Chapter 28
Ocular Manifestations of Acquired Muscle Disease
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Acquired muscle disease describes an etiologically diverse collection of systemic diseases characterized by muscle weakness and wasting. The clinical manifestations of these disorders vary greatly in their extramuscular findings, which in many cases can be the most prominent or serious component of the disease. For an acquired muscle disease to be included in this discussion, the disease must exhibit some degree of visual or ocular motor dysfunction. This chapter deals with muscle diseases acquired after birth. Many disorders have an inherited basis but initially present after the first decade of life. Congenital myopathies, myopathies of early childhood, and disorders of the myoneural junction (e.g., myasthenia gravis, botulism) are not covered in this review.
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Myotonic dystrophy (MD) is a multisystem disease resulting from an unstable triplet expansion of nucleotides on chromosome 19.1,2 This instability explains a clinical phenomenon characterized by the progressive worsening of disease with each successive generation. For most of the last century the phenomenon of increasing severity in successive generations, referred to as anticipation, wasconsidered an artifact of observation. Unlike most dominantly inherited disorders that cause relatively consistent findings from one generation to the next, MD can affect increasingly younger patients in each generation with progressively severe disease. After the MD gene locus was identified on chromosome 19, the genetic basis for anticipation became apparent. There was an unmistakable correlation between the severity of MD and the size of the deoxyribonucleic acid (DNA) repeat region.3 Whereas the number of CTG repeats at the MD locus in the normal population is small (4 to 37), expanded repeats of 50 or more are associated with clinical manifestations of MD. As the number of repeats enlarges, the age of onset decreases and the disease morbidity increases. Congenital MD is often associated with 1000 or more CTG repeats5 (Thornton). On the average, children of parents with MD average 740 repeat segments more than their affected parent. Although manifestations of MD such as age of onset and severity of clinical disease3,4 have been shown to correlate with the length of the repeat fragments, there is considerable overlap in the size of the repeat sequence across levels of disease severity. The details of the molecular pathogenesis of MD are incompletely understood. The CTG repeat mutation occurs in the gene encoding a protein kinase. Loss of function of this enzyme appears to underlie many, but not all of the manifestations of MD. The full clinical syndrome is probably of polygenic origin, and it is postulated that the CTG repeat mutation may alter the expression of other genes.

Testing for unstable repeat fragments of DNA now has a central role in the diagnostic workup of any patient suspected of MD. Genetic testing for MD is more reliable, more sensitive, and more specific than electromyography or muscle biopsy.5

The phenotypic expression of the MD gene mutation includes muscle wasting, weakness, myotonia (delayed muscle relaxation following contraction), abnormal cardiac conduction, mental retardation, testicular atrophy, hyperinsulinemia, and frontal baldness. In severe cases, atrophy of the temporalis and masseter muscles give rise to a hatchet facies with flattened cheeks and drooping jaw. The ocular manifestations include cataract, ptosis, and blepharitis. Abnormalities of ocular motility are uncommon. Nearly a third of patients have lower than normal intraocular pressure presumably resulting from decreased aqueous production.6 The cataract in MD often contains iridescent deposits within a thin band of the anterior and posterior cortex. These red, blue, green, and white flecks are visible on slit lamp examination. Their distribution in the lens cortex is thought to be highly specific for MD and distinguishes these deposits from the more common iridescent refractile flecks in age-related cataracts.7 A variety of pupillary abnormalities have been described in MD, but most patients have normal pupillary response to light. Pigmentary changes in the macula resemble those of pattern dystrophy but are not a common cause of reduced vision.8 Peripheral retinal pigment epithelial atrophy and clumping has been described and probably causes few, if any, clinical symptoms.8,9

There is no known effective treatment. A variety of medications may partially alleviate the symptoms of myotonia.10 Cardiac arrhythmias and heart failure are treated according to usual protocols. Respiratory insufficiency from hypoventilation resulting from diaphragmatic weakness or abnormalities in central ventilatory regulation can be exacerbated by medications used to treat other complications of MD such as depression.


