Ophthalmic Hyperguide. Oculoplastics: Ophthalmoplegia Plus Syndromes

Neurologic, ophthalmologic, and systemic disorders with common chronic progressive external ophthalmoplegia (CPEO) have been identified. Chronic progressive external ophthalmoplegia may also occur in isolation of any other system involvement. To correctly diagnose the underlying disorder in a patient with CPEO, a baseline understanding of the common disorders and pathways to diagnosis is necessary. The term ophthalmoplegia plus was coined by David Drachman, MD, in 1968 and refers to disorders with abnormalities, often neurologic, in addition to CPEO. Knowledge of these disorders has increased significantly since then; however, overlap between clinical phenotypes and genetic defects for the most common causes of CPEO remains.

Chronic progressive external ophthalmoplegia should be considered a sign of disease, rather than a disease. In addition to slowly progressive, bilateral, typically symmetric ocular immobility, bilateral ptosis is often present (Slide 1). Mitochondrial myopathy is the most common cause of CPEO, but CPEO may be a component of other disorders that should be considered in the differential diagnosis (Table 1).

Table 1. Differential Diagnosis of Bilateral Ophthalmoplegia and Ptosis

Mitochondrial disease

CPEO - isolated
Kearns-Sayre
MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)
MNGIE (mitochondrial neurogastrointestinal encephalomyopathy)

Refsum's disease
Spinocerebellar ataxia
Friedreich's ataxia
Charcot-Marie-Tooth disease
Abetalipoproteinemia (Bassen-Kornzweig syndrome)
Myasthenia gravis (congenital or acquired)
Congenital myopathies
Oculopharyngeal muscular dystrophy
Myotonic dystrophy

Mitochondrial Genetics

Since the discovery of the first disease-causing mitochondrial deoxyribonucleic acid (DNA) point mutation in 1988, understanding of genetics and pathophysiologic mechanisms in mitochondrial diseases has expanded considerably. Mitochondrial function and oxidative phosphorylation (adenosine triphosphate production) is dependent on proteins encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Inheritance of mtDNA is maternal, unlike the classic Mendelian inheritance patterns of nDNA. Dysfunction of either mtDNA or nDNA, or of communication between the two, can potentially result in clinical disease. Besides affecting a mitochondrial protein involved in oxidative phosphorylation directly, a nDNA mutation may also affect replication of mtDNA. When this occurs, depletion or multiple deletions may occur in the mtDNA with a similar end result of clinical disease. Mutations in mtDNA or in mitochondrial protein-encoding nDNA may arise sporadically or via the maternal or Mendelian inheritance patterns described above. Human mtDNA has a mutation rate 10-20 times higher than nDNA.

Unlike nDNA, each cell contains hundreds of copies of each mtDNA. A single cell may contain a percentage of mutant mtDNA and the rest wild type, normal mtDNA. This concept of heteroplasmy may explain some of the phenotypic variability that occurs in mitochondrial disease. The more mutant mtDNA that is present in a given tissue, the more likely that tissue is to manifest disease (e.g., retina, extraocular muscles, or brain). It is generally thought that there is a threshold effect, with 60% mutant mtDNA required for dysfunction of a given tissue. Tissues with high energy requirements, such as skeletal muscle or brain, may be more prone to dysfunction.

Mitochondrial CPEO

Chronic progressive external ophthalmoplegia is the most common manifestation of mitochondrial myopathy. Ninety percent of patients with mitochondrial myopathy have CPEO and, in many patients, it is the presenting manifestation. Generally, the ocular mobility impairment occurs because of weak extraocular muscles and thin, atrophic extraocular muscles can sometimes be seen on orbital imaging. Because of the slowly progressive, bilateral nature of the ocular motility deficit, patients usually do not have diplopia and may not even be aware of a problem. Most patients also have bilateral ptosis (in two thirds of patients, bilateral symmetric, slowly progressive ptosis is the initial symptom months or years later by ophthalmoplegia). Mild extremity skeletal muscle weakness is often present. Co-existing ophthalmologic abnormalities may include corneal opacities, cataracts, and pigmentary retinopathy. Hearing loss and peripheral neuropathy may also occasionally be present. Onset is usually during the second or third decade, but late-onset cases are well-documented.

