The maintenance of binocular vision requires harmonious function of the visual sensory system, gaze centers, ocular motor nerves, neuromuscular junction, and ocular muscles. This chapter deals with nonparalytic strabismus, paralytic strabismus (ophthalmoplegia), gaze palsies, ptosis, and nystagmus. The discussion of visual and pupillary disorders is in Chapter 16 .
Strabismus (squint), or abnormal ocular alignment, affects 3–4 % of preschool children. Many individuals have a latent tendency for ocular misalignment, heterophoria, which becomes apparent only under stress or fatigue. During periods of misalignment, the child may have diplopia or headache. Constant ocular misalignment is heterotropia. Children with heterotropia suppress the image from one eye to avoid diplopia. If only one eye fixates continuously, visual acuity may be lost permanently in the other (developmental amblyopia).
In nonparalytic strabismus, the amount of deviation in different directions of gaze is relatively constant (comitant). Each eye moves through a normal range when tested separately ( ductions ), but the eyes are disconjugate when used together ( versions ). Many children with chronic brain damage syndromes, such as malformations or perinatal asphyxia, have faulty fusion or faulty control of conjugate gaze mechanisms (nonparalytic strabismus). In neurologically normal children, the most common cause of nonparalytic strabismus is either a genetic influence or an intraocular disorder. Ocular alignment in the newborn is usually poor, with transitory shifts of alignment from convergence to divergence. Ocular alignment usually establishes by 3 to 4 weeks of age but may not occur until 5 months. Approximately 2 % of newborns exhibit tonic downward deviation of the eyes during the waking state. Constant ocular alignment usually begins after 3 months of age. The eyes assume a normal position during sleep and are able to move upward reflexively.
Esotropia is a constant inward deviation (convergence) of the eyes. It is called alternating esotropia when fixation occurs with both eyes. Unilateral esotropia is when fixation occurs continuously with the opposite eye. Early onset esotropia presents before 6 months of age. The observation of accommodative esotropia is usually between 2 and 3 years of age, and may be undetected until adolescence.
Children with infantile esotropia often alternate fixation between eyes and may cross-fixate, i.e., look to the left with the right eye and to the right with the left eye. The misalignment is sufficient that family members see that a problem exists. Some children fixate almost entirely with one eye and are at risk for permanent loss of visual acuity, developmental amblyopia, in the other.
Accommodative esotropia occurs when accommodation compensates for hyperopia. Accommodation more sharply focuses the blurred image. Because convergence accompanies accommodation, one eye turns inward. Some children with accommodative esotropia cross-fixate and use each eye alternatively, while the other maintains fixation. However, if one eye is more hyperopic than the other eye, only the better eye fixates and the unused eye has a considerable potential for amblyopia.
An ophthalmologist should examine the eyes to determine whether hyperopia is present.
Eyeglasses correct hyperopic errors. The treatment of early onset esotropia, in which only one eye fixates, consists of alternate eye patching to prevent ambliopia. Early corrective surgery is required for persistent esotropia. Esotropia presenting after 6 years of age raises concern for a posterior fossa disorder such as a Chiari malformation.
Exotropia is an outward divergence of the eyes. It may be intermittent (exophoria) or constant (exotropia).
Exophoria is a relatively common condition that begins before 4 years of age. It is most often evident when the child is fatigued and fixating on a far object or in bright sunlight. The natural history of the condition is unknown. Exotropia may be congenital but poor vision in the outward-turning eye is also a cause.
Exotropia is an indication to examine the eye for intraocular disease.
In children with intermittent exotropia, the decision to perform corrective surgery depends on the frequency and degree of the abnormality. When exotropia is constant, treatment depends on the underlying cause of visual loss.
The causes of paralytic strabismus include disorders of the ocular motor nerves, the ocular muscles, or neuromuscular junction. Table 15-1 summarizes the muscles, the nerves, and their functions. The eyes no longer move together and diplopia is experienced. Strabismus and diplopia worsen when the child looks in the direction of action of the paralyzed muscle.
|Superior rectus||Oculomotor||Elevation, intorsion, adduction|
|Inferior rectus||Oculomotor||Depression, extorsion, adduction|
|Inferior oblique||Oculomotor||Extorsion, elevation, abduction|
|Superior oblique||Trochlear||Intorsion, depression, abduction|
Testing of eye movements is uncommon in newborns and ophthalmoplegia often missed. It is common for strabismus to remain unnoticed for several months and then discounted as transitory esotropia. Therefore, consider congenital ophthalmoplegia even when a history of ophthalmoplegia at birth is lacking.
