Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

Chapter 46

Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles Monique M. Ryan and Elizabeth C. Engle

GENERAL PRINCIPLES The extraocular muscles (EOMs) have many anatomic, physiologic, and molecular characteristics distinct from those of other striated muscles. These unique characteristics, which likely developed in response to the specialized demands placed on EOMs, including tonic position, maintaining contractures, conjugate smooth pursuit and saccades, and dysconjugate vergence movements, may account for the often predictable involvement or sparing of extraocular muscle in specific pediatric neuromuscular disorders. This selective involvement of the EOM can assist the clinician in formulating differential diagnoses for neuromuscular conditions. Extraocular muscle dysfunction in neuromuscular disease typically presents with ptosis, ophthalmoplegia, or incomitant strabismus, or a combination of these symptoms. Ptosis, or blepharoptosis, is drooping of the upper eyelid as a result of dysfunction of the levator palpebrae superioris muscle. Ophthalmoplegia is the inability to move the globe into one or more fields of gaze, and may or may not be accompanied by strabismus. Strabismus is pathologic misalignment of the eyes, resulting in loss of binocular vision. With paralytic (incomitant) strabismus, the angle of deviation of the eyes varies with the direction of gaze. This is the form of strabismus typically associated with neuromuscular disease. In this chapter, we review isolated ocular motor neuropathies, congenital ptosis, congenital cranial dysinnervation syndromes, and pediatric neuromuscular disorders associated with abnormalities of eye movement. Strabismus syndromes associated with pediatric neuromuscular conditions are summarized in Table 46.1.

THE EXTRAOCULAR LOWER MOTOR UNIT Four recti and two oblique muscles move the globe, and the levator palpebrae superioris raises the eyelid. These

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muscles are innervated by the oculomotor (CN III), trochlear (CN IV), and abducens (CN VI) cranial nerves. Axons of the paired oculomotor nuclei (nIII), each composed of contiguous midbrain subnuclei, form two branches. The inferior branch projects uncrossed axons to the medial rectus, inferior rectus, inferior oblique, and pupillary constrictor muscles. The superior branch projects crossed axons to the superior rectus and both crossed and uncrossed axons to the levator palpebrae superioris (LPS) muscle. Notably, the axons innervating the LPS arise from a single midline subnucleus located at the caudal aspect of the oculomotor complex. The paired trochlear nuclei (nIV) in the caudal midbrain send axons across the tectum to exit the brainstem and innervate the contralateral superior oblique muscle. The axons of the paired abducens nuclei (nVI) in the pons innervate the ipsilateral lateral rectus. The anatomy of the ocular cranial nerves and nuclei is depicted schematically in Figures 46.1 46.3 and described in greater detail in the following discussion. The globe is suspended in the bony orbit by the EOMs, connective tissue fascia, and fat. Because the two orbits point outward at approximately 25 degrees in the anterior-posterior plane, the vertical recti and oblique muscles are not aligned with the primary visual axis. The action of each muscle therefore depends somewhat on the position of the globe at the time of the action. The lateral and medial recti are antagonists in the horizontal plane, abducting and adducting the globe, respectively. The superior and inferior recti are partial antagonists in the vertical plane. The superior rectus primarily elevates and secondarily intorts and adducts the globe, and the inferior rectus primarily depresses and secondarily extorts and adducts the globe. The two obliques are partial antagonists and have greatest effect when the globe is adducted. The superior oblique intorts, depresses, and abducts the

B.T. Darras, H. Royden Jones, Jr., M.M. Ryan & D.C. De Vivo (Eds): Neuromuscular Disorders of Infancy, Childhood and Adolescence, Second edition. DOI: http://dx.doi.org/10.1016/B978-0-12-417044-5.00046-9 © 2015 Elsevier Inc. All rights reserved.

Chapter | 46 Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

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TABLE 46.1 Strabismus in Pediatric Neuromuscular Disorders Disorder

Ocular Misalignment

Other Visual Abnormalities

Ataxia-telangiectasia

Erratic vertical EOMs

Ocular motor apraxia Nystagmus

Cockayne syndrome

Esotropia, exotropia

Nystagmus, pigmented retinal dystrophy, enophthalmos, cataracts, corneal opacities

MELAS

External ophthalmoplegia

Ptosis

Leigh disease

Horizontal gaze palsy, tonic downgaze deviation, external ophthalmoplegia

Internuclear ophthalmoplegia, dorsal midbrain (Parinaud’s) syndrome, ptosis, optic atrophy

Kearns-Sayre syndrome

External ophthalmoplegia

Pigmented retinopathy, ptosis

CPEO

External ophthalmoplegia

Ptosis

Convergence insufficiency, upgaze limitation

Internuclear ophthalmoplegia, pigmented retinopathy

Mitochondrial Disorders

Nutritional/Metabolic Abetalipoproteinemia with vitamin E deficiency Other Disorders CIDP

CN III palsy

Joubert syndrome

Congenital fibrosis syndromes, skew deviation, horizontal tonic gaze deviation, supranuclear EOM deficits

Torsional/pendular nystagmus, ocular motor apraxia, retinal dystrophy, ptosis, colobomata

Abbreviations: CIDP, chronic inflammatory demyelinating polyneuropathy; CN, cranial nerve; CPEO, chronic progressive external ophthalmoplegia; EOMs, extraocular muscles; MELAS, syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. Source (where not otherwise noted): Brodsky et al. (1996).1

FIGURE 46.1 Schematic lateral view of the brainstem and left orbit in a normal individual. The lateral rectus is cut to expose the contents of the orbit. The cranial nerve nuclei, cranial nerves, and extraocular muscles are labeled. (CN, cranial nerve; n, nucleus.) From Engle E, 1998,2 with permission from Oxford University Press.

globe, and the inferior oblique extorts, elevates, and abducts the globe. The extraocular muscles are reciprocally innervated such that when an agonist muscle contracts, its antagonist relaxes, and they are yoked in pairs

(i.e. the right lateral rectus and left medial rectus) so that the eyes move together. The extraocular lower motor unit has a number of unique features allowing a range of pathologic responses that differs from those of other skeletal muscles (reviewed by Porter and Baker, 1996).3 The histology of EOM is significantly different from that of the skeletal striated muscles, and it appears to be more resistant to pathologic stressors.4 The architecture of EOM differs from that of limb muscle in at least three ways. EOMs have longer fibrous tendinous insertions than limb muscle. Biopsy specimens may inadvertently be taken from these elongated tendons, resulting in a misdiagnosis of pathologic fibrosis.5,6 Anatomic and neuroimaging studies have revealed the existence of connective tissue pulleys in the orbit that serve as functional mechanical origins of the four recti muscles. Anterior to these pulleys, the paths of the recti shift with gaze to follow the scleral insertions, whereas posterior to the pulleys, these paths are stable in the orbit.7,8 The recti and oblique muscles are divided into global and orbital layers (Figure 46.2). The global layer, adjacent to the optic nerve and globe, extends over the entire length of each EOM, while the orbital layer, adjacent to the orbital

924 PART | VII Special Clinical Problems

FIGURE 46.2 Light photomicrographs of monkey lateral rectus muscle. Top: Low-magnification cross-section of the muscle indicating orbital and global muscle layers. The orbital layer extends around much of the perimeter of the muscle, whereas larger fibers in the global layer fill the central portion of the muscle. Bottom: (Left) High-magnification micrograph of the orbital layer illustrating (1) orbital singly innervated and (2) orbital multiply innervated fiber types. (Right) Highmagnification micrograph of the global layer illustrating the (3) global red singly innervated, (4) global intermediate singly innervated, (5) global white singly innervated, and (6) global multiply innervated fiber types. Original magnification 3 21 (Top), 3 410 (L and R). Courtesy of Dr. John Porter, Cleveland.

walls, is absent in the most anterior aspect of each EOM. The two layers differ from one another in their distribution of fiber types and the richness of their vascular supply, and may have variable insertion points upon the EOM.8 10 The morphology of EOM fibers differs from those of limb skeletal muscle in at least two ways. Normal EOM myofibers are rounder and smaller, with greater variability in size, and are surrounded by a greater amount of perimysial and endomysial connective tissue than is limb skeletal muscle.3,4 EOM fiber typing is different from that of limb skeletal muscle; the traditionally recognized fiber classification schemes cannot be applied to EOM.9,11 Typing of EOM fibers is based on (1) distribution into global and orbital layers; (2) single versus multiple nerve contacts per fiber; and (3) mitochondrial/oxidative enzyme content. This fiber type scheme identifies six fiber types: orbital singly, orbital multiply, global red singly, global intermediate singly, global pale singly, and global multiply innervated fibers (see Figure 46.2).9,11 The levator palpebrae superioris differs from other EOMs. This muscle appears to use a ligament as a fulcrum to translate its anterior-posterior line of force into

FIGURE 46.3 Schematic anterior view of the human brainstem showing details of the cranial nerve nuclei that innervate the extraocular muscles. (nIII 5 oculomotor nucleus; nIV 5 trochlear nucleus; nVI 5 abducens nucleus.) The nIII subnuclei are shown as follows, with the muscle they innervate in brackets: 1 5 ventral lateral [medial rectus]; 2 5 medial [superior rectus]; 3 5 intermediate lateral [inferior oblique]; 4 5 dorsal lateral [inferior rectus]; 5 5 central caudal [levator palpebrae superioris]; 6 5 Edinger-Westphal [visceral motor]. From Engle E, 1998,2 with permission from Oxford University Press.

upward movement of the eyelid, has no differentiation of orbital and global layers, and lacks multiply innervated fiber types.12 The gene and protein expression profiles of EOM myofibers differ from skeletal limb muscle both during development and in maturity.13 18 While EOMs contain the normal components of the dystrophin-glycoprotein complex, including dystrophin, dystroglycans, sarcoglycans, syntrophins, dystrobrevin, and merosin, they also retain embryonic myosin,19,20 fetal acetylcholine receptors,21 23 and sarcolemmal-wide expression of polysialated neural cell adhesion molecules.19 These isoforms are more typically associated with developing or regenerating muscle fibers but may be used by EOM as an adaptation for these muscles’ normal functional demands.19 The molecular and cellular biology of the oculomotor motor neuron is distinct from that of spinal motor neurons. For example, the homeobox gene PHOX2A, which is mutated in congenital fibrosis of the extraocular muscles (CFEOM2) (see the following), is essential for development of oculomotor and trochlear motor neurons, but not spinal motor neurons.24 The alpha motor neurons of nIII, nIV, and nVI form very small motor units, often innervating only three to ten muscle fibers. In addition, a single EOM fiber can be innervated by axons from more than one motor unit (multiply innervated fibers). These motor neurons have an impressively high firing rate, often an order of magnitude higher than that of spinal motor neurons.

Chapter | 46 Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

EXAMINATION APPROACH TO EXTRAOCULAR MOVEMENT DISORDERS When interpreting abnormal eye movements or ptosis, or both, several basic approaches may be helpful. Priorities in examination are to: 1. Determine if the abnormality is attributable to a single cranial nerve or to multiple nerves. 2. Determine if the abnormality exists in isolation (e.g. congenital strabismus) or occurs in association with dysfunction of other skeletal muscle groups, syndromic malformations, or features of systemic disease. 3. Determine if the disorder is congenital or acquired. This distinction cannot be made simply by asking whether eye movements appeared normal at birth. The normal development of volitional eye movements such as fixation, visual following, and binocular alignment in the first few months of life may delay recognition of a congenital eye movement disorder. Conversely, acquired deficits may develop insidiously and thus be confused with congenital deficits. Serial examinations over time (including observation of old photographs) and attention to compensatory features (e.g. a large fusion angle suggesting congenital strabismus) may help. 4. Determine whether the dysfunction is static, progressive, recurrent, or resolving.

Examination Lid Function Ptosis can be quantified using the following methods: 1. Measure the distance between the upper lid margin and the midcorneal reflex when the globe is in normal primary position. Ptosis is present when this distance is ,2 mm or varies by more than 2 mm between the eyes. 2. Measure the amount of the superior portion of the cornea covered by the upper lid when the globe is in primary position; normal is approximately 2 mm. With ptosis, more than 4 mm of cornea is covered. 3. Measure the vertical width of the palpebral fissure; it is normally approximately 9 15 mm.

