Keywords
Extraocular, ptosis, strabismus, ophthalmoplegia, pediatric, oculomotor, trochlear, abducens
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 .
| 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 |
| Mitochondrial Disorders | ||
| 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 |
| Nutritional/Metabolic | ||
| Abetalipoproteinemia with vitamin E deficiency | Convergence insufficiency, upgaze limitation | Internuclear ophthalmoplegia, pigmented retinopathy |
| 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 |
The Extraocular Lower Motor Unit
Four recti and two oblique muscles move the globe, and the levator palpebrae superioris raises the eyelid. These 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 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). The histology of EOM is significantly different from that of the skeletal striated muscles, and it appears to be more resistant to pathologic stressors. 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. 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. 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 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.
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. EOM fiber typing is different from that of limb skeletal muscle; the traditionally recognized fiber classification schemes cannot be applied to EOM. 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 ). 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 upward movement of the eyelid, has no differentiation of orbital and global layers, and lacks multiply innervated fiber types.
The gene and protein expression profiles of EOM myofibers differ from skeletal limb muscle both during development and in maturity. While EOMs contain the normal components of the dystrophin-glycoprotein complex, including dystrophin, dystroglycans, sarcoglycans, syntrophins, dystrobrevin, and merosin, they also retain embryonic myosin, fetal acetylcholine receptors, and sarcolemmal-wide expression of polysialated neural cell adhesion molecules. 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.
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. 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.
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 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 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.
Localizing Syndromes
The anatomy of the oculomotor nuclei and nerve produces clinical features helpful in the localization of oculomotor palsies. 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 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. 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.
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. 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.
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.
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.
Etiology
Third nerve palsies are rare, and less common than fourth or sixth nerve palsies in childhood. About ⅔ are partial, and ⅓ complete. As many as 47% of all pediatric oculomotor palsies are congenital. 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%).
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. 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. 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, or developmental anomalies of the midbrain or cerebellum. 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. Such regeneration may lead to miosis, rather than dilation, of the affected pupil. Another common finding is amblyopia, usually in the paretic eye but occasionally in the nonparetic eye.
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.
Acquired CN III Palsies
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%), 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. Painful ophthalmoplegia often involves more than one cranial nerve, and suggests acquired conditions such as infection, tumor, orbital pseudotumor, hemorrhage, thrombosis, aneurysm, or Tolosa-Hunt 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).
| Etiology | III Cranial Nerve | IV Cranial Nerve | VI Cranial Nerve |
|---|---|---|---|
| TRAUMA | 25–72% | 8–50% | 20–42% |
| Diffuse axonal injury | + | ||
| Ischemic | + | ||
| Shearing forces | + | + | + |
| Subdural hematoma | + | + | |
| Cavernous sinus thrombosis | + | + | + |
| Postoperative | + | + | + |
| NEOPLASIA | 5–31% | Rare | 17–39% |
| Cavernous sinus | |||
| Meningioma | + | + | + |
| Schwannoma | + | + | + |
| Pituitary fossa | |||
| Pituitary adenoma | + | + | + |
| Craniopharyngioma | + | + | + |
| Dermoid/epidermoid | + | + | + |
| Teratoma | + | + | + |
| Sellar germ cell tumor | + | + | + |
| Cerebellar | |||
| Astrocytoma | + | + | |
| Medulloblastoma | + | + | |
| Brainstem glioma | + | + | ++ |
| Other neoplasms | |||
| Pinealoma | + | + | |
| Meningioma | + | + | |
| Schwannoma | + | + | |
| Acoustic neuroma | + | + | |
| Ependymoma | + | + | |
| Nasopharyngeal carcinoma | + | + | |
| Clivus chordoma | |||
| Infiltrating neoplasms | |||
| Leptomeningeal sarcoma | + | + | + |
| Lymphoma | + | + | + |
| Carcinomatous meningitis | + | + | + |
| Mesencephalic cyst | + | ||
| VASCULAR | 3–13% | 1–2% | |
| Subdural hemorrhage | + | + | |
| Aneurysm | + | + | + |
| Cavernous hemangioma | + | + | + |
| Arteriovenous malformation | + | + | |
| Carotid-cavernous fistula | + | ||
| INFECTION | 9–25% | ||
| Meningitis | + | + | + |
| Encephalitis | + | + | + |
| Mastoiditis, Gradenigo’s syndrome | + | ||
| INFLAMMATORY | |||
| Sarcoidosis | + | + | + |
| Tolosa-Hunt syndrome | + | + | + |
| Orbital pseudotumor | + | + | + |
| RHEUMATOLOGIC/AUTO-IMMUNE | |||
| Polyarteritis nodosa | + | ||
| Multiple sclerosis, ADEM | + | + | + |
| Guillain-Barré syndrome | + | + | + |
| Sjögren’s syndrome | + | ||
| OTHER | |||
| Migraine | 7–19% | + | |
| Toxins | + | + | |
| Increased intracranial pressure | + | + | |
| Thyroid eye disease | + | + | + |
| Iatrogenic | + | + | |
| Cryptogenic | <20% | 0–21% | 9–36% |
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.