Oculomotor Nerve Palsy/III Cranial Nerve
Congenital oculomotor nerve palsy usually is unilateral and complete. Pupillary reflex paralysis is variable. Other cranial nerve palsies, especially abducens, may be associated. The palsy is often unrecognized at birth. Most oculomotor nerve palsies are idiopathic, but some are genetic or caused by orbital trauma. The affected eye is exotropic and usually amblyopic. Lid retraction on attempted adduction or downward gaze may be evidence of aberrant regeneration.
Magnetic resonance imaging (MRI) excludes the possibility of an intracranial mass compressing the nerve. Exophthalmos suggests an orbital tumor. An unreactive, dilated pupil excludes the diagnosis of myasthenia gravis, but a normal pupil requires testing for myasthenia.
Extraocular muscle surgery may improve the cosmetic appearance but rarely improves ocular motility or visual function.
Trochlear Nerve Palsy/IV Cranial Nerve
Congenital superior oblique palsy is usually unilateral. Birth trauma is usually the suspected cause, but the actual cause is rarely established. Most congenital cases are idiopathic. The head tilts away from the paralyzed side to keep the eyes in alignment and avoid diplopia. The major ocular features are hypertropia, greatest in the field of action of the involved superior oblique muscle; underaction of the paretic superior oblique muscle and overaction of the inferior oblique muscle; and increased hypertropia when the head tilts to the paralyzed side (positive Bielschowsky test ).
Head tilt, or torticollis (see Chapter 14 ), is not a constant feature. Once examination confirms a superior oblique palsy, important etiological considerations other than congenital include trauma, myasthenia gravis, and brainstem glioma.
Prisms are effective for small angle deviations; otherwise patients require surgery.
Abducens Nerve Palsy/VI Cranial Nerve
Congenital abducens nerve palsy may be unilateral or bilateral and is sometimes associated with other cranial nerve palsies. Lateral movement of the affected eye(s) is limited partially or completely. Most infants use cross-fixation and thereby retain vision in both eyes. In the few reported cases of congenital palsy with pathological correlation, the abducens nerve is absent and its nucleus is hypoplastic.
Möbius syndrome is the association of congenital facial diplegia and bilateral abducens nerve palsies (see Chapter 17 ). Duane syndrome is aplasia of one or both nuclei of the abducens nerve with innervation of the atrophic lateral rectus by fibers of the oculomotor nerve ( ). Ten percent of cases are genetic; the gene locus is on chromosome 8. The characteristic features are lateral rectus palsy, some limitation of adduction, and narrowing of the palpebral fissure because of globe retraction on attempted adduction. Möbius and Duane syndromes are rhombencephalic maldevelopment often associated with lingual, palatal, respiratory or long track motor and coordination deficits ( ).
MRI excludes the possibility of an intracranial mass lesion and hearing testing is required.
Surgical procedures may be useful to correct head turn and to provide binocular single vision, but they do not restore ocular motility.
Brown syndrome results from congenital shortening of the superior oblique muscle or tendon. The result is mechanical limitation of elevation in adduction. Usually, only one eye is involved.
Elevation is limited in adduction but is relatively normal in abduction. Passive elevation (forced duction) is also restricted. Other features include widening of the palpebral fissure on adduction and backward head tilt.
The diagnosis of Brown syndrome requires the exclusion of acquired shortening of the superior oblique muscle. The causes of acquired shortening of the superior oblique muscle include juvenile rheumatoid arthritis, trauma, and inflammatory processes affecting the top of the orbit (see section on Orbital Inflammatory Disease later in this chapter).
Surgical procedures that extend the superior oblique muscle can be useful in congenital cases.
Congenital Fibrosis of the Extraocular Muscles
Inheritance of congenital fibrosis of the extraocular muscles (CFEOM) is by autosomal dominant inheritance and the abnormal gene maps to chromosome 12p ( ). If all affected members of a family have typical CFEOM, the phenotypic classification is CFEOM1. CFEOM2 is associated with bilateral ptosis with the eyes fixed in an exotropic position. Genetic transmission is as an autosomal recessive trait. A CFEOM3 caused by TUBB3, R262C, and D417N amino acid substitutions has been described and is associated with abnormalities of extraocular muscle innervation and function. CFEOM3 has subarachnoid CN3 hypoplasia, occasional abducens nerve hypoplasia, and subclinical cranial nerve II hypoplasia that can resemble CFEOM1. Clinical and MRI findings in CFEOM3 are more variable than those in CFEOM1 and are often asymmetrical. Lateral rectus innervation by the inferior rectus motor nerve is an overlapping feature of Duane retraction syndrome and CFEOM1. These findings suggest that CFEOM3 is an asymmetrical, variably penetrant, congenital cranial dysinnervation disorder leading to secondary EOM atrophy ( )
Affected children have congenital bilateral ptosis and restrictive ophthalmoplegia, with their eyes partially or completely fixed in a downward position. CFEOM is a relatively static disorder that is phenotypically homogeneous when completely penetrant. Some children have mild delay in achieving milestones during infancy, and some have a mild facial diplegia. The head is tilted back to allow vision, and diplopia is not associated despite the severe misalignment of the eyes.
