to the adult form, but The precise characterization of these defects requires the more frequently familial, showing slower progression, charac- combined use of clinical, electromyographic, in vitro elec- terized by more severe ophthalmoplegia, and having a higher trophysiological, and morphological data. It is probably rate of spontaneous remissions.778 Children with myasthenia impractical to perform all tests needed for accurate charac- often first present to the ophthalmologist with symptoms terization of the myoneural defect on each infant suspected such as ptosis, diplopia, strabismus, and ophthalmoplegia.90,285 with the diagnosis, especially when the infant is ill. However, Juvenile myasthenia is otherwise similar to the adult variety in determination of the specific subtype of congenital myasthe- presentation, pathogenesis, clinical course, and response to nia would be helpful for therapeutic purposes and would therapy. While it has been observed that there is an increased enhance our understanding of the heretofore incompletely incidence of autoimmune disorders in children with acquired understood disorders that constitute congenital myasthenia. autoimmune myasthenia gravis and their first-degree relatives, Certainly, a detailed history should be obtained on each child acquired autoimmune myasthenia gravis is probably not a regarding the onset and severity of feeding difficulty, breath- familial disease. However, some studies reveal the juvenile ing dysfunction, choking episodes, drooling, facial weak- variety to be more frequently familial,571,574 to show more ness, ophthalmoparesis, ptosis, hypotonia, and muscular severe ophthalmoplegia, and to have slower progression and a fatiguability. This would start the process of differentiation higher rate of spontaneous remissions. An acute fulminating between the different syndromes involved. For example, a form of myasthenia gravis has been described, with onset syndrome characterized by defective AChR shows neonatal between 2 and 10 years of age, with respiratory crisis as the respiratory difficulty, feeding difficulty, and ophthalmoparesis, presenting feature of the disorder.264 332 7 Complex Ocular Motor Disorders in Children

Many medications have been reported to incite or worsen myasthenia, is not readily explained by Hering’s law. In such myasthenia.796,811 These drugs may interfere with neuromuscu- cases, the possibility of concurrent thyroid eye disease must lar transmission pre or postsynaptically.811 Cardiovascular drugs be excluded.412 (antiarrhythmics and beta adrenergic receptor-blocking agents), Children with diffuse myasthenic ophthalmoplegia rarely anticholinergics, anticonvulsants, antirheumatics, immunosup- present with myopia.652 Myopia occurs when medial rectus pressives, psychotropics, and antibiotics have all been reported weakness leads to exotropia, which necessitates excessive in association with myasthenia.811 Many antibiotics, including accommodative convergence to maintain single binocular kanamycin, ampicillin, imipenem with cilastatin, ciprofloxacin, vision. These children are caught in the unpleasant situation erythromycin, and clarithromycin, have also been reported to of having to sacrifice clear vision to avoid diplopia. Jacqueline cause myasthenia.624,656 Interferon-alpha, a drug frequently used Winterkorn, M.D., has observed another unique ocular motor in the treatment of malignancies and viral hepatitis, has been sign of myasthenia that can be elicited in patients with diffuse found to exacerbate myasthenia.83,768 Wasserman reported ocu- ophthalmoplegia. An optokinetic drum is spun horizontally lar myasthenia in a 10-year-old girl taking nitrofurantoin that for approximately 30 s, as the patient attempts to follow the resolved after discontinuation of the drug.796 targets. The drum is then spun diagonally and the resultant Rarely, myasthenia gravis in children can be precipitated optokinetic movements are observed. In myasthenic ophthal- by a viral illness.260,530 Molecular mimicry between the moplegia, the resultant movements are vertical rather than acetylcholine receptor and viral proteins may be involved diagonal because the horizontal component has been prefa- in the pathogenesis of postinfections myasthenia gravis. tigued. Conversely, if the drum is first spun vertically for 30 s Autoimmune manifestations of hyperthyroidism and myas- and then diagonally, the resultant optokinetic movements are thenia gravis occasionally overlap.682 The finding of lid horizontal (Winterkorn sign). In nonmyasthenic ophthal- retraction in a myasthenic child should lead to suspicion of moplegia, optokinetic preconditioning does not alter the this phenomenon. trajectory of the patient’s diagonal optokinetic responses. A large proportion of young patients with juvenile myas- Systemic myasthenia is often first suspected when weak- thenia gravis are seronegative.25,26,256,708 Careful differentiation ness is demonstrated to be fatigable (worsening with use or from late-onset congenital myasthenic syndromes is necessary exercise and relieved by periods of rest). The diagnosis of in these cases. Children younger 5 years of age, who present myasthenia may be confirmed with certain ancillary tests, with ocular symptoms of myasthenia gravis, frequently including serologic testing for antibodies, clinical neuro- respond to anticholinesterase medications without requiring physiologic testing (repetitive stimulation of motor nerves, immunomodulating therapy and have low rates of progressing needle electromyography, including single fiber testing), and to generalized involvement.569,600 However, one retrospective pharmacologic testing. Because children with acquired auto- study found a 43% prevalence of systemic involvement.524 immune ocular myasthenia gravis have a higher incidence of Several studies have found that pediatric myasthenia gravis seronegativity and normal clinical neurophysiologic testing, shows a female-to-male ratio of about 4:1.5,361,524 the diagnosis often depends on other measures. Myasthenia can often be diagnosed on clinical grounds There are three main confirmatory procedures for myas- when ptosis or ophthalmoplegia is accompanied by certain thenia: response to acetylcholinesterase inhibitors, electro- neuro-ophthalmologic signs. These include fatiguable pto- physiologic testing, and antibody assays. In general, all share sis, orbicularis weakness, variable strabismus, quiver-like the same problem of a lower sensitivity in ocular myasthenia eye movements, and a Cogan lid twitch sign. A Cogan lid gravis than in generalized myasthenia gravis.58 The sensitivity twitch is elicited by having a patient rapidly refixate the eyes of the edrophonium test is approximately 95% in generalized from a depressed position to the primary position, with a myasthenia gravis602 and is similar in patients with ocular myas- positive lid twitch sign indicated by the lids overshooting thenia gravis with ptosis.257 However, diplopia fails to respond briefly upward before settling in their usual ptotic position. If in approximately one-third of patients, and long-standing the lid is first fatigued by sustained upward gaze, the lid myasthenia may not respond at all. The repetitive nerve twitch sign becomes more exaggerated. Apparently, the short stimulation test is positive in most patients with generalized relaxation of the upper lid allowed by fixating an object in myasthenia gravis, but may be normal in well over 50% of downgaze allows for transient recovery of strength by the patients with ocular myasthenia gravis.256,257 Single-fiber myasthenic levator muscle. EMG of the orbicularis oculi is currently the most sensitive Although ptosis is the most common sign, lid retraction test for ocular myasthenia.481 When coupled with the standard may occasionally be encountered, especially unilaterally in EMG, it usually distinguishes myasthenia from other disor- patients with contralateral ptosis. This seemingly paradoxi- ders such as mitochondrial myopathy or oculopharyngeal cal finding is explained by Hering’s law of equal innervation, dystrophy.643 The sensitivity of single-fiber EMG is more as the patient attempts to elevate the contralateral ptotic lid. than 90% in generalized myasthenia gravis669 and approxi- Bilateral lid retraction, which is also rarely reported in mately 85% in ocular myasthenia gravis.764 Since needle Diffuse Ophthalmoplegia in Children 333

EMG and repetitive nerve stimulation are usually positive in positive. False-negative results are more common than false- systemic myasthenia, these tests should first be performed to positive ones. Therefore, if the clinical findings are sugges- rule out denervation or atrophy in patients with limb weak- tive of myasthenia, repeating an initially negative Tensilon ness. Only when these tests are negative, or when there are test is recommended. False-positive results have been purely ocular signs, is single-fiber EMG indicated.481 Because reported in patients with compressive lesions (brain tumors, it is painful and requires patient cooperation, it may be diffi- intracranial aneurysm), botulism, Eaton–Lambert syndrome, cult or impossible to perform in young children. amyotrophic lateral sclerosis, poliomyelitis, transverse Positive acetylcholinesterase antibodies are found in 90% myelitis, Guillain–Barré syndrome, and myositis.211,557 of cases of systemic myasthenia, but in only 50% of cases of Because severe bradyarrhythmias, conduction pauses, and ocular myasthenia. Because myasthenic children have a cardiac arrests have been reported, albeit rarely,389 cardiac higher frequency of negative anticholinesterase antibodies, a monitoring and pretreatment with atropine should be consid- negative test is not especially useful in this setting. The recent ered in “at-risk” patients. identification of muscle-specific kinase (MuSK) as a target In young children, neostigmine (Prostigmine) is adminis- of the autoimmune process in a subset of patients indicates tered intramuscularly, which produces a more prolonged that autoimmune myasthenia gravis includes at least two response in myasthenic patients than does edrophonium distinct immunologic disorders directed against different chloride. Neostigmine can produce a more prolonged clini- antigens in the postsynaptic membrane of the neuromus- cal response (onset, 10 min; duration, 60 min), which can cular junction.24 Autoantibodies targeting MuSK have allow for more leisurely assessment of the response. Doses been demonstrated in approximately 40% of seronegative are 0.04 mg/kg/dose administered intramuscularly or subcu- patients.257,368,668,784 Although the numbers are small, our taneously, with a maximum of 0.5 mg/dose. Side effects experience is that the anti-MuSK variant tends to be more related to excess parasympathetic activity can also last up to severe and less responsive to therapy. 60 min and, as clinically indicated, are treated with atropine The Tensilon (edrophonium hydrochloride) test is the in a dose of 0.02 mg/kg/dose, intravenously, with a maxi- most commonly utilized. For children less than 34 kg, a test mum 0.05 mg/kg/dose in younger children and 1 mg/dose in bolus of intravenous edrophonium should be 0.1 cc or 1 mg, adolescents. followed by repeated boluses at 1-min intervals to the point To avoid the complications of pharmacological testing, a of positive response or maximum injection of 5 mg total “sleep test” has been devised wherein the patient is evaluated dose. Cardiac monitoring is advisable. The dose of atropine for improvement of ocular signs immediately after a 30-min given for excess parasympathetic response (primarily brady- period of sleep (or eye closure) and for worsening of these cardia or bradyarrhythmias) should be 0.02 mg/kg/dose, with signs shortly thereafter (Fig. 7.11).588 The “ice test,” performed a maximum of 0.5 mg/dose in younger children and a maxi- in an outpatient setting, can similarly differentiate a mum of 1 mg/dose in adolescents (Fig. 7.10). Results of the neuromuscular transmission defect from other causes of Tensilon test may be equivocal, falsely negative, or falsely ptosis.234,235,254,300,453 In this test, a surgical glove filled with ice

Fig. 7.10 Positive Tensilon test in juvenile myasthenia gravis. Child presented with variable ptosis and exotropia (a) that showed resolution upon administration of intravenous Tensilon (b) 334 7 Complex Ocular Motor Disorders in Children

Fig. 7.11 Sleep test. Left: Child with myasthenic ptosis. Right: Resolution of ptosis following 5 min of gentle eye closure. Good WV, Hoyt CS. Strabismus Management. Boston, MA: Butterworth-Heinemann; 1996 chips is placed over the ptotic eyelid for 2 min after the eye- additional review of the effectiveness of this operation as a lid has been fatigued by prolonged upgaze. Measurement of therapeutic option. the millimeters of ptosis before and after the cooling is used Because the disease is immune-mediated, unlike in con- to objectively measure response with lessening of the ptosis, genital myasthenia, immunosuppression and plasmapheresis suggesting the presence of myasthenia. The ice test is based have a therapeutic role. Systemic therapy of myasthenia on the observation that increased temperature has a detri- helps control ocular symptoms in most patients.220,221,711 In mental effect, and decreased temperature a beneficial effect, addition to producing superior resolution of ocular misalign- on muscle force generation in myasthenia gravis.85 Both tests ment and diplopia,460 treatment with oral prednisone appears and the sleep test often produce dramatic resolution of myas- to reduce the conversion of ocular to systemic myasthenia thenic ptosis, and some of the observed effect of the ice test gravis.457–460,528,556 After an initial period with immune sup- may be attributable to resting of the closed lid. pressing dose of corticosteroids, the benefit may be main- The medical treatment of juvenile myasthenia is similar tained with doses that do not suppress the immune system to that of the adult variety in that the ptosis shows a good and appear to cause few major systemic adverse effects.458 therapeutic response while the strabismus often does not.436 There is a theoretical basis for using corticosteriod treat- In a recent retrospective study, children with ocular myasthe- ment to prevent generalized myasthenia, even at doses that nia were found to have a high incidence of ptosis (96%) and do not cause immunosuppression.457 Corticosteroid treat- strabismus (88%), most commonly with exotropia and verti- ment of in vitro human muscle cultures increases the number cal heterotropia, and amblyopia (21%). The ptosis showed a of acetylcholine receptors98,414 and prevents receptor loss good therapeutic response in 87%, but the strabismus induced by the serum from generalized myasthenia gravis improved in only 29%.436 Combined pyridostigmine and patients. Neuromuscular junctions increase in size, and the prednisone were most commonly used. Treatment with a length, number, and depths of postsynaptic folds increase short course of prednisone and long-term azathioprine is after weeks of corticosteroid exposure.43 In patients with reported to reduce the risk and severity of generalized symp- ocular misalignment, strabismus surgery has been used to toms and to promote remission of the disease. manage both stable3,64,197,335,594 and unstable563 diplopia with Although thymomas are rare in myasthenic children,7 long-standing success. thymectomy has been observed to be associated with an Brain tumors rarely produce clinical findings that are indis- increased rate of clinical remission in children with autoim- tinguishable from myasthenia.413,633,730 These findings are mune myasthenia gravis.497,649 Early surgery (within 2 years attributed to a putative compression of the central caudal of clinical onset), bulbar involvement without ocular signs of nucleus in the dorsal midbrain.413 Ragge and Hoyt633 described generalized weakness, clinical onset during adolescence an adolescent girl with neurofibromatosis type I and a dorsal (12–16 years of age) and presence of other autoimmune dis- midbrain astrocytoma who had fatiguable ptosis, upgaze pare- orders were associated with increased probability of clinical sis, and a positive “lid twitch” sign. These findings improved remission after thymectomy.649 Surgeons have developed a significantly following radiotherapy of the astrocytoma, con- technique of using video-assisted thorascopic thymectomy firming that the muscular fatiguability was central in origin. that has significantly decreased operative morbidity com- Straube and Witt730 described four patients with posterior fossa pared to transsternal thymectomy.749 Unanswered questions, tumors who presented only with fluctuating weakness of the regarding the impact of thymectomy early in life on the external ocular muscles and/or the pharyngeal muscles, lead- developing immune system, have kept thymectomy limited ing to an incorrect diagnosis of ocular myasthenia. Moreover, to children with generalized weakness and will likely lead to as noted earlier, false-positive results of Tensilon testing may Olivopontocerebellar Atrophy 335 occur in some instances involving tumors or even aneurysms. Supranuclear ophthalmoplegia may be accompanied by Branley et al97 reported a 7-year-old girl who developed an gaze-evoked nystagmus in patients with SCA1, SCA3, and oculomotor nerve palsy of subacute onset due to a cerebral SCA6, and by rebound nystagmus in SCA1 and SCA3.136 artery aneurysm. The condition was initially confused with Impaired saccadic velocity and latency are characteristic of myasthenia gravis because the ptosis improved after Tensilon SCA2 and SCA2. In SCA1, saccadic amplitude is signifi- administration (false-positive result), but the key clinical dis- cantly increased, resulting in hypermetria.132 A supranuclear tinguishing findings were the presence of aberrant innervation ophthalmoplegia with severe saccadic slowing is highly and pupillary involvement, which are not features of myasthe- characteristic of SCA2,133 which may show selective involve- nia. Chemotherapeutic agents, such as, vincristine, may also ment of vertical saccades, impaired VOR, and gaze-evoked cause neurological findings (ptosis, ophthalmoplegia, jaw nystagmus.132,136 The constellation of impaired VOR, sacca- pain) that can confound the diagnostic picture in children with dic dysmetria, and slow-wave jerks are common to both intracranial tumors.15 SCA3 and Friedreich’s ataxia.565 The association of these ocular motor disorders with dystonia, spasticity, facial and lingual fasciculations, diplopia, and parkinsonism should Olivopontocerebellar Atrophy suggest the diagnosis of Machado–Joseph disease (SCA3).187,687 Many reports have described a striking “ocular The nomenclature regarding olivopontocerebellar atrophy and stare” or “prominent eyes,” which are thought to result from the related hereditary spinocerebellar ataxias has undergone lid retraction rather than proptosis.229,734 revision, first to the clinically based autosomal dominant cere- SCA1–4 (previously known as ADCA type 1) are associ- bellar ataxias and, more recently, to the genetically defined spi- ated with optic atrophy and ophthalmoplegia. SCA7 (previ- nocerebellar ataxias.611a Olivopontocerebellar atrophy (OPCA) ously known as ADCA II) is distinguished by the presence of is a pathological label implying not only olivopontocerebellar pigmentation macular dystrophy that includes early granu- changes, but also cases with more widespread lesions involving larity and mottling, and is later associated with pigmentation the CNS.65 OPCA may also be part of the pathological hall- changes that gradually spread to the periphery, with late optic mark of other disorders such as mitochondrial encephalomyo- atrophy and attenuation of retinal vessels.238,308,309,372,392,663,752 pathies, prion disorders, and hereditary metabolic diseases. In The ADCA type II locus, which corresponds to SCA7, has 1983, Harding347 developed a clinicogenetic classification, been mapped to chromosome 3p12-p21. SCA7 (or ADCA which has been subsequently modified according to molecular type II) is caused by an unstable CAG repeat in the SCA genetic advances. Older diagnostic categories, such as olivo- gene. Larger expansions are associated with earlier onset, a pontocerebellar atrophy, are now known to carry mutations for more severe and rapid clinical course, and a higher frequency spinocerebellar ataxia (SCA1, SCA2, and SCA3).65 of decreased vision, ophthalmoplegia, extensor plantar The hereditary ataxias and loci now comprise around 80 responses, and scoliosis. The mutation is highly unstable, loci, with 28 belonging to spinocerebellar ataxia and desig- with an increase in repeats with paternal transmission corre- nated as SCA1–28 in order of discovery. Several SCA sub- lating with marked anticipation. This instability of transmis- types (SCA1, SCA2, SCA3, SCA6, SCA7) are caused by sion is more marked than with other SCA subtypes. A CAG trinucleotide expansions in their respective genes. supranuclear ophthalmoplegia is commonly seen in more Autosomal dominant cerebellar atrophy 1 (ADCA1), which than half of SCA patients. The responsible gene for SCA7 presents with a range of findings, including ataxia, pyrimadal has been cloned. Molecular testing of DNA from whole and extrapyramidal signs and ophthalmoplegia, corresponds blood is now available to detect the SCA7 CAG repeat to to the current classifications SCA1–4. ADCA2, which is confirm the diagnosis genetically. similar but includes retinal degeneration, corresponds to The fundamental neurologic lesions of the spinocere- SCA7. ADCA3, which involves relatively pure cerebellar bellar ataxias are localized to the cerebellum, and the signs, corresponds to SCA6 and 7.136 Clinically, patients pontine, inferior olivery, arcuate, and pontobulbare nuclei.445 diagnosed with OPCA correspond to those with SCA1, Cerebellar atrophy fundamentally involves Purkinje cells SCA2, and SCA3. SCA1 maps to 6p23, SCA2 to 12q24, and and predominates in the neocerebellum. CT scanning and SCA3 to 14q24.3-q31. Macular and retinal degeneration are MR imaging show the characteristic brainstem and cere- seen predominantly in SCA7, but occasionally in SCA2.660 bellar atrophy, with the most sensitive diagnostic feature Patients with SCA7 have abnormal electroretinograms show- being the diameter of the middle cerebellar peduncle.596 ing predominantly cone dysfuntion.547a MR imaging shows Intermediate and T2-weighted MR images may show cruci- severe OPCA in SCA2, similar but milder changes in SCA1, form hyperintensity (“hot cross bun” sign) of the ventral and very mild atrophy with sparing of the olives in SCA3.132 part of the pons, accounted for by demyelination and glio- An SCA panel can be ordered when the one of the spinocer- sis of transverse fibers of the pons secondary to atrophy of ebellar ataxias are suspected. nuclei pontis.65 336 7 Complex Ocular Motor Disorders in Children

