Myopathies affecting the extraocular muscles in children

OVERVIEW — Most generalized myopathies do not affect the extraocular muscles. However, there are some notable exceptions. Chronic progressive external ophthalmoplegia (CPEO) is a nonspecific term that is used to describe a range of myopathies that affect the extraocular muscles. These progressive ophthalmoplegias include:

●Isolated CPEO

●Kearns-Sayre syndrome

●Oculopharyngeal muscular dystrophy

●Myotonic dystrophy

●Myotubular myopathy

The progressive forms of ophthalmoplegia should be distinguished from the static forms of ophthalmoplegia, which include:

●Agenesis of extraocular muscles

●Congenital fibrosis syndromes (see "Causes of vertical strabismus in children", section on 'Congenital fibrosis of the extraocular muscles')

●Congenital myopathies (eg, centronuclear myopathy, central core myopathy, multicore myopathy) (see "Congenital myopathies")

The extraocular muscles often are involved in the mitochondrial myopathies, such as Kearns-Sayre syndrome [1]. Mitochondrial myopathies also can manifest with facial, bulbar, and limb myopathy; neurologic findings (eg, ataxia, spasticity, peripheral neuropathy, deafness, dementia); other ocular findings (eg, optic atrophy, pigmentary degeneration of retina); cardiac conduction abnormalities; gastrointestinal motility; and endocrine, skin, and skeletal abnormalities. (See "Approach to the metabolic myopathies".)

Other ocular myopathies beyond the scope of this review are associated with generalized muscle involvement (eg, proximal or distal limb muscle involvement) or neurodegenerative diseases (eg, spinocerebellar degeneration, Werdnig-Hoffmann syndrome). (See "Congenital myopathies" and "Autosomal dominant spinocerebellar ataxias" and "Spinal muscular atrophy".)

CLINICAL MANIFESTATIONS

Chronic progressive external ophthalmoplegia — Patients with chronic progressive external ophthalmoplegia (CPEO) usually present with a painless, slowly progressive (and sometimes asymptomatic) ophthalmoplegia. The ocular motility defect is typically bilateral and symmetric, and for this reason few patients complain of diplopia, even if they have dramatic or complete ophthalmoplegia. Patients also have bilateral ptosis of variable severity. The pupil is spared (external ophthalmoplegia). In addition, optic atrophy and retinal pigmentary degeneration may be present in some patients, particularly those who have mitochondrial disorders. The clinical course usually is sufficient to make the diagnosis and exclude alternative etiologies, such as myasthenia gravis.

During childhood, CPEO may be isolated or occur in conjunction with other myopathies, including:

●Kearns-Sayre syndrome

●Oculopharyngeal muscular dystrophy

●Myotonic dystrophy

●Myotubular myopathy

Kearns-Sayre syndrome — Kearns-Sayre syndrome is a mitochondrial cytopathy that is characterized by CPEO, retinal pigmentary changes, and heart block. Patients are typically normal at birth. Progressive ophthalmoplegia usually develops between 5 and 20 years of age, although it may occur earlier. Most cases are sporadic.

The ocular findings include bilateral and symmetric involvement of the horizontal and vertical muscles, bilateral ptosis, and normal pupils. An atypical pigmentary retinopathy ("salt and pepper") may be present; some patients have a corneal opacity. The ophthalmoplegia progresses slowly over many years and is often asymptomatic because it is insidious and bilaterally symmetric. As the extraocular myopathy progresses, generalized muscle weakness and other systemic manifestations may occur.

Nonocular manifestations include:

●Cardiac – Heart block, sometimes even sudden death (may require monitoring with sequential electrocardiograms or treatment with a pacemaker) [2,3]

●Neurologic – Deafness and vestibular dysfunction, cerebellar ataxia, corticospinal dysfunction, electroencephalogram abnormalities, elevated cerebrospinal fluid protein (>100 mg/dL), or widespread muscular dystrophy

●Endocrine and metabolic – Short stature, gonadal failure, diabetes mellitus, thyroid disease, hyperaldosteronism; hypomagnesemia; and bone, tooth, and calcification abnormalities [4,5]

●Renal – Renal tubular involvement is rare [4,5]

Laboratory findings may include elevated plasma lactate and pyruvate concentrations. Skeletal or ocular muscle biopsy demonstrates defects in the mitochondrial respiratory chain and "ragged red fibers" histologically.

Oculopharyngeal muscular dystrophy — Oculopharyngeal muscular dystrophy is another type of CPEO that usually has onset at approximately 40 years of age, although earlier onset may occur [6,7]. Most patients have a common ancestor from Quebec. In the French-Canadian population, oculopharyngeal muscular dystrophy usually follows an autosomal-dominant inheritance pattern with 100 percent penetrance [2]. However, autosomal-recessive and sporadic forms occur in other ethnic groups. (See "Oculopharyngeal, distal, and congenital muscular dystrophies".)