The clinical findings and the family history are the basis for diagnosis. Laboratory studies are useful only to exclude other possibilities.
The goal of treatment is improvement of vision by correcting ptosis.
Congenital Myasthenia Gravis
Several clinical syndromes of myasthenia gravis occur in the newborn (see Chapter 6 ). Congenital myasthenic syndromes (CMS) are genetic disorders of the neuromuscular junction. They are classified as presynaptic, synaptic, or postsynaptic. Postsynaptic disorders are divisible by the kinetic defects into fast channel and slow channel and a third disorder of acetylcholine receptor (AChR) deficiency. Approximately 10 % of CMS cases are presynaptic, 15 % are synaptic, and 75 % are postsynaptic.
Primary AChR deficiency with or without minor kinetic defect, primary kinetic defect with or without AChR deficiency, endplate acetylcholinesterase (AChE) deficiency, rapsyn deficiency, Dok-7 myasthenia, choline acetyltransferase (ChAT) deficiency, congenital Lambert–Eaton-like and other presynaptic defects, plectin deficiency, sodium channel myasthenia, paucity of synaptic vesicles, and reduced quantal release have been identified as causes of congenital myasthenia ( ). AChR deficiency causes most postsynaptic cases ( ). Genetic transmission is by autosomal recessive inheritance. Other underlying defects include abnormal acetylcholine resynthesis or immobilization, reduced endplate acetylcholinesterase, and impaired function of the AChR. In 25 % of patients with AChR deficiency, AChR mutations are undetectable. Among these patients, rapsyn ( receptor-associated protein at the synapse ) deficiency is an important causative factor ( ).
Although transmission of these disorders is by autosomal recessive inheritance, a male-to-female bias of 2:1 exists. Symmetric ptosis and ophthalmoplegia are present at birth or shortly thereafter. Mild facial weakness may be present but is not severe enough to impair feeding. If partial at birth, the ophthalmoplegia becomes complete during infancy or childhood. Generalized weakness sometimes develops. Electrophysiological studies in patients suffering from sudden apnea suggest a defect in acetylcholine resynthesis and choline acetyltransferase (ChAT). Refractoriness to anticholinesterase medications and partial or complete absence of AChE from the endplates suggest a mutation in COLQ ( ).
Suspect the diagnosis in any newborn with bilateral ptosis or limitation of eye movement. Intramuscular injection of edrophonium chloride produces a transitory improvement in ocular motility. Repetitive nerve stimulation of the limbs at a frequency of 3 Hz may evoke a decremental response after 5 to 10 minute stimulation that is reversible with edrophonium chloride. The 50 Hz repetitive stimulation may also show a 10 % decrease in CMAP between the first and fifth stimulation. This suggests that the underlying defect, although producing symptoms only in the eyes, causes generalized weakness at birth. Commercial testing is available for rapsyn mutations.
No evidence of an immunopathy exists and immunosuppressive therapy is not a recommendation. Thymectomy and corticosteroids are ineffective. Anticholinesterases may decrease facial paralysis but have little or no effect on ophthalmoplegia. The weakness, in some children, responds to 3,4-diaminopyridine (DAP), an agent that releases acetylcholine ( ) combined with anticholinesterases. DAP is now commercially available in the United States. The FDA granted DAP an orphan designation for Lambert-Eaton myasthenic syndrome.
Congenital drooping of one or both lids is relatively common, and the drooping is unilateral in 70 % of cases. The cause is unknown, but the condition rarely occurs in other family members. The three forms of hereditary congenital ptosis are simple, with external ophthalmoplegia, and with blepharophimosis. Genetic transmission of the simple form is either by autosomal dominant ( ) or X-linked inheritance.
Congenital ptosis is often unnoticed until early childhood or even adult life and then diagnosed as an “acquired” ptosis. Miosis is sometimes an associated feature and suggests the possibility of a Horner syndrome, except that the pupil responds normally to pharmacological agents. Some patients have a synkinesis between the oculomotor and trigeminal nerves; jaw movements produce opening of the eye ( Marcus-Gunn phenomenon ).