It is important to remember that several metabolic disorders A history of honey ingestion or soil eating is frequently that present in infancy or childhood (abetalipoproteinemia, obtained. Because Clostridium botulinum is ubiquitous and hexosaminidase A deficiency, cholestanolosis, the leukody- is commonly ingested without adverse effects, a number of strophies, [metachromatic, Krabbe’s disease, and adrenoleu- host factors may render a particular individual predisposed. komyeloneuropathy], and Refsum disease) can be associated Constipation, immune dysfunction, gastric pH, and unusual with a progressive and unremitting ataxia that can first appear gut flora, among others, may permit the colonization and in early adulthood.598 Of the vitamin deficiencies, vitamin E germination of Clostridium spores and subsequent local deficiency is most often associated with the development of production of toxin. progressive ataxia, associated with areflexia, and loss of pro- Infant botulism has been described in infants ranging prioception and vibration sensation (abetaliproteinemia or from 10 days to 8.5 months old, but 98% of those affected Bassen–Kornzweig disease).348 Affected patients develop are between 2 weeks and 6 months old.35 The earliest clinical pigmentary retinopathy and progressive gaze restriction. sign of disease is usually constipation, which can be present Some patients have vitamin E deficiency without fat malab- for several days before other signs appear.34,745 Bulbar signs sorption, inherited in an autosomal recessive manner, with later predominate and include impaired sucking with poor symptoms similar to Freidreich’s ataxia. feeding, a feeble cry, tachycardia due to loss of vagal tone.34 Isolated internal ophthalmoplegia may evolve into diffuse ophthalmoplegia with ptosis. Crouch et al reported an infant who had bilateral sixth nerve palsies following resolution of Botulism infant botulinum.192 Other signs of cranial nerve palsy include drooling, diminished gag reflex, and facial weakness. Signs of total (internal and external) ophthalmoplegia, dry Generalized muscular weakness progresses in a descending mouth, descending paralysis, obstipation, absence of fever, fashion from the cranial nerves to the limbs. Generalized and lucid sensorium, as cardinal symptoms should raise sus- weakness, hypotonia, hyporeflexia, and cranial nerve weak- picion of botulism. Clostridium botulinum produces seven ness constitute the “floppy infant” syndrome. Respiratory distinct protein toxins, of which A, B, and E are the most arrest and death may follow, but most infants recover com- commonly responsible for human botulism.815 The botulism pletely in 1–5 months. toxin causes neural paralysis of skeletal muscle by disruption While mild cases are often managed on an outpatient of both spontaneous and stimulus-induced release of acetyl- basis, the age distribution of infant botulism closely mirrors choline from the presynaptic nerve terminal and by interfer- that of the Sudden Infant Death syndrome (SIDS), and botu- ing with exocytosis of vesicle contents. The toxin enters the lism toxin has been recovered from 5% of autopsy specimens body via the following four routes: (1) ingestion of pre- of infants with the diagnosis of SIDS.37 Cases of infant botu- formed toxin, as in the case of food poisoning; (2) toxin pro- lism may also be mistakenly diagnosed as crib death, failure duction by Clostridium spores or bacteria infecting a wound; to thrive, sepsis, dehydration, viral infection, idiopathic hypo- (3) colonization of the gastrointestinal tract by Clostridium tonia, poliomyelitis, meningitis, brainstem encephalitis, or botulinum, with subsequent production of toxin; it is by this other neuromuscular disorders such as myasthenia. To add to mechanism that infant botulism and the “infant form of botu- the diagnostic quandary, some patients with botulism may lism” that affects some adults occurs; and (4) the “hidden” give false-positive response to intravenous edrophonium form in which no identifiable route of entry of toxin or bac- chloride.190 One important differentiating feature of botulism teria into the body can be identified. is the dilated, poorly reactive pupils, which are not seen in Botulism spores are ubiquitous, and have been isolated ocular myasthenia. The differential diagnosis also includes from yard and houseplant soil and vacuum cleaner dus.38 In Reye’s syndrome, Guillain–Barré syndrome, hypothyroidism, adults, the disease usually results from ingestion of pre- tick paralysis, and toxins. formed botulinum toxin in contaminated foods such as The diagnosis is made when toxin or organisms are recov- poorly sterilized canned goods or raw fish. Infant botulism, ered from stool samples. However, the level of botulinum first described in 1976,619 is caused by ingestion of live toxin is too low to be detected in the sera of patients with Clostridium botulinum organisms or spores, which subse- infant botulism. Electromyographic (EMG) studies are quently release toxin in the intestine. Most pediatricians highly useful in the diagnosis of botulism, with a character- advise against feeding honey to infants younger than 1 year of istic EMG pattern that has been given the acronym BSAP, for age, as it has been documented as a source of spores causing “brief duration, small-amplitude, overly abundant, motor- infant botulism.38,745 unit action potentials.” Fibrillation potentials suggesting Infant botulism was first recognized in 1976 and has since functional denervation are observed in about half the cases. become the most frequently reported form of botulism.684,689,804 Repetitive fast rates of stimulation (20–50 Hz) result in Most reported cases have been from North America. marked incremental response, a finding not present in older Olivopontocerebellar Atrophy 337 children and adults with botulism, probably due to the large spasm, and a dorsal midbrain syndrome with upward gaze amount of toxin present. Other conditions showing an incre- paralysis, but intact Bell’s phenomenon, have also been mental EMG response, such as Eaton–Lambert (not seen in reported.16,66,529 The presence of these latter disorders and infants), hypermagnesemia, and aminoglycoside toxicity, similar findings pointing to brainstem involvement fuels the can be readily excluded on clinical and laboratory grounds. controversy about the nature of the disease as a peripheral Logistical problems in terms of application of EMG to the (infranuclear, due to involvement of sensory fibers in the investigation of infant botulism include the need to transport peripheral nerves and dorsal roots) or CNS (supranuclear) the cumbersome equipment to the intensive care unit and disorder or as a combination of both.529 electrical interference there with the EMG recording. Other cranial nerves may be affected, the most common Spontaneous recovery occurs through sprouting of new being the facial nerve. Dysphasia and dysarthria may result nerve endings with formation of new myoneural junctions. when the lower cranial nerves are involved. Monoparesis, Treatment of affected patients includes insertion of a naso- hemiparesis, or quadraparesis have been described. Patients gastric tube with suction, enemas, antitoxin administration may have sensory symptoms, including parasthesias, dyses- (benefit controversial), and mechanical ventilation, if indi- thesia, and headaches. Other symptoms and signs include cated. The recently introduced botulinum immune globulin disturbance of consciousness, seizures, myoclonus, tremors, (BIG) appears promising. In a recent clinical trial, it reduced fever, vomiting, irritability, positive Babinski sign, and respi- the severity of illness and reduced the mean length of hospi- ratory insufficiency. The CSF, if examined 2–3 weeks or later tal stay from 5.7 to 2.6 weeks without complications.39 after onset, usually shows mild elevation in protein, with about 10% of cases in the literature showing pleocytosis. Some authors consider the Fisher variant to be due to Fisher Syndrome: A Variant of Guillain–Barré pathologic changes exclusively within the peripheral nervous system. This concept is supported by reports of normal MR Syndrome imaging scans in affected patients.655 While pure cases of Fisher syndrome are apparently attributable to peripheral The Guillain–Barré syndrome (acute infectious polyneurop- neuropathy and are not uncommon, overlapping cases occur athy) consists of progressive, usually symmetric muscular that bridge the spectrum from the benign Fisher variant to weakness that appears several days after a nonspecific infec- the more virulent Guillain–Barré syndrome. For instance, tious prodrome. Mild sensory disturbances, such as pain and cases that include limb paralysis do not, strictly speaking, parasthesias, are commonly present. The paralysis usually fall within the original definition of the Fisher syndrome and affects the lower extremities and then ascends. Cranial nerve are transitional forms to the Guillain–Barré syndrome. On palsy may appear at any time during the clinical course. the basis of current evidence, some authors believe that Results of EMG studies are usually consistent with involve- Fisher syndrome represents an encephalomyeloneuritis.66 ment of the lower motor neurons or peripheral nerves. The triad of severe external ophthalmoplegia, ataxia, Fisher syndrome is a variant of Guillain–Barré syndrome and areflexia in an otherwise alert child is fairly unique. with the distinct triad of ataxia, areflexia, and ophthalmoplegia The characteristic history and physical findings are usually without concurrent peripheral neuropathy. Fisher syndrome sufficient to establish the presumptive diagnosis, but dif- constitutes about 5% of all reported cases of Guillain–Barré ferentiation from posterior fossa tumors may be difficult syndrome. There appears to be a gender predilection, with the without neuroimaging. Wernicke syndrome and phenytoin male/female ratio being 2:1. Of the 223 cases reported before intoxication can show a similar syndrome complex, but 1993, the average age was 43.6 years (range, 14 months to 80 these entities can be excluded by the clinical history. Both years), with 14.3% of these being children.66 Fisher syndrome and botulism may show a similar early Most patients with Fisher syndrome suffer a preceding presentation consisting of extraocular muscle weakness viral prodrome, usually respiratory, 1–3 weeks prior to onset and mydriasis. Other conditions included in the differen- of the syndrome.66 Most patients reach maximum neurologic tial diagnosis of Fisher syndrome are brainstem stroke, deficit within 1 week of onset. Diplopia and ataxia are the pituitary apoplexy, cerebral sinus thrombosis, tick fever, most common presenting symptoms. Associated ophthal- and diphtheria. moplegia is complete (including the parasympathetic fibers While some cases may follow a more virulent course, to the pupillary sphincter muscle) in about half of patients most cases of Fisher syndrome resolve spontaneously with Fisher syndrome,66 but pure external ophthalmoplegia within 1–3 months. Corticosteroids as well as plasmaphere- or internal ophthalmoplegia may occur. Isolated ocular motor sis have been used, but there is little evidence to support nerve palsy and combinations of horizontal and vertical gaze their efficacy in the limited form of the condition without palsies may be noted. Internuclear ophthalmoplegia, one- brainstem signs. Intravenous immunoglobulin may be and-a-half syndrome, gaze-evoked lid nystagmus, convergence helpful in severe cases.30 338 7 Complex Ocular Motor Disorders in Children

Serological, immunological, and pathological studies all of Bickerstaff brainstem encephalitis in which the patients had implicated a role for complement-mediated damage to areflexia. Both conditions have been described following neuronal and Schwann cell membranes in Guillain–Barré Mycoplasma pneumoniae infection.724 Treatment with intrave- syndromes.329 In vivo and in vitro models of Fisher syndrome nous immunoglobulin or use of plasmapharesis has been have shown that anti-GQ1b ganglioside antibodies target the reported to produce clinical improvement, although it is presynaptic motor nerve terminal axon and surrounding unproven that they affect the natural history of this disorder. peripsynaptic Schwann cells, thereby mediating destructive injury through deposition of membrane attack complex (MAC). The anti-GQ1b antibody has been detected in the sera from patients during the acute phases of Fisher syndrome, Tick Paralysis Bickerstaff brainstem encephalitis, and Guillain–Barré syndrome with ophthalmoparesis.828 These cases seem to Tick paralysis should be considered in the differential diag- demonstrate a close relationship between ophthalmoparesis nosis of Fisher syndrome in children in tick-infested areas and serum anti-GQ1b antibody.159 who develop ophthalmoplegia and ascending paralysis.149 It has been hypothesized that ganglioside epitopes on The diagnosis is confirmed by finding a tick embedded in the Campylobacter jejuni are the key to the development and skin and observing for signs of improvement after tick characterization of Guillain–Barré syndrome.446 The pres- removal. No other tests for confirming tick paralysis exist. ence of these bacterial epitopes in neuropathy patients Tick paralysis is thought to be caused by a toxin secreted in correspond to autoantibody reactivity. In one study, patients tick saliva that reduces motor neuron action potentials and infected with C. jejuni (Asn51) regularly expressed the GQ1b the action of acetylcholine.263,307 Symptoms usually begin epitope (83%), whereas those with cst-II (Thr51) had the 4–7 days after tick feeding. Ascending flaccid paralysis GM1 (92%) and GD1a epitopes. Patients infected with progresses over several hours or days; sensory loss does not C. jejuni (Asn51) more often were positive for anti-GQ1b usually occur, and pain is absent.714 When the tick is not IgG (56% vs. 8%), and had ophthalmoparesis (64% vs. 13%) removed, the mortality rate resulting from respiratory paral- and ataxia (42% vs. 11%). Patients who had C. jejuni (Thr51) ysis is approximately 10%.575,686 more frequently were positive for anti-GM1 (88% vs. 35%) and anti-GD1a IgG (52% vs. 24%) and had limb weakness. Thus, the genetic polymorphism of C. jejuni appears to determine autoantibody reactivity as well as the clinical Wernicke Encephalopathy presentation of Guillain–Barré syndrome, possibly through modification of the host-mimicking molecule. Although classically considered an adult disorder, in 2003, an epidemic of Wernicke encephalopathy developed in Israeli infants fed a thiamine-deficient soy-based formula.427 These infants showed no neurologic signs for the first 6 months on Bickerstaff Brainstem Encephalitis the thiamine-deficient diet.627 Apathy, vomiting, and diffuse ophthalmoplegia brought these infants to medical attention Bickerstaff’s brainstem encephalitis is a clinical syndrome of and helped to establish the diagnosis. Wernicke encephalop- ophthalmoplegia, cerebellar ataxia, and central nervous athy preferentially affects neurons in particular areas of the system signs.16,72 Diagnostic criteria include a progressive, nervous system such as the putamen, parts of the thalamus, relatively symmetric external ophthalmoplegia and ataxia with and the periaqueductal gray matter. Thiamine turnover is disturbance of consciousness or hyperreflexia.724 Positive anti- higher in these areas and these structures have high rates of GQ1b antibodies support the diagnosis.587,724 Conditions that oxidative metabolism in neonates, which could make them mimic the disorder, including brainstem tumors, must be more vulnerable.748 excluded. There is a clinical continuum between Bickerstaff brainstem encephalitis and Fisher syndrome.724 However, CNS signs, such as disturbance of consciousness and cogwheel rigidity, are more in keeping with brainstem encephalitis. Miscellaneous Causes of Ophthalmoplegia In general, Bickerstaff brainstem encephalitis is a disease of the CNS, while Fisher syndrome is primarily a disease of the Involvement of the respiratory and renal systems in the child peripheral nerves.587 However, some clinical and pathologic with diffuse ophthalmoplegia should suggest the diagnosis overlap is found. It is interesting to note, for example, that one of Wegener granulomatosis.488 A new autosomal recessive in three patients in the original description of Fisher syndrome ophthalmoplegic disorder affecting highly inbred Arab families had drowsiness, whereas Bickerstaff described four cases in Israel produces limited upgaze, slow saccades, and impaired Transient Ocular Motor Disturbances of Infancy 339