Proximal myotonic myopathy (PROMM) has, until recently, been considered part of the spectrum of MD. Like MD, it is an autosomal dominant disorder characterized by myotonia, proximal muscle weakness, and cataracts, but affected patients do not demonstrate CTG repeats on chromosome 19.5 The genetic locus for PROMM is uncertain. The disease is characterized by early involvement of proximal limb muscles and a more benign clinical course. There are few mental changes and premature death is rare. Generational anticipation is not a feature of PROMM. Although less common than MD, the prevalence of PROMM in some parts of central Europe is nearly equal to MD.11 Specific ocular manifestations of PROMM await careful description.

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The term muscular dystrophy is used to describe a genetically determined group of degenerative diseases of muscle characterized by progressive weakness. The classification of the muscular dystrophies is based on age of onset, distribution of affected muscles, rate of progression, pattern of inheritance, and the exclusion of other causes of muscle weakness.12 Muscle biopsy usually shows a variety of nonspecific degenerative changes and is useful in ruling out other simulating conditions. Duchenne's muscular dystrophy is the most common of the muscular dystrophies. The genetic defect occurs at the p21 position of the X chromosome and results in the production of abnormal dystrophin polypeptides, which leads to the ultimate breakdown of muscle.13 Dystrophin functions in conjunction with other related proteins to make up the sarcoglygan complex of skeletal muscle. Mutational defects in dystrophin cause disruption of the sarcoglygan complex that normally couples mechanical and chemical signals of muscle fibers.14 Although dystrophin serves important biochemical roles in skeletal, cardiac, and smooth muscles, the polypeptide is also found in the central nervous system including the retina. In the retina, dystrophin is localized to the photoreceptor terminal; its function at this site remains to be determined.15

Ocular involvement in any of the muscular dystrophies is rare except in oculopharyngeal muscular dystrophy (OPMD). The reason why extraocular muscles are spared in the muscular dystrophies is unexplained. This counterintuitive finding has suggested to some investigators that the extraocular muscles possess a tissue-specific property that protects them from myofiber degeneration.16


The ocular manifestations of OPMD include progressive ptosis and variable degrees of ophthalmoplegia. Ptosis is rarely complete, and the symmetric disturbance in ocular motility rarely results in diplopia. Intrinsic eye muscles are spared. Patients usually present in the fifth and sixth decades with difficulty swallowing, although in some, ptosis may develop before dysphagia. Other extraocular findings include decreased palatal mobility, impaired gag reflex, laryngeal weakness and dysphonia, and shoulder-girdle weakness and atrophy.

This autosomal dominant disease has been described most often in persons of French Canadian heritage.17,18 The primary genetic locus appears to be on chromosome 14. GCG expansion repeats have been demonstrated in families with OPMD, but polygenic factors may determine disease expression. The repeats in OPMD are meiotically stable. Thus, families with OPMD do not show genetic anticipation. Two distinguishing pathologic features of OPMD are rimmed vacuoles and intranuclear inclusions, similar to those noted in other trinucleotide repeat disorders.

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Ion channels are macromolecular structures formed by protein complexes within the lipid wall. They control the flow of ions in and out of the cell, which in turn give rise to electrical depolarization and hyperpolarization. Ion channels produce either action potentials or graded potentials, which are the basis for communication among neurons. Because ion channel integrity is determined by a complement of genes that encode the structural proteins that make up the macromolecular complex, a single gene mutation can potentially alter the entire structure and, thus, the function of the ion channel. Mutations affecting chloride, sodium, or calcium channels are known to cause several muscle diseases.


Malignant hyperthermia (MH) is a hereditary disease characterized by episodes of hypermetabolism. These episodes run a variable course and are often triggered by an anesthetic agent, usually inhalation anesthetics or muscle relaxants. Although symptoms usually occur during surgery, they can be first noted in the postoperative period. In addition, some patients with MH may have had previous anesthesia without symptoms.