Box 15.1 lists the differential diagnosis of ptosis. Distinguishing congenital ptosis from acquired ptosis is essential. The examination of baby pictures is more cost-effective than MRI to make the distinction. If miosis is present, test the eye with pharmacological agents (Paredrine ® and cocaine test for denervation) to determine whether denervation rather than sympathetic hypersensitivity is present indicating a Horner syndrome. Concurrent paralysis of extraocular motility is evidence against congenital ptosis.
Congenital fibrosis of extraocular muscles
Horner syndrome ∗
∗ Denotes the most common conditions and the ones with disease modifying treatments
Oculomotor nerve palsy ∗
Horner syndrome ∗
Mitochondrial myopathies (see Chapter 8 )
Myasthenia gravis ∗
Oculomotor nerve palsy ∗
Oculopharyngeal dystrophy (see Chapter 17 )
Early corrective surgery to elevate the lid improves appearance and vision.
Acute Unilateral Ophthalmoplegia
Box 15.2 summarizes the causes of acquired ophthalmoplegia. The discussion of many of these conditions is in other chapters.
Brainstem encephalitis ∗
∗ Denotes the most common conditions and the ones with disease modifying treatments(see Chapter 10 )
Subacute necrotizing encephalopathy (see Chapter 10 )
Brainstem glioma ∗
Craniopharyngioma (see Chapter 16 )
Pineal region tumors
Familial recurrent cranial neuropathies (see Chapter 17 )
Increased intracranial pressure (see Chapter 4 )
Meningitis (see Chapter 4 )
Idiopathic ∗ (postviral)
Polyradiculoneuropathy (see Chapter 7 )
Cavernous sinus hemangioma
Sellar and parasellar tumors (see Chapter 16 )
Sphenoid sinus tumors
Cavernous sinus thrombosis
Fiber-type disproportion myopathies (see Chapter 6 )
Mitochondrial myopathies (see Chapter 8 )
Oculopharyngeal dystrophy (see Chapter 17 )
Orbital inflammatory disease
Vitamin E deficiency
The definition of acute ophthalmoplegia is reaching maximum intensity within 1 week of onset. It may be partial or complete ( Box 15-3 ). Generalized increased intracranial pressure is always an important consideration in patients with unilateral or bilateral abducens palsy (see Chapter 4 ).
∗ May be recurrent†
† May be associated with pain
Brainstem stroke ∗
Cavernous sinus fistula
Cavernous sinus thrombosis
Idiopathic ocular motor nerve palsy ∗
Increased intracranial pressure (see Chapter 4 )
Myasthenia gravis ∗
Ophthalmoplegic migraine ∗†
Orbital inflammatory disease ∗†
Orbital tumor †
The full discussion of arterial aneurysms is in Chapter 4 , because the important clinical feature in children is hemorrhage rather than nerve compression. This section deals only with possible ophthalmoplegic features.
Aneurysms at the junction of the internal carotid and posterior communicating arteries are an important cause of unilateral oculomotor palsy in adults but are a rare cause in children. Compression of the nerve by expansion of the aneurysm causes the palsy. Intense pain in and around the eye is frequently experienced at the time of hemorrhage. Because the parasympathetic fibers are at the periphery of the nerve, mydriasis is an almost constant feature of ophthalmoplegia caused by aneurysms of the posterior communicating artery. However, pupillary involvement may develop several days after onset of an incomplete external ophthalmoplegia. A normal pupil with complete external ophthalmoplegia effectively excludes the possibility of aneurysm.
Sometimes, aneurysms affect the superior branch of the oculomotor nerve earlier and more severely than the inferior branch. Ptosis may precede the development of other signs by hours or days.
Contrast-enhanced MRI and magnetic resonance angiography (MRA) or CT angiogram identify most aneurysms.
Surgical clipping is the treatment of choice whenever technically feasible. Oculomotor function often returns to normal after the procedure.
Symptoms begin between 2 and 13 years of age, with a peak between ages 5 and 8 years. The period from onset of symptoms to diagnosis is less than 6 months. Cranial nerve palsies, usually abducens and facial, are the initial features in most cases. Later, contralateral hemiplegia and ataxia, dysphagia, and hoarseness develop. Hemiplegia at onset is associated with a more rapid course. With time, cranial nerve and corticospinal tract involvement may become bilateral. Increased intracranial pressure is not an early feature, but direct irritation of the brainstem emetic center may cause vomiting rather than increased pressure. Intractable hiccup, facial spasm, personality change, and headache are early symptoms in occasional patients.
Brainstem gliomas carry the worst prognosis of any childhood tumor due to their location. The course is one of steady progression, with median survival times of 9 to 12 months.