Fig. 7.12 Transient esotropia in neonate. Infant showed 30 prism diopters of left esotropia (a) with mild limitation of abduction of left eye that totally resolved by 5 months of age (b). Estropia was caused by perinatal trauma to abducens nerve convergence without ptosis or pupillary abnormalities. first several weeks of life should not be classified as congenital In addition, there is involvement of the face, orbicularis, and esotropia (which usually first appears after 6 weeks of age) neck muscles, giving the appearance of a long, thin face. until other conditions such as sixth nerve palsy and Möbius Onset is probably in childhood. Linkage studies identified syndrome are ruled out (Fig. 7.12). It should also be recog- markers on chromosome 17p13.1-p12, an interval to which nized that the eyes of premature infants may transiently several genes for sarcomeric heavy chain map.500 display exotropia with limited adduction. These findings have been speculated to result from immaturity of the medial longitudinal fasciculus in the premature infant. Large convergent movements of the eyes, producing Transient Ocular Motor Disturbances esotropia, are often observed in the first 2 months of life.374,375 of Infancy These convergent eye movements resolve spontaneously, giving way to normal ocular alignment. The fact that these Healthy neonates may exhibit a variety of benign, transient large-angle convergent eye movements are predictive of supranuclear eye movement disturbances. These include the normal binocular alignment374,375 belies the notion that horizontal heterophorias, tonic downgaze and upgaze, opso- infantile esotropia results from excessive convergence.112 clonus, skew deviations, and transient idiopathic nystagmus in infants. As each of these disorders may forebode serious neurological disease, especially in older children, their benign nature in healthy neonates must be recognized to Transient Idiopathic Nystagmus avoid unnecessary diagnostic testing. Good et al described six infants with transient idiopathic nys- tagmus. Four of these infants had other visual abnormalities, including regressed retinopathy of prematurity, coloboma, Transient Neonatal Strabismus and delayed visual maturation, which may have precipitated the nystagmus. They interpreted the transient nystagmus as Several nursery studies have shown that the eyes of other- indicative of a fragile period of postnatal maturation of the wise healthy, full-term neonates are commonly misaligned. ocular motor system.304 It is also recognized that some infants In one study of 1,219 neonates,583 48.6% had orthotropia, with delayed visual maturation may exhibit transient 32.7% had exotropia, 3.2% had esotropia, and 15.4% were nystagmus.71 not sufficiently alert to allow determination of ocular align- ment. No cases of congenital esotropia were found in any neonate, supporting the concept that congenital esotropia does not manifest at birth. Follow-up studies of these patients Tonic Downgaze have shown that the vast majority of children with transient heterophorias become orthotropic between 2 and 3 months Tonic downward deviation of the eyes may occur as a of age, a stage coincident with development of stereoscopic transient phenomenon in neonates and does not necessarily vision.31,712 Unlike exotropia, which may be found transiently indicate underlying neurologic dysfunction.275,761,813 Both in the neonatal period, the finding of large esotropia in the eyes are tonically deviated downward while the infant is 340 7 Complex Ocular Motor Disorders in Children awake, but can be maneuvered upward with oculocephalic or vestibulo-ocular stimulation; the condition resolves during sleep, with both eyes returning to the midline. It usually resolves within the first 6 months of life. Two infants who displayed this transient tonic downgaze also showed associ- ated upbeat nystagmus, with complete resolution of both findings within the first few months of life.295 The authors proposed that immaturity of the vestibular system was the cause. In some cases, these transient episodes of downgaze can be followed by abnormal body movements.813 The benign, transient form of tonic downgaze differs from the “setting sun sign” associated with hydrocephalus by the absence of eyelid retraction. Yokochi825 described downward deviations of the eyes of neurologically affected infants that were paroxysmal rather than constant, as in the foregoing benign variety. The paroxysms were not associated with sei- Fig. 7.14 Setting sun sign in hydrocephalus. Child presented with zure activity. He considered this to be a sign found in brain- pronounced lid retraction and mild to moderate tonic downward devia- tion of eyes. Disproportionately large head and dilated ventricles on damaged infants with cortical visual impairment. The neuroimaging confirmed diagnosis of hydrocephalus paroxysms spontaneously resolved with time in many patients. We examined a blind infant with profound bilateral combination of lid retraction (Collier’s sign) and tonic down- optic nerve hypoplasia, absent septum pellucidum, and gaze. Acquired hydrocephalus in older patients does not pro- developmental delay who showed sudden episodic down- duce tonic downgaze, suggesting a specific susceptibility of ward deviations of the eyes occurring every 1–2 min and the neonatal brain to the mass effect of hydrocephalus on mid- lasting 5–10 s (Fig. 7.13). The downward deviation was brain structures responsible for downgaze or suggesting a associated with lid lag. The patient also showed intermittent higher sensitivity of the pretectal area in infants to hydroceph- side-to-side head shaking. Episodic downgaze may be one of alus, leading to more severe upgaze palsy (causing the eyes to the presenting signs of Leigh subacute necrotizing encepha- deviate downward) than is seen in older patients. Tamura and lomyelopathy.511 Mak et al511 reported a previously healthy Hoyt735 reported 11 premature infants with intraventricular infant who, at 6 months of age, showed episodic downgaze hemorrhages who showed acute tonic downward deviation of with limited horizontal movements that resolved after 5 days, the eyes, esotropia, and upgaze palsy. All patients showed then recurred several times along with other abnormalities associated hydrocephalus, shunting of which resulted in grad- before a diagnosis of Leigh disease was made. ual improvement in upgaze, with persistence of the large-angle It is not clear whether congenital hydrocephalus alone esotropia. The authors suggested that the gradual recovery of results in tonic downgaze. The setting sun sign, a feature of upgaze indicates that the upgaze palsy may not be simply due congenital hydrocephalus (Fig. 7.14), may be considered a to the acute effects of the hydrocephalus. Rather, they sug- gested that the associated intraventricular hemorrhages act as a mass lesion, compressing (and hence paralyzing) the upgaze centers or irritating (and hence stimulating) the downgaze cen- ters within the mesencephalon. They speculated that injury to these mesencephalic structures may contribute to the delay in recovery of upgaze after shunting. We most commonly see tonic downgaze in conjunction with esotropia in infants with periventricular leukomalacia, where it can occur in the absence of intraventricular hemorrhage.118 As with intraventricular hemorrhage, the tonic downgaze spontaneously resolves, and infants are usually left with an A-pattern esotropia with supe- rior oblique muscle overaction. The telltale ocular intorsion can easily be missed if the retinas are examined in the esotro- Fig. 7.13 Episodic tonic downgaze. Blind infant with profound bilateral pic position, which places the eyes in the vertical rather than optic nerve hypoplasia, absent septum pellucidum, and developmental the torsional field of action of the overacting superior oblique delay showed sudden episodic downward deviations of eyes occurring muscles. We have proposed that a posterior canal predomi- every 1–2 min and lasting 5–10 s. These have occurred since birth. Downward deviation was associated with lid lag. Infant also showed nance caused by injury to bilateral central brainstem pathways intermittent side-to-side head shaking mediating upward pitch could explain this constellation of Transient Ocular Motor Disturbances of Infancy 341

finding.115 Neuroimaging often shows associated thalamic tonic conjugate upward deviation of the eyes that was injury which may explain this combination of findings.118 relieved by sleep. The children had impaired downgaze In congenital hydrocephalus that is not caused by intra- below the primary position, with downbeating nystagmus ventricular hemorrhage, however, the upgaze palsy and/or on attempted downgaze and apparently normal horizontal the setting sun sign responds quickly to reduction of intrac- movements. The patients were otherwise neurologically ranial pressure. For instance, Hoyt and Daroff379 described a intact, with the exception of mild ataxia. Results of meta- 3-month-old infant with intermittent hydrocephalus second- bolic, electroencephalographic (EEG), and neuroradiologic ary to a tumor of the thalamus and septum pellucidum. The investigations were unremarkable. All eventually improved, infant displayed tonic downgaze and esotropia whenever the with one child showing a favorable therapeutic response to ventricular pressure increased; eye movements normalized levodopa. when the ventricular pressure became normal. Such cases The following year, Ahn et al11 described three infants demonstrate that a mass effect, independent of the effect of who had tonic upgaze with no associated seizure activity or the hydrocephalus itself, need not be present for tonic down- neurologic disease. The vestibulo-ocular reflexes were gaze to develop in infants with hydrocephalus. intact, revealing a full range of vertical movements. These Children with hydrocephalus are predisposed to esotropia episodes were initially noted in the first month or two of life through several different mechanisms: (1) early-onset child- and were most conspicuous when the infant was ill or hood esotropia, which is more common in neurologically fatigued. These episodes diminished with time.11 Mets532 impaired children; (2) unilateral or bilateral sixth nerve described a 9-month-old otherwise healthy infant with large- palsy; and (3) intraventricular hemorrhage in premature angle esotropia who displayed extreme sustained spasms of infants, which may involve the thalamus and mesencephalon upgaze. This infant was noted to have full vertical range of and produce neuro-ophthalmologic signs of a thalamic ocular motion at times and could fixate in primary gaze. No infarction (tonic downward deviation of the eyes, upgaze EEG abnormality was found. These episodes resolved at palsy, and esotropia). The esotropia in these patients usually age 3% months, but the esotropia with associated amblyopia persists even after the vertical gaze deficits resolve. Visually required patching therapy and strabismus surgery. Tonic significant upgaze limitation can be relieved with bilateral upgaze is not an epileptic phenomenon, and paroxysmal inferior rectus recessions in Parinaud’s syndrome.128 tonic upgaze may be exacerbated by treating coincident epi- Tonic downgaze may be observed in very ill patients with lepsy with valproate.502 impaired consciousness who have medial thalamic hemor- Phenomenologically, benign paroxysmal upgaze and con- rhage, severe encephalopathy, acute obstructive hydroceph- genital downbeat nystagmus are closely related conditions. alus, or severe subarachnoid hemorrhage. In this setting, it Congenital downbeat nystagmus is distinguishable only by the should be distinguished from V-pattern pseudobobbing, presence of corrective downward refixational saccades.115a wherein the eyes show an abrupt downward jerk followed It is likely that benign hereditary downbeat nystagmus and by a slow, upward drift to primary position. Keane420 reported the syndrome of benign tonic upward deviation of the eyes this finding in five patients with acute obstructive hydro- with ataxia are variants of the same disorder. In several cephalus who had arrhythmic, repetitive, downward and affected children, tonic upgaze has evolved into downbeating inward ocular deviations at a rate of 1 per 3 s to 2 per sec- nystagmus.605,605a We have proposed that, tonic upgaze an ond. The fast downward movements render the condition anterior canal predominance.115,116 similar to ocular bobbing, but it differs by the presence of a Tonic upgaze is difficult to distinguish from the “over- V pattern, a generally faster rate, and associated pretectal, looking” that was reported by Taylor741 in patients with neu- rather than pontine, signs. Keane speculated that V-pattern ronal ceroid lipofuscinosis. Instead of looking at the object pseudobobbing represents a variant of convergence-retrac- of regard directly, affected children look above the object. tion nystagmus that signals the need for prompt shunt place- Initially attributed to relative preservation of the inferior ment or revision. visual field associated with certain retinal disorders, it was later reported not to be disease-specific, but rather to repre- sent a sign of bilateral central scotomas (and vision of 20/200 or worse) in children from a variety of causes.303 Recently, Tonic Upgaze Cruysberg reported that some patients with overlooking dis- play a tonic upgaze and a dystonic neck extension, the two Tonic upgaze is less common than tonic downgaze. It also conditions are not always distinct.194 When not associated tends to be more episodic. In 1988, Ouvrier and Billson605 with overlooking, tonic upgaze is more often associated with described four patients with a new condition they termed neck flexion than neck extension.502 “benign paroxysmal tonic upgaze of childhood.” This con- Intermittent episodes of upward ocular deviation may be dition was characterized by onset during infancy of episodic a manifestation of oculogyric crisis or of a seizure disorder, 342 7 Complex Ocular Motor Disorders in Children typically petit mal. Oculogyric crisis denotes an extreme, epi- neuroblastoma, opsoclonus has been reported as a benign sodic upward rotation of the eyes, often obliquely to the right transient finding in healthy neonates. It usually resolves in or to the left. The deviation is usually sustained and is often 1–3 months, passing through a phase of ocular flutter. Given associated with rhythmical jerking or twitching of the eyelid. the apparent rarity of this observation, it is probably prudent to Each oculogyric movement lasts several seconds, after which consider this benign transient variant a diagnosis of exclusion, the eyes return to the horizontal position before deviating especially in light of the serious nature of other potentially again a few seconds later until the “crisis” passes, typically in causative lesions such as neuroblastoma. When opsoclonus 1 or 2 h. Patients may have associated thought disorders. accompanies neuroblastoma, it imparts a poor long-term Dopamine-blocking agents (neuroleptics) are the most com- neurological prognosis,551 but a highly favorable prognosis mon cause of drug-induced acute dystonic reactions such as for survival.572 oculogyric crisis, but other drugs have been incriminated, including carbamazepine, lithium carbonate, metoclopr- amide, and sulpiride, among others. Oculogyric crisis has also been reported after Tensilon administration.586 Similar Transient Vertical Strabismus in Infancy eye movements have been observed in patients with various CNS disorders, such as herpetic encephalitis, pantothenate A transient vertical deviation of the eyes with or without a kinase-associated neurodegeneration, and Rett syndrome,270 horizontal component has been reported in the neonatal and in one patient with cystic glioma in whom the onset of period without associated evidence of posterior fossa dys- crisis was positional.722 Oculogyric crisis can be aborted with function and is referred to as skew deviation.381 Some infants use of anticholinergics (e.g., Cogentin) and subsequently exhibiting this sign may subsequently develop large-angle controlled by reducing the dosage of the offending medica- esotropia typical for congenital esotropia or nystagmus com- tion or changing it altogether. Patients with petit mal seizures pensation syndrome.381 Whether this transient vertical devia- may show eye movements similar to oculogyric crisis, usu- tion of the eyes is an early manifestation of dissociated ally with concurrent eyelid flutter.28 Eye movement tics (see vertical divergence and whether it is a reliable premonitory later in this chapter) may also superficially resemble intermit- sign for the subsequent development of congenital esotropia tent episodic tonic upgaze. Barontini56 concluded that either is not known. dystonia or downgaze palsy can underlie the phenomenon of tonic upgaze. Acquired tonic upward deviation is also seen in comatose patients, wherein it indicates a very poor prognosis, or in patients with brainstem disease causing downgaze Congenital Cranial Dysinnervation paralysis. Syndromes Cherubism, a rare inherited disorder that involves the facial bones and produces facial fullness because of boney The congenital cranial dysinnervation syndromes comprise a enlargement occurring between 2 and 4 years of age should group of disorders characterized by deficient innervation to also be considered in the differential diagnosis of tonic the extraocular muscles and facial musculature.321,621,750 These upgaze.273 This disorder was so named by Jones in 1933 congenital neuromuscular disorders result from develop- because the marked fullness of the jaws and cheeks and the mental errors in innervation of the ocular and facial muscles.821 upward displacement of the eyes in patients were thought to They result from mutations in a number of genes, including resemble the heavenward gaze and round faces of Renaissance ROBO3,400 PHOX2A,573 SALL4,14 HOXA1,747 and KIF21A,821 cherubs.404 Although this lesion was originally considered to that are essential to the normal development of brainstem be a form of fibrous dysplasia, cherubism was eventually motor neurons or axons.87 accepted as a clinicopathologic entity, with features identical Recognized disorders congenital ptosis, congenital fibro- to giant cell reparative granuloma.161 This condition can be sis of the extraocular muscles, Duane’s syndrome and its complicated by proptosis and optic neuropathy.358 variants, Möbius sequence, horizontal gaze palsy with pro- gressive scoliosis, and congenital facial palsy.321 They pres- ent with varying degrees of ptosis and ophthalmoplegia from birth, together with signs of aberrant innervation. Many of Neonatal Opsoclonus these disorders were previously considered to be myopathic in origin. However, the congenital cranial dysinnervation Opsoclonus denotes bursts of chaotic repetitive back-to-back disorders also include sensory disorders due to trigeminal saccades in different directions (see Chap. 8). Although nerve maldevelopment that cause congenital corneal usually indicative of an underlying viral encephalitis or anesthesia. Congenital Cranial Dysinnervation Syndromes 343

Congenital Ptosis different branches of the same nerve. A pathologic synkinesis occurs when muscles are reinnervated by nerves other than their own following a nerve injury. Pathologic synkinesis may Our long-standing understanding of congenital ptosis as a be congenital (Duane’s syndrome, synergistic divergence, primary myopathy has been overturned, as clinical signs of Marcus Gunn jaw winking) or acquired (facial synkinesis or congenital cranial dysinnervation have been demonstrated.106 oculomotor synkinesis after trauma). The notion of congenital ptosis as a primary myopathy was The Marcus Gunn jaw winking (MGJW) synkinesis usu- first challenged in 1996 when Steel and Harrad found an ally presents as variable unilateral ptosis noted at birth or unrecognized form of oculomotor synkinesis in 44% of shortly thereafter. Unlike ordinary congenital ptosis, when patients with unilateral congenital ptosis.723 Affected patients the infant nurses, the ptotic lid jerks upward with each suck- displayed excessive elevation of the ipsilateral eye beneath ling movement. In a series of nearly 1,500 cases of congeni- the ptotic eyelid in upgaze, but no vertical deviation in pri- tal ptosis,70 the Marcus Gunn phenomenon accounted for 80 mary gaze. This upshoot disappeared when the ptotic eyelid patients (5%). Of these 80 patients, 42 showed right eye was manually elevated. The authors insightfully attributed involvement, 35 showed left eye involvement, and three had this phenomenon to a misdirection of levator innervation to bilateral synkinesis. No gender preponderance was identi- the ipsilateral superior rectus muscle. They proposed that fied, and only two cases were familial. Fifty-four percent of manual elevation of the ptotic eyelid reduced innervation to patients showed amblyopia, and 26% showed anisometropia. the levator muscles, thereby extinguishing the aberrant supe- Some form of strabismus was found in 56%, including 19 rior rectus innervation. cases of superior rectus palsy, 19 cases of double elevator In 2000, Harrad and Shuttleworth352 described another palsy, and two cases of Duane’s retraction syndrome. The group of patients with long-standing unilateral ptosis that natural history of the disorder remains unsettled, with some resolved in upgaze and increased in downgaze, suggesting authors noting that the synkinetic movement becomes less that superior rectus innervation had become misdirected to a conspicuous with age, although patients may learn to camou- paretic levator muscle. These clinical observations suggest flage the lid excursions. that prenatal and postnatal routing of the superior division of The pathogenesis of the MGJW synkinesis is controver- the oculomotor nerve is a delicate process that may be sub- sial. The prevalent concept is that the disorder results from ject to directional modification, perhaps on the basis of the aberrant innervation of the levator palpebrae muscle by a relative innervational recruitment by its two target muscles.106 branch of the motor division of the trigeminal nerve that sup- For reasons that are unclear, an inverse Bell’s phenomenon plies the muscles of mastication, hence the designation (unilateral or bilateral) is occasionally observed postopera- trigemino-oculomotor synkinesis. However, Sano672 has pre- tively following levator resection. This phenomenon reverts sented EMG evidence that the jaw winking phenomenon is a to normal within 2 weeks.68 release phenomenon representing an exaggeration of a nor- Congenital ptosis may be associated with other forms of mally found but clinically undetectable physiologic cocon- ocular motor synkinesis. Khan et al429 described a large fam- traction. Utilizing EMG studies of normal subjects, he ily in which two siblings exhibited ptosis with abnormal syn- demonstrated cofiring of the oculomotor-innervated extraoc- kinetic elevation on ipsilateral abduction. One was bilaterally ular muscles and the muscles of mastication innervated by affected, while the other had unilateral findings. A third the motor branch of the trigeminal nerve. He argues that con- demonstrated classic bilateral congenital ptosis, while a genital brainstem lesions may “release” phylogenetically fourth demonstrated Duane’s syndrome. Its association with older neural mechanisms, such as synkinetic movements congenital fibrosis syndrome is detailed below. Indeed, con- from higher central control, which are similar to other synki- genital ptosis can now be viewed as a limited form of con- netic movements such as the palmomental and primitive genital fibrosis syndrome selectively affecting the superior grasp-feeding reflexes. division of the third nerve. Several genes for isolated con- Muller’s muscle is doubly innervated by an efferent sym- genital ptosis have now been identified.248,527 pathetic nerve and an afferent proprioceptive nerve.828a Muller’s muscle acts as a serial muscle spindle (similar to that seen in jaw closing periodontal receptors).828a Stretching Marcus Gunn Jaw Winking of Muller’s muscle has been found to produce involuntary levator muscle contraction (the Hoffman reflex). These pro- (Trigemino-Oculomotor Synkinesis) prioceptive fibers function as mechanoreceptors to induce reflex contracture of the levator muscle against gravity as a A normal synkinesis denotes simultaneous contraction of type of length servomechanism. The central modulation of muscles normally innervated by different peripheral nerves or these levator and jaw closing pathways by motor trigeminal 344 7 Complex Ocular Motor Disorders in Children nucleus may give rise to the innervational crossover that including the levator, are affected (generalized fibrosis syn- manifests in the form of Marcus Gunn jaw winking.53a drome). Historically, investigators have divided congenital Sano672 has classified the trigemino-ocular motor synki- ocular fibrosis into different subtypes that include congenital nesis into two major groups: (1) external pterygoid-levator fibrosis of the inferior rectus with ptosis, strabismus fixus, synkinesis (the most common type) with lid elevation upon congenital unilateral enophthalmos with ocular muscle fibrosis thrusting the jaw to the opposite side (ipsilateral external and ptosis,362 and the vertical retraction syndrome. pterygoid firing), upon projecting the jaw forward (both Fixed downgaze and associated ptosis with sparing of external pterygoids firing), or upon opening the mouth pupillary function and similar findings in other family mem- widely; and (2) internal pterygoid-levator synkinesis (rela- bers provide critical clues to the diagnosis. Patients with tively rare) with lid elevation upon teeth clinching. CFEOM may show rapid convergent movements of the eyes In the typical case of MGJW, firing of the motor branch of on attempted upgaze, simulating convergence retraction the trigeminal nerve is associated with firing of the oculomotor nystagmus.104 The diagnosis of CFEOM should therefore be branch to the levator. A rare variant of this phenomenon, termed suspected when “convergence-retraction” nystagmus is the inverse Marcus Gunn phenomenon,504 shows firing of the accompanied by ptosis rather than lid retraction. Although motor branch of the trigeminal nerve synkinetically, with inhibi- this phenomenon could theoretically result from the mechan- tion of the oculomotor branch to the levator. Here, the affected ical tethering effect of tight inferior rectus muscles in eyelid falls as the mouth opens or as the jaw moves to the oppo- attempted upgaze, the fact that these convergent movements site side, without associated activity of the orbicularis oculi. persist following recession of the inferior rectus muscles Pathologic synkineses may cluster together. For instance, suggests that they arise from a supranuclear deficiency of the MGJW synkinesis (congenital trigemino-oculomotor elevation, as suggested by several investigators.1,78,168,262 synkinesis) has been reported in association with Duane’s CFEOM has traditionally been regarded as a primary myo- syndrome (congenital oculomotor-abducens synkinesis) and pathy localized to the extraocular muscles on the basis of with synergistic divergence.120,337 This association generally biopsy studies of affected muscles. Both light and electron occurs in the setting of congenital fibrosis syndrome.104,120,337 microscopy studies show replacement of extraocular muscles Other forms of ocular motor synkinesis have also been by dense fibrous connective tissue and collagen.350 Histology reported in patients with Marcus Gunn jaw winking. “Eye of an affected levator showed reduction or absence of stria- bobbing” was attributed to coactivation of the superior rectus tions and Z bands and vacuolation of muscle cells. Muller muscle in one patient with Marcus Gunn jaw winking.603 muscle fibers appeared intact. Anomalous insertions of Trigemino-abducens synkinesis444,466 and pseudo-inferior affected muscles may occur, presumably resulting from a mat- oblique muscle overaction have also been described.387 urational defect at or before the seventh week of gestation.29 A frontalis suspension operation is usually recommended Involved eyes may also have anomalous adhesions between for cases severe enough to come to surgery. Some contro- the muscles, Tenon’s capsule and globe, and inelasticity or fra- versy exists regarding whether to disinsert the ipsilateral gility of the conjunctiva so that conjunctival recession may levator and whether to also disinsert the contralateral levator also be necessary.266,487 Like in Duane syndrome, the involved and perform a frontalis suspension on the opposite side to extraocular muscles in congenital fibrosis syndrome are simul- achieve a greater degree of symmetry. taneously tight and hypoplastic. Affected muscles often appear small and atrophic on orbital imaging studies.805 On the basis of the presence of multiple synkinetic eye Congenital Fibrosis Syndrome movements in a patient with CFEOM, Brodsky et al, in 1989, proposed that is caused by failure of normal neuronal connec- Congenital fibrosis of the extraocular muscles (CFEOM) is tions with the extraocular muscles to become established early characterized by the presence of congenital restrictive oph- in embryogenesis.120 Assaf independently concluded that con- thalmoplegia, fixed downgaze, horizontal strabismus, ptosis, genital fibrosis syndrome must arise from a CNS abnormal- and a compensatory backward tilting of the head.751 In this ity.44,45 Our subsequent report of additional patients with disorder, the extraocular muscles and the levator muscles are CFEOM, who displayed both synergistic divergence and replaced by fibrous tissue to a variable extent.350 The disorder MGJW,120,337 provided clear evidence that congenital fibrosis may be unilateral or bilateral and may be clinically limited to of the extraocular muscles can result from the absence of nor- specific muscles in a given individual. The resultant ocular mal innervation to orbital striated muscles early in develop- motility deficits depend on which of the extraocular muscles ment (Fig. 7.15). Unlike the synergistic divergence of Duane are involved. The inferior rectus muscle is most commonly syndrome, the paradoxically abducting eye simultaneously involved, followed by the levator muscle and the lateral rectus abducted and depressed, suggesting that the synergistic diver- muscle. In the presence of ptosis, inferior and lateral rectus mus- gence was attributable to aberrant innervation of the superior cle involvement may mimic unilateral or bilateral congenital oblique muscle. A primary failure to establish normal neuronal oculomotor palsy. Rarely, all of the extraocular muscles, connections with the extraocular muscles and levator muscle Congenital Cranial Dysinnervation Syndromes 345

