Chronic Progressive External Ophthalmoplegia (CPEO)

Chronic progressive external ophthalmoplegia (CPEO), also known as progressive external ophthalmoplegia (PEO), 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 so accomodating (focussing) and pupillary function is not affected.[2]

Mitochondrial disorders result in an array of clinical manifestations. These disorders can affect unique anatomic structures such as the eye (Leber hereditary optic neuropathy) or multiple systems, resulting in a variegated presentation (ataxia neuropathy syndrome [ANS], of which sensory, ataxia, neuropathy, dysarthria, and ophthalmoplegia [SANDO] is one).[3]  Kearns-Sayre syndrome (KSS) affects the heart and eyes.[4] Pearson syndrome can manifest as pancytopenia, pancreatic problems, and renal tubular maladies.[3, 5]

CPEO is the most frequent manifestation of mitochondrial myopathies.[6, 7] 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. However, individuals with a similar clinical presentation may have various mitochondrial defects.[3] There can also be causations due to dletions or defect in nuclear DNA (nDNA), which regulate mtDNA, for exapmle, POLG1.[2]

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 level 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,[8] such as diabetes mellitus, hypoparathyroidism, and hearing loss.[3, 4]

CPEO can also be a sign in the following disorders: oculopharyngeal dystrophy, myasthenia gravis, and Graves disease.

Mitochondrial DNA (mtDNA) encodes for essential components of the respiratory chain. Deletions of various lengths of mtDNA, nuclear DNA (nDNA),[9, 10] mt-tRNA mutations,[11] and mutations in 12S rRNA and 16S rRNA[12] result in defective mitochondrial function. This dysfunction is particularly problematic 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.[13, 14]  The most common deletion is in the mtDNA.[2]

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. With large-scale deletion of mitochondrial DNA, progressive replacement of muscle by fat cells has been reported.[15]

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.[16]

Frequency

Worldwide

Worldwide, the prevalence of mitochondrial disease is 11.5 cases per 100,000 population.[3]

United States

CPEO is rare. Approximately 1000-4000 children are born with mitochondrial disease annually in the United States.[17]

Sex

In KSS, boys and girls are affected equally.

Age

In KSS, onset of CPEO is before age 20 years.

Inheritance

CPEO can be inherited in an autosomal-recessive pattern, autosomal-dominant pattern, or mitochondrial pattern or can occur sporadically. The genes TWNK and SLC25A4 are involved in the autosomal-dominant pattern of inheritance, whereas the genes POLG and RRM2B are involved in both the autosomal-dominant and autosomal-recessive patterns of inheritance. The MTTL1 gene is most often associated with the mitochondrial inheritance pattern, along with other mtRNA and mtDNA genes.[18]

The prognosis in Chronic Progressive External Ophthalmoplegia is guarded. Patients often will present with ptosis and then progress to the abnormal plegia. Additional problems, such as cardiac dysfunction, can result in severe morbidity and mortality. Concurrent management of other affected organ systems is of the most importance to offset symptoms and in proved quality of life. There is no current cure for this condition.

 

 

The following support group is available to patients[19] :

United Mitochondrial Disease Foundation

8085 Saltsburg Road Suite 201

Pittsburgh, PA 15239

USA 

412-793-8077

info@umdf.org

https://umdf.org

 

MitoAction

P.O. Box 310

Novi, MI 48376

USA

888-648-6228 

info@mitoaction.org 

https://mitoaction.org

 

CureMito

McKinney, TX

USA

646-483-7073

info@curemito.org

http://www.curemito.org/

with special emphasis on SURF1 Leigh syndrome for which gene therapy is being tried. (TSHA-104 is an investigational AAV9-based gene therapy administered intrathecally for the treatment of SURF1-associated Leigh syndrome)[1]

 

Chronic progressive external ophthalmoplegia (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.[20] 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

A complete ophthalmologic examination should be performed, to include the following:

• Dilated retinal examination

• 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 below may also be helpful for categorizing physical findings.

Note the image below.

However, many atypical presentations of CPEO have been reported.[21, 22, 23]

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.