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. 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. Rarely, recurrent ophthalmoplegia may occur in the absence of headache, in what may represent a migraine equivalent. 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 ), while the CSF examination is normal.
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.
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 reflexes. 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.
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. 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.
Anatomy
The trochlear is the only cranial nerve to emerge from the dorsal aspect of the brainstem, the only one to cross 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.
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, convergence-retraction nystagmus, lid retraction, light-near dissociation, or a combination of these symptoms. A contralateral Horner syndrome or intranuclear ophthalmoplegia indicates involvement of the fourth nerve within the midbrain. Ipsilateral limb ataxia or contralateral sensory loss may reflect involvement of the cerebellar peduncle or sensory lemniscus, respectively. 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.
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.
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 ).
| Step 1 | Step 2 | Step 3 | ||
|---|---|---|---|---|
| Primary | R gaze | L gaze | R tilt | L tilt |
| R hypertropia | ||||
| RSO | RSO | RSO | ||
| RIR | RIR | RIR | ||
| LIO | LIO | LIO | ||
| LSR | LSR | LSR | ||
| L hypertropia | ||||
| LSO | LSO | LSO | ||
| LIR | LIR | LIR | ||
| RIO | RIO | RIO | ||
| RSR | RSR | RSR | ||
Etiology
Most trochlear palsies are congenital (refer to Congenital Cranial Dysinnervation Disorders section below) or arise as a result of trauma. Differentiation between congenital 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. Facial asymmetry, with retrusion and upslanting of the mouth on the side of the head tilt, is also indicative of chronicity. 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. Similarly, amblyopia is rare because the compensatory head tilt enables fusion of the images from both eyes. MRI findings can also be helpful in distinguishing congenital and acquired trochlear palsies . 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 ). Orbital fractures may damage the nerve, tendon, trochlea, or the muscle itself. Trauma may also cause decompensation of a congenital palsy. 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 V-pattern esotropia is generally present, and is often large.
Inflammatory and infectious causes of trochlear palsies include the Tolosa-Hunt and Guillain-Barré syndromes, Herpes zoster ophthalmicus, and, less commonly, sarcoidosis and even tetanus. 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.
Skew deviation is vertical misalignment due to disruption of supranuclear pathways in the midbrain tegmentum, dorsolateral medulla, cerebellum, or vestibular system. Although most commonly due to trauma, it is also occasionally seen with the Chiari malformation (type II), myelomeningocele, hydrocephalus, or even pseudotumor cerebri. Skew deviation may or may not be comitant, and may alternate periodically over time or with lateral gaze position.
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. 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. 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.
Weakness of the superior oblique may also be found in myasthenia gravis or thyroid eye disease. 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.
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.
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.
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. Children will often present with a head turn toward the affected eye. 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.”
Etiology
In contrast to CN III and CN IV palsies, congenital abducens palsies are rare (8–13%) in comparison with acquired 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.
Congenital CN VI Palsies
Transient neonatal abducens palsies probably result from perinatal cranial trauma, and generally resolve within 6 weeks. In some infants, a presumed abducens palsy manifests simply as neonatal esotropia. 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. Tumors frequently associated with sixth nerve palsy are listed in Table 46.2 ; pontine glioma predominates.
The sixth cranial nerve may be injured by trauma where it crosses the clivus, by direct damage to the petrous bone in basilar skull fractures, or by entrapment in medial orbital fractures. The abducens nerve is also vulnerable to traumatic injury during resection of posterior fossa tumors. 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. Unilateral or bilateral traction injury may result from hydrocephalus (or uncommonly from lumbar puncture).
Inflammatory abducens neuropathies (17% of total CN VI palsies) are usually partial. CN VI is affected in as many as 16% of cases of bacterial meningitis. 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.
