eMedicine Specialties > Ophthalmology > Neurologic Disorders

Chronic Progressive External Ophthalmoplegia

Author: Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Contributor Information and Disclosures

Updated: Dec 5, 2008

Introduction

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 it is usually associated with skeletal muscle weakness.

Kearns-Sayre syndrome (KSS) is a related mitochondrial myopathy that demonstrates the following: CPEO, onset before age 20 years, 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 will ultimately 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 years.

Clinical

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 is usually 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.

Because of 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 are usually healthy at birth. Boys and girls are affected equally. CPEO and pigmentary retinopathy appear before age 20 years. 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 is often noted with progressive facial muscle weakness and neck and shoulder weakness. Extremities tend to be involved to a lesser degree.
• Neurologic abnormalities may include the following:
  • Cerebellar ataxia
  • Pendular nystagmus
  • Vestibular dysfunction and/or hearing loss
• Endocrine dysfunction is common and may include the following:
  • Short stature
  • Hypoparathyroidism
  • Diabetes
  • Gonadal dysfunction
  • Hyperaldosteronism

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 myasthenia gravis, Graves disease, and oculopharyngeal dystrophy. The table presented in Media file 1 may also be helpful for categorizing physical findings.

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.

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