Pupil Assess pupil size and reactivity. If anisocoria is present, it should be observed under varied illumination; in Horner syndrome, the anisocoria is more apparent in darkness and a lag in pupillary dilation may be observed, whereas with pupillary constrictor paresis, the difference is more evident under bright light. A relative afferent pupillary

925

defect, indicating optic nerve dysfunction, is detected by swinging a bright light source from one pupil to the other, watching for dilation in the affected eye. Slit lamp examination may identify sectoral irregularities in the iris, an indication of reinnervation.

Ocular Alignment Assess ocular alignment by the alternate cover test or Maddox rod testing. A patient with a phoria prefers to fixate with one eye and will shift eye position only when the preferred eye is covered; if a tropia is present, fixation will shift when either eye is occluded. The degree of horizontal or vertical misalignment can be quantified using prisms. The Bielschowsky three-step test is valuable for identification of trochlear nerve palsies (see “Trochlear Palsy (CN IV)” section). Information as to whether ocular misalignment is long-standing may be obtained via stereoacuity tests.

Ductions Assess ductions by having the patient follow a hand-held target to all cardinal positions of gaze; observe the range, speed, and smoothness of these movements in each eye, as well as whether the two eyes move conjugately. The examiner can best observe both eyes simultaneously by fixating on the patient’s nose. When there is limitation of movement to a given position of gaze, it may be difficult to distinguish between weakness of an EOM (e.g. lateral rectus) and restriction or overaction (or both) of its antagonist (medial rectus). The speed and smoothness of movement may serve as a clue; sudden slowing toward the end of an excursion suggests restriction of the antagonist. The definitive tests, however, are those of forced duction and active force generation. Forced duction testing is performed by grasping the anesthetized extraocular muscle, tendon, or globe itself, and pulling it through its range of motion; the examiner directly feels any mechanical restriction. In young children, this procedure often requires general anesthesia. Active force generation requires the alert patient’s cooperation to attempt eye movements while the examiner grasps muscle, tendon, or globe and senses muscle force.

Horizontal and Vertical Saccades Assess horizontal and vertical saccades by asking the patient to rapidly switch fixation between the examiner’s nose and targets held in each extreme of the visual field. Slow saccades suggest muscle weakness or, in the case of the medially directed saccades, an internuclear ophthalmoplegia; saccades that begin rapidly but slow toward the end of their excursion suggest restriction of the opposing EOM. Repeated saccades may reveal the fatigability

926 PART | VII Special Clinical Problems

associated with myasthenic syndromes. Hyper- or hypometric saccades suggest cerebellar disease. Occasionally, disturbances in smooth pursuit suggest a particular pattern of EOM involvement—for example, the upshoot seen during medial pursuit in Duane’s syndrome (see below). Both horizontal and vertical head thrusts take advantage of vestibular input to indicate the true range of motion of the eyes where voluntary maneuvers fail to do so; in addition, they provide helpful information about central control of eye movements. Identification of nystagmus indicates central dysfunction but may also provide an indirect indication of limitation, such as with the abducting nystagmus seen when medial deviation of the opposite eye is limited. Finally, additional general ophthalmologic testing assists in identifying visual pathway dysfunction that may affect ocular motility. This testing may include assessment of visual acuity at far and at near, color perception, the visual fields, and the funduscopic appearance of the optic nerves and the central and peripheral retina. The latter also may be particularly helpful to identify complex neurologic syndromes of which abnormal EOMs are a single component.

CRANIAL NERVE PALSIES Oculomotor Palsy (CN III) Anatomy The oculomotor nucleus consists of a series of closely associated subnuclei arranged along the dorsal-ventral and rostral-caudal dimensions of the tectum of the midbrain (see Figure 46.3). A midline dorsal and caudal subnucleus provides bilateral innervation to the levator palpebri. Together with the contralateral axons from the superior rectus subnucleus, these axons form the superior division of the nerve. All EOMs other than the superior recti are innervated ipsilaterally via the inferior division of the nerve. Pupillary fibers emerge from the single midline Edinger-Westphal nucleus in the complex, and run superficially within the nerve fascicle to the ipsilateral ciliary muscle and iris sphincter.1

close proximity of the oculomotor nucleus to other brainstem structures, acquired nuclear lesions are often associated with other neurologic signs such as somnolence and hemiplegia. Lesions affecting the oculomotor nerve fascicle cause ipsilateral signs because the axons serving the superior recti have already decussated within the nuclear complex.25 Because the oculomotor nerve fibers pass through the reticular formation, red nucleus, and substantia nigra, a lesion along their course may lead to ipsilateral ataxia (dentatorubrothalamic tract) or contralateral hemitremor, hemichorea, or hemiballismus (red nucleus and substantia nigra). In the interpeduncular cistern, CN III may be subject to compression from aneurysms, although this is very rare in childhood. Early involvement of the pupil in oculomotor palsies points to compressive lesions, as the dorsomedial placement of the pupillary fibers in the nerve fascicle renders them susceptible to compression.1 Just before entering the cavernous sinus, the third nerve is susceptible to compression at the free edge of the tentorium and the clivus. Uncal herniation generally causes an ipsilateral, and rarely a contralateral, oculomotor palsy in which the pupil is involved early. Ipsilateral involvement of CN III, CN IV, and CN VI localizes to the cavernous sinus or orbital apex. Involvement of the trigeminal nerve is often more extensive with cavernous sinus lesions, whereas the presence of proptosis or visual loss from optic neuropathy, or both, defines the orbital apex syndrome. In the cavernous sinus, the nerve lies dorsally and deep in the lateral wall, superior to the trochlear nerve; as it enters the superior orbital fissure, it divides into superior and inferior divisions. The superior division innervates the superior rectus and levator palpebrae superioris, whereas the inferior division innervates the inferior and medial recti, inferior oblique, and ciliary ganglion. Thus, an isolated superior division palsy causes globe depression and ptosis, whereas an isolated inferior division palsy results in abduction, elevation, and mydriasis.26 Lesions at the apex or within the superior orbital fissure typically produce divisional palsies, but because the fibers are segregated within the nerve along much of the fascicular course, more proximal lesions can also produce these findings.

Localizing Syndromes The anatomy of the oculomotor nuclei and nerve produces clinical features helpful in the localization of oculomotor palsies.1 Third nerve palsies can be localized to the nucleus if they include contralateral involvement of the superior rectus and bilateral involvement of the levator palpebri (and probably also of the medial recti). They may localize to the nerve if ptosis and ophthalmoplegia are ipsilateral, and to only the superior division of the nerve if the ophthalmoplegia is limited to vertical limitations as seen in CFEOM (see the following). Given the

Fundamental Signs and Symptoms Oculomotor palsies classically present with ptosis, mydriasis, and external ophthalmoplegia. With a complete third nerve palsy, the pupil is large and does not constrict to light or vergence efforts, and near accommodation is impaired. The affected eye is depressed and abducted, and limited in adduction and elevation. Ptosis is severe. Correspondingly, patients complain of ptosis, blurred vision especially at near (due to inability to accommodate sufficiently), and diplopia.

Chapter | 46 Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

Although the major clinical features are the same in congenital and acquired forms of oculomotor palsy, subtle differences in presentation (e.g. presence of amblyopia, synkinesis, pupillary involvement, or fluctuating symptomatology) may help distinguish the two forms.

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Acquired CN III Palsies

acquired conditions such as infection, tumor, orbital pseudotumor, hemorrhage, thrombosis, aneurysm, or TolosaHunt syndrome. In contrast, synkinesis or sparing of the pupil suggests a more benign cause. Diplopia in acquired oculomotor palsy is usually oblique in primary position, but varies with the relative degree of weakness in each muscle, and may be obscured if ptosis is severe enough to occlude the paretic eye. Although intorsion due to inferior oblique involvement is not often detected clinically, the patient may perceive a tilted sense of vertical (not always in the paretic eye or in the expected direction).50 Acquired partial oculomotor palsies suggest pathology at extremes of the oculomotor nerve: either discrete lesions in the midbrain, involving an oculomotor subnucleus, or focal intraorbital lesions. Nuclear causes include focal metastasis, ischemia, or demyelination, while orbital causes include myasthenia gravis, trauma, tumor, or inflammation.1,43,51,52 Recurrent transient oculomotor palsies in childhood are most commonly due to ophthalmoplegic migraine. This uncommon inflammatory cranial neuropathy is much more frequent in children than adults. Onset is generally before age 10. Each episode typically begins with a severe ipsilateral hemicranial headache, with ophthalmoplegia developing within hours to days (rarely up to 14 days), and generally resolving after 3 to 4 days. Deficits rarely persist as long as a month, and synkinesis may develop.1,53 55 Although a complete oculomotor palsy is most frequent, isolated pupillary involvement can occur, and involvement of the fourth and sixth cranial nerves, oculomotor divisions, and levator palpebrae are also reported in ophthalmoplegic migraine.55 Rarely, recurrent ophthalmoplegia may occur in the absence of headache, in what may represent a migraine equivalent.56,57 Magnetic resonance imaging (MRI) studies commonly show enlargement and contrast enhancement of the interpeduncular portion of the oculomotor nerve during, and occasionally following, ophthalmoplegic migraines (Figure 46.4),53,55,59 while the CSF examination is normal.55 Tolosa-Hunt syndrome is an acute syndrome of orbital pain and ophthalmoplegia caused by granulomatous inflammation within the cavernous sinus or orbit, which responds rapidly and dramatically to oral steroids but may recur. Myasthenia gravis should be suspected whenever ptosis or diplopia fluctuate in severity.52

Acquired oculomotor palsies are more often partial than complete, and may be isolated or associated with more generalized neuromuscular processes (Table 46.2). The most common causes of oculomotor palsies are trauma (up to 72%),29,31,33 neoplasm (5 31%), inflammation or infection (9 25%), migraine (7 19%), and other vascular pathologies (3 13%). As many as 20% of cases are cryptogenic.28,48,49 Painful ophthalmoplegia often involves more than one cranial nerve, and suggests

Isolated Pupillary Dysfunction Pediatric CN III palsies occasionally present with isolated pupillary dilatation. This must be distinguished from Adie’s tonic pupil and from a contralateral Horner syndrome. Adie’s pupil may develop cryptogenically or as a parainfectious, posttraumatic, or migrainous phenomenon, and is often associated with depressed deep tendon

Etiology Third nerve palsies are rare, and less common than fourth or sixth nerve palsies in childhood.27,28 About 2/3 are partial, and 1/3 complete.27 As many as 47% of all pediatric oculomotor palsies are congenital.29 Acquired causes include trauma (12 37%), infection and other inflammation (6 21%), tumor (3 17%), and migraine (3 9%). Aneurysms and other vascular events account for 3% to 11%. The cause remains undetermined less often in children (2 14%) than in adults (25 32%).27,28,30 33 Congenital CN III Palsies Congenital oculomotor palsies in otherwise normal children are thought to relate to perinatal trauma, possibly due to molding of the skull during labor or with forceps use.31,34 Under these circumstances, the nerve may be compressed against the tentorium by displacement of the temporal lobe or by a diffuse increase in intracranial pressure.35 In other cases, the nucleus or nerve, or both, fails to develop (see later discussion of CFEOM). Congenital oculomotor palsies may be associated with contralateral hemiplegia,34,36 or developmental anomalies of the midbrain or cerebellum.37 39 A frequent clue to the congenital nature of an oculomotor palsy is the presence of aberrant regeneration with synkinesis, which presumably occurs in response to aplasia of the nucleus or disruption of the nerve.40 Such regeneration may lead to miosis, rather than dilation, of the affected pupil.30,34 Another common finding is amblyopia, usually in the paretic eye but occasionally in the nonparetic eye.27,31 Partial congenital oculomotor palsy may manifest as a divisional palsy or as isolated dysfunction of CN III-innervated muscles, in particular the levator, inferior rectus, inferior oblique, or pupillary constrictor. These disorders likely represent a spectrum of developmental anomalies of the subnuclei and muscles.6,41 47