Characteristic features include difficulty with swallowing, more prominent ptosis than extraocular muscle involvement, weakness of the orbicularis muscle, and cytoplasmic inclusions on muscle biopsy [6]. The diagnosis is usually made by the family history and clinical presentation.

Myotonic dystrophy — Myotonic dystrophy, another systemic myopathy that affects the extraocular muscles, has two forms: congenital and classical. The congenital form occurs in infants born to mothers with myotonic dystrophy. The infants present with profound hypotonia, facial diplegia, feeding problems, respiratory difficulties, and skeletal deformities, such as clubfeet. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis".)

The classical form of the disease has onset in adolescence or adulthood. Ocular findings include orbicularis weakness; myotonia on lid closure; ptosis; poor eccentric gaze holding; slow saccades; sluggish, miotic pupils; blepharitis; dry-eye syndrome; low intraocular pressure (hypotony); lens changes (eg, polychromatic cataracts, posterior cortex star, posterior subcapsular cataract); and pigmentary changes in macula. (See "Cataract in children", section on 'Disease-associated'.)

Nonocular findings include frontal baldness, testicular atrophy, cardiac abnormalities (eg, cardiomyopathy, conduction defects), narrow hatchet facies, and slack jaw.

The electromyography (EMG) demonstrates myopathic potentials and myotonia. Muscle histology may reveal internal nuclei, type I fiber atrophy, and ring fibers [8].

Myotubular myopathy — Centronuclear myotubular myopathy is a rare X-linked congenital myopathy. Male infants have marked hypotonia and skeletal muscle weakness. Respiratory muscle impairment leads to respiratory failure. Facial weakness, ptosis, and extraocular muscle weakness typically occur, and impaired bulbar function contributes to feeding difficulty. Heterozygous female carriers may present with limb girdle and facial weakness. A more common form of the disorder occurs in both males and females and consists of relatively mild weakness and hypotonia that may be unrecognized in the neonatal period. Myotubular myopathy should be considered in the differential diagnosis of any infant who has hypotonia and either ptosis or ophthalmoplegia. (See "Approach to the infant with hypotonia and weakness" and "Congenital myopathies", section on 'Centronuclear (myotubular) myopathies'.)

Similar clinical manifestations may be seen in neonatal or congenital myasthenia gravis [9], a disorder that must be excluded. Administration of an acetylcholinesterase inhibitor results in improvement in symptoms (eg, oxygenation, ventilation, or sucking) in infants with myasthenia gravis but not those with myotubular myopathy. (See "Neuromuscular junction disorders in newborns and infants", section on 'Congenital myasthenic syndromes'.)

Muscle biopsy in infants with myotubular myopathy demonstrates predominance of small type I fibers and centrally placed nuclei.

EVALUATION

History and examination — In most cases, the diagnosis of chronic progressive external ophthalmoplegia (CPEO) can be made from the clinical course (painless, progressive, pupil-sparing ophthalmoplegia). Pain, pupil involvement, acute onset, fatigue, or fluctuating course suggest an alternate diagnosis (table 1).

Examination of family members and a complete family history are important because the inheritance pattern can provide a clue to the underlying etiology. Myasthenia gravis should be excluded since a "chronic, fixed" myasthenia can mimic CPEO. (See "Clinical manifestations of myasthenia gravis", section on 'Ocular function'.)

Patients with CPEO should be evaluated by a neurologist and an ophthalmologist to exclude other disorders that mimic isolated CPEO, identify systemic diseases associated with CPEO (eg, mitochondrial disease), and evaluate for cardiac or other neurologic features of Kearns-Sayre syndrome.

Laboratory evaluation — The laboratory evaluation of patients in whom a metabolic myopathy is being considered may include a number of tests (table 2), not all of which are necessary in every patient. In patients in whom a mitochondrial disorder is being considered, serum and cerebrospinal lactate concentrations may be elevated, but this test is neither sensitive nor specific [10]. (See "Approach to the metabolic myopathies", section on 'Evaluation and diagnosis'.)

Muscle biopsy may be indicated for definitive diagnosis of Kearns-Sayre syndrome, myotonic dystrophy, or myotubular myopathy. Characteristic findings are as follows:

●Kearns-Sayre syndrome – Ragged red fibers and evidence of cytochrome C oxidase deficiency

●Oculopharyngeal muscular dystrophy – Cytoplasmic inclusions [6]

●Myotonic dystrophy – Internal nuclei, type I fiber atrophy, and ring fibers [8]

●Myotubular myopathy – Predominance of small type I fibers and centrally placed nuclei

Electromyography (EMG) may be helpful in selected cases. Myopathic potentials and myotonia are present in myotonic dystrophy, but the EMG may not be diagnostic in early cases or in cases isolated to the extraocular muscles (isolated CPEO). EMG in other disorders may confirm evidence of myopathy but is not specific. EMG of the extraocular muscles is rarely performed except in institutions with research interests.

