Chronic Progressive External Ophthalmoplegia

Chronic progressive external ophthalmoplegia (CPEO) is one manifestation in a constellation of associated mitochondrial DNA mutation known as mitochondrial myopathy or cytopathy that cause ocular motility disturbances.

Introduction

CPEO is a rare disease that may affect those of all ages, but typically manifests in the young adult years. Among the mitochondrial myopathies, CPEO is the most common manifestation, estimated at two-thirds of all incidences of mitochondrial associated myopathies. Patients typically present with ptosis or drooping lids, which often is the presenting symptom. Other diseases like Graves’ disease, myasthenia gravis and glioma that may cause an external ophthalmoplegia must be ruled out.

While progressive external ophthalmoplegia may be a symptom of numerous diseases, we will be focusing on CPEO as the primary disease state caused by mitochondrial abnormalities. Kearns-Sayre syndrome (KSS), which at times is referred to as a severe form of CPEO with pigmentary retinopathy, complete heart block and occurs before the age of 20, will not be included in this discussion.

Signs and Symptoms

CPEO is a slowly progressing disease. The first presenting symptom of ptosis is often unnoticed by the patient until the lids droop to the point of producing a visual field defect. Often, patients will tilt the head backwards to adjust for the slowly progressing ptosis of the lids. In addition, as the ptosis becomes complete, the patients will use the frontalis (forehead) muscle to help elevate the lids. The ptosis is typically bilateral, but may be unilateral for a period of months to years before the fellow lid becomes involved.

Ophthalmoplegia or the inability/difficulty to move the eye is usually symmetrical. As such, diplopia is not often a complaint of these patients. In fact, the progressive ophthalmoplegia is often unnoticed till decreased ocular motility limits peripheral vision. Often someone else will point out the ocular disturbance to the patient. Patients will move their heads to adjust for the lost of peripheral vision caused by inability to abduct or adduct the eye. All directions of gaze are affected, however, downward gaze appears to be best spared. This is in contrast to Progressive Supranuclear Palsy (PSP) which affects all directions of gaze in addition to downward gaze.

Weakness of extraocular muscle groups including, the orbicularis oculi muscle as well as facial and limb muscles may be present in up to 25% of patients with CPEO. As a result of the orbicularis oculi weakness, patients may suffer from exposure keratopathy (damage to cornea) from the inability to close the eyes tightly. Frontalis muscle weakness may exacerbate the ptotic lids with the inability to compensate for the ptosis. Facial muscles may be involved which lead to atrophy of facial muscle groups producing a thin, expressionless face with some having difficulty with chewing. Neck, shoulder and extremity weakness with atrophy may affect some patients and can be mild or severe.

Mild visual impairment was seen in 95% of patients that were evaluated using the Visual Function Index (VF-14). ^[1]

The ciliary muscles that control the lens shape and the iris muscles are often unaffected by CPEO.

Genetics

Mitochondrial DNA which is transmitted from the mother, encodes proteins that are critical to the respiratory chain required to produce adenosine triphosphate (ATP). Deletions or mutations to segments of mtDNA lead to defective function of oxidative phosphorylation. This may be made evident in highly oxidative tissues like skeletal muscle and heart tissue. However, extraocular muscles contain a volume of mitochondria that is several times greater than any other muscle group. As such, this results in the preferential ocular symptoms of CPEO.

Multiple mtDNA abnormalities exist which cause CPEO. One mutation is located in a conserved region of mitochondrial tRNA at nucleotide 3243 in which there is an A to G nucleotide transition. This mutation is associated with both CPEO and Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). ^[5]

A common deletion found in one-third of CPEO patients is a 4,977 base pair segment found between a 13 base pair repeat.

The mtDNA that is affect maybe a single or multiple point deletion, with associated nuclear DNA deletions. One study showed that mtDNA deletion seen in CPEO patients also had an associated nuclear DNA deletion of the Twinkle gene which encodes specific mitochondrial protein; Twinkle. ^[2]

Whether a tissue is affected is correlated with the amount of oxidative demands in relation to the amount of mtDNA deletion.

Diagnosis

It is important to differentiate CPEO from other pathologies that may cause an ophthalmoplegia. There are specific therapies used for these pathologies.

CPEO is diagnosed via muscle biopsy. On examination of muscle fibers stained with Gomori trichrome stain, one can see an accumulation of enlarged mitochondria. This produces a dark red staining of the muscle fibers given the name “ragged red fibers”. While ragged red fibers are seen in normal aging, amounts in excess of normal aging give a diagnosis of a mitochondrial myopathy.

Polymerase Chain Reaction (PCR), from a sample of blood or muscle tissue can determine a mutation of the mtDNA

Elevated acetylcholine receptor antibody level which is typically seen in myasthenia gravis has been seen in certain patients of mitochondrial associated ophthalmoplegia. ^[3]

It is important to have a dilated eye exam to determine if there is pigmentary retinopathy that may signify KSS which is associated with cardiac abnormalities.

Treatment

There is currently no defined treatment to ameliorate the muscle weakness of CPEO. Treatments used to treat other pathologies causing ophthalmoplegia has not been shown to be effective.

Experimental treatment with tetracycline has been used to improve ocular motility in one patient. ^[4] However, most neuro-ophthalmologists do not ascribe to any treatment.

Ptosis associated with CPEO may be corrected with surgery to raise the lids, however due to weakness of the orbicularis oculi muscles, care must be taken not to raise the lids in excess causing an inability to close the lids. This results in an exposure keratopathy. Therefore, rarely should lid surgery be performed and only by a neuro-ophthalmologist familiar with the disease.

Those that have diplopia as a result of asymmetric ophthalmoplegia maybe corrected with prisms or with surgery to create a better alignment of the eyes.

References

1. Yu Wai Man CY, Smith T, Chinnery PF, Turnbull DM, Griffiths PG. Assessment of visual function in chronic progressive external ophthalmoplegia. Eye. 2006 May;20(5):564-8. PMID: 15920569

2. Houshmand M, Panahi MS, Hosseini BN, Dorraj GH, Tabassi AR. Investigation on mtDNA deletions and twinkle gene mutation (G1423C) in Iranian patients with chronic progressive external ophthalmoplegia. Neurol India. 2006 Jun;54(2):182-5. PMID: 16804265

3. Behbehani R, Sharfuddin K, Anim JT. Mitochondrial ophthalmoplegia with fatigable weakness and elevated acetylcholine receptor antibody. J Neuroophthalmol. 2007 Mar;27(1):41-4. PMID: 17414872

4. Omar A, Johnson LN. Tetracycline delays ocular motility decline in chronic progressive external ophthalmoplegia. Neurology. 2007 Apr 3;68(14):1159-60. No abstract available. PMID: 17404203

5. Millar N., Newman N. Walsh & Hoyt’s Clinical Neuro-Ophthalmology, The Essentials. 5th edition, 1999

External Links and Pictures

- http://www4.ocn.ne.jp/~nurophth/CPEO1.jpg
- http://webeye.ophth.uiowa.edu/eyeforum/cases/case24.htm
- http://journals.tubitak.gov.tr/medical/issues/sag-04-34-3/sag-34-3-9-0401-8.pdf