Fig. 7.15 Congenital fibrosis syndrome with synergistic divergence (b) Retraction of the right upper eyelid with mouth opening. (c) Position (simultaneous abduction during attempted lateral gaze) and Marcus of the eyes with eyelids manually elevated. (d) In attempted left gaze, the Gunn jaw winking. (a) Bilateral ptosis, exotropia, and fixed downgaze. right eye abducts and depresses. From Brodsky104 with permission would predispose to neuronal misdirection, which allows for appropriate neuromuscular connections with their target limited preservation of innervated muscle fibers and replace- extraocular muscles, a finding supported by subsequent ment of the remaining muscle by fibrous tissue.120,702 Clinically, genetic studies.8–10,104,120,247,823 Because most patients with only deficient innervation could explain the superimposition of CFEOM do not display signs of neuronal misdirection, and synkinetic eye movements on a diffuse congenital ophthal- because anomalous fibrous bands and adhesions are some- moplegia,291 Other forms of aberrant innervation have since times discovered to be attached to the globe during strabis- been documented in CFEOM.428 mus surgery,266,487 we now suspect that the genetically A neuropathologic study by Engle et al249 demonstrated determined dysgenesis of CFEOM can directly influence the that congenital fibrosis of the extraocular muscles 1 is asso- extraocular muscles, in addition to developing cranial nerves. ciated with abnormal development of the oculomotor axis, It is therefore likely that the underlying pathophysiology of primarily affecting the superior division of the oculomotor congenital fibrosis syndrome must lie along a spectrum from nerve, corresponding to alpha motoneurons in the midbrain, a primary absence of normal innervation to localized orbital the target extraocular muscles, and the levator and superior dysgenesis of the extraocular muscles. rectus muscles. This study established that CFEOM can Neuroanatomic abnormalities are often missed on routine result from the failure of developing cranial nerves to form intracranial MR imaging, which frequently shows no overt 346 7 Complex Ocular Motor Disorders in Children

CFEOM2 is autosomal recessive, and its gene is localized on chromosome 11q13.1.793 Affected individuals have bilat- eral ptosis and restrictive ophthalmoplegia, with eyes partially or completely fixed in an exotropic position.750 Patients have severely limited ability to depress or adduct either globe. ARIX, previously called PHOX2A, is the gene that is mutated in CFEOM2550,793,822 ARIX is a transcription factor essential for the development of oculomotor and trochlear nuclei in mice and zebra fish.318 It is therefore believed that CFEOM2 results from hypoplasia of the oculomotor and trochlear nerve nuclei as a result of mutations in both copies of ARIX. CFEOM3 is an autosomal dominant disorder with variable expression and probably incomplete penetrance.750 The gene maps to markers on 16p24.2-q24.3.215 Severely affected patients have ptosis, with eyes fixed in a downward and exotropic posi- Fig. 7.16 CFEOM. Axial MR imaging showing bilateral hypoplasia tion and bilateral severe restriction of eye movements (a pheno- of the ocular motor nerves. Courtesy of Joseph Demer, M.D. type resembling that of congenital fibrosis of the extraocular muscles 1). Mildly affected patients have normally positioned structural malformations of the brain.104 However, high- globes, with limitation of vertical gaze. Moderately affected resolution images of the ocular motor nerve commonly show patients may have asymmetric involvement, with one eye hypoplasia or absence of the oculomotor nerves and involved severely affected and the other mildly affected. Mackey and col- extraocular muscles (Fig. 7.16).205,432,494 leagues508 reported a family that maps to the CFEOM3, with To date, three genetic CFEOM loci have been identified involvement primarily of the vertically acting extraocular mus- and three clinical phenotypes have been delineated.252,508,753 is cles. Because the involved extraocular muscles are both tight the most common form. The key clinical findings include and hypoplastic, the surgical management of congenital fibrosis bilateral nonprogressive ophthalmoplegia, bilateral ptosis, and syndrome presents a unique set of challenges.103 Free tenoto- an infraducted (downward) primary position of each eye with mies obviate the need for suture placement into the rectus mus- limited supraduction.252 CFEOM1 pedigrees demonstrate cles, which can be technically difficult due to severe restriction.103 autosomal dominant inheritance with full penetrance and min- Free tenotomies of tight rectus muscles are technically simple imal variation in expression.820 CFEOM1 has been mapped to and rarely produce surgical overcorrection.103 The need for the centromeric region of chromosome 12.250–252,769 It has now resections can be determined by examining the position of the been demonstrated that congenital fibrosis of the extraocular eyes under nondepolarizing paralyzing anesthesias.823 It is also muscles type 1 results from heterozygous mutations in the well to remember that surgical weakening of tight inferior rec- KIF21A gene encoding a kinesin motor protein.820 Although tus muscles can reduce their secondary adducting action and the specific function of the KIF21A protein and its stalk are produce exotropia.103 In our experience, raising the globe does yet to be determined, the mouse ortholog, KIF21a, was found not produce improvement in associated ptosis, so surgical cor- to be an anterograde microtubule-based motor protein rection of ptosis often needs to be performed in conjunction expressed predominantly in neuronal tissues. Engle et al have with inferior rectus tenotomy. Surgical correction of ptosis found that human KIF21A is expressed most abundantly in should be modest to avoid exposure keratopathy. Despite mul- developing neuronal tissues, suggesting that it plays an impor- tiple surgeries, some degree of ocular misalignment usually tant role in neuronal development consistent with the congeni- persists.103 tal fibrosis of the extraocular muscles 1 phenotype.150,430,820 As kinesins affect axonal transport after development (microtu- bule function), it remains unclear how a kinesin mutation could lead to neural agenesis. Because KIF21A has also been Congenital Horizontal Gaze observed in other tissues, including skeletal muscle, it remains Palsy with Scoliosis to be determined whether the primary pathology of congenital fibrosis of the extraocular muscles, resulting from KIF21A In 1974, Dretakis and Kondoyannis described the autosomal mutations, is in the nervous system (neurogenic), the extraoc- dominant syndrome of horizontal gaze palsy and progressive ular muscles (myopathic), or both. For example, the frequent scoliosis.223 In 2004, Jen et al400 described 11 patients with finding of fibrous bands in the orbits of patients with congeni- autosomal recessive congenital horizontal gaze palsy caused tal fibrosis of the extraocular muscles is clearly incompatible by a mutation of the ROBO3 gene on chromosome 11. with a purely neurogenic mechanism. Affected children are born with absent horizontal eye move- Congenital Cranial Dysinnervation Syndromes 347