928 PART | VII Special Clinical Problems

TABLE 46.2 Etiology of Acquired Ocular Motor Palsies in Childhood Etiology

III Cranial Nerve

IV Cranial Nerve

VI Cranial Nerve

TRAUMA

25 72%

8 50%

20 42%

Diffuse axonal injury

1

Ischemic

1

Shearing forces

1

1

1

Subdural hematoma

1

Cavernous sinus thrombosis

1

1

1

Postoperative

1

1

1

NEOPLASIA

5 31%

Rare

17 39%

Meningioma

1

1

1

Schwannoma

1

1

1

Pituitary adenoma

1

1

1

Craniopharyngioma

1

1

1

Dermoid/epidermoid

1

1

1

Teratoma

1

1

1

Sellar germ cell tumor

1

1

1

1

1

1

Cavernous sinus

Pituitary fossa

Cerebellar Astrocytoma

1

1

1

11

Pinealoma

1

1

Meningioma

1

1

Schwannoma

1

1

Acoustic neuroma

1

1

Ependymoma

1

1

Nasopharyngeal carcinoma

1

1

Medulloblastoma Brainstem glioma

1

Other neoplasms

Clivus chordoma Infiltrating neoplasms Leptomeningeal sarcoma

1

1

1

Lymphoma

1

1

1

Carcinomatous meningitis

1

1

1

Mesencephalic cyst

1

VASCULAR

3 13%

Subdural hemorrhage

1

1

Aneurysm

1

1

1

Cavernous hemangioma

1

1

1

1 2%

(Continued )

Chapter | 46 Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

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TABLE 46.2 (Continued) Etiology

III Cranial Nerve

IV Cranial Nerve

Arteriovenous malformation

1

1

VI Cranial Nerve 1

Carotid-cavernous fistula INFECTION

9 25%

Meningitis

1

1

1

Encephalitis

1

1

1 1

Mastoiditis, Gradenigo’s syndrome INFLAMMATORY Sarcoidosis

1

1

1

Tolosa-Hunt syndrome

1

1

1

Orbital pseudotumor

1

1

1

RHEUMATOLOGIC/AUTO-IMMUNE Polyarteritis nodosa

1

Multiple sclerosis, ADEM

1

1

1

Guillain-Barre´ syndrome

1

1

1

1

Sjo¨gren’s syndrome OTHER Migraine

7 19%

Toxins

1

Increased intracranial pressure

1 1 1

1 1

Thyroid eye disease

1

1

Iatrogenic

1

1

Cryptogenic

,20%

0 21%

9 36%

ADEM 5 acute disseminated encephalomyelitis.

reflexes.1,60 Adie’s tonic pupil is differentiated from an oculomotor palsy by the presence of light-near dissociation (strong constriction when viewing near targets, with poor reaction to light or accommodation). Slit lamp examination frequently reveals asymmetrical segmental constriction of pupillary fibers, often with vermiform iris movements, once reinnervation has had time to occur. Although there is supersensitivity of the pupil to 0.1% pilocarpine in lesions more than 2 weeks old, this may also be found in CN III palsies.61 In its complete form, Horner syndrome consists of ipsilateral ptosis of both upper and lower lids, miosis, and decreased sudomotor function. In congenital Horner syndrome, ocular hypotony may occur and iris heterochromia is common. Lesions along the sympathetic pathway may be secondary to birth or surgical trauma, perinatal infection, the Arnold-Chiari malformation,

neuroblastoma, and other tumors.62,63 Localization may be refined by identification of concurrent involvement of the fourth or sixth nerves (see the following) and by the use of 1% hydroxyamphetamine or 4% cocaine drops to distinguish between involvement of first, second, and third order neurons.

Trochlear Palsy (CN IV) Trochlear palsy is the most common congenital ocular motor palsy, the most common cause of acquired vertical diplopia, and, overall, the most common isolated cranial nerve palsy.28,64

Anatomy The trochlear is the only cranial nerve to emerge from the dorsal aspect of the brainstem, the only one to cross

930 PART | VII Special Clinical Problems

(A)

(B)

FIGURE 46.4 Ophthalmoplegic migraine. Coronal (A) and gadolinium-enhanced axial (B) T1-weighted images during (left) and following (right) an episode of ophthalmoplegic migraine in a 13-year-old girl, showing reversible swelling and contrast enhancement of the cisternal portion of the left CN III (arrow). From Prats et al., 1999, r SAGE Publications.58 Reprinted by permission of SAGE Publications.

completely, and the longest and thinnest of the ocular motor nerves. The trochlear nucleus is located ventral and lateral to the Sylvian aqueduct at the level of the inferior colliculus, dorsal to the medial longitudinal fasciculus and caudal to the oculomotor nuclear complex. The nerve fascicle leaves the nucleus, courses along the aqueduct, crossing in its roof inferior to the inferior colliculus, and exits the dorsal midbrain contralateral to the nucleus. The cisternal portion travels laterally around the midbrain to its ventral aspect, then passes along the free edge of the tentorium and along the lateral aspect of the clivus to enter the cavernous sinus. Here, it lies in the lateral wall just inferior to the oculomotor nerve, entering the orbit through the superior orbital fissure and running medially across the superior rectus muscle to the superior oblique muscle.65

Localizing Syndromes Associated neurologic signs aid localization of fourth nerve lesions. The dorsal midbrain syndrome, or Parinaud syndrome, may include trochlear palsy with upgaze weakness, downgaze limitation, convergence spasm, convergenceretraction nystagmus, lid retraction, light-near dissociation, or a combination of these symptoms.1,65 A contralateral Horner syndrome or intranuclear ophthalmoplegia indicates involvement of the fourth nerve within the midbrain.66 Ipsilateral limb ataxia or contralateral sensory loss may reflect involvement of the cerebellar peduncle or sensory lemniscus, respectively.67 Concurrent involvement of the third and fourth nerves may localize to the midbrain, the cavernous sinus or orbital apex, where the trigeminal nerve may also be affected.65

Chapter | 46 Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

TABLE 46.3 The Bielschowsky Three-Step Test Step 1 Primary

Step 2 R gaze

Step 3

L gaze

R tilt

RSO

RSO

L tilt

R hypertropia RSO RIR

RIR

LIO

LIO

LSR

RIR LIO LSR

LSR

L hypertropia LSO

LSO

LSO

LIR

LIR

RIO

RIO

RSR

RSR

LIR RIO RSR

Step 1: Determine which eye is higher in primary gaze. Steps 2 & 3: Determine in which position the deviation is greater. Chart indicates which EOMs may be weak, to yield the observed deviation. Note: The Three-Step Test can yield false localizing results when more than a single EOM palsy is present, and under a few other unusual circumstances.a f Abbreviations: EOMs, extraocular muscles; IO, inferior oblique; IR, inferior rectus; L, left; R, right; SO, superior oblique; SR, superior rectus. a Donahue SP et al., 1999.69 b Ohtsuki H et al., 2000.70 c Kushner BJ, 1989.71 d Kushner BJ, 1981.72 e Getman I and Goldstein JH, 1983.73 f Cartwright MJ and Wyatt DB, 1989.74

Fundamental Signs and Symptoms In children, fourth nerve palsy often presents with a head tilt away from the affected eye. This helps neutralize the vertical diplopia and rotation of the image from the paretic eye that the patient will perceive with the head erect and gaze in primary position. In addition to the direction of head tilt, the patient’s perception in primary position, as well as version testing, will localize the paretic eye. Viewing a horizontal edge, the patient may perceive two images of the edge tilted with respect to one another, and intersecting as if forming an arrow that points to the paretic side. This is less common in children than adults and is not found in congenital trochlear palsies.50,68 The Bielschowsky Three-Step Test helps to differentiate between trochlear palsy and its mimickers, such as dissociated vertical deviation, skew deviation, and double elevator palsy (Table 46.3).

Etiology Most trochlear palsies are congenital (refer to Congenital Cranial Dysinnervation Disorders section below) or arise as a result of trauma. Differentiation between congenital

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and acquired trochlear palsy may be difficult because the congenital form is often well compensated and thus asymptomatic prior to adolescence or adulthood, when it may decompensate and be mistaken for an acute palsy. Review of photographs from infancy may reveal a long-standing head tilt, suggesting a congenital lesion.1 Facial asymmetry, with retrusion and upslanting of the mouth on the side of the head tilt, is also indicative of chronicity.76 Children with congenital trochlear palsy do not generally perceive a tilted image, presumably due to a combination of the head tilt and more complex central physiologic mechanisms.68 Similarly, amblyopia is rare because the compensatory head tilt enables fusion of the images from both eyes.1 MRI findings can also be helpful in distinguishing congenital and acquired trochlear palsies77. Finally, forced duction testing reveals decreased resistance of the superior oblique in congenital palsies, and normal resistance in acquired forms. Up to 50% of acquired pediatric trochlear nerve palsies are due to trauma or neurosurgery (see Table 46.2).28,30,33,78 Orbital fractures may damage the nerve, tendon, trochlea, or the muscle itself.79,80 Trauma may also cause decompensation of a congenital palsy.81 Acquired bilateral trochlear palsy is most often due to trauma, and is thought to result from injury at the fascicular decussation. Such cases usually present with a chin-down head position, rather than a head tilt, and with a right hypertropia in left gaze and a left hypertropia in right gaze (alternating adducting hypertropia). A Vpattern esotropia is generally present, and is often large.1,82 Inflammatory and infectious causes of trochlear palsies include the Tolosa-Hunt and Guillain-Barre´ syndromes, Herpes zoster ophthalmicus, and, less commonly, sarcoidosis and even tetanus.83 86 Recurrent CN IV weakness may be seen in the Tolosa-Hunt syndrome, sarcoidosis, ophthalmoplegic migraine (see earlier discussion), and a familial syndrome involving multiple recurrent cranial nerve palsies.

Differential Diagnosis Ocular motility disturbances, which may be confused with trochlear nerve palsy, include double elevator palsy, dissociated vertical deviation, the ocular tilt reaction, and inferior oblique overaction.87 Skew deviation is vertical misalignment due to disruption of supranuclear pathways in the midbrain tegmentum, dorsolateral medulla, cerebellum, or vestibular system.1 Although most commonly due to trauma, it is also occasionally seen with the Chiari malformation (type II), myelomeningocele, hydrocephalus, or even pseudotumor cerebri.88 Skew deviation may or may not be comitant, and may alternate periodically over time or with lateral gaze position.1

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Double elevator palsy consists of an inability to elevate an eye in any horizontal position of gaze, and may be caused by inferior rectus restriction, superior rectus paresis, or supranuclear lesions.89 The greater elevation of the contralateral eye may be confused with a superior oblique palsy of that eye. In contrast with fourth nerve palsies, this hypertropia is comitant and may be associated with ptosis or pseudoptosis. In dissociated vertical deviation, each eye deviates in the same vertical direction when it is covered. A head tilt is often present.1 In true fourth nerve palsy, however, when the affected eye is covered it deviates upward, whereas when the unaffected eye is covered it deviates downward. Other helpful clues to the presence of dissociated vertical deviation include the presence of latent nystagmus or exodeviation, or both. The ocular tilt reaction consists of a skew deviation, head tilt, and ocular torsion. It may be seen with lesions of the ipsilateral interstitial nucleus of Cajal or a contralateral Wallenberg syndrome.90 Weakness of the superior oblique may also be found in myasthenia gravis or thyroid eye disease.91,92 Finally, torticollis causes a head tilt that may raise suspicion of a superior oblique palsy, but is characterized by resistance to passive tilt of the head in the opposite direction and associated with palpable sternocleidomastoid muscle thickening.1

Abducens Palsy (CN VI) Anatomy The abducens nuclei lie close to the midline in the caudal paramedian pontine tegmentum, lateral to the medial longitudinal fasciculus and medial to the vestibular nucleus. Each includes two subpopulations of neurons: motor neurons of the abducens nerve and interneurons of the contralateral medial longitudinal fasciculus. The fascicle of the ipsilateral facial nerve wraps around the abducens nucleus. The fascicular portion of CN VI runs ventrally through the paramedian pontine reticular formation, near the trigeminal nerve and superior olivary nucleus, then lateral to the corticospinal tract before exiting from the caudal pons about 1 cm from the midline, turning at a right angle to head rostrally. The nerve crosses the clivus and runs along the basilar artery, penetrating the dura through or above the inferior petrosal sinus. It then turns right, enters the cavernous sinus and then the superior orbital fissure, innervating the lateral rectus muscle as it passes along its medial side. Some sympathetic fibers destined for the ophthalmic branch of the trigeminal nerve join the abducens nerve briefly along its intracavernous portion, accounting for a concurrent Horner syndrome in some cavernous sinus lesions.93,94

