Chronic progressive external ophthalmoplegia (CPEO) is a type of eye disorder characterized by slowly progressive inability to move the eyes and eyebrows. It is often the only feature of

mitochondrial disease Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy o ...

, in which case the term CPEO may be given as the

diagnosis Diagnosis (: diagnoses) is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in a lot of different academic discipline, disciplines, with variations in the use of logic, analytics, and experience, to determine " ...

. In other people suffering from mitochondrial disease, CPEO occurs as part of a

syndrome A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek language, Greek σύνδρομον, meaning "concurrence". When a sy ...

involving more than one part of the body, such as

Kearns–Sayre syndrome Kearns–Sayre syndrome (KSS), oculocraniosomatic disorder or oculocranionsomatic neuromuscular disorder with ragged red fibers is a mitochondrial myopathy with a typical onset before 20 years of age. KSS is a more severe syndromic variant of chr ...

. Occasionally CPEO may be caused by conditions other than mitochondrial diseases.

Signs and symptoms

CPEO is a rare disease that may affect those of all ages, but typically manifests in the young adult years. CPEO is the most common manifestation of

mitochondrial myopathy Mitochondrial myopathies are types of myopathy, myopathies associated with mitochondrial disease. Adenosine triphosphate (Adenosine triphosphate, ATP), the chemical used to provide energy for the cell, cannot be produced sufficiently by oxidative ...

, occurring in an estimated two-thirds of all cases of mitochondrial myopathy. Patients typically present with ptosis (drooping eyelids). Other diseases like

Graves' disease Graves' disease, also known as toxic diffuse goiter or Basedow's disease, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyro ...

myasthenia gravis Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, ...

and glioma that may cause an external

ophthalmoplegia Ophthalmoparesis refers to weakness (-paresis) or paralysis (-plegia) of one or more extraocular muscles which are responsible for eye movements. It is a physical finding in certain neurologic, ophthalmologic, and endocrine disease. Internal ...

must be ruled out.

CPEO itself

CPEO is a slowly progressing disease. It may begin at any age and progresses over a period of 5–15 years. 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 (the inability or difficulty to move the eye) is usually symmetrical, therefore, patients are not affected by diplopia (double vision). 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 loss 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 Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease involving the gradual deterioration and death of specific volumes of the brain, linked to 4-repeat tau pathology. The condition leads to symptoms including Balance di ...

(PSP), which typically affects vertical gaze and spares horizontal gaze. Mitochondrial retinopathy has been described in CPEO which presents with a spectrum of distinct retinal phenotypes. This includes mild, focal pigmentary abnormalities on funduscopy and widespread granular pigmented fundus alterations. Mild, asymptomatic retinopathy might be underreported; severe retinopathy may be associated with significant vision loss.

Occurring alongside CPEO

Weakness of extraocular muscle groups including, the

orbicularis oculi The orbicularis oculi is a sphincter-like muscle in the face that closes the eyelids. It arises from the nasal part of the frontal bone, from the frontal process of the maxilla in front of the lacrimal groove, and from the anterior surface and b ...

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). The ciliary muscles that control the lens shape and the iris muscles are often unaffected by CPEO. Additional symptoms are variable, and may include exercise intolerance,

cataracts A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision of the eye. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colours, blurry or double vision, halos around ligh ...

, hearing loss, sensory axonal neuropathy,

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

, clinical depression,

hypogonadism Hypogonadism means diminished functional activity of the human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...

, and

parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity, and balance disorder, postural instability. Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic f ...

is characterized by onset before 15 years of age of CPEO, heart block and pigmentary retinopathy.

Genetics

Mitochondrial DNA Mitochondrial DNA (mtDNA and mDNA) is the DNA located in the mitochondrion, mitochondria organelles in a eukaryotic cell that converts chemical energy from food into adenosine triphosphate (ATP). Mitochondrial DNA is a small portion of the D ...

which is transmitted from the mother, encodes proteins that are critical to the respiratory chain required to produce

adenosine triphosphate Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...

(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 The extraocular muscles, or extrinsic ocular muscles, are the seven extrinsic muscles of the eye in human eye, humans and other animals. Six of the extraocular muscles, the four recti muscles, and the superior oblique muscle, superior and inferior ...

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). 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 affected 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. Whether a tissue is affected is correlated with the amount of oxidative demands in relation to the amount of mtDNA deletion.In most cases, PEO occurs due to a sporadic deletion or duplication within the mitochondrial DNA. However, transmission from the mother to the progeny appears only in few cases. Both

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

and

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

inheritance can occur, autosomal recessive inheritance being more severe. Dominant and recessive forms of PEO can be caused by genetic mutations in the ''

ANT1 Antenna, better known as ANT1, is a free-to-air television network airing in Greece. The alternate spelling is wordplay in Greek; ''ena'' (ένα) is the Greek number ''1'' (one), thus ''ANT1'' is pronounced the same as ''Antenna'' (Αντένν ...

'', '' POLG'', '' POLG2'' and '' PEO1'' genes.

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

Gömöri trichrome stain Gömöri trichrome stain is a histological stain used on muscle tissue. It can be used to test for certain forms of mitochondrial myopathy Mitochondrial myopathies are types of myopathy, myopathies associated with mitochondrial disease. Adeno ...

, 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 The polymerase chain reaction (PCR) is a method widely used to make millions to billions of copies of a specific DNA sample rapidly, allowing scientists to amplify a very small sample of DNA (or a part of it) sufficiently to enable detailed st ...

(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. It is important to have a dilated eye exam to determine if there is pigmentary retinopathy that may signify

which is associated with cardiac abnormalities. MRI may be helpful in the diagnosis, in one study volumes of medial rectus, lateral rectus, and inferior rectus muscles in CPEO were not smaller than normal (in contrast to the profound atrophy typical of neurogenic paralysis). Although volumes of the superior rectus muscle-levator complex and superior oblique were significantly reduced.

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. Coenzyme Q₁₀ has also been used to treat this condition. 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. The most common strabismus finding is large angle exotropia which can be treated by maximal bilateral eye surgery, but due to the progressive nature of the disease, strabismus may recur. Those that have

diplopia Diplopia is the simultaneous perception of two images of a single object that may be displaced in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often voluntary. However, when occ ...

as a result of asymmetric ophthalmoplegia may be corrected with prisms or with surgery to create a better alignment of the eyes.

References

External links

{{DEFAULTSORT:Chronic Progressive External Ophthalmoplegia Autosomal recessive disorders Disorders of ocular muscles, binocular movement, accommodation and refraction Mitochondrial diseases Muscular disorders