Fig. 7.17 Congenital horizontal gaze palsy with scoliosis. T2-weighted fast spin echo axial MR imaging shows butterfly configuration of the medulla with flattening of the ventral surface, reduced anterior–posterior diameter and midline medullary cleft. Courtesy of Joseph Demer, M.D. ments and had variable strabismus, horizontal nystagmus, and defective vertical smooth pursuit. Convergence can be preserved, and some people use convergence substitution as a substitute for horizontal gaze.241 All patients developed progressive scoliosis during early childhood. The disorder is found in both consanguineous and nonconsaguinous fami- Fig. 7.18 Möbius syndrome. Note characteristic flattening of lower lies.241 Heterozygotes were unaffected. This disorder pro- facial features. Courtesy of Joseph Demer, M.D. duces a pathognomonic brainstem malformation. MR imaging shows a hypoplastic pons and medulla,622 with over- erally.566 Affected children have mask-like facies, with the all diminished anterior–posterior dimension (Fig. 7.17). The mouth constantly held open (Fig. 7.18). The upper facial nerves ventral surface of the pons is flat. The medulla fans out both are affected more than the lower facial nerves, and facial asym- dorsally and ventrally in a butterfly configuration. There is a metry is common due to asymmetric facial strength. The eyes prominent midline cleft in the medulla that extends down to may be straight, esotropic or, rarely, exotropic.191,200,518a,555 Those the cervicomedullary junction. Affected patients had electro- with straight eyes tend to have horizontal gaze palsy,200 and physiologic evidence of ipsilateral corticospinal and dorsal some use convergence substitution to look to the side. column-medial lemniscus tract innervation. In contradistinc- Such children may be thought to have isolated bilateral tion to most other congenital cranial dysinnervation disorders, sixth nerve paresis if the slow convergence movement and the abducens nerves are normal in size and configuration.241 the associated pupillary constriction are not recognized. ROBO3 mutations may disturb brainstem morphogenesis by Another subset exhibits retraction of the globe on attempted failing to promote decussation of long motor and sensory adduction.518a As in Duane syndrome, congenital ocular motor tracts in the pons and medulla. Impaired decussation of pontine synkinesis may contribute to the horizontal conjugate gaze ocular motor pathways may explain the absence of horizontal paresis in some cases. Additional deficits affecting other cra- eye movements in this disorder.88 nial nerves, particularly V, IX, and XII, may produce feeding and sucking difficulties in the neonatal period and subsequent speech difficulties, with or without atrophy of the tongue.16 Möbius Sequence Rarely, the sixth cranial nerves may be spared.754 Möbius sequence may be associated with a wide variety Möbius sequence is a rare congenital disorder characterized of associated limb malformations (talipes equinovarus, by congenital facial weakness with horizontal gaze palsy296 brachydactyly, syndactyly, congenital amputations) as well or impairment of ocular abduction.781 Dysfunction of other as hypoplasia or absence of the branchial musculature, cranial nerves, orofacial malformations, limb malformations, particularly the pectoralis muscle (Poland anomaly).16,454 and musculoskeletal system defects are common associated Miller et al553 refer to the subgroup with associated limb features, but they are not obligatory for the diagnosis. anomalies as terminal transverse defects with orofacial mal- Möbius sequence is a sporadic multiple-malformation com- formations (TTV-OFM), a term originally used by Temtamy plex that affects the face and horizontal gaze mechanisms bilat- and McKusick.16 Endotracheal intubation may be especially 348 7 Complex Ocular Motor Disorders in Children difficult in children with Möbius sequence, owing to struc- without active neuronal degeneration and focal necrosis with tural abnormalities of the mandible and palate.22 neuronal loss, gliosis, and calcifications in the brainstem.781 Cardiovascular abnormalities (most commonly dextrocar- MR imaging shows brainstem hypoplasia when measuring dia, patent ductus arteriosus, and ventricular septal defects), the pons (Fig. 7.17), supporting the hypothesis that Möbius micrognathia, structural abnormalities of the pinna, and sequence is a developmental disorder of the entire lower mild mental retardation and autism are also occasionally brainstem604,612,780 with other cranial nerve aplasia.225 Absence present.16,54,193,403,545,547 Other abnormalities can include an of the facial nerves despite residual function in some facial A-shaped mouth, lagophthalmos, a “hidden” smile and laughter, muscles suggests that other cranial nerves may aberrantly syndactyly, a hypoplastic, asymmetric tongue that cannot be innervate some of the facial muscles.780 The finding of croco- protruded over the lips, and a groove over the midline of the dile tears in patients with Möbius sequence also supports this tongue. The ocular abduction deficit may be caused by con- association. A variant of Möbius sequence with normal genital horizontal gaze paresis, Duane’s syndrome, simple brainstem anatomy has recently been recognized.225 abducens palsy, or congenital fibrosis.781 Some investigators have suggested that ischemia of the Children with Möbius sequence have difficulty relating to lower cranial nuclei due to an insufficient blood supply in the people in their environment because of an inability to convey pontine branches is the cause of Möbius sequence.80,226 their reaction of joy or sorrow. They are often incorrectly Intrauterine brainstem infarction could result from premature assumed to be mentally retarded and are predisposed to regression or obstruction of the primitive trigeminal arteries social and psychiatric problems.21a,547a,555 The successful before the establishment of a sufficient blood supply from the management of Möbius sequence entails a multidisciplinary vertebral arteries, which may explain the variability in clini- approach that includes the medical, speech, education, and cal expression.16 Brainstem calcifications, which have been mental health disciplines.16 Strabismus surgery can restore attributed to vascular insufficiency,16,219 are not indicative of a ocular alignment,718,777 and regional muscle transfer and specific mechanism and could equally support a maldevelop- microvascular free tissue transfer have been used to provide mental pathogenesis.782 Neuropathologic studies have empha- innervated dynamic muscle to restore facial move- sized the presence of brainstem atrophy and/or necrosis in ment.164,547,742 Because of their orofacial abnormalities, chil- Möbius sequence.188a Patients with Möbius sequence are pre- dren with Möbius sequence are at higher risk of postoperative disposed to primary respiratory failure and recurrent apnea, respiratory failure following general anesthesia.302 which correlates with both tegmental necrosis with calcifica- Although Möbius sequence is now classified as one of the tions and marked brainstem hypoplasia at autopsy. congenital cranial dysinnervation disorders, it is more than a The association of Möbius sequence with thalidomide cranial nerve or nuclear developmental disorder. Möbius embryopathy and misoprostol exposure191,518,774 demonstrates sequence is a rhombencephalic developmental disorder with that early embryonic exposure to teratogens may produce a hypoplasia of the entire brainstem, including the traversing similar malformation complex.543a Möbius sequence is usually long tracts, and signs of neuronal degeneration and other considered sporadic, however, rare instances of autosomal congenital brain abnormalities.782 Neurophysiologic studies dominant, autosomal recessive, and X-linked recessive inheri- suggest dysfunction at infranuclear, nuclear, and supranu- tance have been reported. Cytogenetic studies have suggested clear levels.148,779 Aberrant regeneration may contribute to the two loci for Möbius sequence: 1p22 and 13q12.2-13.782 horizontal conjugate gaze paresis in some cases of Möbius sequence. The associated feeding and respiratory problems, along with poor motor development, are consistent with this Monocular Elevation Deficiency, hypothesis.781 Often, the clinical features (facial weakness and impairment of ocular abduction) are only the most salient or “Double Elevator Palsy” clinical features of a more extensive developmental disorder with probably diverse pathogenetic mechanisms. “Double elevator palsy” is a descriptive term denoting a con- Neither etiology nor pathogenesis of this syndrome have genital deficiency of monocular elevation that is equal in yet been elucidated and are likely to be diverse in nature.780 abduction and adduction. Generally speaking, an inability to Two major pathogenetic explanations have been suggested: a elevate one eye may occur on a restrictive or paretic basis and primary genetic cause, implying a maldevelopment of the may be congenital or acquired. The patient or his family brainstem, and a primary ischemic cause, possibly due to frequently reports that one eye shoots up and disappears embryological or environmental toxic factors mediating an under the upper eyelid while, in fact, the contralateral eye is interruption in the blood supply of the brainstem during early the one with abnormal motility. The patient frequently has embryologic development.781 These postulated pathogenetic associated hypotropia and ptosis or pseudoptosis. The term mechanisms are based on a few postmortem observations, “double elevator palsy” was originally coined to reflect what which include hypoplasia of the cranial nerve nuclei with or was then thought to be the basis for the disorder, namely, con- Congenital Cranial Dysinnervation Syndromes 349 genital palsy of the ipsilateral inferior oblique and superior inferred.534 Scott and Jackson690 have noted that the appear- rectus muscles,801 a concept that has since been abandoned. It ance of an accentuated lower lid fold on attempted upgaze has since become apparent that the concomitant limited ele- predicts the presence of an inferior rectus contracture. vation, very characteristic of double elevator palsy, may result While the location of the “lesion” in the restrictive variety from at least three disparate pathophysiologic disorders, of the monocular elevation deficiency is readily apparent, namely, inferior rectus restriction, superior rectus paresis, and generally pointing to tightness in the inferior rectus muscle a supranuclear disturbance of monocular elevation.261 In truly complex, the location of a lesion in the other two classes of paretic cases, dual palsy of the inferior oblique and superior the monocular elevation deficiency is not as well deter- rectus muscles does not occur; paresis of the superior rectus mined.535 Cases resulting from isolated superior rectus weak- muscle alone (the dominant elevator of the globe) is sufficient ness could theoretically result from disorders, affecting the to produce the clinical picture. The term monocular elevation muscle or its nerve supply anywhere from the superior rectus deficiency is a more accurate descriptive term. subnucleus to the orbit. Congenital absence of the superior The monocular elevation deficiencies undoubtedly over- oculomotor division could produce double elevator palsy lap with the congenital cranial dysinnervation syndromes with hypotropia and neurogenic ptosis. Hoyt described a (discussed below).577 Several large series have shown that patient who developed sudden monocular elevation deficit most patients with monocular elevation deficiency have a and features of superior rectus paresis, which he attributed to restrictive abnormality to elevation.533,534,690 Some of these superior rectus subnucleus infarction precipitated by coexist- cases represent unilateral inferior rectus muscle fibrosis, ing polycythemia vera.378 Mather and Saunders reported a which can present with a tight inferior rectus muscle, case of bilaterally absent superior rectus muscles.522 hypotropia, and secondary ptosis in CFEOM3.207,350,750 As oculomotor fascicular fibers destined to the elevators of Congenital inferior rectus fibrosis and neurogenic double the eye and eyelid are believed to course laterally in the fas- elevator palsy may closely mimic each other because both cicle as it traverses the midbrain, a midbrain infarction involv- may exhibit defective elevation associated with ptosis or ing a lateral portion of the oculomotor fascicle can cause an pseudoptosis. Conversely, a long-standing hypotropia asso- acquired unilateral ptosis and elevation deficit.145,382 A con- ciated with neurogenic double elevator palsy may result in genital lesion at this location could theoretically explain the secondary contracture of the inferior rectus muscle and cause paretic infranuclear form of monocular elevation deficiency. a positive forced duction test. Similar cases of inferior rectus MR imaging has shown hypoplasia of the involved superior tightness may result from perinatal orbital trauma.338 rectus muscle in one case,138 and focal thickening of the infe- The diagnosis of contralateral superior oblique palsy rior rectus in another.435 However, the absence of these find- should be considered in any child who has a monocular ele- ings on neuroimaging in the great majority of cases support a vation deficiency, because fixation with the “paretic eye” can prenuclear deficit in the unilateral center for upgaze.435,607 produce a contralateral inferior rectus contracture. Other Olson and Scott noted that 9 of 31 patients with monocu- conditions to be considered include orbital blowout fractures lar elevation deficiency had dissociated vertical divergence and orbital fat adherence syndrome. Patients with inferior manifesting in the affected eye.597 The findings of Bell’s phe- rectus restriction due to orbital blowout fracture may also nomenon, dissociated vertical divergence, normal velocity of show a component of inferior rectus paresis.461 upgaze saccades when moving from a downward to primary On the basis of studies utilizing scleral search coil tech- position, negative Bielschowsky Head Tilt test, and elevation niques, Ziffer et al839 suggested the existence of at least three during stage II of general anesthesia provide evidence of a distinct etiologic categories: primary inferior rectus restric- supranuclear etiology.548 tion, primary superior rectus palsy, and congenital supranu- Supranuclear disturbances of monocular eye movements clear elevation defects. The inferior rectus restriction may be are rare. The neuroanatomic substrate of unilateral supranu- present primarily or may secondarily result from long-standing clear upgaze deficiency is controversial. It has been attrib- superior rectus weakness. Examination for the status of uted to either lesions of the contralateral pretectum or lesions Bell’s phenomenon and other reflex upward movements is involving the upgaze efferents from the ipsilateral rostral very useful. An intact Bell’s phenomenon, or the ability to interstitial nucleus of the medial longitudinal fasciculus. produce an upward movement of the eye with the oculo- Most reports have been in adults in association with meta- cephalic maneuver, suggests a supranuclear disturbance. static tumors. Lessell485 reported a man with bronchogenic An absent Bell’s phenomenon would indicate either inferior carcinoma who developed left monocular elevation deficit, rectus restriction or superior rectus palsy. The two can be but with orthotropia in primary position and an intact Bell’s distinguished by saccadic velocity analysis, forced ductions, phenomenon. A metastatic tumor was found in the right pre- and active force generation. If restriction is absent and the tectum at autopsy, which was speculated to have caused the eyes are orthotropic in the primary position, a superior rectus double elevator palsy by interrupting axons destined for the paresis is most unlikely, and a supranuclear disturbance is ipsilateral superior rectus subnucleus and the contralateral 350 7 Complex Ocular Motor Disorders in Children inferior oblique subnucleus. Ford et al274 described a 52-year- synchronous with chewing. The eye movements persisted old woman who developed right monocular elevation paresis after levator excision and fascia lata sling procedures. The who was demonstrated to have a focal, right-sided tumor of authors speculated that the up-and-down eye movements the mesodiencephalic junction in the region of the riMLF. probably represented aberrant innervation of the superior Acquired unilateral double elevator palsy has been described rectus muscle in a manner analogous to the abnormal inner- in a child with a pineocytoma.570 The most recent evidence vation of the levator muscle in MGJW. incriminates a lesion of the vertical saccadic burst or pause Surgical treatment consists of inferior rectus recession neurons of the riMLF. A genetic factor is suggested by (in cases with a positive forced duction test),690 partial or the finding of identical twins concordant for supranuclear full tendon width transpositions of the horizontal rectus double elevator palsy on the same side, with preservation of muscles (in cases with a negative forced duction Bell’s phenomenon.62 test),141,227,349,441 or innervation surgery with large recession The possible neuroanatomic origins of monocular eleva- of the contralateral superior rectus muscle (in cases with a tion deficit are summarized in Table 7.9. Patients with supe- negative forced duction test and some residual supraduc- rior oblique palsy who habitually fixate with the paretic eye tion).629 Newer modifications of this procedure may include may present with limited monocular elevation of the contral- posterior fixation sutures to the transposed muscles and ateral (hypotropic) eye due to inhibitional palsy of the con- placement posterior fixation sutures on the normal superior tralateral antagonist.208 This so-called “fallen eye syndrome” rectus muscle.709 may lead to a contralateral inferior rectus contracture and Inferior rectus recession alone or in combination with thereby cause a monocular elevation deficiency. The correct other procedures ameliorates the restrictive variety of double diagnosis may be inferred by the three-step test and the com- elevator palsy. Treatment of neurogenic double elevator palsy parison of ductions to versions. Cases of vertical retraction includes conventional vertical rectus muscle surgery (recess syndrome, wherein congenital unilateral restriction of eleva- and/or resect) and vertical transposition of the tendons of the tion is associated with retraction of the globe and narrowing medial rectus-lateral rectus superiorly (Knapp procedure).135 of the palpebral fissure,683 have been speculated to arise from The pseudoptosis disappears on correction of the vertical a vertical innervational misdirection similar to that observed deviation, and any residual true ptosis can be addressed after in Duane’s syndrome and in some cases of congenital fibrosis ocular alignment is optimized.142 syndrome.291 The association of an isolated monocular elevation defi- ciency with congenital ptosis in general, and MGJW in par- ticular, implies that aberrant misdirection may play a role in Brown Syndrome the pathogenesis of some cases of double elevator palsy.819 Undoubtedly, a subgroup of patients with monocular eleva- Brown syndrome can be distinguished from double elevator tion deficiency fall into the classification of congenital cra- palsy by its increasing limitation of elevation in the adducted nial dysinnervation syndromes (discussed below). This view position.808a Brown syndrome must also be distinguished is supported by reports showing that the superior rectus mus- from the much less common inferior oblique palsy by the cle itself may be involved in the aberrant phenomenon. For presence of little or no associated superior oblique overac- example, Oesterle et al603 described a 9-month-old infant tion, a Y-pattern producing exotropia in extreme upgaze, and with congenital ptosis without jaw winking who showed an a positive forced duction test. Brown syndrome results from up-and-down movement of the left eye synchronous with a congenital or, less commonly, an acquired dysfunction nursing movements of the jaw. A 5-year-old girl with left involving the trochlear-superior oblique tendon complex.808a ptosis, jaw winking, and left double elevator palsy showed Either form may be constant or intermittent (Fig. 7.19). up-and-down movements of the left upper lid and the left eye Intraoperative forced duction testing can help distinguish an inferior rectus restriction from a severe Brown syndrome. Retropulsion of the globe into the orbit while performing Table 7.9 Neuroanatomic differential diagnosis of monocular eleva- forced supraductions reduces or eliminates an inferior rectus tion deficiency restriction, but exacerbates tightness due to Brown syndrome. Absence or hypoplasia of the superior rectus (e.g., Crouzon’s disease) Pulling on the globe does the opposite. Many acquired and Inferior rectus contracture (e.g., congenital fibrosis syndrome, “fallen eye syndrome”) some congenital cases of Brown syndrome improve sponta- Lateral oculomotor fascicular lesion neously so that a conservative approach is reasonable. It has Superior division oculomotor paresis recently been argued that congenital superior oblique palsy Superior rectus myoneural junction disease (e.g., myasthenia gravis) with misinnervation to the medial or inferior rectus muscle Superior rectus subnucleus lesion can produce a motility pattern that is indistinguishable from Supranuclear lesion Brown’s syndrome due to a tight superior oblique tendon.447 Other Pathologic Synkineses 351

Fig. 7.19 Intermittent Brown syndrome: Teenager complained of intermittent diplopia. On attempted gaze up and to his left, full ocular ductions and versions were noted on some trials (a), but intermittently, right eye failed to elevate in adduction (b)

Although classically viewed as a restriction syndrome, known oculo-auricular phenomenon, horizontal gaze evokes Neugebauer and colleagues have argued that Brown syndrome a synkinetic retraction of the external ear muscles.808 Curling may be a congenital cranial dysinnervation syndrome.577 of both auricles during strong lateral gaze is said to be present Using high-resolution dynamic MR imaging, Kolling and in 40% of the normal population.765,808 This reflex is seen colleagues demonstrated absence of the fourth nerve within more easily in people who have prominent ears.765 the orbit and hypoplasia of the superior oblique muscle on the As discussed in Chap. 6, other forms of ocular motor syn- affected side in patients with Brown syndrome.447 They have kineses can occur in isolation or cluster together. A trigem- suggested that reinnervation of a paretic superior oblique ino-abducens synkinesis may occur after trauma, and facial muscle by branches from the medial or inferior rectus muscles synkinesis is a common finding after facial nerve palsy. can produce a motility pattern that is indistinguishable from It should be noted that various forms of aberrant innervation Brown’s syndrome due to a tight superior oblique tendon.447 have been reported in the thalidomide embryopathy, espe- Treatment is undertaken for persistent cases with signifi- cially Duane’s retraction syndrome and aberrant lacrima- cant strabismus in the primary position and/or a significant tion544 (crocodile tears). Platysma-levator synkinesis has compensatory anomalous head position. Superior oblique been documented in a child with congenital third nerve palsy, weakening (tenotomy or placement of a silicone spacer to demonstrating the potential for aberrant regeneration from a lengthen the tendon),818 with or without inferior oblique portion of the facial nerve.102 weakening, is the treatment of choice in persistent congenital Rarely, deglutition-trochlear synkinesis may be noted,526 or idiopathic acquired cases with symptomatic diplopia or with the affected patient showing torsional diplopia associ- marked compensatory chin elevation. Local corticosteroid ated with swallowing. This phenomenon suggests a synki- injections around the trochlea may be helpful in acquired netic movement coupling the trochlear nerve with the bulbar inflammatory cases. The occurrence of Brown’s syndrome in musculature that is innervated by the trigeminal, facial, and multiple siblings331 and in monozygotic twins817 supports a hypoglossal nerves. Boehme and Graef described a 10-year- genetic basis in some cases. Causes of acquired Brown syn- old boy with a right-sided Horner’s syndrome and a paresis of drome include trauma, a rheumatoid nodule in the vicinity of the recurrent laryngeal nerve, following neuroblastoma resec- the trochlea, peribulbar anesthesia, blepharoplasty, pansinus- tion, whose right pupil distorted into an oval shape when he itis, frontal sinus osteoma, metastatic lesions, localized swallowed.77 They postulated that aberrant vagal sprouts had inflammation (orbital pseudotumor), surgical manipulation established connections with the cervical sympathetic chain. in the area of the trochlea, and surgical tucking of the superior Some phenomena resemble synkinetic movements, but are oblique tendon. difficult to explain on the basis of aberrant reinnervation. In some patients, voluntary gaze may evoke such phenomena as vertigo, tinnitus, blepharoclonus, eyelid nystagmus, eyelid closure, facial twitching, arm movements, or seizures.226,693,789,790 The patho- Other Pathologic Synkineses genesis of these “synkinetic” movements is unclear, but has been speculated to involve ephaptic transmission.693 Gaze-evoked Physiological synkineses are well-recognized. Opening the upper lid jerks (lid nystagmus) may also be seen in patients mouth causes the eyes to simultaneously open, a reflex that is with Fisher’s syndrome.666 and in patients with midbrain useful in the ocular examination of children. In the less pseudomyasthenia (e.g., due to mesencephalic astrocytoma).114 352 7 Complex Ocular Motor Disorders in Children

Internuclear Ophthalmoplegia Other mechanisms invoke the possibility that the abducting nystagmus may result from: (1) increased con- The hallmark of internuclear ophthalmoplegia (INO) is vergence tone to improve adduction of the weak eye; (2) weakness or absence of adduction in one or both eyes on interruption of descending internuclear neurons that run lateral gaze, with nystagmus in the abducting eye.481,706,834 in the medial longitudinal fasciculus from the oculomotor Despite this adduction limitation, the eyes remain orthotro- internuclear neurons to the abducens nucleus; (3) associ- pic in the primary position. The adduction weakness may be ated injury to fibers other than those of the medial longi- profound and quite noticeable on testing of ocular ductions tudinal fasciculus; and (4) an associated gaze-evoked and versions or may be so subtle as to be discernible only by nystagmus, with the component of the nystagmus expected noting slow adducting saccades in the affected eye. Refixation in the adducted eye being dampened by the coexisting from abduction to primary position causes the contralateral adduction paresis.481,834 eye to momentarily overshoot the target.707 The slow, floating In unilateral cases, diplopia in the primary position is nature of the adducting saccades can be effectively elicited often vertical rather than horizontal and is attributable to a by having the patient fixate an optokinetic nystagmus target concurrent skew deviation. It can be eliminated with two to moving temporally with respect to the eye with limited three prism diopters of vertical prism incorporated into adduction, which elicits a dysconjugate horizontal nystag- glasses. Nystagmus and oscillopsia may complicate bilateral mus of greater intensity in the abducting eye.707 cases. The oscillopsia is a result of deficient vertical vestibulo- Convergence is usually preserved, except in rostral cases ocular reflex and pursuit movements or the abduction nys- that simultaneously affect the medial rectus subnucleus. tagmus. The role of strabismus surgery in selected patients However, decreased convergence in the setting of bilateral has been recently analyzed.463 INO with multiple sclerosis may be due to central scotomas A lesion, encompassing both the medial longitudinal caused by optic atrophy, as opposed to a primary conver- fasciculus and the ipsilateral PPRF or the abducens nucleus, gence disorder. Older children may complain of diplopia. A results in an ipsilateral horizontal gaze palsy and an INO. skew deviation often accompanies unilateral INO, while ver- The only preserved horizontal movement is abduction of tical upbeating nystagmus in upgaze often accompanies the contralateral eye. This constellation of findings is called bilateral INO. Unlike most forms of skew deviation in which the “one-and-one-half syndrome.” Bilateral INO with uni- the lower eye is ipsilateral to the lesion, the higher eye is usu- lateral abducens paresis gives a similar motility deficit. ally on the same side of the lesion in patients with INO. As The one-and-one-half syndrome has a similar spectrum of INO resolves, the clinical picture evolves from absent or causes as INO. decreased adduction to slow adduction to normal-appearing In premature infants, one occasionally notes large-angle adduction with retention of the abducting nystagmus (i.e., exotropia with decreased or no response of the medial recti abducting nystagmus is the last to resolve). to vestibular manipulations with rotation or calorics. This Internuclear ophthalmoplegia signifies intrinsic brain- has been interpreted as possible bilateral INO, suggesting a stem disease involving the pons or midbrain.706 It results maturational delay in the development of the medial longitu- from injury to axons that originate from interneurons in dinal fasciculus. Such exotropia has a good prognosis for the abducens nucleus and project via the medial longitudinal spontaneous ocular alignment as the medial longitudinal fas- fasciculus to the contralateral medial rectus subnucleus of ciculus matures, compared to the constant large-angle exotro- the oculomotor nuclear complex. A number of mecha- pia of infancy that shows no evidence of adduction nisms have been suggested to explain the dissociated weakness.381 This latter variety is usually observed in the set- nystagmus in the abducting eye.836 One popular explana- ting of neurologic disease, but a subset is seen in otherwise tion suggests that increased innervation to the medial healthy infants in a manner analogous to congenital esotro- rectus to overcome the adduction weakness is accompa- pia. Duane type 2 syndrome, medial rectus entrapment in a nied, under the influence of Hering’s law of equal innervation, nasal orbital wall fracture with associated paresis, myasthe- by a commensurate increase in the innervation to the normal nia gravis, and Fisher syndrome may produce a similar motil- lateral rectus muscle of the contralateral eye. While ity pattern and must be excluded. increased innervation to the paretic medial rectus muscle Causes of INO in infants and children include demyeli- would improve adduction, the increased innervation to nating disease, stroke, brainstem tumors (particularly pon- the normal lateral rectus of the other eye would result in tine glioma),180 vasculitis,439 inborn errors of metabolism, abducting saccadic overshoot followed by backward post- parainfectious encephalitis, structural malformations (Chiari 816 218,644 13 saccadic drift. This mechanism is supported by the obser- malformation), drug intoxication, B12 deficiency, vation that abducting nystagmus may also be noted in and trauma. Bilateral INO may be accompanied by exotro- patients with adduction weakness resulting from medial pia, bilateral ptosis, and supraduction deficits in the midline rectus muscle recession.786 mesencephalic cleft syndrome.131,465 Another increasingly Cyclic, Periodic, or Aperiodic Disorders Affecting Ocular Structures 353 important cause of INO is HIV encephalitis. Myasthenia to be learned from these cyclic phenomena is the importance of gravis is a recognized cause of pseudo-INO.422 Those with observing certain ocular disorders over time. The nature bilateral and intermittent exotropia (WEBINO syndrome) of the cyclic phenomenon and the duration of a complete can be treated surgically with large bimedial resections (suc- cycle define each disorder. cessful in our hands) or bilateral lateral rectus recessions.4 Cyclic esotropia is a relatively rare condition that is also However, most cases without exotropia remit spontaneously. referred to as alternate day, circadian, or clock-mechanism In adults, recovery is more likely in demyelinating than in esotropia.333 The designation “circadian,” which denotes a vascular lesions and slower when there are other signs of 24-h cycle, is a misnomer because the usual cycle duration is brainstem injury.82,233 The relative prognosis for INO in children 48 h. The typical case shows a 24-h period of manifest has not been established. esotropia measuring 40–50 prism diopters, alternating with a 24-h period of normal ocular alignment (Fig. 7.20). Less common are cycles of 24, 72, or 96 h in duration. The esotropia is nonaccommodative and nonparalytic, with normal eye Cyclic, Periodic, or Aperiodic Disorders movements in both eyes when straight and also when esotropic. Affecting Ocular Structures On days when the eyes are crossed, diplopia is rare, fusional amplitudes are defective or absent, and sensory anomalies are frequent. Whether other cyclic phenomena occur in asso- A number of heterogeneous ocular disorders have in common ciation with this condition is debatable. Friendly et al279 mon- a cyclic, periodic, or aperiodic pattern, that is, an involuntary itored numerous psychological and physiologic functions process that repeats over time (Table 7.10). A major lesson and found no associated cyclical phenomenon. In contrast, Roper-Hall and Yapp654 described cyclical changes in behavior, frequency of micturition, and EEG activity. Table 7.10 Cyclic, periodic, or aperiodic disorders affecting ocular Cyclic esotropia may first appear in infancy, but the diagno- structures sis may be delayed months to years, with the average age at Alternating anisocoria Cyclic esotropia diagnosis ranging from 2 to 4 years, although some cases may Cyclic superior oblique palsy occur abruptly in adulthood. Generally, the condition occurs Cyclic vertical deviation spontaneously without apparent cause, but may be precipitated Migrating pupil by strabismus surgery, retinal reattachment surgery, ocular Oculomotor palsy with cyclic spasm trauma, optic atrophy, or CNS disease.333 The natural history of Periodic alternating esotropia this condition is not definitively known, but the cyclicity is Periodic alternating gaze deviation thought to diminish with time, leading to a constant esotropia Periodic alternating lid retraction after several months to years. The mechanism of cyclic esotro- Periodic alternating nystagmus 737 Periodic alternating skew deviation pia remains unknown, and no correlative abnormalities of the 282 Periodic head turns in congenital nystagmus hypothalamic pituitary axis have been found. Some cases are Periodic mydriasis associated with neurologic disease,282,625 one case was triggered Ping-pong gaze by traumatic sixth nerve palsy,385 and one by surgery for inter- Rhythmic pupillary oscillations (periodic pupillary phenomenon) mittent exotropia.762 These reports suggest that patients