Localizing Syndromes Abducens palsies lend themselves well to precise localization, because lesions at various sites result in distinct constellations of symptoms. Nuclear lesions cause an isolated defect in abduction if only the nVI motor neurons are involved. Alternatively, an ipsilateral horizontal gaze palsy will result if the lesion includes the juxtaposed medial longitudinal fasciculus interneurons crossing to the contralateral oculomotor nucleus. A lesion in the dorsolateral pons results in Foville’s syndrome—horizontal gaze palsy, ipsilateral facial palsy and analgesia, deafness, and loss of taste in the anterior two thirds of the tongue. A lesion in the ventral pons causes Millard-Gubler syndrome (ipsilateral facial paralysis and contralateral hemiplegia). Pontine lesions may also cause an ipsilateral internuclear ophthalmoplegia or Horner syndrome. Accompanying trigeminal nerve dysfunction, CN VII and CN VIII palsies, nystagmus, and cerebellar signs indicate a lesion at the cerebellopontine angle. Isolated abducens palsies are seen with compression at the clivus, while lesions in the middle fossa may cause facial pain, hypesthesia, or weakness. Those in the cavernous sinus or superior orbital fissure are generally indistinguishable on the basis of clinical signs; in either location, the abducens palsy is frequently accompanied by palsies of CN III, CN IV, and the first branch of the trigeminal nerve, or by an ipsilateral Horner syndrome.1,64,94

Fundamental Signs and Symptoms Because the abducens nerve innervates a single muscle with a single action, the fundamental sign of abducens palsy is straightforward: weakness in abduction of the affected eye. In complete palsies, this causes inability to abduct the eye past the midline. The esotropia is of greater magnitude in the direction of gaze of the affected eye and with distant viewing, and increases when the patient fixates with the affected eye. In mild palsies, the deficit in range may be subtle, and may be identified only by observation of slowed saccades in the direction of the palsy or by formal measurements of ocular alignment using prisms.1 Children will often present with a head turn toward the affected eye.95 Another helpful sign in identifying a subtle palsy is medial-beating nystagmus of the contralateral eye on attempted ipsilateral lateral gaze. Long-standing palsies may result in development of a secondary medial rectus contracture causing a restrictive noncomitant esotropia. In the latter case, ipsilateral saccades will begin with normal rapid speed, then suddenly slow in midcourse, as if “hitting a wall.”1

Etiology In contrast to CN III and CN IV palsies, congenital abducens palsies are rare (8 13%) in comparison with acquired

Chapter | 46 Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

forms. Of the acquired forms, the most common causes are trauma (20 42%), neoplasm (18 39%), infection (6 17%), raised intracranial pressure (3 14%), benign/ viral (3 18%), and vascular (1 3%). Cryptogenic palsies account for 9% to 36% of cases.28,33,96,97 Congenital CN VI Palsies Transient neonatal abducens palsies probably result from perinatal cranial trauma,1 and generally resolve within 6 weeks.98,99 In some infants, a presumed abducens palsy manifests simply as neonatal esotropia.100 Congenital forms persisting beyond the neonatal period include two forms of congenital cranial dysinnervation disorders (CCDDs), horizontal gaze palsy, and Duane’s retraction syndrome. Abducens palsies are also seen in 90% of children with Moebius syndrome (see following). Acquired CN VI Palsies Acquired abducens palsies in childhood are commonly due to neoplasms, in which case they arise as a result of tumor infiltration or mass effect, secondary obstructive hydrocephalus, or as a sequela of surgery.97,101 Tumors frequently associated with sixth nerve palsy are listed in Table 46.2; pontine glioma predominates. The sixth cranial nerve may be injured by trauma97 where it crosses the clivus, by direct damage to the petrous bone in basilar skull fractures, or by entrapment in medial orbital fractures.80,97 The abducens nerve is also vulnerable to traumatic injury during resection of posterior fossa tumors.1 Trauma may also cause increased intracranial pressure or, rarely, caroticocavernous fistulae. Relatively mild trauma apparently resulting in a sixth nerve palsy should raise suspicion of an occult tumor.102 Unilateral or bilateral traction injury may result from hydrocephalus (or uncommonly from lumbar puncture).103,104 Inflammatory abducens neuropathies (17% of total CN VI palsies) are usually partial.97 CN VI is affected in as many as 16% of cases of bacterial meningitis.105 Mastoiditis may directly cause abducens palsies (Gradenigo’s syndrome, often also accompanied by intense temporal-parietal pain and ipsilateral facial palsy) or, more commonly, form a nidus for venous thrombosis and subsequent increased intracranial pressure. Otitis media or sinusitis may also be complicated by inflammation of the petrous bone and sixth nerve weakness.106 As many as 36% of acquired abducens palsies are idiopathic.97 Benign isolated complete CN VI palsies may develop acutely, often preceded by a febrile, presumably viral illness.107 See Case Example 46.1. Benign recurrent abducens palsy is acute in onset, complete, isolated from other neurologic signs or those of increased intracranial pressure, resolves within 6 to 8 weeks, and usually recurs in the same eye.108 111

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Recurrent abducens palsies have been associated with Epstein-Barr and varicella infections, and with immunizations.112,113 Less commonly, they are seen with migraine, in association with recurrent CN III weakness, or with vascular anomalies. Recurrent CN VI palsy is more frequent in females and on the left side.1,107,111 Increases or decreases in intracranial pressure may result in unilateral or bilateral abducens palsy, presumably caused by nerve compression. Such palsies are usually partial.1 Aneurysms (usually in the cavernous sinus) rarely cause abducens palsies in childhood.114

Differential Diagnosis Abducens palsy must be distinguished from congenital esotropia, which also presents with esodeviation but is comitant and usually not seen before 6 to 8 weeks of age.99,100 A horizontal gaze palsy (caused by an ipsilateral lesion to the abducens nucleus or paramedian pontine reticular formation) requires the patient to turn his or her head to see in the affected direction of gaze. This may mimic a unilateral abducens palsy, in which the patient turns his or her head in order to avoid development of diplopia. In abducens palsies, however, diplopia and head turning are abolished by patching of the paretic eye.95 Spasm of the near reflex (convergence spasm) may limit abduction and hence mimic bilateral abducens palsies. Frequently caused by head trauma and less commonly seen with Arnold-Chiari malformations or other disorders, it is accentuated with near viewing, and may be identified on the basis of the pupillary constriction that is part of the near reflex.115 Lateral rectus weakness is occasionally seen with pediatric myasthenia gravis and thyroid eye disease.52,116 Orbital pseudotumor and orbital myositis may cause restriction of lateral rectus contraction.1,117 Restriction or contracture of the medial rectus may mimic or result from CN VI palsies (see earlier discussion). Unlike cyclic oculomotor palsy, cyclic esotropia, which may follow traumatic abducens palsy, is not due to a true nerve paresis.118 Affected children alternate between periods of 12, 24, 36, or 48 hours of normal alignment, and periods of similar length during which they manifest esotropia. Despite the intermittent strabismus, a full range of eye movements is preserved.1,88

Investigations and Imaging of Cranial Nerve Palsies Evaluation of ocular motor palsies should include cranial imaging, ideally by magnetic resonance imaging with detailed views of the cavernous sinus, clivus, cranial nerves, and orbit. In children in whom no cause is identified for a persistent acquired ocular motor palsy,

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CASE EXAMPLE 46.1 An 8-month-old boy had a 2-week history of intermittent eye crossing. His mother observed that, at times, his eyes appeared normally aligned, but these periods were becoming briefer and less frequent. She also commented that he was increasingly turning his head to the left. Two weeks before the strabismus was noted, he had had an upper respiratory infection with otitis media. Examination revealed a large esotropia in left gaze. Abduction of the left eye was limited to the midline, and fixation alternated between the two eyes. The neurologic examination was otherwise normal. A cranial MRI scan revealed normal ventricles and parenchyma, with enlargement of the extra-axial cerebrospinal fluid spaces. Alternateday patching was instituted. His incomitant esotropia remained stable over the next 6 months.

reimaging after intervals of 1 to 2 years may be indicated in order to exclude an occult mass lesion.1,49 Magnetic resonance angiography may also be considered for acquired CN III palsy, although intracranial aneurysms and other vascular anomalies are rare in childhood.48 Magnetic resonance venography may be indicated for CN VI palsy with evidence of increased intracranial pressure. Lumbar puncture is frequently indicated for both exclusion of central nervous system infection and measurement of intracranial pressure. Other investigations to be considered are the Tensilon test and assessment of forced ductions. Targeted genetic testing should be obtained where appropriate.

Treatment and Prognosis of Cranial Nerve Palsies General Principles Three types of disability deserve attention in the management of ocular motor palsies: amblyopia, ocular misalignment, and ptosis. Amblyopia typically results from the child’s suppression of the image from one eye in order to avoid diplopia. Occlusion of one eye by ptosis or inaccurate focusing due to failure of accommodation may exacerbate amblyopia and result in strabismus.119,120 Children are most at risk of developing amblyopia between 6 weeks and 4 years of age. Intermittent patching may prevent both amblyopia and acquired medial rectus contracture. Patching should be continued until the palsy resolves or surgical correction is attempted. Botulinum toxin has been used to weaken selective muscles as an alternative to surgery, but its efficacy is debated.1,121 A number of methods for surgical correction of persistent misalignment have been reported. Their success depends both on the degree of residual paresis and on the

Comment The isolated deficit in abduction and noncomitant esotropia were indicative of a left sixth nerve palsy, which was felt to be benign given the otherwise normal examination and imaging findings. Presentation beyond the first 3 to 4 months of life makes an acquired palsy more likely than a congenital one. Alternating fixation gives the false impression that first one eye, then the other, is turning inward. Weakness appears intermittent at first because the patient is able to overcome the deficit with effort for brief periods. Later the patient minimizes the misalignment by head turning. Patching of the eyes prevents the development of amblyopia. Surgical correction may be considered once the deviation is stable for 6 months.

complex coordination between the various EOMs required to achieve normal conjugate horizontal and vertical movements.122 In general, the primary goal of strabismus surgery is to allow single binocular vision in primary gaze. The secondary goal is to extend such vision to reading, then to extend it to as wide an angle as possible in any direction from primary gaze, and finally, to improve cosmetic appearance.1

Oculomotor Palsy Surgical procedures to correct adduction deficits entail recession and resection of the horizontal rectus muscles, or division and transfer of the superior oblique tendon.1,123 To correct vertical misalignment, either of the horizontal recti may be transposed vertically, or recession-resection procedures may be performed on the vertical recti.124 Surgical correction of severe residual ptosis may best be deferred until ocular alignment has been optimized, because occlusion of the involved eye may be serving a useful function in preventing diplopia. When there is minimal residual levator function, a frontalis suspension may be performed. The long-term prognosis for childhood oculomotor palsy varies with the cause and with the corrective procedure employed. Overall, visual acuity is reduced long term in 50% to 60% of patients, but virtually all of those with congenital oculomotor palsy recover normal acuity. Only 15% recover full motility, and a similar proportion recover stereopsis.125,126

Trochlear Palsy In most cases of nontraumatic acquired trochlear nerve palsy, muscle strength, ocular misalignment, and head tilt gradually improve spontaneously, generally within 3 to 6 months.1 During this period there is no need for patch occlusion because the patient uses a head tilt to fuse images. Thus, management consists of expectant observation.

