The causes of nondysgenetic myopathic ptosis fall into two categories: dystrophic myopathic ptosis and mitochondrial myopathies (MMs). Dystrophic myopathic ptosis is characterized by progressive weakness and breakdown of skeletal muscles and includes oculopharyngeal muscular dystrophy (OPMD), oculopharyngodistal myopathy (ODM), and myotonic dystrophy (MD).³,⁴ OPMD is an autosomal dominant disease with 100% penetrance and pronounced expressivity.⁵,⁶ More than 20 mutations have been found in the PABPN1 gene, which is the gene responsible for OPMD and maps to the long arm of chromosome 14 at 14q11. Gross examination of the levator muscle and the Müller muscle shows heavy infiltration with fat, while the levator aponeurosis appears intact.⁷ Light microscopy shows the characteristic rimmed vacuoles within muscle fibers which point to a dystrophic process, while electron microscopy shows intranuclear tubulofilamentous inclusions.⁵ Both of these findings are highly suggestive of OPMD.⁵ Other histological changes that lend further support to a dystrophic process include loss of muscle fibers, abnormal variation in fiber size, increase in the number of nuclei, and expanded interstitial fibrous and fatty connective tissue.⁵

MD type 1 is an autosomal dominant disorder caused by abnormalities in the dystrophia myotonica protein kinase (DMPK) gene mapped to chromosome 19 at 19q13. MD is considered one of the trinucleotide repeat disorders, which is a kind of genetic mutation whereby the number of trinucleotide repeats exceeds the normal threshold. The number of CTG nucleotide repeats in the DMPK gene increases with each successive generation and results in a phenomenon called “anticipation,” whereby the phenotype is characterized by an increase in generational severity and earlier onset.⁸,⁹ More than 1000 CTG repeats result in congenital onset and severe disease. Maternal inheritance also results in a more severe phenotype than paternal inheritance.⁹ Histopathology shows that both atrophic and swollen muscle fibers may be observed grossly, as well as with light microscopy.¹⁰,¹¹

MMs are a group of genetic diseases characterized by a primary dysfunction in the mitochondrial respiratory chain, which causes a deficit in adenosine triphosphate energy production, particularly in skeletal muscle, but other metabolically active tissues such as the nervous system are also involved.¹² Mitochondrial function is controlled both by mitochondrial and nuclear DNA; therefore hereditary transmission of MM can occur either maternally or in a traditional Mendelian fashion. Several mutations in mitochondrial DNA (mtDNA) and at least seven genes have been demonstrated to cause MM.⁸ MMs with ocular involvement include chronic progressive external ophthalmoplegia (CPEO); Kearns-Sayre syndrome (KSS); mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes; mitochondrial
encephalopathy with ragged red fibers; and neurogastrointestinal encephalopathy.¹²,¹³,¹⁴ Because all MMs with extraocular involvement share the same ophthalmic manifestations (a pupil-sparing progressive external ophthalmoplegia with ptosis), in a sense CPEO may be considered both a disease of its own and a symptom of several other MMs.¹² Some authorities even reject CPEO as a separate disease entity, suggesting it is merely a symptom in a disease spectrum that may occur alone at the milder end of the spectrum (isolated CPEO), or may be associated with other systemic manifestations (CPEO-plus).¹³