Fig. 7.20 Cyclic esotropia. Patient presented with history of intermittent esotropia but was found on further followup to have cyclic esotropia. She showed orthotropia (a) and esotropia (b) alternating daily 354 7 Complex Ocular Motor Disorders in Children with cyclic esotropia are basically strabismic with cycles of The duration of a complete cycle of PAGD (3–4 min) remission.536 This abolition of cyclic esotropia after visual is similar to that of periodic alternating nystagmus (PAN), improvement appears analogous to previously reported cases suggesting that the two conditions may have a similar neuro- of periodic alternating nystagmus that resolved after visual anatomic substrate, the difference being an added saccadic rehabilitation by removing a cataract or clearing a vitreous palsy in the case of PAGD. This concept is supported by the hemorrhage. It is therefore advisable to provide maximal opti- findings in a patient with recurrent cerebellar medulloblas- cal/refractive correction prior to considering extraocular mus- toma who sequentially demonstrated PAN, bilateral gaze cle surgery. The treatment of cyclic esotropia consists of palsy, PAGD, and then resumption of PAN.425 strabismus surgery to correct the maximum deviation that stops When encountered in a comatose patient, PAGD is usually the overt cycles. Richter641 likened the effect of surgery to considered a sign of bilateral cerebral hemispheric dysfunc- “removing the hand of the clock without altering its motor.” tion with a relatively intact brainstem.728 In this setting, the Cyclic esotropia has been reported in the aftermath of total duration of the abnormal movements is usually short, a cataract, retinal detachment, intracranial surgery,625,642,756 few hours to days, disappearing a few hours before death. intermittent exotropia,568 infantile esotropia,536 and accom- Ping-pong gaze superficially resembles PAGDs, but the modative esotropia.224 Cyclic esotropia should not be con- movements are much faster, although some authors have fused with periodic alternating esotropia.344 The latter is a used the two terms interchangeably.638,692 It consists of conju- rare condition with cycles of similar duration to periodic gate horizontal ocular deviations that alternate rapidly every alternating nystagmus (about 200 s). The few reported cases few seconds. Ping-pong gaze is usually seen in comatose or occurred in association with congenital periodic alternating semicomatose patients and typically denotes cerebellar or gaze deviation.342 Such patients probably had the neuroana- bilateral cerebral hemispheric lesions, but a relatively intact tomic substrate of periodic alternating nystagmus, but with brainstem. Ping-pong gaze has been speculatively ascribed superimposed saccadic palsy leading to absent fast phases of to damage of the descending supranuclear inhibitory input nystagmus. on the horizontal gaze centers. Periodic alternating gaze deviation (PAGD) is a rare disor- Periodic alternating skew deviation is a rare condition in der consisting of a slow, conjugate horizontal deviation of the which the patient develops right hypertropia lasting one to eyes from one side to the other.344,480,720 It may occur at any several minutes, alternating with left hypertropia in a cyclic age (some cases have been reported in infancy) and is associ- fashion. In some patients, the condition may be aperiodic ated with concurrent, controversive, cyclic face turning to or intermittent. Downbeat nystagmus may also be present. maintain fixation. During a complete cycle, the eyes rotate In one patient, a focal lesion affecting the interstitial nucleus conjugately toward one side for 1–2 min, usually with com- of Cajal was demonstrated with computed tomography. In pensatory head turning to the opposite side; return to the mid- contrast to seesaw nystagmus, periodic alternating skew line for a changeover period lasting 10–15 s; then conjugately deviation has slower movements, larger excursions, and no deviate to the other side for 1–2 min, with compensatory head torsional component. Periodic eye movement disorders with turning to the side opposite the direction of ocular rotation a cycle duration of about 200 s, which include PAN, PAGD, (Fig. 7.21). The patient may be orthotropic or esotropic. and periodic alternating skew deviation, may have similar During eye closure, the alternating turning of the head ceases, pathophysiologic mechanisms and have been reported to even though the eyes continue the rhythmic movement. While occur in combinations in the same individual.425,491 the eyes are deviated, they exhibit abnormal voluntary move- One case of cyclic superior oblique palsy developed in a ments, convergence, optokinetic nystagmus, and oculocepha- 10-year-old patient following trauma to the left trochlear lic responses, but all of these normalize during the changeover area.809 Typical left superior oblique palsy alternated daily phase. Caloric testing can override the eye and head move- with orthotropia. A patient with cyclic vertical deviation of ments, and the cycling stops during sleep. an unspecified nature, with a cyclic duration of 48 h, has Periodic alternating gaze deviation may occur on a con- been reported following craniofacial surgery.537 Other cyclic genital basis (Fig. 7.20) or may be acquired. Most docu- ocular motor disorders include paroxysmal ocular tilt reaction mented cases reported so far have been due to posterior fossa and oculomotor palsy with cyclic spasm. In patients with abnormalities. It has been reported in association with pon- oculomotor palsy with cyclic spasm, the pupil may report- tine vascular lesions, Arnold–Chiari malformation, Dandy– edly be the only structure to cycle although, more commonly, Walker malformation, congenital hydrocephalus, occipital the extraocular muscles and levator muscle are also involved encephalocele, cerebellar medulloblastoma, spinocerebellar in the cyclic spasms. degeneration, and Joubert’s syndrome with cerebellar vermis Cyclic or alternating phenomena may affect the pupils. hypoplasia.342,425,480,720,728 In congenital or early onset PAGD, Keane described a patient with traumatic oculomotor palsy cerebellar vermis atrophy is the most common neuroradio- in whom the ipsilateral pupil, although unreactive to light, logic abnormality. showed continuous rhythmic involuntary oscillations. Cyclic, Periodic, or Aperiodic Disorders Affecting Ocular Structures 355

Fig. 7.21 Congenital PAGD. Two-year-old girl with Joubert syndrome changeover period lasting seconds, then (c) conjugately deviated to displayed PAGD with cycle duration of about 200 s. During complete other side over 90 s, with compensatory head turning to side opposite cycle, (a) eyes rotated conjugately to right over 90 s, usually with com- direction of ocular rotation. (d) MR imaging showed profound cerebel- pensatory head turning to opposite side, (b) returned to midline for a lar vermis hypoplasia

He speculated that dysfunction of the central parasympa- pupillary dilatation, with the dilated pupil showing little or no thetic nervous system may have been responsible. Alternating light reactivity in some cases, but normal reactivity in others.121 anisocoria is a rare condition characterized by alternating This may occur in otherwise neurologically normal children, 356 7 Complex Ocular Motor Disorders in Children but a similar phenomenon has been observed in a quadriplegic discharge in a peripheral nerve. Neuromyotonia describes patient with a posttraumatic syringomyelic cyst.440 The neurotonia accompanied by fibrillations, fasciculations, pathophysiology of this phenomenon is unclear, but it may myokymia, or sustained contraction of a muscle group. be due to either episodic oculosympathetic spasm producing Ocular neuromyotonia describes sustained contraction of one alternating Claude Bernard–Horner’s syndrome or episodic or more extraocular muscles due to involuntary firing of oculosympathetic interruption producing Horner’s syn- the supplying ocular motor nerve. drome. Some other pupillary disorders have been intermit- Ocular neuromyotonia is a relatively rare ocular motility tent rather than rhythmic and include intermittent mydriasis, disorder that manifests with brief paroxysmal monocular cyclic sympathetic spasm with concentric dilatation lasting deviations with associated diplopia.701 Episodes generally last 40–60 s, and “tadpole pupils,” in which the sympathetic 10–60 s (range, 5 s to 3 min) and may recur 20 or more times spasm is sectoral.746 per day. Some episodes occur spontaneously, while others are Conditions with cycle duration of a few minutes sometimes triggered by gaze in the direction of the involved muscle. become apparent when the clinician notices a reversal of a pre- Between attacks, affected patients usually show normal ocu- viously noted finding – for example, observation of conjugately lar motility, although some may show subtle evidence of turned eyes to the right in a patient whose eyes were previously aberrant innervation manifesting as minimal lid retraction in noted to be conjugately turned to the left brings forth the diag- downgaze. The paroxysms result from tonic involuntary con- nosis of PAGD. Conditions with a cycle duration of 24 h or traction of extraocular muscles innervated by the third (all longer cannot be definitively diagnosed from data collected muscles supplied by the nerve or any combination thereof), during a single office visit. For instance, a patient with cyclic fourth, or sixth cranial nerves.57,486 Spontaneous discharges esotropia may be initially evaluated on a “crossed” day and be from axons with unstable cell membranes are presumed to labeled as congenital or acquired esotrope. If the subsequent underlie this condition. In some cases, ocular neuromyotonia visit occurs on a “crossed” day, it may only consolidate the may coexist with primary aberrant regeneration.160 earlier false diagnosis. If it occurs on a “straight” day, the clini- Histopathologic studies of peripheral nerves in nonocular cian may suspect spontaneous resolution or an accommodative cases of neuromyotonia have shown segmental demyelina- element with variable angle and either question the observation tion as well as axonal degeneration, sprouting, and remyeli- of esotropia in earlier visits or correctly suspect cyclic esotro- nation.794 Most patients have a history of brain irradiation, pia. Conversely, initial evaluation of a patient with cyclic typically for the treatment of tumors of the skull base, such esotropia on a “straight” day may lead to missing the diagnosis, as pituitary tumors or craniopharyngiomas.486,798 Idiopathic dubbing the condition pseudostrabismus. cases with no specific cause have been reported.798 The inter- Cyclic phenomena in children are not limited to the neuro- val between radiotherapy and onset of neuromyotonia may ophthalmologic disorders discussed here, but involve other be months to years. Two cases have been reported in teenag- organ systems as well. Other biologic phenomena, such as ers following radiation therapy for parasellar lesions.199,562 sweating, salivation, and pulse rate, also have intrinsic peri- A favorable response to membrane-stabilizing medications, odicity, as do many manifestations of psychiatric dysfunc- such as carbamazepine is reported in many patients, supporting tion. Periodicity appears to be the norm in many biologic pathoetiology consisting of spontaneous or impulse-induced phenomena, and a normal person displays a complex array of repetitive discharge of hyperexcitable trigger zones in ocular biorhythms involving the various body systems.640 Numerous motor nerves. In some instances, the neuromyotonia has not periodic or rhythmic disorders have been described – for recurred on cessation of the medication. Some cases may example, periodic recurrence of fever, swelling of joints, remit spontaneously. fluctuations of circulating blood cells (periodic hematopoie- Several conditions not associated with radiation therapy may sis), and edema. Accumulating evidence points to the exis- come to be classified as ocular neuromyotonia. Adie’s pupil and tence of a biologic clock mechanism that keeps time with superior oblique myokymia are two common forms of ocular extraordinary accuracy and is independent of internal and neuromyotonia seen in neuro-ophthalmologic practice. external stimuli.

Ocular Motor Adaptations and Disorders in Ocular Neuromyotonia Patients with Hemispheric Abnormalities

Myotonia denotes delayed muscle relaxation after sustained Cerebral hemispheric abnormalities are often associated with contraction as a result of muscle membrane dysfunction. In ocular motor abnormalities that may be subtle or profound contrast, neurotonia or pseudomyotonia represents delayed depending upon the size, location, and other characteristics muscle relaxation as a result of impulse-induced repetitive of the lesion. These are reviewed in detail elsewhere. Eyelid Abnormalities in Children 357