Chronic progressive external ophthalmoplegia is usually sporadic with large-scale deletions in the mtDNA, but maternal mitochondrial inheritance via mtDNA mutations and autosomal dominant and recessive inheritance via nDNA have been reported. With sporadic onset, deletions and duplications in the mtDNA occur and a state of heteroplasmy in skeletal muscle, with between 20% and 90% mutant mtDNA, gives rise to the clinical extraocular muscle myopathy. Recent literature has elucidated three specific gene mutations associated with autosomal dominant inheritance via nDNA: ANT1 (chromosome 4q), TWINKLE (chromosome 10q), and POLG (chromosome 15q).

Kearns-Sayre Syndrome

Kearns-Sayre syndrome (KSS) is a subtype of mitochondrial CPEO with prominent neurologic and/or systemic findings and early onset. Diagnostic criteria are as follows:

Other commonly associated abnormalities are listed in Table 2. Brain pathology consists of spongiform degeneration and brain magnetic resonance imaging (MRI) may reveal hyperintense T2-weighted changes in the basal ganglia, thalami, cerebellum, and white matter. Skeletal muscle shows the characteristic ragged red fibers indicative of mitochondrial myopathy, as it does in isolated mitochondrial CPEO.

Table 2. Associated Findings in Kearns-Sayre Syndrome

Hearing impairment
Peripheral neuropathy
Impaired intellect
Short stature
Hypoparathyroidism

The pigmentary retinopathy characteristically affects the posterior pole with a "salt and pepper" appearance in the macula and peripapillary regions that increases in prominence with age. Vision loss is typically mild if present and occurs in only 40% to 50% of patients.

MELAS and MNGIE

Chronic progressive external ophthalmoplegia may also occur as a component of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).

In MELAS, stroke-like episodes typically occur before age 40. Encephalopathy is manifested as seizures or dementia, ragged red fibers are present in muscle, and lactic acidosis is usually present. Retrochiasmal visual loss is common. The classic mutation in MELAS is an Aà G transition in a transfer RNA encoded by the mtDNA. This mutation has been identified in patients with CPEO in the absence of MELAS as well, demonstrating the clinical overlap between the heterogenous phenotypic manifestations of mitochondrial disease and the genetics.

Characteristic symptoms with MNGIE include CPEO, encephalopathy, mild peripheral neuropathy, and gastrointestinal dysmotility. The gastrointestinal symptoms are most prominent and are manifested as recurrent nausea, vomiting, and diarrhea. Onset and rate of progression varies, and patients typically die in early adulthood. Inheritance is usually autosomal recessive via a nDNA mutation affecting the thymidine phosphorylase gene (chromosome 13q). This mutation results in multiple deletions and depletion of mtDNA in skeletal muscle. Discovery of elevated serum thymidine levels may confirm the diagnosis. Although most cases result from thymidine phosphorylase gene mutation, patients with polymerase gamma mutations and the MNGIE phenotype have been reported, providing another example of overlap between phenotype and genetics because the polymerase gamma mutations typically cause isolated CPEO.

Diagnostic Considerations

The above disorders should be considered in patients with unexplained chronic progressive ophthalmoplegia, especially when other findings typical of mitochondrial dysfunction such as ptosis, deafness, weakness, ataxia, short stature, pigmentary retinopathy, cardiac conduction defects or diabetes are present. The presence of proptosis or pain with ophthalmoplegia should suggest alternative disorders, as these findings are not features of mitochondrial extraocular myopathy.

When a mitochondrial disorder is suspected, diagnostic work-up may include serum lactate and pyruvate; brain MRI with gadolinium; lumbar puncture with cerebrospinal fluid lactate, pyruvate, protein, and cell counts; electrocardiogram; skeletal muscle biopsy with evaluation for ragged-red fibers and partial cytochrome c oxidase deficiency; and genetic analysis for mtDNA or nDNA defects associated with mitochondrial disease.

MRI findings in patients with ophthalmoplegia plus syndromes rarely establish the diagnosis because they are nonspecific but may provide evidence of the extent of disease. The most common findings are cerebral or cerebellar atrophy or hyperintense T2-weighted lesions of the cerebral white matter and basal ganglia. Diagnosis is typically established with muscle biopsy.

No cure exists for these disorders and therapy remains largely ineffective. Coenzyme Q (ubiquinone) has been used most commonly, but usually does not lead to clinical improvement. Correct diagnosis must be established to avoid misdiagnosing other treatable conditions and so that adequate genetic counseling may be provided to a patient's family. Identification of disease components, such as cardiac conduction defects that may prove fatal if missed, is also essential.

Introduction

Mitochondrial Genetics

Mitochondrial CPEO

Kearns-Sayre Syndrome

MELAS and MNGIE

Diagnostic Considerations

Bibliography