Chapter | 46 Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

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Amblyopia is rare; when it does develop, it suggests that the head tilt cannot sufficiently compensate for diplopia, there is another concurrent ocular motility deficit, or that central fusion mechanisms have been disturbed (generally in association with trauma).127 In some cases, superior oblique myokymia (see separate discussion) may develop.128 For congenital cases, and acquired cases that do not resolve spontaneously, surgical treatment is usually required. In contrast to oculomotor palsy, an additional goal is attainment of normal head position, optimal cosmesis, and fusion within a reasonable functional range of eye movements. The choice of procedure depends partly on compensatory responses of other EOMs.1 Overall, the success rate for restoration of a normal head posture is 75%; for vertical deviation of less than 3 diopters, the success rate is 60%.129

Abducens Palsy Most acquired abducens palsies resolve spontaneously within 3 to 4 months. Prognosis varies with cause and is best in idiopathic cases.130 132 Younger children have higher rates of permanent strabismus (66%) and amblyopia (20%).132 Recurrent palsies usually involve the same eye, and resolve within 8 to 12 weeks.111 Treatment is that of the underlying condition. Esotropia may persist owing to spread of comitance, incomplete recovery, or acquired contracture of the medial rectus muscle.1 If residual strabismus is stable for at least 6 months, surgical correction by transposition of the vertical rectus muscles to the lateral rectus or recession of the contralateral medial rectus may be performed.133

CONGENITAL PTOSIS SYNDROMES Blepharoptosis Eyelid position and movement result from the balance between the opening forces generated by the tonically active levator palpebrae superioris and Muller’s muscles, and closing forces generated actively by the (normally quiescent) orbicularis oculi muscle and passively by stretching of the eyelid’s ligaments and tendons.134 Deficiency of levator tonus results in blepharoptosis (ptosis). Ptosis can be congenital or acquired, and can result from upper motor neuron, lower motor neuron, nerve, neuromuscular junction, or primary muscle dysfunction. Congenital ptosis can occur in isolation or in association with other ocular, neuromuscular, or systemic findings. When it occurs with oculomotor nerve palsy, CFEOM, or the Marcus Gunn phenomenon, it is likely neurogenic in origin. When seen with congenital myasthenia or a congenital myopathy, it localizes to the neuromuscular junction or muscle, respectively.

FIGURE 46.5 A mother and two daughters, all affected by isolated congenital ptosis, and an unaffected son. The autosomal dominant trait in this family maps to the chromosome 1 PTOS1 locus. The mother has moderate right- and mild left-sided ptosis, and both daughters have moderate to severe bilateral ptosis with a compensatory backward tilt to the head. From Engle et al., 1997,135 with permission from the University of Chicago Press.

Isolated Congenital Ptosis Isolated congenital ptosis (congenital myopathic ptosis or developmental ptosis) is characterized by a deficiency in levator excursion with an elevated or absent lid crease (Figure 46.5). This is unilateral in B75% of cases. Surgical correction is typically performed between 6 months and 5 years of age, particularly if there is a risk of secondary amblyopia. Levator muscle biopsies at the time of corrective surgery typically reveal a reduction or absence of myofibers and the presence of connective tissue,136 and some investigators have noted an inverse correlation between the degree of ptosis and the number of residual striated muscle fibers.137 These observations led to the hypothesis that isolated congenital ptosis results from a myogenic defect. Such biopsy findings, however, could also arise secondary to reduced muscle innervation from maldevelopment of oculomotor caudal central subnucleus motor neurons or their axons. Determining the molecular basis of congenital ptosis should help resolve this issue. Toward this goal, an autosomal dominant PTOS1 locus (OMIM #178300) on chromosome 1p34.1-p32 (Figure 46.5),135 an X-linked PTOS2 locus

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FIGURE 46.6 Patient with Duane’s retraction syndrome attempting to look to her right (left photo), straight ahead (middle photo), and to her left (right photo). Her left eye has restricted lateral movement on attempted abduction, and upshoot with narrowing of the palpebral fissure secondary to co-contraction on attempted adduction.

(OMIM #300245) on chromosome Xq24-q27.1,139 and a translocation disrupting ZFH-4 on chromosome 8140 have been mapped, but the causative gene mutations not yet reported. Some individuals with congenital ptosis also have limitation of upgaze. This combination of findings can be neurogenic or myogenic, due either to an error in determining the identity or course of the superior division of the oculomotor nerve that carries axons from nIII to these two muscles, or abnormal development of the levator and superior rectus muscles. These two muscles share a common epimysium and only begin to separate from one another at 7 weeks’ gestational age.141 143

Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES, OMIM #110100) is a developmental malformation of the lid and surrounding tissues. Individuals with BPES have ptosis with poor levator function and absent lid crease, palpebral fissures narrowed both horizontally and vertically (blepharophimosis), and a skin fold running inward and upward from the lower lid (epicanthus inversus). BPES can be simplex or can occur as an autosomal dominant trait, in which case the eyelid abnormalities can occur in isolation (BPES type II) or in association with ovarian failure (BPES type I). BPES types I and II map to chromosome 3q23144 146 and result from mutations in the Forkhead transcription factor, FOXL2.147 FOXL2 is expressed predominantly in the developing eyelid and perioptic mesenchyme, and in the adult ovary.

CONGENITAL CRANIAL DYSINNERVATION DISORDERS In 1950, H.W. Brown categorized five types of incomitant strabismus (Duane syndrome, strabismus fixus, vertical retraction syndrome, Brown syndrome, and congenital

fibrosis syndrome) under the umbrella term “congenital fibrosis syndromes,” based on the observation that they all presented as congenital, nonprogressive restrictive ophthalmoplegia with active limitation and passive restriction of globe movement.148 The restrictive nature of the ophthalmoplegia with positive forced duction testing and a “tight” feel to the EOMs at surgery, and the finding of connective tissue on surgical biopsies of the EOMs, led Brown and others to propose that these disorders resulted from primary EOM fibrosis. As described in the following discussion, more recent neuropathologic and genetic studies of Duane syndrome and CFEOM have established that a primary defect in motor neuron development accounts for at least a subset of these disorders. Thus, these syndromes have been recategorized as congenital cranial dysinnervation disorders (CCDDs), an umbrella term encompassing maldevelopment of the ocular as well as other cranial nerves.149 152

Duane Syndrome Duane syndrome is the most common of the CCDDs, accounting for 1% to 5% of strabismus cases.153,154 The affected eye or eyes in individuals with Duane syndrome, also called Duane retraction syndrome (DRS), have limited horizontal gaze and retraction of the globe into the orbit with narrowing of the palpebral fissure on attempted adduction (Figure 46.6). The syndrome was named for Alexander Duane, who published a 1905 paper collating 54 cases.155 In his series, abduction was virtually absent in 75%, adduction was abnormal in 96%, oblique movements (upshoot, downshoot) occurred on attempted adduction in 57%, and retraction was present in 95% of cases. Many patients had strabismus and abnormal head position in primary gaze. None had accommodation or pupil abnormalities, while associated malformations and family history were not addressed. The preponderance of affected females, unilateral cases, and left eye affection noted by Duane has been borne out by many subsequent studies. Despite the congenital, nonprogressive nature of

Chapter | 46 Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

the disorder, cases are diagnosed equally in infancy, childhood, and adulthood.156,157 DRS has been categorized clinically into three types, with types I and III more common than type II.158 Type I is defined as poor abduction with normal or slight limitation of adduction, type II as poor adduction with normal or slight limitation of abduction, and type III as a combination of poor abduction and adduction. Globe retraction and palpebral fissure narrowing with adduction occurs in all three categories. Many individuals with DRS have strabismus and may maintain a compensatory head turn; esotropia is more common in type I and exotropia in type II. Most patients have good visual acuity; only 10% develop amblyopia. Up to 50% of patients with DRS have additional congenital anomalies, particularly of the skeleton, ear, eye, and kidney.2,156,159 Although historically believed to result from a primary myogenic process,155,160,161 DRS is now accepted as neurogenic in etiology. Postmortem examinations have revealed absence of the abducens nucleus and nerve on the affected side(s), and partial innervation of the lateral rectus muscle(s) by branches from the oculomotor nerve(s).162,163 Many subsequent magnetic resonance imaging studies have verified this pathology. Electromyographic studies have demonstrated that the globe retraction results from the simultaneous co-contraction of the medial and lateral recti, consistent with the aberrant and paradoxical innervation of these muscles.164,165 Multiple genetic causes of DRS have been reported over the last decade, but even in combination these account for a small percent of DRS cases. Among these, CHN1 mutations result in isolated DRS while SALL4, HOXA1, and several chromosomal disorders result in syndromic DRS. In addition, syndromic DRS can result from teratogens, particularly following in utero thalidomide exposure between 21 and 26 days’ human gestation.166,167 Autosomal dominant isolated DRS can result from heterozygous missense mutations in CHN1, which encodes alpha2-chimerin, a Rac guanosine triphosphatase-activating protein (RacGAP)168 Affected individuals have a higher incidence of bilateral DRS and additional vertical eye movement abnormalities compared to individuals with nonCHN1 DRS.169 172 Magnetic resonance imaging reveals the anticipated abducens nerve hypoplasia and aberrant lateral rectus innervation, while some affected individuals also have hypoplasia of the oculomotor nerve and oculomotorand trochlear-innervated muscles.169,170,172 CHN1 mutations hyperactivate alpha2-chimarin and lower RacGTP levels. Modeling of these mutations in developing chick and zebrafish oculomotor axons reveal errors in axon growth and guidance.168,173 CHN1 mutations are not a common cause of simplex DRS.174 Dominant mutations in the transcription factor SALL4 cause Duane-radial ray syndrome (DRRS), also referred

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to as Okihiro syndrome, acro-renal-ocular syndrome, or IVIC syndrome.175 179 SALL4 mutations cause incompletely penetrant unilateral or bilateral DRS accompanied by radial dysplasia ranging from hypoplasia of the thenar eminence to absent forearm. Deafness, renal anomalies, and imperforate anus can also be co-inherited, while multigene deletions encompassing SALL4 can result in even more extensive phenotypes.180 Magnetic resonance imaging of individuals with DRS harboring SALL4 mutations reveals marked abducens hypoplasia with probable innervation or co-innervation of the lateral rectus muscle by the oculomotor nerve.181 While several Sall4 mutant mouse lines have been reported, these have not provided insight into the etiology of DRS in DRRS; Sall42/2 embryos die at BE6.5, and in the one line examined in detail, Sall42/1 mice had normal-appearing ocular cranial nuclei and extraocular muscles.182 The HOXA1-related syndromes result from recessive mutations in the transcription factor HOXA1, and include the overlapping Bosley-Salih-Alorainy syndrome (BSAS, OMIM, #601536)183 and Athabaskan brainstem dysgenesis syndrome (ABDRS).184 Affected individuals have Duane syndrome type 3 or horizontal gaze palsy with absent abducens nerves, and most have bilateral sensorineural hearing loss caused by an absent cochlea and rudimentary inner ear development. Individuals may also have intellectual disability, autism, moderate-to-severe central hypoventilation, facial weakness, swallowing difficulties, vocal cord paresis, conotruncal heart defects, and/or skull and craniofacial abnormalities.183 186 HOXA1 mutations are not, however, a common cause of isolated DRS.187 Among a variety of cytogenetic anomalies reported in patients with simplex and syndromic DRS, those in the chromosome 8q12 8q13 region (the DURS1 locus) are most commonly reported. The region has yet to be untangled, but current data suggest that the DURS1 locus could result in DRS by dosage effect in the region of 8q1, through deletion on 8q13 and/or a duplication of 8q12.188

Congenital Horizontal Gaze Palsy Congenital horizontal gaze palsy can occur in isolation but is more frequently found in association with progressive scoliosis or Moebius syndrome, or co-segregating in families with dominant forms of Duane syndrome. Horizontal gaze palsy with progressive scoliosis (HGPPS) is a recessive disorder defined by almost complete limitation of horizontal eye movements with intact vertical gaze, and scoliosis that begins in the first decade of life and is often severe and debilitating.189 HGPPS results from mutations in the axon guidance receptor ROBO3.190,191 There is failure of axons and cell bodies to