MRI delineates the tumor well and differentiates tumor from inflammatory and vascular disorders ( Figure 15-1 ).
Radiation therapy is the treatment of choice. Several chemotherapeutic programs are undergoing experimental trials, but none has established benefit.
Box 11.2 summarizes the causes of stroke in children. Small brainstem hemorrhages resulting from emboli, leukemia, or blood dyscrasias have the potential to cause isolated ocular motor palsies, but this is not the rule. Other cranial nerves are also involved, and hemiparesis, ataxia, and decreased consciousness are often associated features.
Carotid-Cavernous Sinus Fistula
Arteriovenous communications between the carotid artery and the cavernous sinus may be congenital but trauma is the usual cause in children. The injury may be closed or penetrating. The carotid artery or one of its branches ruptures into the cavernous sinus, increasing pressure in the venous system. The results are a pulsating proptosis, redness and swelling of the conjunctiva, increased intraocular pressure, and ophthalmoplegia. If a bruit is present over the eye, compression of the ipsilateral carotid artery reduces the volume.
Carotid arteriography reveals rapid cavernous sinus filling, poor filling of the distal intracranial branches, and engorgement of and retrograde flow within venous drainage pathways.
Transarterial balloon embolization or coiling of the affected cavernous sinus is the mainstay of treatment.
Cavernous Sinus Thrombosis
Cavernous sinus thrombosis may produce either unilateral or bilateral ophthalmoplegia. The cause is usually the anterograde spread of infection from the mouth, face, nose, or paranasal sinuses.
The development of fever, malaise, and frontal headache following dental infection is the typical history. Proptosis, orbital congestion, ptosis, external ophthalmoplegia, pupillary paralysis, and blindness may follow the initial symptoms. The infection begins in one cavernous sinus and spreads to the other. If untreated, it may extend to the meninges. Even with vigorous antibiotic treatment, the mortality rate is 15 %.
The ocular signs may suggest orbital cellulitis or orbital pseudotumor. The cerebrospinal fluid is normal early in the course. A mixed leukocytosis develops, and the protein concentration is moderately elevated even in the absence of meningitis. Once the meninges are involved, the pressure becomes elevated, the leukocytosis increases, and the glucose concentration falls.
Cranial CT may show clouding of infected paranasal sinuses. MRA shows decreased or absent flow in the cavernous portion of the carotid artery.
Intravenous antibiotic therapy is similar to the course used to treat meningitis. Surgical drainage of infected paranasal sinuses is sometimes necessary.
The abducens nerve lies adjacent to the medial aspect of the petrous bone before entering the cavernous sinus. Infections of the middle ear sometimes extend to the petrous bone and cause thrombophlebitis of the inferior petrosal sinus. The infection involves not only the abducens nerve but also the facial nerve and the trigeminal ganglion. The resulting syndrome consists of ipsilateral paralysis of abduction, facial palsy, and facial pain.
The combination of unilateral abducens and facial palsy also occurs after closed head injuries. The diagnosis of Gradenigo syndrome requires the demonstration of middle-ear infection. CT of the mastoid bone shows the infection. Lumbar puncture reveals a cellular response and an elevation of protein content.
Prompt antibiotic therapy prevents permanent nerve damage.
Idiopathic Cranial Nerve Palsy
The sudden onset of a single, otherwise unexplained, cranial neuropathy is usually attributed to an immune-mediated reaction to a prior viral infection. However, a cause-and-effect relationship between viral infection and ocular motor palsies is not established. Abducens nerve palsy is more common than either oculomotor or trochlear nerve palsies. Bilateral involvement is unusual.
The chief complaint is a painless diplopia. Examination reveals a paralytic strabismus. Girls are more often affected than are boys and the left eye more often than the right. Restoration of full motility is within 6 months, but shorter-duration recurrences occur in half of children.
Examination of the cerebrospinal fluid and MRI of the head and orbit exclude tumor and infection. Tumors in and around the orbit are sometimes difficult to demonstrate, and, if ophthalmoplegia persists, a repeat MRI may be necessary. Myasthenia gravis is a diagnostic consideration. An edrophonium chloride test may be useful, but myasthenia gravis is unlikely when there is a fixed single nerve deficit.
Isolated cranial nerve palsies are not an indication for corticosteroid therapy. In children less than 9 years of age, intermittent patching of the normal eye may be necessary if the affected eye never fixates.