Children with congenital hemianopsia develop a compen- one was associated with neurological and behavioral disorders, satory saccadic strategy, wherein they overshoot the intended and one was isolated. The latter resolved spontaneously. visual target then “find it” as the eyes drift back.380 Some Shawkat reported opsoclonus-like ocular tics associated with patients with congenital homonymous hemianopsia have facial tics in an otherwise healthy child that resolved sponta- been noted to also show concurrent exotropia, usually also of neously. Affected children are sometimes able to imitate early onset. Some investigators have suggested that the their tics in the clinic on request, which is a useful indicator exotropia in these patients is a compensatory phenomenon that consciousness is not impaired during the tics, allowing for the hemianopic field defect, essentially allowing the the examiner to rule out epilepsy. patient to have panoramic vision. For this to occur, anoma- lous retinal correspondence has to coexist, otherwise the patient would be diplopic.306,363 Some investigators raise the possibility that the exotropia in such patients is an epiphe- Eyelid Abnormalities in Children nomenon, possibly reflecting the type of strabismus one sees 380 in many children with neurologic disease. Congenital Ptosis It is not clear whether the concurrent exotropia in these children simply represents strabismus precipitated by infan- tile neurologic disease, or develops as a physiological com- As detailed above, congenital ptosis occurs most frequently pensatory phenomenon leading to the development of as a congenital cranial dysinervation disorder. Because con- anomalous retinal correspondence and panoramic vision, or genital ptosis can also be the presenting sign of several other exists as a combination between these two mechanisms. The neuro-ophthalmologic disorders (Table 7.11), however, spe- fact exotropia is so common in these children, who often cific attention to ocular motility, pupillary examination, and show an uncanny ability to navigate through visual space coexisting neurologic signs is imperative. Congenital ptosis without difficulty despite their homonymous hemianopia, must also be differentiated from pseudoptosis due to ipsilat- suggests that the exotropia serves an important compensa- eral hypotropia, enophthalmos, or contralateral lid retraction. tory function. Therefore, the clinician should understand the Motility abnormalities may include congenital oculomotor potentially devasting sensory implications of performing nerve palsy and double elevator palsy. The latter is a reason strabismus surgery to straighten the eyes.286 to be conservative with ptosis correction to prevent corneal exposure postoperatively due to absent Bell’s phenomenon. Pupillary abnormalities associated with unilateral ptosis may include a large unreactive pupil due to oculomotor palsy Eye Movement Tics or a miotic pupil either due to Horner syndrome or to con- genital oculomotor palsy with aberrant regeneration involving Tics are quick, jerky, sudden, and repetitive movements of the pupil. Causes of pupillary abnormalities associated with circumscribed groups of muscles without apparent cause or bilateral early-onset ptosis include Fisher’s syndrome and purpose. They occur frequently in children and most often botulism. resolve spontaneously. Tics most commonly affect facial Rarely, a cerebral hemispheric lesion causes unilateral or musculature, but may rarely affect the extraocular muscles, bilateral ptosis (termed cerebral ptosis) in the absence of causing eye movement tics.696 It is important to recognize other neurological signs.452 Lowenstein et al501 described two eye movement tics as such and not confuse them with more children with hemispheric arteriovenous malformations serious disorders. The few cases of eye movement tics reported to date have been mostly associated with facial tics, but isolated ocular tics may occur and may thus mimic nys- Table 7.11 Differential Diagnosis of Congenital Ptosis tagmus. Frankel and Cummings276 reported eye rolling tics in Blepharophimosis syndrome a group of patients with Tourette syndrome. The tics con- Cerebral ptosis sisted of eye rolling, gaze abnormalities, staring, or forced Congenital fiber-type disproportion gaze deviations resembling oculogyric crises. Two of the Congenital fibrosis syndrome cases described a corneal sensation preceding their tics. All Congenital myotonia Horner syndrome of these children also had blepharospasm, and most were Hypotropia with pseudoptosis taking neuroleptic or other medications. Neuroleptics have Marcus Gunn jaw winking been implicated in the pathogenesis of a variety of move- Microphthalmia, enophthalmos ment disorders, including tics and oculogyric crisis. Binyon Myasthenia gravis and Prendergast73 reported three cases with conjugate eye Myotubular myopathy movement tics: one was associated with Tourette’s syndrome, Oculomotor nerve palsy 358 7 Complex Ocular Motor Disorders in Children and contralateral ptosis that progressed over several years. Frequent eye blinking may be a manifestation of ocular In both cases, the ptosis resolved following resection of the surface, tear film, or eyelid disorders at any age. It may also arteriovenous malformation. One should consider the rare accompany lacrimal drainage obstruction. Children with possibility of cerebral ptosis in the child with progressive congenital glaucoma are classically described as presenting nonmyasthenic ptosis, especially when a history of seizures with the triad of epiphora, photophopia, and blepharospasm, or recurrent unilateral headaches is obtained. but may also show frequent blinking, as do children with The finding of unilateral congenital ptosis with lid swelling significant intraocular inflammation. Excessive blinking and should suggest the diagnosis of dural arteriovenous fistula.313 blepharospasm also occur in conditions with damage to When accompanied by supraduction deficit, bilateral inter- the basal ganglia, such as Wilson disease and Huntington nuclear ophthalmoplegia, and exotropia, bilateral ptosis disease.127 should suggest the possibility of midline mesencephalic cleft Seizure activity is associated with a variety of neuro- malformation.131,465 Tatli et al reported bilateral ptosis with ophthalmologic signs and symptoms that include nystagmus, lower extremity muscle weakness and dysautomomia gaze deviations, spasm of the near reflex, hemianopsia, corti- as probable paraneoplastic effects of neuroblastoma in a cal blindness, as well as a variety of eyelid signs. Lid signs 28-month-old girl.739 An extensive workup for myasthenia may consist of eyelid nystagmus or eyelid fluttering resem- gravis was negative, and no paraneoplastic autoantibodies bling tics and spells of eyelid spasms. For instance, Cogan were identified. et al179 described a 7-year-old girl with methylmalonic acidu- ria and homocystinuria who exhibited spells of fluttering of the eyelids and elevation of the eyes. The EEG showed 2.5-s polyspike and wave discharge during the spells, characteris- Excessive Blinking in Children tic of petit mal seizures. Excessive blinking and eyelid myo- clonia has been reported in association with typical absence The spontaneous blink rate in infants under 18 months of age seizures,28 and this condition has been reported in monozy- is low, ranging from 2 to 5 blinks per minute, whereas in gotic twins.202 Finger waving and rapid eyelid blinking is a older children, it is about 10, reaching approximately 20 feature of photoconvulsive epilepsy. blinks by the age of 20 years and remaining relatively con- Eyelid myoclonia may occur on eye closure in association stant throughout adulthood. Benign tics, (blinking eyes, with electrical status epilepticus without altered conscious- twitching mouth, movements of head, jerking shoulders or ness.776 Patients with occipital lobe epilepsy may exhibit a other body parts) are common in children, with a prevalence variety of neuro-ophthalmologic manifestations, including as high as 12% between the ages of 6 and 12 years.471 Benign elementary visual hallucinations, ictal or postictal amaurosis, tics involving the eyes, may manifest as excessive intermit- eye movement sensations, eye and/or head deviation, visual tent blinking without associated ocular or systemic disorders. field deficits, and early forced blinking or eyelid flutter.807 Eye winking or blinking tics in children represent exagger- Seizure activity may also be associated with abnormal eye ated contractions of the orbicularis muscle. The tics usually movements such as gaze deviations (usually to the contralat- increase in frequency when the child is bored, anxious, or eral side) and nystagmus.415,426,758 The terms “lid nystagmus,” tired. Most these tics are benign and transient, improving “upper lid jerks,” and “lid hopping” have all been applied to a spontaneously with time, without any discernible causation. neuro-ophthalmologic phenomenon in which a series of rapid, Unlike essential blepharospasm of adults, there is little, if rhythmic, jerky movements of the upper lids occurs alone or any, functional visual impairment. in conjunction with specific movements of the eyes or head.114 Although tics have been thought to result from an under- Most previously reported cases have been associated with lying psychological conflict,509 recent evidence suggests that posterior fossa disease and can be subdivided into lid nystag- they may be of organic origin but triggered or exacerbated by mus evoked by convergence and lid nystagmus evoked by stress. Elston et al236 described a family in which different horizontal gaze.377,664 Children have been described with signs members in three generations suffered eye-winking tics, and symptoms of myasthenic ophthalmoplegia in whom excessive blinking, and/or blepharospasm. The proband in gaze-evoked lid hopping signaled the presence of intrinsic that study had eye-winking tics in childhood, then developed midbrain tumors.114,633 Other rare causes of lid nystagmus excessive blinking evolving to blepharospasm by the age of include the lateral medullary syndrome, pretectal lesions, and 21 years. They also described five patients with adult-onset Fisher syndrome.666 While horizontal eye movements in blepharospasm, or Meige’s syndrome, who had a history of myasthenia gravis may be accompanied by occasional twitch- excessive blinking dating back to childhood. They specu- ing or fluttering movements of the upper lids, lid nystagmus lated that eye-winking tics, excessive blinking, and blephar- is uncharacteristic of neuromuscular disease and should ospasm may represent age-dependent manifestations of a prompt neuroimaging. Lid nystagmus would appear to neces- common pathophysiologic disorder.236 sitate a dissociation between the output of the levator and the Eyelid Abnormalities in Children 359 superior rectus subnuclei within the oculomotor nuclear and for boys (male-to-female ratio ranges from 3:1 to 5:1). complex. Convergence-evoked lid nystagmus often signifies The condition is familial in about one-third of cases, appears a structural lesion within the posterior fossa. Howard377 to be transmitted as an autosomal dominant trait, and has described a patient with convergence-evoked eyelid nystag- been mapped to the long arm of chromosome 18. mus without ocular upbeating nystagmus, who had a large Symptoms usually appear between ages 5 and 10 years, vascular lesion distorting the blood supply to the pontomes- with presenting features consisting of multifocal tics of the encephalic and pontomedullary junctions. Safran et al664 face and head. In addition to clonic motor tics (most com- described two similar patients with convergence-evoked eye- monly blinking and facial twitching) and vocal/phonic tics lid nystagmus. Patient 1, a 29-year-old man, developed a cer- seen in all patients, many patients exhibit one or more dystonic ebellar syndrome after sustaining severe head injuries. Patient tics that may include oculogyric deviations, blepharospasm, 2, a 12-year-old girl, had a tumor of the anterior cerebellar and dystonic neck movements.398 The globes may also show vermis. Treatment with corticosteroids (patient 1) and surgery dystonic tics. For example, Frankel and Cummings276 reported (patient 2) led to gradual resolution of the eyelid nystagmus, eye rolling tics in a group of patients with Tourette syndrome which the authors attributed to cerebellar dysfunction. who also had blepharospasm. The motor tics are followed by The cause of tic disorders may lie in the dopaminergic vocal tics such as grunting, sneezing, coughing, barking, system of the brain, as well as in genetic and other biological coprolalia (compulsive monosyllabic swearing), and echola- factors.406 Coats et al171 found the most common etiologies of lia. Tiqueurs may be able to voluntarily suppress the tics, but excessive eye blinking to be anterior segment or lid abnor- a resulting mounting tension eventually leads to further malities in children. Occasionally, children show frequent discharge of tics. Patients may show associated obsessive- eye blinking as a manifestation of Tourette syndrome.406 compulsive traits, self-mutilation, attention-deficit disorders, Some children may exhibit lower eyelid pulling as a transient learning disabilities, and serious psychiatric illness. Haloperidol behavior lasting weeks to months.147 These children are oth- and pimozide are useful in controlling the symptoms. erwise healthy, and the condition is thought to initially be Epileptic disorders and their treatment may cause eye roll- triggered by ocular irritation, but then develops into a “bad ing or eyelid myoclonia.188 When accompanied by absence habit.” This functional disorder is readily distinguishable spells, eyelid myoclonia is highly suggestive of Jeavon’s syn- from eye poking (oculodigital sign) encountered in children drome (i.e., eyelid myoclonia and absences). In this condi- who are blind secondary to congenital retinal disease (i.e., tion, there is marked jerking of the eyelids with upward Leber congenital amaurosis, retinopathy of prematurity, reti- deviation of the eyes, associated with spike-wave discharges nal dysplasia)394 and vigorous eye rubbing seen in patients that are often irregular, immediately after eye closure and with Down syndrome. invariably evoked by intermittent photic stimulation. This Eyelid myokymia may occur alone or in association with diagnosis is likely when the eyelid myoclonia is combined facial myokymia. Facial and eyelid myokymia are character- with photosensitivity and pathognomonic when it also occurs ized by unilateral involuntary fine rippling movements, spread- after eyelid closure (in some cases, it can look like the child is ing across the surface of affected muscles. Facial myokymia purposefully closing the eyes to initiate a seizure). EEG shows has been reported in association with multiple sclerosis, characteristic eye closure-related discharges and photosensi- Guillain–Barré syndrome, Bell’s palsy, rattlesnake bites, brain- tivity. Rhythmic or random closing of the eyes is often seen in stem tumors, and others. The clinical features of facial myo- other forms of idiopathic generalized epilepsy, with absences kymia are sufficiently distinctive to avoid confusion with other or the eyelid jerking that may occur at the opening or the ini- facial dyskinesias such as essential blepharospasm, tardive tial stage of the discharges in typical absence seizures of dyskinesia, facial tics, focal seizures, aberrant regeneration of childhood or juvenile myoclonic epilepsy. the facial nerve, hemifacial spasm, and benign facial fascicula- Toxicity from the antiepileptic drug clobazam in a 4-year- tions. Some cases of facial myokymia have occurred in asso- old boy has been reported to cause episodes of eye rolling, ciation with spastic paretic facial contracture, which is ataxia, and back arching, which were nonepileptic.50,188 characterized by tonic spasm of the paretic facial muscles, with Chung et al found ictal eye closure to be a reliable indicator typical prominence of the nasolabial fold and deviation of the of psychogenic nonepileptic seizures.165 nose toward the affected side. We have examined a patient The workup of tics is conservative, consisting mainly of with diffuse disseminated encephalomyelitis who showed left observation, unless otherwise dictated by the presence of facial myokymia, spastic paretic facial contracture, and one-and- associated clinical findings. Explanation and reassurance of one-half syndrome and who also showed scattered lesions in patients and their families is helpful in steering them away the brainstem on MR imaging. from becoming too focused on the tics. Neuroleptics and Gilles de la Tourette syndrome is a bizarre but relatively other drugs should be reserved for severe cases. The long- common disorder that comprises multiple involuntary motor term prognosis of tics is good, with about two-thirds of cases tics and obscene utterances. There is a predilection for whites spontaneously remitting.186 360 7 Complex Ocular Motor Disorders in Children

Hemifacial Spasm of epilepsy should also be considered, as hemifacial spasm has been reported as part of a seizure phenomenon.21,41,356 Hemifacial spasm is primarily a disorder of middle-aged and The presence of hemifacial spasm in an infant should older individuals, but a variety of cases have been reported in therefore be considered an ominous sign. childhood. Hemifacial spasm is characterized by involuntary, Langston and Tharp470 described a case of infantile hemi- intermittent unilateral twitching of the muscles innervated facial spasm beginning at 6 weeks of age. Surgical explora- by the facial nerve, almost uniformly including the orbicu- tion at 5½ years of age revealed a ganglioneuroma of the laris oculi. They differ from tics in several ways, including fourth ventricle. Flueler et al271 described three infants who the inability of the patient to suppress the twitches or initiate presented with the onset of hemifacial spasm in the first year them, and the absence of compulsion to make them. In about of life. One patient had occlusion of the straight sinus and half the patients, a particular position of the head (most com- large collateral vessels at the base of the brain, supporting monly, the contralateral lateral decubitus position) dimin- the concept of vascular compression of the facial nerve at ishes or halts the spasms. The patient may hear ipsilateral its exit from the brainstem as a mechanism for the produc- clicking sounds if the stapedius muscle is involved. tion of hemifacial spasm. Each of the other two patients had Hemifacial spasm should be differentiated from blephar- an intrinsic mass compressing the fourth ventricle: one was ospasm and facial myokymia. Essential blepharospasm con- located in the lower pons and extended into the cerebellar sists of bilateral, localized, repetitive spasms of the orbicularis vermis and right cerebellar peduncle; the other involved the oculi muscle that, in severe cases, leads to visual impairment. cerebellar vermis and right middle cerebellar peduncle. The rare case of bilateral hemifacial spasm can be distin- Interestingly, hemifacial spasm has been described in some guished from essential blepharospasm because the bilateral cases of Joubert syndrome, which includes cerebellar vermis contractions do not occur synchronously. Essential blephar- aplasia or hypoplasia.438 Unlike the usually benign nature of ospasm is not seen in children, but excessive blinking due to the late childhood and adult variety, it appears that early- tics or blepharospasm due to ocular disorders, such as con- onset hemifacial spasm should raise suspicion of an underly- genital glaucoma, may bear superficial resemblance to essen- ing CNS malignancy. Neuroimaging is therefore warranted tial blepharospasm. Facial myokymia consists of continuous, in cases of hemifacial spasm with onset in the first 2 years of fascicular rippling movements of the face that usually begin life. In older children with typical, isolated, hemifacial in the orbicularis muscle. It is not affected by voluntary or spasm, neuroimaging should be obtained when atypical fea- reflex activity of the face. The most common causes include tures (headaches, facial pain, cranial neuropathy, cerebellar multiple sclerosis and brainstem glioma. dysfunction) are present.46 Most adult cases of hemifacial spasm are caused by vascu- In the toddler with apparent hemifacial spasm, the diagno- lar compression of the facial nerve at the root exit zone of the sis of accommodative esotropia should also be considered.122 brainstem.397,806 The offending vessels are usually arterial, In this setting, a young child may have to exert a hemifacial most commonly the anterior or the posterior inferior cerebel- contraction to close one eye to prevent diplopia. For this rea- lar artery or the posterior inferior cerebellar artery.667 This son, a cycloplegic refraction should be included in the diag- neurovascular compression theory was challenged by an MR nostic evaluation of hemifacial spasm.122 Both botulinum imaging/MR angiography study that concluded that the devel- injection and surgical decompression of the facial nerve have opment and severity of hemifacial spasm were not associated been used with good results in both adults and children.153,704 with a specific blood vessel or multiple neurovascular contact Microvascular decompression of the facial nerve is consid- points.367 “Cross talk” between the sensory and motor ered the definitive treatment by some authors. Jho and branches of the seventh nerve has been suggested as an under- Jannetta402 described improvement of hemifacial spasm with lying pathophysiology. Congenital or acquired cholesteatoma microvascular decompression of the facial nerve in two chil- is the most common associated tumor. Vascular malforma- dren and eight adults who had the onset of hemifacial spasm tions of the posterior fossa have also been implicated. Rare before the age of 20. familial cases suggest a component of genetic transmission. Friedman et al278 described a family in which hemifacial spasm occurred in five members through three generations. Aside from neurovascular compression,490,540 a variety Eyelid Retraction of rare causes of hemifacial spasm have been identified in children. These include venous sinus thrombosis,271 masses The margin of the upper eyelid is normally located 1–2 mm of the fourth ventricle, 271 ganglioneuroma,470 pilocytic astro- below the upper corneoscleral limbus. Upper eyelid retrac- cytoma,538,667 congenital or acquired cholesteotoma,630 tuber- tion is more commonly considered in the adult age group, culous meningitis,670 thickening of the arachnoid membrane,443 where it occurs most commonly in patients with thyroid and possible intrauterine facial nerve injury.831 The diagnosis eye disease, dorsal midbrain syndrome, trauma, proptosis, Eyelid Abnormalities in Children 361 and seventh nerve palsy, amongst other conditions. SCAs, and orbital fat expansion is more common than extraocular such as Machado–Joseph disease, are known to produce a muscle enlargement on imaging studies. Compressive optic peculiar “ocular stare” that is has been attributed to lid retrac- neuropathy is rare.228 Secondhand smoke has been implicated tion rather than proptosis. as a possible pathogenetic factor.152 Unless specific clinical or The causes of eyelid retraction in children are heteroge- neuroimaging findings suggest the diagnosis of Graves orbit- neous (Table 7.12).729 Graves orbitopathy is rare in children. opathy, neurological causes should be primarily considered. When it occurs, it is less severe than in adults,317,766,827 and Bilateral lid retraction in dorsal midbrain syndrome is most cases require no treatment.228 Most children are clini- attributable to disruption of inhibitory fibers from the poste- cally hyperthyroid at the time of diagnosis.228 Exophthalmos rior commissure to the central caudate nucleus.182 Rarely, is notably less common in the prepubescent group, presum- patients with medial midbrain lesions demonstrate a “plus ably because there is room for the orbit to grow and produce minus lid syndrome” characterized by ipsilateral ptosis (from a physical decompression. In our experience, diplopia is rare, injury to the oculomotor fascicle) and contralateral lid retrac- tion (from disruption of bilateral inhibitory fibers to the central caudal nucleus). When the ptosis resolves, the ptotic lid can Table 7.12 Causes of eyelid retraction in children assume a retracted position.283,287 Setting sun sign/hydrocephalus/dorsal midbrain syndrome (Collier sign) Lid retraction in children is often intermittent, as in aber- Congenital, cryptogenic rant reinnervation associated with congenital oculomotor Oculomotor palsy with aberrant innervation Oculomotor palsy with cyclic spasm palsy or the MGJW phenomenon. Cases of neuromyotonia Marcus Gunn jaw winking affecting only the levator muscle would also be expected to Eyelid retraction to darkness (normal in first year of life) show isolated intermittent lid retraction. Cases of oculomo- Neuromyotonia tor palsy with cyclic spasm show intermittent momentary Graves disease/hyperthyroidism elevation of the eyelid on the affected side, but careful scru- Familial periodic paralysis tiny of the ocular alignment and the mandatory pupillary Orbital hemangioma involvement in the cyclic process confirm the diagnosis.499 Optic nerve anomalies with vertical nystagmus Contralateral ptosis with compensatory superinnervation of both A single case of posttraumatic, bilateral, pupillary-involving levators (fixation duress) oculomotor palsy has been reported, wherein the patient Myasthenia gravis showed bilateral nonsynchronous episodic eyelid retractions Hepatic cirrhosis not associated with eye movement or pupillary changes.467 Cushing syndrome Patients with unilateral inferior rectus restriction and alter- Levator muscle fibrosis nating fixation may show intermittent contralateral eyelid Inferior rectus muscle restriction with fixation duress retraction, which occurs as a result of Hering’s law when the Iatrogenic after surgical repair of ptosis Eyelid scarring (e.g., after inflammation from herpes zoster) restricted eye takes up fixation. Claude Bernard syndrome (sympathetic irritation) Healthy infants also frequently display eyelid retraction to Volitional lid retraction darkness, which resembles the setting sun sign (Fig. 7.22). “Startle” reflex to dimming light in infants Eyelid retraction to darkness can be elicited by turning off the