A number of mitochondrial mutations have been reported in patients with CPEO syndromes, and mitochondrial DNA studies may be helpful for diagnosis [11-17]. These tests are not universally available and usually require specialty laboratory testing.

Mutations in the DNA polymerase gamma, catalytic subunit (POLG) gene cause many of the inherited mitochondrial diseases in children and can produce a diverse group of phenotypes including autosomal-recessive progressive external ophthalmoplegia (arPEO) and autosomal-dominant progressive external ophthalmoplegia (adPEO) [18].

Radiologic evaluation — The diagnosis of CPEO is usually made clinically. Neuroimaging studies are performed primarily to exclude alternative etiologies for ophthalmoplegia.

Cranial magnetic resonance imaging (MRI) in patients with CPEO may show signal abnormalities in the brainstem, brain, and thalami, and in extraocular muscle volume [19,20]. In one study, digitally measured extraocular muscle volume in subjects with CPEO was reduced compared with control subjects (215 mm³ versus 366 mm³ for the medial rectus, 202 mm³ versus 365 mm³ for the inferior rectus, and 269 mm³ versus 425 mm³ for the lateral rectus) [20]. This finding may help to distinguish CPEO from other conditions causing ophthalmoplegia. Magnetic resonance spectroscopy may show elevated lactate levels within regions of brain signal abnormalities in patients with Kearns-Sayre syndrome [21].

We recommend obtaining an MRI of the extraocular muscles in all patients with CPEO and magnetic resonance spectroscopy in selected patients (eg, those suspected to have Kearns-Sayre syndrome).

MANAGEMENT — Therapy for chronic progressive external ophthalmoplegia (CPEO) is supportive. Ptosis surgery can be performed in severely affected patients. However, extreme care must be taken to avoid overcorrection because of the risk of exposure keratopathy from the ophthalmoplegia and loss of Bell phenomenon [22,23]. Bell phenomenon is the rolling up of the eyes when the eyelids are closed; it typically occurs during sleep or with forced lid closure, but is lost in patients with CPEO. The loss of Bell phenomenon in conjunction with postoperative lagophthalmos (ie, incomplete eyelid closure) after correction of ptosis may result in corneal exposure, placing the patient at risk for exposure keratopathy.

Strabismus surgery can be performed to align the eyes, although it is not always necessary because involvement in CPEO tends to be bilateral and symmetric. The patients who do not require strabismus surgery tend to adapt to their ophthalmoplegia by turning their head or face to compensate for loss of gaze function. Such patients can be followed annually by the ophthalmologist. They may need special accommodations in school and may have activity restrictions, depending upon the presence and extent of associated myopathy. In addition:

●Patients who have cardiac conduction defects should be referred to a cardiologist for evaluation and ongoing care.

●Therapies that have been tried, with variable success, in patients with mitochondrial cytopathies include the ketogenic diet [24], coenzyme Q [21], and bupivacaine [25].

SUMMARY

●Chronic progressive external ophthalmoplegia (CPEO) is a nonspecific term that is used to describe a range of myopathies that affect the extraocular muscles, including isolated CPEO, Kearns-Sayre syndrome, oculopharyngeal muscular dystrophy, and myotonic dystrophy. (See 'Overview' above.)

●Patients with CPEO usually present with a painless, slowly progressive (and sometimes asymptomatic) ophthalmoplegia. The ocular motility defect is typically bilateral and symmetric. They also have bilateral ptosis of variable severity, but the pupil is spared. Optic atrophy and retinal pigmentary degeneration may be present in some patients. (See 'Clinical manifestations' above.)

●The diagnosis of CPEO usually can be made from the clinical course (painless, progressive, pupil-sparing ophthalmoplegia). Pain, pupil involvement, acute onset, fatigue, or fluctuating course suggest an alternate diagnosis (table 1). Examination of family members and a complete family history can provide a clue to the underlying etiology. Myasthenia gravis should be excluded. (See 'Evaluation' above.)

●The laboratory evaluation of patients in whom a metabolic myopathy is being considered may include a number of tests (table 2), not all of which are necessary in every patient. Muscle biopsy may be indicated for definitive diagnosis of Kearns-Sayre syndrome, myotonic dystrophy, or myotubular myopathy. Electromyography (EMG) may be helpful in selected cases. (See 'Laboratory evaluation' above.)

●Therapy for CPEO is supportive (eg, ptosis surgery, strabismus surgery, referral to cardiologist for patients with cardiac conduction defect). (See 'Management' above.)