The entire mitochondrial DNA (mtDNA) from a 54-year-old man with chronic progressive ophthalmoplegia and hyperCKemia has been sequenced.[24]

A thorough ophthalmic examination is required.focus would be on the function of the levator muscle (blepharoptosis) and extraocular motility and limitations of movement (ophthalmoplegia) in addition to assessment of the anterior segment of the eye is required.Dilated retinal exam looking for pigmentary changes in the peripheral retina is also important.

 

A comprehensive medical evaluation would also be required looking for concomitant conditions.

Complications can include cardiac problems and esophageal dysfunction.

Other organ systems can also be adversely affected such as hearing.

Patients with Kearns-Sayre syndrome (KSS) have been reported to have the following:

• Low magnesium

• Low parathyroid hormone

• Increased lactic acid

• Increased pyruvic acid

• Increased creatine phosphokinase (CPK)

• Increased aldolase

• Increased protein in CSF

Thyroid studies can confirm suspicion of Graves disease.

A positive acetylcholine receptor antibody test may establish the diagnosis of myasthenia gravis. A negative acetylcholine receptor antibody assay does not differentiate chronic progressive external ophthalmoplegia (CPEO) from myasthenia gravis. In addition, false-positive acetylcholine receptor antibodies have been reported in CPEO.[25]

Tensilon testing can be helpful in differentiating myasthenia gravis from CPEO. However, the clinician must remain wary of the effects of edrophonium in a patient harboring a possible cardiac conduction defect, that is, KSS.

Ultrastructural testing of skin biopsies has been used in cases in which muscle biopsy findings are negative.[26]

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:

• Normal brain

• Cortical and cerebellar atrophy

• Increased T2 signal in subcortical cerebral white matter, cerebellar white matter, globi pallidi, thalami, and substantia nigra

A barium swallowing study would be useful to differentiate oculopharyngeal dystrophy.[27]

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.

Muscle biopsy is still the definitive test for mitochondrial disorders, but polymerase chain reaction (PCR) testing also has been shown to be conclusive.[28]

Biopsy of muscle in a patient with chronic progressive external upper plegia shows ragged-red fibers.This is due to the clumped or "ragged" structures that are aggregates of mitochondria. Mitochondria can also appear atypical including being fragmented or swollen. Additionally lipids can accumulate his droplet in the muscle fibers. Deficiency of Cytochrome C oxidase (COX ) enzyme or absence of Has also been found in muscle fibers.

 

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.

As mitochondria are the power source for cells, dysfunction is most manifest in organs and systems that use high oxidative phosphorylation activity, including the brain and neurological pathways, the heart, the muscles, and the lungs.[17]

Individuals with mitochondrial disease, whether children or adults, may be asymptomatic. Others may have variable symptoms, including stroke, seizures, gastrointestinal (GI) manifestations (reflux, severe vomiting, constipation, diarrhea), difficulties with swallowing, failure to thrive, blindness, deafness, cardiac and renal manifestations, muscle failure, cold/heat intolerance, diabetes, lactic acidosis, manifestations of the immune system, and hepatic disease.[17]

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.[29]

For ptosis, adhesive tape and lid crutches can be used to assist patients with advanced chronic progressive external ophthalmoplegia (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.[30]

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.[31]

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.[32]

Kearns-Sayre syndrome (KSS) is a complex disorder requiring the involvement of physicians from various specialties, including neurology, cardiology, ophthalmology, and endocrinology.

Individuals with mitochondrial disease are vulnerable to complications from other illnesses, although these may not pose significant problems in some persons with mitochondrial disease. The highest degree of vulnerability occurs during the duration of the coincident illness and for approximately two weeks thereafter.[17]

Mitochondrial disease that becomes symptomatic in the teenaged or early adult years can be devastating. An otherwise healthy child can progress from normal functionality to impairment, possibly severe enough to result in death.

Genetic counseling is necessary in carrier families to ascertain the risks; however, as the disorders result from a complex array of mitochondrial and even nuclear genotypic errors and can have such a diverse presentation phenotypically, genetic testing cannot always predict the outcome.

It is imperative that patients with chronic progressive external ophthalmoplegia (CPEO) 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.