The discussion of some neonatal forms of myasthenia is in Chapter 6 ; congenital myasthenia is included in the section on Congenital Ophthalmoplegia earlier in this chapter, and limb-girdle myasthenia in Chapter 7 . This section describes the immune-mediated form of myasthenia encountered from late infancy through adult life. The two clinical forms are ocular myasthenia, which primarily or exclusively affects the eye muscles (but facial and limb muscles may be mildly involved), and generalized myasthenia, in which weakness of bulbar and limb muscles is moderate to severe. The term juvenile myasthenia to denote immune-mediated myasthenia gravis in children has no special meaning. The disease is similar in children and adults.
The initial symptoms do not appear until after 6 months of age; 75 % of children first have symptoms after age 10 years. Prepubertal onset is associated with a male preference, only ocular symptoms, and seronegativity for acetylcholine receptor antibodies, whereas postpubertal onset is associated with a strong female preference, generalized myasthenia, and seropositivity. In general, the disease is less severe in boys than in girls.
The initial features of both the ocular and the generalized form are usually ptosis, diplopia, or both. Myasthenia is the most common cause of acquired unilateral or bilateral ptosis. Pupillary function is normal. Between 40 % and 50 % of patients have weakness of other bulbar or limb muscles at the onset of ocular symptoms. Ocular motor weakness is generally not constant initially, and the specific muscles affected may change from examination to examination. Usually both eyes are affected, but one is more affected than is the other.
Children with ocular myasthenia may have mild facial weakness and easy fatigability of the limbs. However, they do not have respiratory distress or difficulty speaking or swallowing. The subsequent courses of ocular myasthenia may be one of steady progression to complete ophthalmoplegia or by relapses and remissions. The relapses are of varying severity and last for weeks to years. At least 20 % of patients have permanent remissions. Prepubertal onset is more commonly associated with spontaneous remission than postpubertal onset.
Children with generalized myasthenia have generalized weakness within 1 year of the initial ocular symptoms. The symptoms include dysarthria, dysphagia, difficulty chewing, and limb muscle fatigability. Spontaneous remissions are unusual. Respiratory insufficiency ( myasthenic crisis ) occurs in one-third of untreated children.
Children with generalized myasthenia, but not those with ocular myasthenia, have a higher than expected incidence of other autoimmune disorders, especially thyroiditis and collagen vascular diseases. Thymoma is present in 15 % of adults with generalized myasthenia but occurs in less than 5 % of children. When thymoma occurs in children, it is likely to be malignant.
The edrophonium chloride test is often set as a standard of diagnosis for both the ocular and generalized forms of myasthenia gravis, but it has limitations and dangers. Edrophonium chloride is a short-acting anticholinesterase administered intravenously at a dose of 0.15 mg/kg. Before initiating the test, an endpoint for the study must be determined. The best endpoint is the resolution of ptosis or the restoration of ocular motility, and test results are difficult to evaluate in their absence. Ptosis generally responds better than ocular motor paralysis to edrophonium chloride.
Some patients with myasthenia are supersensitive to edrophonium chloride. Fasciculations and respiratory arrest may develop following administration. For this reason, first inject a test dose of one-tenth the full dose. Unfortunately, respiratory embarrassment sometimes develops in response to the test dose, and a hand ventilator should be readily available before any drug is given. Atropine is an effective antidote to the muscarinic side effects of edrophonium chloride but does not counteract the nicotinic effects on the motor endplate that result in paralysis of the skeletal muscles.
After the test dose is given, the remainder should be injected one-third at a time (approximately 0.05 mg/kg), allowing up to 1 minute after each injection to test the response. Interpretation may be difficult. The judgment of improved strength is always subjective and influenced by examiner bias. The test becomes more objective when combined with electrophysiological studies. We do not use the edrophonium test for diagnosis because of its inherent dangers and rely more on the clinical features, the serum antibody concentrations, and electrophysiological studies.
Some physicians now use the ice-pack test instead. Place a very cold compress on the ptotic lid for 2 minutes. Partial opening of the lid suggests myasthenia. Five minutes of resting with the eye closed may accomplish the same result without the ice pack.
Results of repetitive nerve stimulation studies are abnormal in 66 % of children when proximal nerves are stimulated but in only 33 % when distal nerves are studied. Abnormal repetitive nerve study findings are unusual in children with ocular myasthenia but are the rule in children with generalized myasthenia. Patients with mild myasthenia show a decremental response at low rates of stimulation (2 to 5 per second) but not at high rates (50 per second). In severe myasthenia, both low and high rates of stimulation produce a decremental response. Single fiber EMG of the frontalis or orbicularis oculi is very sensitive for the diagnosis of myasthenia.