Fig. 7.22 Pseudo-setting sun sign. Healthy infant showed eyelid retraction immediately after room light was turned off (a) that resolved when ambient illumination was restored (b) 362 7 Complex Ocular Motor Disorders in Children room lights while observing the palpebral fissures. It can be a normal in 3–14 months in all cases. Similar cases of isolated clinically useful sign that an apparently blind infant has at accommodative paresis in otherwise healthy young patients least light perception vision. The phenomenon, which appears have been previously reported.163,222 Idiopathic paralysis of the to be limited to the first year of life, disappears when ambient near vision triad has also rarely been described.449 illumination is restored and is thought to represent a primitive Organic causes of accommodative paresis include head/ startle reflex. neck trauma, pharmacologic agents, systemic diseases (diph- theria, diabetes mellitus, decompression sickness), neuro- muscular disease (myasthenia gravis, myotonic dystrophy, Apraxia of Eyelid Opening botulism, tetanus), neurologic diseases (dorsal midbrain syn- drome, encephalitis, Wilson disease, hemispheric hematoma, Apraxia of eyelid opening is a nonparalytic motor disorder of oculomotor nerve palsy, Adie tonic pupil), ocular disease the eyelids. It is characterized by the inability to volitionally (uveitis, trauma, metastasis, glaucoma), and presbyopia. initiate eyelid opening despite intact reflex lid elevation, lack Isolated accommodation palsy can also be functional in origin. of concurrent orbicularis oculi muscle contraction, and intact Accommodative paresis can be one of the earliest symptoms ocular motor nerves. Affected patients open the eyes manu- of dorsal midbrain syndrome, resulting from either hydro- ally or may employ a head thrusting movement to do so.484 cephalus or compression by an extrinsic tumor such as a It may be differentiated from blepharospasm by the absence solid pineal tumor.592 Blurred vision and isolated accommo- of Charcot’s sign (orbicularis contraction forces the eyebrows dative palsy have been reported in patients with symptomatic to a level lower than the superior orbital margin). The condi- pineal cysts,86 which are usually considered to be an inciden- tion usually appears in older patients with extrapyramidal dis- tal radiologic finding (1.2–2.4% of all MR studies).301,477,677 ease, but may be seen in patients with unilateral or bilateral Accommodative paresis is a common component in children hemispheric dysfunction. It may respond favorably to with Down syndrome, leading to the frequent need for bifocals. Botulinum injections.418 The extra accommodative effort exerted by these patients may explain the development of esotropia and the common undercorrections experienced after strabismus surgery for this condition. Pupillary Abnormalities Adie Syndrome Congenital Bilateral Mydriasis Isolated internal ophthalmoplegia is commonly due to trauma Congenital mydriasis is a rare defect that was first described or pharmacological dilatation of the pupil or is a feature of by White and Fulton in 1937.802 Lindberg and Brunvand Adie syndrome. Adie syndrome is rare in childhood,498 having described a 12-year-old girl with congenital bilateral mydri- an average age of onset of approximately 32 years and a pre- asis in association with aneurysmal dilatation of a persistent dilection for females. It is characterized by unilaterally or ductus arteriosus.496 They attributed these findings to a hyp- bilaterally enlarged, tonic pupils that show markedly slow oplastic or aplatic sphincter and ciliary body because there constriction to either light or near stimulation, followed by a was also absent accommodation. Khan et al reported two very slow, tonic, redilatation. Patients with Adie’s syndrome patients with dilated pupils with hypoplasia of the iris, also show regional corneal hypesthesia due to interruption of Moyamoya angiopathy, dolichoectatic internal carotid arter- fibers of the ophthalmic division of the trigeminal nerve ies, and patent ductus arteriosus. The mechanistic link as they traverse the ciliary ganglion. between the ocular and cardiac defects is unclear.433 The light-near dissociation found in Adie syndrome differs in pathophysiology from that seen in mesencephalic disease; it may be attributed to either diffusion of acetylcho- line from partially innervated or reinnervated ciliary muscle Accommodative Paresis to the supersensitive pupillary sphincter muscle343 or by aber- rant misdirection to the pupillary sphincters of nerve fibers A recent report described five children with a syndrome of that originally synapsed in the ciliary muscle.744 An accom- benign transient loss of accommodation. No child had other modation paresis may also be associated, which is under- ocular, neurological, or systemic abnormalities that could be standable if one considers that the ciliary ganglion has 30 associated with accommodative paralysis.18 All had preserved times more neurons destined for the ciliary muscle than for pupillary responses to light and near, and preserved convergence. the iris sphincter. Following acute onset, most of the sprouting All did well with bifocals, and accommodation returned to new axons arise from accommodative neurons, but many of Pupillary Abnormalities 363 these end up in the iris sphincter (i.e., aberrant regeneration). rate.294a Whether the tonic pupils result from result from a para- Hence, although the pupils tend to be large at presentation, neoplastic disorder or from the effects of a generalized neuro- they become smaller with the passage of time and may even- cristopathy is unclear. Recently, a case of reversible posterior tually be confused with Argyll Robertson pupils if the exam- leukoencephalopathy was reported in association with an iner is not aware of their earlier dilated status. Adie’s tonic pupil in a 9-year-old boy following measles vac- With the slit lamp, segmental vermiform movements of cination.49 Botulism should also be considered in the differen- the iris and sectoral palsy are seen. Sectoral palsy produces tial diagnosis of bilateral tonic pupils. In this setting, the tonic shifting of the iris stroma toward the area of active contrac- pupils may persist as a chronic condition.277 tion, a phenomenon known as “iris streaming.”743 An associ- Thompson743 classified patients with tonic pupils into three ated sectoral palsy of the ciliary muscle causes lenticular general categories on the basis of their underlying pathophysi- astigmatism that may blur vision during near tasks. The iris ologic disorders: (1) Local pathologic disorders within the vermiform movements noted at the slit lamp represent normal orbit that involve the ciliary ganglion (e.g., inflammatory pro- contractile activity of those iris sectors still innervated by cesses such as herpes or sarcoid, trauma). These conditions are light-responsive neurons. Citing two young adults who were commonly unilateral. (2) Neuropathic conditions causing dif- found to have long-standing miotic pupils in association with fuse peripheral or autonomic neuropathy. These include syphi- typical features of Adie’s syndrome, Rosenberg658 has argued lis, diabetes, Guillain–Barré syndrome, Ross syndrome,798 and that some cases of Adie syndrome primarily present with several hereditary neuropathies, such as Shy–Drager and miotic pupils in a manner analogous to primary aberrant Charcot–Marie–Tooth diseases. These conditions are typically regeneration of the oculomotor nerve. However, the observa- bilateral. The presence of Adie-like pupils in an infant younger tion of Adie syndrome with dilated pupils in children as than 1 year of age should raise the possibility of familial dys- young as 4 years6 (with subsequent development of miosis) autonomia (Riley–Day syndrome).294 Cryptogenic tonic argues against this hypothesis. pupils, or true Adie syndrome, begins unilaterally, but eventu- Because oculomotor palsy rarely presents with isolated ally at least 20% of patients develop the syndrome bilaterally. mydriasis,495,799 it is important to look closely for an exopho- In addition to the ocular signs, the deep tendon reflexes, espe- ria that increases in adduction and for alternating hyperpho- cially the knee and ankle jerks, may be diminished or absent. rias in vertical gaze to rule out subclinical oculomotor nerve Adie syndrome bears some resemblance to Ross syn- palsy. It is now recognized that cholinergic supersensitivity drome, which is a rare, presumably degenerative peripheral of the iris sphincter may also develop in oculomotor palsy neuropathy characterized by the triad of unilateral or bilateral with pupillary involvement.391 Other clinical signs usually tonic pupil, hyporeflexia, and segmental anhidrosis.798 The attributed to postganglionic damage (light-near dissociation, recent demonstration of subclinical segmental hypohidrosis segmental sphincter palsy) can also be seen,391 so it is impor- in patients with Adie syndrome suggests that the two condi- tant to differentiate Adie pupil from an early or resolving tions may be related.327 oculomotor nerve palsy. The diagnosis of Adie syndrome can be confirmed by One case of Adie syndrome involved a 4-year-old boy demonstrating constriction of the dilated pupil in response to who developed bilateral consecutive, idiopathic Adie syn- a dilute solution of pilocarpine (0.125%), which confirms the drome over a follow-up period of 6 years.6,230 At the age of 4 presence of pupillary supersensitivity due to parasympathetic years, he was diagnosed with right Adie syndrome and was denervation. This supersensitivity may not be demonstrable found to have amblyopia, because the associated accommo- acutely, with some acute cases failing to constrict even to dative difficulty unmasked his latent hyperopia.6 Examination strong solutions of pilocarpine, making a differentiation from at age 10 revealed additional myotonic involvement of the pharmacologic blockade difficult. left pupil and absent or sluggish deep tendon reflexes.230 Pharmacological misadventures are a common cause of Two children with unilateral congenital tonic pupils were isolated pupillary dilation, resulting from instillation of found to have ipsilateral orbital neural-glial hamartoma.124,298 mydriatic agents, exposure to certain plants that contain Two children with Adie pupil have recently been found to have belladonna or atropine-like alkaloids (e.g., jimsonweed ), or an endodermal cyst of the intracranial oculomotor nerve.561,799 exposure to certain perfumes or cosmetics. The mydriatic Tonic pupils have also been described in a child with neuro- pupils associated with ophthalmoplegic migraine, oculomo- blastoma and attributed to a paraneoplastic process.800 Lambert tor palsy with cyclic spasm, botulism, Fisher syndrome, and et al469 reported bilateral tonic pupils in two infants with a the dilated pupil accompanying the dorsal midbrain syn- congenital neuroblastoma, Hirschsprung disease, and central drome do not usually cause a diagnostic problem due to the hypoventilation syndrome. Children with congenital hypoventi- other associated features of these disorders. Various infec- lation syndrome tend to have miotic pupils with light-near tious diseases have been associated with pupillary mydriasis dissociation, convergence insufficiency, and other defects in or tonic pupils, including herpes zoster, measles, diphtheria, autonomic control such as absence of normal variability in heart syphilis, pertussis, scarlet fever, smallpox, influenza, and 364 7 Complex Ocular Motor Disorders in Children hepatitis, but a history of an infectious illness is usually of the sympathetically supplied superior tarsal muscle) and present. Chickenpox may produce a tonic pupil in children, corresponding elevation of the lower eyelid (upside-down which may present during the incubation period, the active ptosis) due to denervation of the lower eyelid retractors. disease stage, or during convalescence.297,359,584,650,659 The The upside-down ptosis may be confirmed by matching mydriasis and decreased accommodation in the setting are the lower limbus to the lower lid margin in each eye; more presumed to reflect direct infectious or inflammatory involve- scleral showing would be found on the normal side. The ment of the ciliary ganglion; however, the coexistent iridocy- resulting narrowing of the palpebral fissure leads to an appar- clitis with iris stromal vasculitis and sphincter necrosis could ent enophthalmos. (3) Anhidrosis if the lesion is proximal to also contribute in some cases. The finding of mutton-fat ker- the carotid bifurcation. Lesions distal to the carotid bifurca- atoprecipitates and/or sectoral iris stromal atrophy would tion do not affect sympathetic innervation of facial sweat favor the latter mechanism. glands. Both acquired and congenital Horner’s syndrome Traumatic injury, either to the iris sphincter or to the cili- rarely causes Harlequin syndrome, a neurocutaneous phe- ary nerves (e.g., panretinal photocoagulation, orbital sur- nomenon in which one half of the face fails to flush during gery), may also produce pupillary mydriasis or tonic pupils.76 thermal or emotional stress as a result of damage to vasodila- Some children may present with isolated episodic unilateral tor sympathetic fibers.101,564 In some cases, however, this con- or bilateral mydriasis accompanied by head pain328,832; these dition cannot be attributed to straightforward sympathetic may represent a variant of ophthalmoplegic migraine or rep- injury.157 Some children show a different pattern of scalp hair resent a migraine equivalent and are usually self-limited.773 growth, with straight hair on the affected side.698 Congenital or perinatal Horner syndrome results in failure of the iris to become fully pigmented, resulting in hetero- chromia, with the ipsilateral iris appearing lighter in color. Horner Syndrome Iris heterochromia takes several months to develop and may be difficult to detect in infants who normally have lightly Horner syndrome results from a lesion affecting the sympa- colored irides. Wallis et al reported the unusual case of a thetic supply to the eye and may be encountered at any age 20-month-old boy with congenital Horner syndrome, with (Fig. 7.23). The clinical features found on the affected side the darker iris on the affected side attributable to concomi- include the following: (1) 1–2 mm of miosis, with greater tant Waardenburg syndrome.792 Much less commonly, het- anisocoria in dim illumination and a dilation lag. The miosis erochromia may also follow acquired lesions in adults.209 results from denervation of the sympathetically innervated Subtle iris heterochromia can sometimes be made more vis- pupillary dilator muscle. Oculosympathetic denervation of ible by examining the child in sunlight. Some congenital the pupillary dilator muscle can be demonstrated by dim- cases may present with ipsilateral facial flushing.665 Patients ming the ambient light and observing an immediate but tran- with acute Horner syndrome may also exhibit decreased sient increase in anisocoria, because the affected pupil does Schirmer response, transient myopia, transient hypotony, not dilate as rapidly as the normal pupil (dilation lag). (2) and transient conjunctival hyperemia. The last three signs are Mild upper lid ptosis measuring 1–2 mm (due to denervation seen only in acquired cases. The location of the causative lesion along the sympathetic pathway may be inferred clinically and confirmed pharma- cologically and/or neuroradiologically.210 For instance, the combination of Horner syndrome and ipsilateral abducens palsy implicates a lesion in the cavernous sinus. Mesencephalic lesions, involving the trochlear nucleus or fascicles before decussation in the superior medullary velum and adjacent sympathetic fibers, may produce an ipsilateral Horner syn- drome and contralateral superior oblique muscle paresis.322 Pharmacological testing consists of topical instillation of autonomically active drugs to confirm oculosympathetic paralysis (cocaine test) and to distinguish a preganglionic from a postganglionic lesion (hydroxyamphetamine test). However, a preganglionic congenital Horner syndrome may show a false-positive hydroxyamphetamine test because of transynaptic degeneration.216 Fig. 7.23 Congenital Horner syndrome. Note right upper lid ptosis, right miosis, and mild heterochromia. Right lower lid shows mild Recently, apraclonidine 0.5% has been touted as a diag- reverse ptosis, covering more of cornea than its left counterpart nostic test for Horner syndrome on the basis of its alpha-2 Pupillary Abnormalities 365 inhibitory effects in normal eyes and weak alpha-1 adrener- Congenital tumors, including neuroblastoma of the neck, gic/excitatory effects in Horner eyes. Apraclonidine makes chest, or abdomen have been reported to underlie some cases the Horner pupil dilate and the normal pupil constrict of congenital Horner syndrome.143,676,678,814,830 Most reported slightly.154,416 The reversal of anisocoria is more obvious with cases of neuroblastoma occurred in the neck,2 where they are the room lights on.155 Apraclonidine is reported to be safe frequently mistaken for infectious adenitis, or in the medi- and effective in the pediatric population because it does not astinum,703 but three patients with abdominal neuroblastoma cross the blood–brain barrier, thereby reducing the incidence have also been described.290,572 Because the cervical sympa- of centrally mediated effects.155 However, a recent report thetic chain does not descend to the abdominal level, the documenting CNS and respiratory depression in three chil- Horner syndrome in these cases was probably caused by dren (one requiring intubation) suggests that its use in chil- metastatic cervical lesions or a second (undiagnosed) pri- dren should probably be avoided.634 mary lesion. Cervical neuroblastoma causing Horner syn- Iris pigmentation, which occurs within the first year of drome can be associated with other paraneoplastic disorders life, requires sympathetic stimulation. Interestingly, Mindel such as cerebellar degeneration.237,810 et al549 reported a 21-year-old woman with neurofibromatosis Other systemic clues to the presence of neuroblastoma type I who had a unilateral congenital Horner syndrome with may be present. Nonophthalmologic symptoms of neuro- heterochromia. The patient showed symmetric Lisch nod- blastoma include pain (due to primary tumor, bone marrow ules, which are melanocytic hamartomas, in both eyes, sug- involvement, or abdominal distension), watery diarrhea (due to gesting that, unlike iris pigmentation, the formation of Lisch paraneoplastic secretion of a vasoactive intestinal peptide),552 nodules is not influenced by sympathetic innervation of the and acute cerebellar encephalopathy,99 which may be related iris. Other causes of heterochromia, such as iris nevus or to antineural antibodies such as anti-Hu, formed in response melanoma, neurofibromatosis, hemosiderosis, hemochroma- to the tumor that react to the normal cerebellum.269 There tosis, Waardenburg syndrome, Fuch heterochromic iridocy- is an unusually high rate of spontaneous regression in the clitis, and essential iris atrophy, should be excluded. neuroblastoma of young infants, even in the disseminated Most cases of congenital or early acquired Horner syn- form.523 Asymptomatic infants may have biologically favor- drome are of a benign nature.289,399,814 Rarely, congenital able tumor with higher rate of spontaneous regression.523 Horner syndrome may occur as an autosomal dominant dis- Horner syndrome acquired in early life may be very difficult order. Hageman et al324 reported a Dutch family with five to distinguish from congenital cases, but close scrutiny of cases of congenital Horner syndrome spanning five genera- previous photographs may be helpful. tions. A history of perinatal trauma, such as brachial plexus In a large retrospective study, Mahoney et al510 found injury (Klumpke paralysis),20,797 neck or cardiothoracic sur- responsible mass lesions in six of 56 children. Two cases with gery, carotid dissection,319,648 peritonsilar lesions, and surgi- congenital Horner syndrome were caused by mass lesions cal or nonsurgical intraoral trauma, may be elicited in many (neuroblastoma in one case, neurofibroma in the other). They cases, but some cases remain cryptogenic despite extensive recommended that the brain, neck, and chest MRI with and investigations. Permanent postganglionic Horner syndrome without contrast, as well as urinary catecholamine metabolite can develop in children with a middle ear infection.370,716 testing, be performed in any child without a surgical history. Brachial plexopathies caused by forceps injury at birth are This study found direct imaging to be more sensitive than the putative cause in some cases.101 urine testing in this setting. Gibbs and colleagues290 reported MR angiography has recently brought to light the associa- a 2-year-old child with congenital Horner syndrome who was tion of congenital Horner syndrome with agenesis of the healthy until the age of 2 years, when a remote neuroblastoma ipsilateral internal carotid artery.213,388,662 Congenital Horner of the adrenal gland was diagnosed. They argued that both syndrome has also been reported with hemifacial atrophy, congenital Horner syndrome and neuroblastoma may repre- synergistic divergence, basilar impression and Chiari malfor- sent widespread dysgenesis of the sympathetic system. The mation, cervical vertebral anomaly and an enterogenous cyst, rare occurrence of underlying tumors, especially neuroblas- and viral infections such as congenital varicella469 or cyto- toma, in a few congenital cases justifies thorough neurodiag- megalovirus infections, and PHACE syndrome.531 In acquired nostic evaluation. Mahoney et al510 recommended palpation pediatric Horner syndrome, it is important to look for Lisch of neck, axilla, and abdomen, spot urine for homovanillic acid nodules and café au lait spots, because schwannomas, plexi- and vanillylmandelic acid as a ratio of creatinine (which can form neurofibromas, or malignant peripheral nerve sheath be falsely negative in patients with small neuroblastomas), tumors may affect the sympathetic tract in neurofibromatosis and MR imaging of the brain, neck, and chest, with and with- 1.137 A case of congenital postganglionic Horner syndrome out contrast (abdomen is unnecessary because the cervical and fibromuscular dysplasia of the ipsilateral internal carotid sympathetic chain does not descend to this level). artery incited speculation that prenatal or neonatal cervical Because of the recognized association of congenital trauma might have been responsible for both findings.637 Horner syndrome with ipsilateral agenesis of the internal 366 7 Complex Ocular Motor Disorders in Children carotid artery, we believe that MR angiography should also be 20. al-Rajeh S, Corea JR, al-Sibai MH, et al. 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