The histopathology of the extraocular muscles in MM patients is indeed consistent with a primary myopathy.¹³ When MM is suspected, the orbicularis oculi and not the levator muscle is usually recommended as a better site for muscle biopsy because of the ease of harvesting, and because the levator muscle proper is nestled within the orbit where it may be difficult to obtain enough tissue for histologic, histochemical, and genetic analyses.¹⁵,¹⁶ On light microscopy, patients usually show red-staining granules (abnormal mitochondria) within the subsarcolemmal zones of muscle fibers on Gomori trichrome stain, or the so-called “ragged red fibers,” which are morphologically correlated to impaired protein synthesis.¹³ Patients may also show decreased cytochrome C oxidase (COX), reduced nicotinamide adenine dinucleotide, and succinate dehydrogenase staining of muscle fibers.¹⁶,¹⁷ Electron microscopy may show a mix of normal and abnormal “ghost” or irregularly shaped mitochondria (heteroplasmy),¹³,¹⁶,¹⁷ while genetic studies may show a single large deletion in mtDNA, or other mitochondrial abnormalities.¹⁶,¹⁷,¹⁸ The recognition of ragged-red fibers was traditionally hailed as the morphological hallmark of MM; however, this assumption predates the molecular/genetic era.¹⁸ The presence of ragged-red fibers in the orbicularis oculi muscle may be a normal aging finding. It may be related to oxidative stress, coupled with the fact that mitochondrial mutations increase as age advances. Therefore, the demonstration of ragged-red fibers alone may not be sufficient to establish the diagnosis,¹⁵,¹⁷ and supplementary electron microscopic/genetic studies are recommended by some authors.¹⁵

Several shared clinical features characterize dystrophic myopathic ptosis. Any new-onset or acquired ptosis with reduced levator function and limitation of ocular motility with or without muscle weakness involving the face or the whole body should alert the clinician to the possibility of dystrophic myopathic ptosis.³ The levator function is usually poor, the Bell phenomenon may be absent, and lagophthalmos and occasionally ectropion may be present if the orbicularis muscle is weak.¹⁹ This disease is a frequent cause of significant visual disability as the visual axis gradually becomes occluded by the upper eyelid.²⁰ Patients also frequently present with a posterior head tilt and deep eyebrow furrows because of chronic contraction of the frontalis muscle.¹⁹

OPMD is an adult-onset disease that usually starts in the fifth or sixth decade of life. There is no sex predilection, and the condition is characterized by progressive ptosis, swallowing difficulties (dysphagia), and proximal limb weakness. Although initially described in a French-Canadian family in 1915, it does have a worldwide distribution and has been reported in more than 30 countries. However, the largest clusters are still observed among Bukhara Jews in Israel and the French-Canadian population, with an estimated prevalence of 1:600 and 1:1000, respectively. Without these two populations, the prevalence is calculated to be 1:100,000.⁵ Ptosis is always bilateral but may be asymmetrical. Extraocular motility usually remains intact, although supraduction may be affected. Saccades are usually reduced in speed even when the extraocular motility appears normal, but complete external ophthalmoplegia is extremely rare (Figure 11.1).⁵,⁸,²¹ Initially, patients complain of dysphagia for solid foods only; then as the disease progresses, liquids become difficult to swallow and the tongue muscles may become weak as well.⁵ Other systemic symptoms in the form of voice/speech impairment (dysarthrophonia), facial weakness, and proximal muscle weakness occur later. Permanent disability in the form of severe malnutrition or immobility requiring a wheelchair rarely occurs.⁵ Although the family history, the typical clinical symptoms, and the characteristic histopathologic findings may help, the diagnosis of OPMD requires molecular genetic testing to confirm the presence of abnormalities in the PABPN1 gene.²²

MD is a rare disease with a prevalence of 1:8000 in the general population. It is a slowly progressive multisystem disorder with onset usually in the second or the third decades of life. It may be associated with significant systemic disability as the disease advances.⁸,⁹,¹⁰,²³ MD has a clinical picture almost identical to CPEO, with ptosis (59%), extraocular muscle abnormalities (82%), and orbicularis weakness (Figure 11.2).¹⁰ Ptosis is usually severe and the levator function rarely exceeds 3 mm.²³ The orbicularis muscle weakness is also much more pronounced in MD and usually results
in severe meibomian gland dysfunction, a situation not unlike patients with facial nerve paralysis.⁸,²³ According to some authors, the presence of a myopathic form of ptosis combined with meibomian gland dysfunction is virtually pathognomonic of MD.⁸ Patients may also experience hypotonia of the face with difficulty raising the eyebrows, as well as generalized hypotonia that may be more commonly distal.¹⁰ Other findings include myotonia (delayed muscle relaxation after contraction), cardiac conduction abnormalities, polychromatic cataracts, hypogonadism, and frontal balding. The overall clinical picture of MD simulates the appearance of “accelerated aging.”⁹