Eight-five percent of patients with generalized immune-mediated myasthenia have elevated serum concentrations of antibodies against the acetylcholine receptor (>10 nmol/L). Patients with ocular myasthenia may be seronegative or have low antibody concentrations. Among those children who are seronegative, many have a genetic disorder secondary to rapsyn mutations and others have antibodies directed against muscle-specific tyrosine kinase ( MuSK ). The distinction between early-onset, seronegative immune-mediated and genetic myasthenia is important: one responds to immunotherapy and the other does not. MuSK antibody concentration testing is commercially available; rapsyn mutation analysis is not.
The basis for managing nongenetic myasthenia in children is experience and retrospective studies, primarily done in adults ( ). Children with ocular myasthenia, but not those with generalized myasthenia, have a reasonable hope of spontaneous remission. Anticholinesterase therapy is the treatment of choice for ocular myasthenia. The initial dose of neostigmine is 0.5 mg/kg every 4 hours in children younger than 5 years of age and 0.25 mg/kg in older children, not to exceed 15 mg per dose in any child. The equivalent dose of pyridostigmine is four times greater. After initiating treatment, the dose slowly increases as needed and tolerated. Diarrhea and gastrointestinal cramps are the usual limiting factors. Do not administer edrophonium chloride to determine whether the child would benefit from higher oral doses of anticholinesterases. It is not an accurate guide and may cause cholinergic crisis in children with generalized myasthenia.
Several retrospective studies in adults suggest that early immunotherapy ( ) and thymectomy reduce the conversion of ocular myasthenia to generalized myasthenia. The evidence is not convincing and not applicable to children .
Ocular myasthenia can be difficult to treat and evaluating the efficacy of treatment is especially difficult. The response to anticholinesterase is often transitory, and the addition of corticosteroids is often without benefit. The efficacy of any drug regimen in ocular myasthenia is difficult to assess because of the fluctuating course of the disease.
The place of thymectomy in the management of myasthenia is not established. Experience indicates that most children who undergo thymectomy early in the course will be in remission within 3 years. However, corticosteroids accomplish the same result, and prior thymectomy does not reduce the need for long-term corticosteroid treatment.
The starting dose of prednisone is 1.5 mg/kg/day, not to exceed 100 mg/day. High-dose corticosteroids may make the patient weaker at first. After 5 days of daily treatment, switch to alternate-day therapy for the remainder of the month. The prednisone dose then tapers by 10 % each month until reaching a dose that keeps the patient symptom free. The usual maintenance dose is 10–20 mg every other day. We have been unsuccessful in eventually stopping prednisone. Concurrent anticholinesterase medication is unnecessary with corticosteroids but is useful if the patient weakens on the alternate days when corticosteroids are not used.
The clinical characteristics and response to treatment of individuals with nongenetic, generalized myasthenia who are seronegative do not differ from the characteristics and response of those who are seropositive, except that seronegative patients are unlikely to show thymic abnormalities and are unlikely to benefit from thymectomy. Plasmapheresis, intravenous immunoglobulin, and high-dose intravenous corticosteroids are useful for acute intervention in patients who have respiratory insufficiency.
The mechanism of ophthalmoplegia in migraine is not established. Although migraine is hereditary, the tendency for ophthalmoplegia is not.
Transitory ocular motor palsy, lasting as long as 4 weeks, may occur as part of a migraine attack in children and adults. The palsy affects the oculomotor nerve alone in 83 % of cases and affects all three nerves in the remainder. Ptosis usually precedes ophthalmoplegia. Partial or complete pupillary involvement is present in 60 % of cases. The average age at onset is 15 years, but the onset may be as early as infancy. In infants, recurrent painless ophthalmoplegia or ptosis may be the only feature of the migraine attack. In older children, ophthalmoplegia usually occurs during the headache phase and is ipsilateral to the headache.
The diagnosis is obvious when ophthalmoplegia occurs during a typical migraine attack in a child previously known to have migraine. Diagnostic uncertainty is greatest when an infant has transitory strabismus or ptosis as an isolated sign. In such cases, a family history of migraine is essential for diagnosis. Even so, MRI studies of the head and orbit are appropriate in most infants with a first episode of ophthalmoplegia.
The management of ophthalmoplegic migraine is the same as other forms of migraine (see Chapter 3 ). In addition, a short course of steroids may shorten the attack.
Orbital Inflammatory Disease
The term orbital inflammatory disease encompasses a group of nonspecific inflammatory conditions involving the orbit. Inflammation may be diffuse or localized to specific tissues within the orbit. The differential diagnosis includes idiopathic inflammatory orbit disease, orbital myositis, dacryoadenitis, sarcoidosis, Graves disease, histiocytosis, orbital pseudotumor, lymphoproliferative disease, Wegener granulomatosis, rhabdomyosarcoma, retinoblastoma, and neuroblastoma ( ).