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CASE EXAMPLE 46.2 An 11-month-old boy was referred to the neuromuscular clinic for evaluation of ptosis and difficulty moving his eyes. He was born at full term by Caesarean section for cephalopelvic disproportion, following an uneventful pregnancy. He was noted to have bilateral ptosis and mild axial hypotonia at birth. When examined at 11 months of age, he held his head retroflexed and had mild tenting of the upper lip. He had marked bilateral ptosis. In primary position, the eyes were infraducted 30 degrees and esotropic. He had no upgaze, minimal horizontal movement of either eye, and had to fix and follow using his entire head. On attempted upgaze, bilateral convergence occurred. Pupils and fundoscopic examination were normal. He had mild axial hypotonia and an otherwise normal examination. The family history was remarkable for nonprogressive congenital bilateral infraducted ophthalmoplegia and ptosis in his father, grandmother,

paternal uncle, and 20 additional members of his extended family. Forced duction testing was positive for marked restriction of globe movement in all fields of gaze. Quadriceps muscle biopsy showed mild fiber type disproportion. Genetic linkage analysis revealed that the family’s phenotype mapped to the CFEOM1 locus on chromosome 12 and segregated the most common KIF21A mutation, resulting in the R954W amino acid substitution. Comment This child demonstrates the classic features of CFEOM1. Over time, his oculomotility disorder did not progress and his mild hypotonia resolved. His visual acuity was monitored closely. He underwent ptosis and strabismus surgeries at several years of age with moderate improvement in primary gaze and head position.

cross the midline of the hindbrain and spinal cord during development, resulting in uncrossed descending corticospinal tracts and ascending sensory tracts.192 This lack of crossing fibers results in the classic HGPPS midline cleft running rostral-caudal in the hindbrain, which can be seen on magnetic resonance imaging.189,190,193

Congenital Fibrosis of the Extraocular Muscles The diagnosis of congenital fibrosis of the extraocular muscles (CFEOM) refers to forms of CCDDs in which there are limited vertical eye movements with positive forced ductions (vertical concomitant strabismus); most individuals with CFEOM also have ptosis, and many have restricted horizontal movements and strabismus as well. While CFEOM subtypes were initially grouped by clinical presentation, CFEOM phenotypes can overlap and thus genetic classification can be more informative. CFEOM phenotypes resulting from mutations in KIF21A, PHOX2A, TUBB3, and TUBB2B are now recognized.24,41,194,195 Dominant missense mutations in KIF21A result primarily in the CFEOM type 1 phenotype (CFEOM1) (see Case Example 46.2); congenital bilateral ptosis, inability to elevate either eye above midline, and typically restricted horizontal gaze; and aberrant residual eye movements (Figure 46.7).41,196 Human autopsy and MRI data revealed hypoplasia of the superior division of the oculomotor nerve, with absence of the corresponding oculomotor neurons and hypoplasia of the superior rectus and levator palpebrae superioris muscles (Figures 46.8 and 46.9).6,197 KIF21A encodes an anterograde kinesin protein

FIGURE 46.7 Three siblings from a CFEOM1 pedigree who harbor a dominant mutation in KIF21A. The two affected children in the foreground have ptosis and infraducted ophthalmoplegia with a compensatory backward head tilt. They have marked restriction of globe movement and positive forced duction testing. The sister in the background is unaffected. From Engle, et al., 1995,138 with permission from the University of Chicago Press.

Chapter | 46 Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

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FIGURE 46.9 Schematic lateral view of the brain stem and left orbit demonstrating the neuropathology of CFEOM1. Compared with the normal orbital anatomy depicted in Figure 46.1, the absent medial and central caudal oculomotor (nIII) subnuclei and the corresponding superior division of CN III are depicted as dotted subnuclei and dashed nerves, respectively. The muscles innervated by the superior division of CN III (superior rectus and levator palpebrae superioris) are secondarily abnormal and depicted in light gray.

FIGURE 46.8 Quasicoronal MRI of orbits just posterior to the globe optic nerve junction in a patient with KIF21A-CFEOM1 illustrating a hypoplastic optic nerve and rectus extraocular muscles, in comparison with a normal control subject. From Demer JL et al., 2005,75 with permission from the copyright holder, the Association for Research in Vision and Ophthalmology.

whose motor domain interacts with and “walks” down microtubules. Wild type Kif21a has been implicated in axonal transport of several cargos and in the inhibition of microtubule growth at the cell cortex in vitro.198 201 It is expressed in most developing and mature neurons in the nervous system, and its expression does not appear to be changed in CFEOM1.202 CFEOM1 mutations specifically alter amino acid residues in the motor and third coiledcoil stalk domain of the KIF21A protein.41,203 These domains interact with one another to autoinhibit Kif21a, and CFEOM1 mutations attenuate Kif21a autoinhibition and enhance its interaction with microtubules.42,201 Kif21a knock-in mice harboring the most common KIF21A mutation recapitulate the human CFEOM phenotype, and have aberrant stalling and branching of axons within the oculomotor nerve.42 A series of recurrent dominant missense mutations in TUBB3 result in variable phenotypes that correlate with the specific mutation, and include CFEOM1 and CFEOM without bilateral ptosis and/or with some ability to elevate one or both eyes above midline, referred to as CFEOM3 (Figure 46.10). In addition to CFEOM, patients with specific TUBB3 mutations may have intellectual or social disabilities, facial weakness, vocal cord paralysis, finger contractures, progressive sensorimotor polyneuropathy, Kallmann syndrome, and/or cyclic vomiting.194,205 In

particular, the TUBB3 E410K syndrome may be misdiagnosed as atypical Moebius syndrome.205 Magnetic resonance imaging reveals oculomotor nerve hypoplasia that can be accompanied by dysgenesis of the corpus callosum, anterior commissure, corticospinal tracts, and/or basal ganglia.194,205 A knock-in disease mouse model revealed axon guidance defects of both cranial nerves and central axon tracts.194 TUBB3 encodes the neuron-specific beta-tubulin isotype III, which is one of multiple betatubulin isotypes that heterodimerize with alpha-tubulin isotypes to form microtubules. The disease-associated missense mutations have been shown to impair tubulin heterodimer formation to varying degrees, although folded mutant heterodimers can still polymerize into microtubules. Modeling each CFEOM-causing mutation in yeast tubulin demonstrated that all alter dynamic instability, whereas a subset disrupts the interaction of microtubules with kinesin motors.194 Similarly, a heterozygous missense mutation in a second beta-tubulin isotype, TUBB2B, has been reported to segregate with CFEOM and polymicrogyria.195 This mutation also incorporates into the microtubule network, where it alters microtubule dynamics and can reduce kinesin localization.195 The specific molecular relationship between KIF21A-CFEOM1, TUBB3-CFEOM3, and TUBB2B-CFEOM3, and the reason that the developing oculomotor nerve is particularly vulnerable to these disease mutations, remain to be elucidated. The genetic cause of one recessive form of CFEOM, CFEOM2, has been reported. Patients with CFEOM2 have congenital nonprogressive bilateral ophthalmoplegia and ptosis with the eyes primarily exotropic and vertically midline, and restriction of horizontal and vertical eye movements; they also can have small minimally reactive

940 PART | VII Special Clinical Problems

FIGURE 46.11 An affected child from an autosomal recessive CFEOM2 pedigree with a homozygous mutation in PHOX2A. The toddler has bilateral ptosis and 60 80 prism-diopter exotropia, right hypertropia, and marked limitation of adduction, elevation, and depression of the globes. He fixes with his exotropic left eye by deviating his head to the right and elevating his left lid with his left index finger. Reprinted from the American Journal of Human Genetics v. 63, Wang et al., 1998,206 with permission from Elsevier. FIGURE 46.10 Members of a family with autosomal dominant CFEOM3 who harbor a dominant mutation in TUBB3. The photographs illustrate the spectrum of the CFEOM3 phenotype, which is much broader than that found in CFEOM1 or CFEOM2. Individuals A and B are severely affected, with bilateral ptosis and a restrictive ophthalmoplegia with the eyes fixed in an infraducted and exotropic position. The individual shown in C and D is moderately affected with hypotropia of the right eye in primary gaze (C) and absent elevation of the right eye on attempted upward gaze (D). The individual shown in E and F is mildly affected, as demonstrated with virtually normal primary gaze (E) but bilaterally restricted upgaze (F). From Doherty et al., 1999,204 with permission from the copyright holder, the Association for Research in Vision and Ophthalmology.

pupils (Figure 46.11).24,207 CFEOM2 results from recessive loss-of-function mutations in the homeodomain transcription factor PHOX2A, which is necessary for the development of oculomotor and trochlear motor neurons in both mouse and zebrafish.208,209

In addition to these identified CFEOM disease genes, a recessive locus for CFEOM and postaxial oligodactyly or oligosyndactyly has been mapped to 21qter,210 and a chromosome 2 to chromosome balanced/unbalanced translocation was reported in a second family.211 Neither of these genes has been reported.

Congenital Trochlear Palsy and Brown Syndrome Congenital trochlear palsy (also referred to as congenital fourth nerve palsy or superior oblique palsy) is characterized by hypertropia of the affected eye which increases in adduction and with ipsilateral head tilt. As many as 80% of all congenital ocular motor palsies affect CN IV.127

Chapter | 46 Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

Even so, the incidence of congenital fourth nerve palsy is thought to be underestimated, because it is often asymptomatic or confused with congenital torticollis. Trochlear nerve dysfunction may be isolated or can be associated with oculomotor dysgenesis in CFEOM2,24 or ocular, oculomotor, auricular, central nervous system, and vertebral abnormalities in the Goldenhar syndrome.212 Occasional familial cases are described.213 215 MR imaging of congenital trochlear palsy reveals hypoplasia of the superior oblique muscle and, in many cases, there is inability to image the trochlear nerve,216,217 leading to its recent classification as a CCDD. Congenital fourth nerve palsy is rarely inherited, and although PHOX2A polymorphisms have been reported in this disorder, these are unlikely to be causative.218,219 Congenital Brown syndrome is characterized by absent elevation of the eye in adduction, improved elevation in primary position, and normal or virtually normal elevation in abduction. Forced duction testing reveals a mechanical restriction on attempts to elevate the adducted globe. Affected individuals may also have primary hypotropia, divergence on upgaze, downshoot or widening of the palpebral fissure in adduction, or anomalous head posture.220,221 Most cases are sporadic. The syndrome can also be acquired, and has been reported in association with trauma and inflammatory disorders. Both congenital and acquired cases can resolve spontaneously or occur intermittently. Although Brown originally proposed that the syndrome resulted from a congenitally short superior oblique tendon sheath, resulting in the name “superior oblique tendon sheath syndrome,” the etiology of Brown syndrome is debated. Proposed etiologies include anomalies of the tendon or trochlea, of the superior oblique muscle, or of the inferior oblique and adjacent structures, and paradoxical innervation of the superior oblique muscle.222 Interestingly, congenital Brown syndrome can occur with other aberrant innervation syndromes such as Duane syndrome, Marcus Gunn phenomenon, and crocodile tears,221 and thus it remains possible that at least some cases are also CCDDs.223,224

Moebius Syndrome Moebius syndrome is named for P. J. Mo¨bius, whose 1892 paper categorized the congenital and early childhood cranial nerve palsies into six groups,225 one of which consisted of six sporadic cases of congenital abducens and facial nerve paralysis. The facial and abduction weakness of Moebius syndrome is congenital and nonprogressive, and usually clinically distinguishable from progressive neuromuscular disorders. Patients with facioscapulohumeral muscular dystrophy,226 myotonic dystrophy,227 and unknown progressive neuromuscular

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disorders,228 however, are occasionally initially misdiagnosed with Moebius syndrome. Although the combination of congenital palsies of abducens and facial nerves has been the historical definition of Moebius syndrome, the diagnosis has been applied in a heterogeneous fashion over the years, including in individuals with only isolated facial weakness. Thus, a group of clinicians and researchers met at the 2007 biannual Moebius Syndrome Foundation research meeting and defined the minimum diagnostic criteria for classical Moebius syndrome as “congenital, uni- or bilateral, non-progressive facial weakness and limited abduction of the eye(s).”229 Applying these minimum diagnostic criteria, Moebius syndrome remains heterogeneous in clinical presentation, and likely in etiology. It frequently occurs in association with additional cranial nerve deficits, orofacial malformations, limb defects, and musculoskeletal, behavioral, and/or cognitive abnormalities.229 239 Moreover, neuropathological240 245 and radiological246 248 reports support multiple disease entities.249 To improve diagnostic assessment of Moebius syndrome and to optimize genetic analysis, MacKinnon and colleagues have proposed that “full vertical motility” be added to minimum diagnostic criteria for Moebius syndrome.250 Classic Moebius syndrome is typically sporadic. Chromosomal anomalies in several sporadic patients defined the MBS1 locus on 13q12.2-q13.251,252 In addition, however, patients diagnosed with Moebius syndrome have been found to harbor mutations in HOXA1 (see previous discussion), HOXB1, and TUBB3, particularly relating to the TUBB3 E410K syndrome.183,205 HOXB1 mutations cause facial weakness, esotropia, and deafness, and thus do not meet criteria for Moebius syndrome.253 Two genetic loci mapped in families with autosomal dominant congenital facial weakness who lack eye movement abnormalities were also initially reported as loci for Moebius syndrome,254,255 but have subsequently been reclassified as hereditary congenital facial paresis 1 and 2 (HCFP1 and HCFP2). In addition, Moebius syndrome can also result from teratogens, in particular following in utero exposure to thalidomide166,256 or misoprostol.257,258 Finally, some have proposed that Moebius syndrome can result from an embryonic vascular disruption.259