As many as 36% of acquired abducens palsies are idiopathic. Benign isolated complete CN VI palsies may develop acutely, often preceded by a febrile, presumably viral illness. See 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. Alternate-day patching was instituted. His incomitant esotropia remained stable over the next 6 months.
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.
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. Recurrent abducens palsies have been associated with Epstein-Barr and varicella infections, and with immunizations. 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.
Increases or decreases in intracranial pressure may result in unilateral or bilateral abducens palsy, presumably caused by nerve compression. Such palsies are usually partial. Aneurysms (usually in the cavernous sinus) rarely cause abducens palsies in childhood.
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. 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.
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.
Lateral rectus weakness is occasionally seen with pediatric myasthenia gravis and thyroid eye disease. Orbital pseudotumor and orbital myositis may cause restriction of lateral rectus contraction. 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. 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.
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, reimaging after intervals of 1 to 2 years may be indicated in order to exclude an occult mass lesion. Magnetic resonance angiography may also be considered for acquired CN III palsy, although intracranial aneurysms and other vascular anomalies are rare in childhood. 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. 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.
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 complex coordination between the various EOMs required to achieve normal conjugate horizontal and vertical movements. 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.
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. To correct vertical misalignment, either of the horizontal recti may be transposed vertically, or recession-resection procedures may be performed on the vertical recti. 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.
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. 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. 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). In some cases, superior oblique myokymia (see separate discussion) may develop. 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. 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%.
Abducens Palsy
Most acquired abducens palsies resolve spontaneously within 3 to 4 months. Prognosis varies with cause and is best in idiopathic cases. Younger children have higher rates of permanent strabismus (66%) and amblyopia (20%). Recurrent palsies usually involve the same eye, and resolve within 8 to 12 weeks. 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. 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.
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. 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.
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 ~75% 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, and some investigators have noted an inverse correlation between the degree of ptosis and the number of residual striated muscle fibers. 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 ), an X-linked PTOS2 locus (OMIM #300245) on chromosome Xq24-q27.1, and a translocation disrupting ZFH-4 on chromosome 8 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.
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 3q23 and result from mutations in the Forkhead transcription factor, FOXL2. 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. 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.
Duane Syndrome
Duane syndrome is the most common of the CCDDs, accounting for 1% to 5% of strabismus cases. 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. 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 the disorder, cases are diagnosed equally in infancy, childhood, and adulthood.
DRS has been categorized clinically into three types, with types I and III more common than type II. 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.
Although historically believed to result from a primary myogenic process, 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). 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.
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.
Autosomal dominant isolated DRS can result from heterozygous missense mutations in CHN1 , which encodes alpha2-chimerin, a Rac guanosine triphosphatase-activating protein (RacGAP) Affected individuals have a higher incidence of bilateral DRS and additional vertical eye movement abnormalities compared to individuals with non- CHN1 DRS. 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 oculomotor- and trochlear-innervated muscles. 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. CHN1 mutations are not a common cause of simplex DRS.
Dominant mutations in the transcription factor SALL4 cause Duane-radial ray syndrome (DRRS), also referred to as Okihiro syndrome, acro-renal-ocular syndrome, or IVIC syndrome. 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. 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. While several Sall4 mutant mouse lines have been reported, these have not provided insight into the etiology of DRS in DRRS; Sall4 −/− embryos die at ~E6.5, and in the one line examined in detail, Sall4 −/+ mice had normal-appearing ocular cranial nuclei and extraocular muscles.
The HOXA1 -related syndromes result from recessive mutations in the transcription factor HOXA1 , and include the overlapping Bosley-Salih-Alorainy syndrome (BSAS, OMIM, #601536) and Athabaskan brainstem dysgenesis syndrome (ABDRS). 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. HOXA1 mutations are not, however, a common cause of isolated DRS.
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.
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. HGPPS results from mutations in the axon guidance receptor ROBO3. There is failure of axons and cell bodies to cross the midline of the hindbrain and spinal cord during development, resulting in uncrossed descending corticospinal tracts and ascending sensory tracts. 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.
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.
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 ). 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 ). KIF21A encodes an anterograde kinesin protein 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. It is expressed in most developing and mature neurons in the nervous system, and its expression does not appear to be changed in CFEOM1. CFEOM1 mutations specifically alter amino acid residues in the motor and third coiled- coil stalk domain of the KIF21A protein. These domains interact with one another to autoinhibit Kif21a, and CFEOM1 mutations attenuate Kif21a autoinhibition and enhance its interaction with microtubules. 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.
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