The disorder is unusual before age 20 years but may occur as early as 3 months of age. Males and females are equally affected. Acute and chronic forms exist. The main features are pain, ophthalmoplegia, proptosis, and lid edema evolving over several days or weeks. One or both eyes may be involved. Ocular motility is disturbed in part by the proptosis but mainly by myositis. Some patients have only myositis, whereas others have inflammation in other orbital structures. Vision is initially preserved, but loss of vision is a threat if the condition remains untreated.
The development of unilateral pain and proptosis in a child suggests an orbital tumor. Bilateral proptosis suggests thyroid myopathy. MRI shows a soft tissue mass without sinus involvement or bone erosion. Orbital involvement by lymphoma or leukemia produces a similar imaging appearance. The extraocular muscles may appear enlarged. Biopsy should be considered in cases where refractory or rebound inflammation is noted during or after steroid treatment ( ).
Orbital inflammatory disease has a self-limited course but treatment is required to prevent vision loss or permanent ophthalmoplegia. Administer prednisone, 1 mg/kg/day, for at least 1 month before tapering. Reinitiate the full dose if the disorder recurs during the taper.
The initial feature of intraorbital tumors is proptosis, ophthalmoplegia, or ptosis. When the globe displaces forward, the palpebral fissure widens and closing the eye fully may not be possible. The exposed portion of the eye becomes dry and erythematous and may suffer exposure keratitis. The direction of displacement of the globe is the best clue to the tumor’s position. Ophthalmoplegia may occur because of forward displacement of the globe, causing direct pressure on one or more ocular muscles.
The differential diagnosis of proptosis in children includes infection and inflammation, hemorrhage and other vascular disorders, orbital tumors, hyperthyroidism and other metabolic disorders, developmental anomalies, and Hand-Schüller-Christian disease and related disorders; some are idiopathic. The most common orbital tumors are dermoid cyst, hemangioma, metastatic neuroblastoma, anterior visual pathway glioma, and rhabdomyosarcoma. Orbit CT and MRI, and biopsy are necessary for the diagnosis and selection of treatment.
Treatment varies with the tumor type. Many require surgical resection.
Trauma accounts for 40 % of isolated acquired ocular motor nerve palsies and 55 % of multiple nerve palsies in children. Hemorrhage and edema into the nerves or muscles may occur from closed head injuries even in the absence of direct orbital injury. In the presence of orbital fractures, the nerves and muscles are vulnerable to laceration, avulsion, or entrapment by bone fragments.
Superior oblique palsy, caused by trochlear nerve damage, is a relatively common consequence of closed head injuries. Usually the trauma is severe, often causing loss of consciousness, but it may be mild. The palsy is more often unilateral than bilateral. Patients with unilateral superior oblique palsy have a marked hypertropia in the primary position and a compensatory head tilt to preserve fusion; 65 % of cases resolve spontaneously. When bilateral involvement is present, the hypertropia is milder and alternates between the two eyes; spontaneous recovery occurs in only 25 % of cases.
Transitory lateral rectus palsy is rare in newborns and the cause attributed to birth trauma. The palsy is unilateral and clears completely within 6 weeks.
Direct injuries to the orbit with associated hemorrhage and swelling do not pose a diagnostic dilemma. CT of the head with orbital views shows the extent of fracture so that the need for surgical intervention can be determined. CT may also show a lateral midbrain hemorrhage as the cause of trochlear nerve palsy.
A delay between the time of injury and the onset of ophthalmoplegia makes diagnosis more problematic. The possible mechanisms of delayed ophthalmoplegia following trauma to the head include progressive local edema in the orbit; progressive brainstem edema; progressive increased intracranial pressure; development of meningitis, mastoiditis, or petrous osteomyelitis; venous sinus or carotid artery thrombosis; and carotid cavernous fistula.
Local trauma and fracture of the orbit may require surgical repair. Surgery directed at rebalancing the extraocular muscles sometimes improves vision after permanent paralysis of ocular motor nerves following head injury. Botulinum toxin is another treatment option for bilateral sixth nerve palsies.
Acute Bilateral Ophthalmoplegia
Many of the conditions that cause acute unilateral ophthalmoplegia (see Box 15-3 ) may also cause acute bilateral ophthalmoplegia. The conditions listed in Box 15-4 often have a high incidence of bilateral involvement. The discussion of thyroid orbitopathy is with the chronic conditions because progression of ophthalmoplegia usually occurs over a period greater than 1 week.