SYNKINESIS SYNDROMES Synkinesis refers to an involuntary action of one or more of the extraocular muscles associated with a voluntary eye or other movement, and typically results from aberrant innervation. As mentioned above, oculomotor synkinesis is common in CFEOM, and particularly in CFEOM1 resulting from mutations in KIF21A. In addition, 45% to 50% of congenital oculomotor palsies are associated with

942 PART | VII Special Clinical Problems

synkinesis, although some of these patients likely had CFEOM.40,260 Acquired synkinesis commonly develops at least 6 weeks after trauma (including neurosurgery) or recurrent ophthalmoplegic migraine (see above), and is believed to result from aberrant regeneration of damaged nerves.261 Ephaptic transmission may occasionally lead to transient synkinesis.262,263 Recognized patterns of synkinesis with oculomotor palsies include synergistic convergence or divergence; lid elevation with adduction or abduction; and Y- or V-pattern exotropia, or globe retraction with attempted vertical gaze.260,264,265 Surgical correction may be required.266 The most common misdirection resulting from abnormal development of the sixth nerve is Duane syndrome (see previous discussion); in addition, activation of the lateral rectus may be associated with superior rectus, levator, or contralateral lateral rectus activation (“synergistic divergence”). In individuals with ptosis, fibers from the trigeminal nucleus may become redirected to the levator palpebrae superioris, such that jaw movements lead to elevation of the ptotic lid (Marcus Gunn jaw-winking), or to exotropia (CN VI). More unusual congenital misdirection syndromes include pupil constriction with drinking, and ipsilateral tearing with abduction or lateral gaze deficits (“crocodile tears”).64,260 Both Marcus Gunn jaw-winking and crocodile tears may be seen in Duane syndrome and in CFEOM. Aberrant innervation of the trochlear nerve does not seem to occur, but superior oblique myokymia has been speculated to follow trochlear palsy in some instances. This is intermittent, low amplitude, irregular but high frequency (up to 50 Hz) oscillation of the superior oblique muscle, which is usually monocular.267 270 Bursts of such movement lasting seconds to minutes tend to occur intermittently throughout the day, for days to weeks at a time. Episodes may be precipitated by head tilt or by returning the eyes from downgaze. They may occur once or repeatedly, with symptom-free intervals lasting months, and generally resolve spontaneously.

OPHTHALMOPLEGIA IN PEDIATRIC NEUROMUSCULAR DISEASE Neuropathic Ocular Weakness Congenital The EOMs are generally spared by the congenital neuropathies and hereditary motor and sensory neuropathies, but are affected in some specific genetic syndromes (see Chapter 15). Pupillary abnormalities are seen in several subtypes of congenital hypomyelinating neuropathy and Dejerine-Sottas syndrome. Ophthalmoplegia may be seen in several infantile-onset forms of demyelinating

Charcot-Marie-Tooth disease (CMT4B, CMT4C, and CMT4E), and CFEOM and axonal Charcot-Marie-Tooth disease co-segregate with specific TUBB3 mutations.194,205 The combination of congenital axonal neuropathy and ophthalmoplegia should raise the question of mitochondrial diseases caused by mutations in SCO2, C10orf2, or TK2.269,271,272 Progressive ptosis and ophthalmoplegia were also seen in a single case of atypical giant axonal neuropathy presenting as progressive gait abnormalities and bulbar dysfunction,273 and strabismus and ophthalmoplegia can be seen in Andermann syndrome274,275 and infantile neuroaxonal dystrophy.276,277 Spinal muscular atrophy is not usually associated with ptosis or external ophthalmoplegia. Most reports of these findings in spinal muscular atrophy predated molecular diagnosis, and likely described variants of this condition.278 283 However, occasional atypical cases are linked to mutations in the survival motor neuron gene.284 The Fazio-Londe/ Brown-Vialetto-Van Laere spectrum of conditions most commonly present between 12 and 36 months with stridor, facial weakness and ptosis. Optic atrophy is common but ophthalmoplegia rare.285,286

Acquired Acquired ophthalmoplegia is quite common in pediatric Guillain-Barre´ syndrome.287 A small proportion of affected children presents with the Miller Fisher syndrome of ataxia, external ophthalmoplegia, and areflexia.288,289 Occasional cases presenting with isolated ophthalmoplegia may be diagnostically challenging.290 Acquired external ophthalmoplegia is also seen in the neuropathic crises of Tangier disease and acute intermittent porphyria291,292 and internal ophthalmoplegia may be identified during the bulbar phase of diphtheria and in acute sensory and autonomic neuropathy.293,294 The extraocular muscles are generally spared in childhood chronic inflammatory demyelinating polyradiculoneuropathy, although diplopia is occasionally reported.295,296 Vitamin E deficiency may present with progressive external ophthalmoplegia (PEO), ptosis, and pigmentary retinopathy,297 and occasionally causes third nerve palsies and aberrant regeneration.298,299 Sarcoidosis may produce diplopia from involvement of any of the EOMs.300

Neuromuscular Junction Disorders Congenital Myasthenic Syndromes The congenital myasthenic syndromes present during the neonatal period or early infancy with ptosis, ophthalmoplegia, poor feeding, and hypoventilation. Numerous defects of presynaptic, synaptic, and postsynaptic function have been identified and are reviewed in detail in Chapter 26 (see Table 46.4).301,302

Chapter | 46 Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

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TABLE 46.4 Ophthalmologic Manifestations of Pediatric Muscle Diseases Ptosis

Strabismus

External Ophthalmoplegia

Pupillary Abnormalities

Retinopathy

Presynaptic Choline acetyltransferase deficiency

111

2

1

2

2

Synaptic Acetylcholinesterase deficiency

1

1

1

111

2

Post-synaptic Receptor deficiencies, abnormalities of clustering or synaptogenesis AChR deficiency Rapsyn DOK7 GFPT1 DPAGT1 Kinetic abnormalities Slow channel Fast channel

111

1

111

2

2

Myotubular myopathy

111

2

111

2

2

Centronuclear myopathy

11

1

11

2

2

Minicore myopathy

1

1

1

2

2

Nemaline myopathy

1

1

2

2

2

Central core disease

1

2

2

2

2

Congenital fiber-type disproportion

11

2

11

2

2

Nesprin deficiency

2

2

111

1

1

Congenital myotonic dystrophy

1

1

2

2

2

Kearns-Sayre syndrome

111

2

111

2

111

MELAS

1

2

1

2

11

MERRF

1

2

1

2

2

Myotonic dystrophy

11

1

1

1

2

Epidermolysis bullosa and muscular dystrophy

11

2

11

2

2

Transient neonatal myasthenia gravis

1

2

1

2

2

Autoimmune myasthenia gravis

11

1

11

2

2

Pediatric Lambert-Eaton myasthenic syndrome

11

1

2

2

2

Infant botulism

11

1

11

11

2

Organosphosphate toxicity

1

1

1

11

2

Thyroid myopathy

1

1

1

2

2

Congenital myasthenic syndromes

Congenital myopathies

Congenital muscular dystrophies

Mitochondrial myopathies

Muscular dystrophies

Myasthenia gravis

1 , occasional;11, frequent; 11 1 , invariable. Abbreviations: AChR, acetylcholine receptor; MELAS, syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes; MERRF, syndrome of myoclonus with epilepsy and ragged red fibers.

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Acquired Disorders of Neuromuscular Transmission Ptosis and external ophthalmoplegia are among the most common manifestations of myasthenia, and may develop in the absence of peripheral weakness. Although a variety of hypotheses attempt to explain the apparent targeting of the EOMs, selective involvement of the EOM in myasthenia is poorly understood. Disease expression in acquired myasthenia gravis is governed by antigenic differences in the acetylcholine receptor (AChR) isoforms. The two muscle AChR isoforms are developmentally regulated and are comprised of alpha, beta, delta, and either gamma (embryonic) or epsilon (adult) subunits.303,304 In peripheral muscle, maturational development of functional neuromuscular junctions results in the replacement of the embryonic by the adult AChR isoform. Mature EOMs, however, continue to express the fetal AChR subtype.305 Myasthenics may develop antibodies preferentially binding fetal acetylcholine receptors, thereby selectively causing weakness of the EOM. A subset of multiply innervated fibers present only in the EOM contract tonically in proportional response to endplate depolarizations, with smaller endplate potentials resulting in decreased force of contraction.22 Antibodies selective to the neuromuscular junctions of multiply innervated fibers specifically cause compromise of neuronal transmission in these fibers. Other manifestations of ocular myasthenia are not explained by these hypotheses. Ptosis is one of the most common manifestations of myasthenia gravis, although the levator palpebrae superioris contains neither multiply innervated fibers nor fetal AChR subunits.306 Preferential involvement of the EOMs may also relate to their physical qualities: the high firing rate, low acetylcholine receptor density, and lower mean quantal content of EOM fibers, the greater accessibility of their end plates to circulating antibodies, or the low tolerance of ocular alignment systems for errors that produce diplopia.22,303,304 The transient neonatal form of myasthenia gravis is seen in 10% to 15% of infants of mothers with acquired myasthenia gravis, and has been attributed to the transplacental passage of maternal anti-AChR antibodies.307 309 Poor sucking, hypotonia, and facial diplegia are apparent within a few hours of birth in most cases. Ptosis (15%) and ophthalmoplegia (8%) are less common. Symptoms are isolated to the ocular musculature at initial presentation in as many as 63% of children with acquired autoimmune myasthenia gravis.310 Ptosis and ophthalmoplegia vary, but typically become more marked towards the end of the day. Ptosis may initially be unilateral but eventually becomes bilateral in most. Ptosis may be more apparent after repeated eyelid closures or saccades, prolonged upgaze, or passive elevation of the opposite

eyelid. Cogan’s eye twitch, with transient eyelid elevation on upgaze after sustained downgaze, is characteristic of myasthenic eye disease. Autoimmune myasthenia may involve one or all of the EOMs, the levator palpebrae superioris, and the orbicularis oculi. Ptosis and ophthalmoplegia are ameliorated by sleep or cooling of the affected muscles, or by administration of anticholinesterases. Eventual systemic involvement is seen in 85% of patients, usually within the first 2 years after disease onset.311 Rare pediatric cases of the Lambert-Eaton myasthenic syndrome are usually associated with an underlying neoplasm, and may present with ptosis or transient diplopia.312 Infant botulism causes ptosis, ophthalmoplegia, and sluggish pupillary reflexes, in addition to bulbar weakness and lethargy.313 Abducens palsies and impaired accommodation have also been identified as early signs of foodborne botulism.314 Arthropod envenomation can result in acquired abnormalities of neuromuscular transmission. Involuntary conjugate roving eye movements, possibly associated with nystagmus, may accompany the systemic manifestations of scorpion envenomation. Presynaptic acetylcholine release is increased with both spider and scorpion bites. Tick paralysis initially causes an ascending paralysis. Tonic pupillary dilatation, external ophthalmoplegia, and facial weakness develop late in the disease course (see Chapter 19). Snake envenomation can cause acute neuromuscular blockade with ptosis, ophthalmoplegia, and descending bulbar dysfunction. Iatrogenic causes of impaired neuromuscular transmission include medications acting presynaptically (such as corticosteroids, antiarrhythmics, aminoglycosides, anticonvulsants, beta-blockers, chloroquine, cisplatin, lithium, and magnesium), or postsynaptically (neuromuscular blockers, anticholinesterases, D-penicillamine, and phenothiazines). Ophthalmoplegia and ptosis may also accompany the systemic manifestations of organophosphate poisoning.315

Myopathies Congenital Myopathies Several congenital myopathies are associated with ophthalmoplegia (Table 46.4). Myotubular myopathy presents in the neonatal period with severe weakness, hypotonia, and ventilatory insufficiency. Ophthalmoplegia and ptosis are apparent in most boys with X-linked myotubular myopathy, and enable clinical differentiation from congenital myotonic dystrophy (see Case Example 46.3). The autosomal forms of this disorder, commonly known as centronuclear myopathy, present in infancy or childhood with facial diplegia, proximal muscle weakness, and more variable involvement of the external ocular musculature.316

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CASE EXAMPLE 46.3 An 11-day-old boy was transferred from an outside hospital to Boston Children’s Hospital for evaluation of hydrocephalus, profound hypotonia, and respiratory insufficiency. He was born at 31 weeks’ gestational age after a pregnancy complicated by polyhydramnios and decreased fetal movements. There was no family history of neuromuscular disorders. At delivery, the infant was limp, apneic, and had no heart rate. He was intubated at 9 minutes of age and had Apgar scores of 0, 4, 6, at 1, 5, and 10 minutes, respectively. Continued ventilatory support was required. Neurologic evaluation revealed an expressionless facies with ptosis, limited abduction of both eyes, a high-arched palate, and tented upper lip. There was poor muscle bulk, generalized areflexia, equinovarus deformities of both ankles, and no antigravity movement. Sensation appeared intact. His examination was otherwise unremarkable but for undescended testes. Serial head ultrasounds showed stable ventriculomegaly with no parenchymal abnormalities.

