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Ophthalmology > NEUROLOGIC DISORDERS
Chronic Progressive External Ophthalmoplegia
Article Last Updated: May 17, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: Tracey A Schmucker, MD, Staff Physician, Department of Ophthalmology, University of Arkansas for Medical Sciences
Coauthor(s):
Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Editors: Edsel Ing, MD, FRCSC, Assistant Professor, Department of Ophthalmology & Vision Sciences, University of Toronto, Sunnybrook and Women's Health Sciences Center, Toronto East General Hospital; Simon K Law, MD, PharmD, Assistant Professor of Ophthalmology, Jules Stein Eye Institute; Chief of Section of Ophthalmology Surgical Services, Department of Veterans Affairs Healthcare Center, West Los Angeles; Brian R Younge, MD, Military Consultant to the Surgeon General, Associate Professor, Department of Ophthalmology, Mayo Clinic; Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri; James P Gills, MD, Founder, St Luke's Cataract and Laser Institute; Professor, Department of Ophthalmology, University of South Florida College of Medicine
Author and Editor Disclosure
Synonyms and related keywords:
CPEO, abiotrophic ophthalmoplegia, CPEO with ragged red fibers, oculocraniosomatic neuromuscular disease, ocular myopathy, Olson disease, Kearns-Sayre-Daroff syndrome, Kearns-Sayre syndrome, progressive external ophthalmoplegia plus, extraocular muscle paralysis
Background
Chronic progressive external ophthalmoplegia (CPEO) is a disorder characterized by slowly progressive paralysis of the extraocular muscles. Patients usually experience bilateral, symmetrical, progressive ptosis, followed by ophthalmoparesis months to years later. Ciliary and iris muscles are not involved.
CPEO is the most frequent manifestation of mitochondrial myopathies. CPEO in association with mutations in mitochondrial DNA (mtDNA) may occur in the absence of any other clinical sign, but usually it is associated with skeletal muscle weakness.
Kearns-Sayre syndrome (KSS) is a related mitochondrial myopathy that demonstrates the following: CPEO, onset before age 20, and pigmentary retinopathy. KSS also has at least one of the following: cardiac conduction defects, cerebrospinal fluid (CSF), protein of greater than 100 mg/dL, and a cerebellar syndrome. Other abnormalities in KSS can include mental retardation, Babinski sign, hearing loss, seizures, short stature, delayed puberty, and various endocrine disorders.
CPEO can also be a sign in the following disorders: oculopharyngeal dystrophy, myasthenia gravis, and Graves disease.
Pathophysiology
Mitochondrial DNA encodes for essential components of the respiratory chain. Deletions of various lengths of mtDNA results in defective mitochondrial function, particularly in highly oxidative tissues (eg, muscle, brain, heart). Extraocular muscles are affected preferentially because their fraction of mitochondrial volume is several times greater than that of other skeletal muscle.
Impaired protein synthesis in these mitochondria accounts for the histological hallmark of the mitochondrial myopathies. When muscle fibers are stained with Gomori trichrome stain, an abnormal accumulation of enlarged mitochondria is seen beneath the sarcolemma. These fibers are called ragged red fibers due to their unusual appearance and dark red color.
A variable proportion of deleted mtDNA has been found to be present in different tissues from the same patient. The balance of oxidative demands of a given tissue and the proportion of deleted mtDNA it contains ultimately will determine whether the tissue is affected clinically.
Frequency
United States
CPEO is rare.
Sex
In KSS, boys and girls are affected equally.
Age
In KSS, onset of CPEO is before age 20.
History
CPEO tends to begin in young adulthood. Ptosis usually is the first clinical sign, and ophthalmoplegia may not become apparent for months to years. The ptosis usually is bilateral and symmetrical. As the ptosis progresses, the patient may use the frontalis muscle to elevate the eyelids, adopt a chin-up head position, and eventually resort to manual elevation of the eyelids, as ptosis often becomes complete. Cases have been documented of patients who develop ophthalmoplegia but not ptosis. Unilateral or asymmetric ptosis may develop.
Due to the symmetric nature of this disorder, patients often do not complain of diplopia. They may be unaware of their decreased motility until it becomes severe. In many cases, downward gaze is preserved to a greater extent than up-gaze or horizontal movement. The course of CPEO is characterized by constant progression without periods of remission or exacerbation. Patients also may complain of dryness of the eyes due to exposure keratopathy.
In contrast to myasthenia gravis, patients with CPEO usually report little to no variability in their ptosis.
In KSS, children usually are normal at birth. Boys and girls are affected equally. CPEO and pigmentary retinopathy appear before age 20. The retinal pigment undergoes atrophy, usually in a salt-and-pepper pattern without the bony spicule formation typical of retinitis pigmentosa. Ophthalmoplegia generally precedes the development of cardiac conduction disturbances. Sudden death may occur from these disturbances, and patients should have regular cardiac exams, regardless of age. Patients also may have the following: intraventricular septal hypertrophy, mitral valve prolapse, and left ventricular dysfunction.
- Weakness of somatic muscles often is noted with progressive facial muscle weakness and neck and shoulder weakness. Extremities tend to be involved to a lesser degree.
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- Neurologic abnormalities may include the following:
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- Cerebellar ataxia
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- Pendular nystagmus
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- Vestibular dysfunction and/or hearing loss
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- Endocrine dysfunction is common and may include the following:
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- Short stature
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- Hypoparathyroidism
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- Diabetes
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- Gonadal dysfunction
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- Hyperaldosteronism
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Physical
- A complete ophthalmologic exam should be performed, to include the following:
- Dilated retinal exam
- Cranial nerve testing
- Forced duction testing
- In KSS, the salt-and-pepper retinopathy usually occurs initially in the posterior fundus. Pallor of the optic disc, attenuation of retinal vessels, visual field defects, and posterior cataract formation common to retinitis pigmentosa rarely, if ever, occur.