Minicore myopathy is characterized by hypotonia, slowly progressive proximal weakness, and paresis of the facial and neck musculature. Ptosis is uncommon, and external ophthalmoplegia is seen in only 10% of cases, generally those associated with ryanodine mutations.317 Central core disease is not usually associated with abnormal EOM. Ptosis is most commonly seen in the subset of patients with the King-Denborough syndrome, and ophthalmoplegia in patients with recessive central core disease.318,319 Progressive external ophthalmoplegia has also been reported in multicore myopathy in association with short-chain acyl-CoA dehydrogenase deficiency.320 Nemaline myopathy commonly causes facial weakness and ptosis. External ophthalmoplegia is not usually seen in primary nemaline myopathy,321 and its presence should raise suspicion of mitochondrial disease.322 External ophthalmoparesis and ptosis are seen in a minority of children with congenital fiber-type disproportion, and may be predictors of severe weakness and early mortality in this condition.323 Childhood muscle disorders with external ophthalmoplegia and type 1 fiber predominance have been variably termed congenital myopathy with uniform type 1 fibers and minimal change myopathy. The genetic basis of these uncommon syndromes remains unclear (Cancilla et al., 1971; Bender et al., 2007; Sugie et al. 1982; Hansen et al., 1977; Lo et al., 1990).324 330

Muscular Dystrophies The congenital muscular dystrophies tend to be associated with variable developmental and maturational abnormalities of the central nervous system and eyes, and may also

A tracheostomy was placed at 4 weeks of age, at which time muscle biopsy demonstrated increased fiber size variation, with a large number of both type 1 and type 2 fibers containing prominent central nuclei or clear central zones surrounded by a peripheral myofibrillar rim. DNA sequence analysis subsequently demonstrated a point mutation within intron 4 of the MTM1 gene, which was predicted to cause aberrant splicing of MTM1 RNA. The same mutation was identified on screening of maternal DNA. Comment This child’s presentation was consistent with a congenital myopathy, with the finding of ptosis and external ophthalmoplegia suggesting the diagnosis of myotubular myopathy. Ventriculomegaly has been reported in myotubular myopathy. DNA sequencing confirmed the diagnosis and will enable prenatal diagnosis in further pregnancies.

affect the heart, retina, and cochlear system, but almost invariably spare the extraocular muscles. The necrosis, regeneration, and fibrosis seen in the peripheral muscles are absent from the EOMs, for reasons that remain unresolved but may relate to retention of developmental protein isoforms, variable innervation, fiber size, or typing, or the low absolute forces generated by the EOMs. Alternately, the EOMs may have the capacity for upregulation of utrophin, a sarcolemmal protein that may substitute for dystrophin in maintenance of sarcoplasmic integrity, and/or for adequate sequestration of increased calcium released by dystrophic sarcolemmal damage.331 Although “classical” congenital muscular dystrophy (CMD) spares the ocular movements, limitation of upgaze and lateral eye movement is occasionally seen in merosindeficient CMD.332 There are also several case reports of children with merosin-positive or undefined CMD with ptosis or ophthalmoplegia, or both.333,334 Subsequent investigations have identified a nesprin mutation in one such kindred.335 Some cases are likely to relate to mitochondrial pathology.336 Ptosis and ophthalmoplegia are not seen in the Fukuyama, Walker-Warburg, or muscle-eye-brain forms of CMD, or in the dystrophinopathies, sarcoglycanopathies, or disorders of the dystrophin-associated glycoproteins. The muscular dystrophy associated with autosomal recessive epidermolysis bullosa simplex (MD-EBS), and caused by mutations in plectin, is unusual in that it frequently affects the EOM.337,338 This syndrome presents at birth with bullous skin eruptions and progressive nail dystrophy. Progressive limb-girdle muscle weakness and ptosis become apparent in infancy or later. In several cases, the presence of fatigability and fluctuating ptosis and ophthalmoplegia have raised the question of an

946 PART | VII Special Clinical Problems

associated disorder of neuromuscular transmission, and a positive response to treatment with 3,4-diaminopyridine was seen in one patient.339 Although peripheral and facial weakness are marked in congenital myotonic dystrophy, involvement of the EOMs is uncommon in this condition.340 Ptosis is seen in up to 65% of older patients with myotonic dystrophy, but diplopia and external ophthalmoplegia are relatively uncommon.341 Slowing of saccades and disturbances of smooth pursuit in this condition have been attributed to a combination of peripheral muscle weakness and lesions within the primary visual pathways. Other ocular findings may include cataracts, macular dystrophy, and pupillary abnormalities.341

Oculopharyngeal Muscular Dystrophy First described by Taylor in 1915, oculopharyngeal muscular dystrophy (OPMD) is most commonly seen in French-Canadian families.342 This uncommon muscular dystrophy is characterized by slowly progressive ptosis and dysphagia, which most commonly develop during the fifth decade of life. Limitation of ocular movements and development of moderate facial and proximal limb weakness are seen late in the disease course. OPMD results from stable expansions of a (GCG)6 repeat sequence in the first exon of the poly(A) binding protein 2 (PABP2) gene on chromosome 14q11.2-13.342 The existence of a “childhood-onset” form of OPMD remains in doubt. The youngest genetically confirmed case reported to date, a (GCG)9 homozygote, was symptomatic from 21 years of age.343 A number of OPMD variants have been described, with early onset or atypical features including profound ophthalmoplegia, significant distal weakness, and early respiratory failure.344 348 Marked elevation of the serum creatine kinase level is present in some cases. In most cases, muscle biopsies demonstrate dystrophic changes, rimmed vacuoles, and cytoplasmic or nuclear filaments, or both. These overlap syndromes have features of OPMD, oculopharyngodistal myopathy, and the inclusion body myopathies. Some have been shown not to link to PABP2.344

Other Myopathies Oculopharyngodistal Myopathy This rare myopathy can be inherited in both an autosomal recessive and dominant fashion. Affected patients have ptosis and progressive weakness of the extraocular, bulbar, facial, and distal muscles from the second or third decade (Figure 46.12). Creatine kinase levels are elevated and muscle biopsy specimens are markedly dystrophic with fiber degeneration, increased internal nuclei, and rimmed vacuoles containing cytoplasmic filaments. Oculopharyngodistal myopathy is distinguished from

OPMD by the early development of ophthalmoplegia and the severity of distal weakness.350,351 Inclusion Body Myopathies The inclusion body myopathies are a heterogeneous group of hereditary or sporadic disorders, the pathologic hallmarks of which are the presence of “rimmed vacuoles” (cytoplasmic vacuoles containing peripheral granular material) and cytoplasmic and nuclear inclusions, consisting of filaments measuring 15 to 21 nm. The autosomal recessive hereditary inclusion body myopathies may present in childhood with an unusual distribution of weakness and with foot drop and quadriceps sparing.352 Autosomal dominant hereditary inclusion body myopathies can also present in childhood, usually with limb-girdle weakness.353 Most hereditary inclusion body myopathies spare the EOMs, but inclusion body myopathy with joint contractures and ophthalmoplegia (IBM3) invariably causes progressive external ophthalmoplegia, which may present as early as the first decade.354 Endocrine Myopathies Most cases of thyrotoxic myopathy do not result in ophthalmoparesis, and exophthalmic ophthalmoplegia, when present, is variably associated with thyrotoxicosis.355 Graves’ ophthalmopathy is more benign in children than adults.356 Other endocrine myopathies spare the EOMs. Channelopathies Ptosis and ophthalmoplegia are not seen in myotonia or paramyotonia congenita, or in the periodic paralyses, although these conditions may cause lid lag, blepharospasm, and eyelid myotonia. Fluctuating ptosis and ophthalmoplegia were present in a single kindred with an X-linked syndrome of episodic muscle weakness precipitated by fever or anesthesia. A vacuolar myopathy similar to that seen in the periodic paralyses was identified on muscle biopsy.357 Mitochondrial Disorders The elevated oxidative enzyme activity and high mitochondrial content of the EOMs may explain their high fatigue resistance and preferential involvement in mitochondrial disorders. Tissue-specific expression in these diseases is probably determined by the extent of mitochondrial heteroplasmy. Degeneration is more marked in the extraocular than peripheral muscles in Kearns-Sayre syndrome, but ragged red fibers, myofibrillary degeneration, and abnormal mitochondria have been identified in the EOMs of patients with other mitochondrial disorders (such as MELAS and MERRF), even in the absence of clinical involvement.358,359 Ptosis and chronic progressive

Chapter | 46 Disorders of the Ocular Motor Cranial Nerves and Extraocular Muscles

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FIGURE 46.12 Oculopharyngodistal myopathy. Affected individual has (A) Bilateral ptosis on primary gaze; (B) Distal wasting of the upper and lower extremities; ophthalmoplegia on attempted (C) upgaze, (D) downgaze, (E) rightward gaze and (F) leftward gaze. Photographs courtesy of Dr. Eiichiro Uyama. Reprinted from Uyama et al., Neuromuscular Disorders, vol. 8, 1998,349 with permission from Elsevier.

external ophthalmoplegia (PEO) are often the initial manifestations of Kearns-Sayre syndrome, which is also defined by the findings of pigmentary retinopathy, high cerebrospinal fluid protein content, heart block, and ataxia.359 Isolated chronic PEO manifests only with ptosis and limited extraocular movements, although involvement of the somatic musculature is commonly apparent on muscle biopsy. The autosomal dominant form of PEO is rarely symptomatic before 20 years of age, but recessive forms can present in childhood, sometimes in association with severe childhood-onset cardiomyopathy.360 Autosomal recessive PEO is also seen with ptosis, sensorimotor peripheral neuropathy, and gastrointestinal pseudo-obstruction in the

multisystem syndrome known as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).361 Arthrogryposis Ptosis and PEO are uncommon in the arthrogryposis syndromes, but may be seen in forms associated with severe congenital myopathy,362 and in some forms of distal arthrogryposis.363,364 Spinocerebellar Ataxias Most spinocerebellar ataxias (SCAs) spare the EOMs. Marinesco-Sjo¨gren syndrome may cause strabismus,

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ptosis, and cataracts365 and ophthalmoplegia develops during childhood in “infantile onset” SCA and the autosomal recessive form of SCA 8. Of the autosomal dominant SCAs, myokymia is seen in SCAs 2 and 3, PEO, diplopia, and ptosis in SCA3, and ptosis in SCA7. Several of the autosomal dominant SCAs also result in supranuclear gaze disorders, nystagmus, and abnormal saccades.366,367

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