- CPEO must be differentiated from the conditions outlined below. The table presented in Media file 1 may also be helpful for categorizing physical findings.
- Isolated neurologic findings
- Myasthenia gravis
- Graves disease
- Oculopharyngeal dystrophy
Causes
The mitochondrial myopathies and encephalopathies are a complex group of disorders arising from mtDNA mutations. Little correlation exists between the size and the location of the deletion and the clinical phenotype (ie, CPEO vs KSS). Mutations usually occur sporadically, but they also can be inherited as a point mutation of maternal mitochondrial tRNA or as autosomal dominant and autosomal recessive deletions of mtDNA.
Botulism
Myasthenia Gravis
Other Problems to be Considered
Thyroid eye disease (Graves disease)
Oculopharyngeal muscular dystrophy
Orbital pseudotumor
Sarcoidosis of the extraocular muscles
Bilateral pupil sparing third nerve palsy
Vitamin E deficiency: abetalipoproteinemia
Cholestatic liver disease with impaired secretion of bile salts
Bowel resection
Amyloidosis with bilateral orbital infiltration
Myotonic dystrophy
Miller-Fisher variant of Guillain-Barré syndrome
Congenital acetylcholinesterase deficiency
Lab Studies
- Patients with KSS have been reported to have the following:
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- Low magnesium
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- Low parathyroid hormone
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- Increased lactic acid
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- Increased pyruvic acid
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- Increased creatine phosphokinase (CPK)
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- Increased aldolase
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- Increased protein in CSF
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- Thyroid studies can confirm suspicion of Graves disease.
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- A positive acetylcholine receptor antibody test may establish the diagnosis of myasthenia gravis. A negative acetylcholine receptor antibody assay does not differentiate CPEO from myasthenia gravis.
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- Tensilon testing can be helpful in differentiating myasthenia from CPEO. However, the clinician must remain wary of the effects of edrophonium in a patient harboring a possible cardiac conduction defect, ie, KSS.
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Imaging Studies
- Magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound may show thin, symmetrical extraocular muscles in CPEO, in contrast to enlarged extraocular muscles sometimes seen with Graves disease. Patients with CPEO and KSS display a wide spectrum of MRI findings, to include the following:
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- Normal brain
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- Cortical and cerebellar atrophy
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- Increased T2 signal in subcortical cerebral white matter, cerebellar white matter, globi pallidi, thalami, and substantia nigra
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- A barium swallowing study would be useful to differentiate oculopharyngeal dystrophy.
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Other Tests
- Electroretinography and visual-evoked potential testing may be abnormal with or without retinal pigmentary abnormalities. Electroretinography typically shows reduction of oscillatory potentials, scotopic b-wave amplitudes, and photopic b-wave amplitudes. Visual-evoked potential testing abnormalities include p100 latency.
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- Muscle biopsy is still the definitive test for mitochondrial disorders, but polymerase chain reaction (PCR) testing also has been shown to be conclusive.
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Histologic Findings
Biopsy of muscle with oculopharyngeal dystrophy shows a marked reduction in muscle fibers without the characteristic ragged red fibers seen in mitochondrial disorders due to red-rimmed vacuoles and intranuclear inclusions.
Medical Care
Several small studies have shown evidence of clinical improvement in patients treated with CoQ10. A decrease in serum levels of pyruvate and lactate were observed, and general neurologic function was noted to improve.
For ptosis, adhesive tape and lid crutches can be used to assist patients with advanced CPEO. A case study involving a patient with exposure keratopathy after previously unsuccessful lid surgery discusses successful treatment with a combination spectacle-mounted lid crutch and moisture chamber.
Surgical Care
Bell phenomenon is absent in many patients with CPEO; therefore, ptosis surgery often is contraindicated. Because a silicone sling is reversible, it could be a possibility for some patients.
Patients with oculopharyngeal dystrophy who experience severe dysphagia may be treated with cricopharyngeal myotomy, but a gastrostomy tube often is more practical.
Strabismus surgery can be helpful in carefully selected patients if diplopia occurs and the patient has had a stable deviation for several months.
Consultations
KSS is a complex disorder requiring the involvement of physicians from various specialties, including neurology, cardiology, ophthalmology, and endocrinology.
Further Outpatient Care
- It is imperative that patients receive regularly scheduled follow-up care in all areas, especially with cardiology, as primary cardiac dysfunction can occur at any time. This dysfunction often can be managed with an artificial pacemaker.
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Complications
- Cardiac problems and esophageal dysfunction
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Prognosis
- Prognosis is guarded with a generally progressive disorder.
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Patient Education
- The following support group is available to patients: United Mitochondrial Disease Foundation, PO Box 1151, Monroeville, PA, 15146-1151.
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Medical/Legal Pitfalls
- This is a complex disorder but should be diagnosed as early as possible.
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Special Concerns
- A case documenting 2 pregnancies in a woman with CPEO discusses complications during these pregnancies of preterm labor and hypertension, but it cannot statistically relate these complications directly to CPEO.
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| Media file 1:
This table outlines the differential diagnoses of chronic progressive external ophthalmoplegia. |
 |  View Full Size Image | |
Media type: Graph
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Chronic Progressive External Ophthalmoplegia excerpt Article Last Updated: May 17, 2006
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