The prevalence of MH among patients with ptosis and strabismus may be higher than that in the general population.19 The disorder is inherited in an autosomal dominant manner but is genetically heterogeneous and affects different loci.20 The defect common to MH is a mutation in the calcium-receptor subunit of the membrane channel.21 Some, but not all families, have mutations of the ryanodine receptor gene on chromosome 19q13. In its most severe form, MH causes muscle rigidity, high fever, metabolic acidosis, markedly elevated creatine kinase (CK) levels, myoglobinemia, and cardiovascular collapse.19 Rigidity of muscles is usually first noted in the masseter and temporalis muscles. Fever, tachycardia, and tachypnea develop rapidly thereafter and reflect the excessive accumulation of cytoplasmic calcium.

The apparent decline in mortality from MH may be due to greater awareness of the disease and improved effectiveness of pharmacologic therapy to lower myoplasmic calcium concentration.22 Dantrolene sodium is the drug of choice for the treatment of MH. Oral dantrolene has been shown to prevent MH in humans and is effective in treating the fully developed syndrome when given intravenously.23 Haloperidol, which promotes reuptake of calcium into the sarcoplasmic reticulum, may also be useful during the acute stage of the disease. The most effective approach to MH, however, is prevention by obtaining a careful history of prior anesthetic exposure and family history of complications with anesthesia. Several laboratory tests are useful in confirming the diagnosis of MH.22


The term periodic paralysis includes a group of conditions characterized by transient, generalized, diffuse paralysis. Muscle function usually returns to normal spontaneously in hours after an attack. At least five different periodic paralysis syndromes have been identified.24

Hypokalemic periodic paralysis (HPP) is the most frequent type and is transmitted in an autosomal dominant fashion. HPP is due to a mutation in muscle calcium channel subunit gene on chromosome 1. The mutation produces a reduction of the calcium current in the t-tubule. The effects of insulin on potassium are exaggerated. During attacks, potassium flows into muscle cells and the muscles become electrically inexcitable.

Attacks begin by adolescence and decrease after age 40. They may be provoked by exercise followed by sleep, by stress, by alcohol, or by meals rich in carbohydrates and sodium. Attacks last from 3 to 24 hours. The clinical findings in a classic case includes generalized weakness to overt paralysis associated with a low serum potassium concentration. There are few ocular findings during an attack, although ptosis and lid lag have been described.25 Patients have normal interepisode examinations except that some have eyelid myotonia. There is considerable genetic heterogeneity among patients with periodic paralysis including different mutations within the same pedigree and variability in serum potassium concentration.26–29

Attacks may be prevented by low-carbohydrate, low-sodium diets and by acetazolamide, dichlorphenamide, spironolactone, or triamterene. Acute attacks may be treated with oral, or if necessary, parenteral potassium and electrocardiographic monitoring. In addition, because thyrotoxic periodic paralysis resembles HPP, thyroid function should be measured when HPP is suspected.

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Mitochondrial cytopathies constitute a heterogeneous group of clinical diseases that are related to inborn errors of mitochondrial metabolism. These primary defects of mitochondrial metabolism have been inferred or suspected based on several lines of evidence including maternal inheritance pattern, ragged red fiber morphology on muscle biopsy, and biochemical analysis. More recently, however, the mitochondrial basis for these diseases has been confirmed by genetic analysis of mitochondrial DNA (mtDNA). Each mitochondrion contains its own DNA and capacity for DNA transcription, translation, and replication. Two to 10 circular mtDNA molecules are present in human mitochondria and each contains 37 genes. Mitochondria divide in a manner similar to bacteria. During cellular mitosis, intracytoplasmic mitochondria are randomly segregated into daughter cells. During fertilization, the human sperm cytoplasm contributes few mitochondria to the zygote compared with the much larger egg. Any abnormal mtDNA will be inherited by either male or female offspring, but only the female will be able to pass the abnormal gene on to the subsequent generation.

Mitochondrial cytopathies express considerable phenotypic variability. Although the reasons for different patterns of organ involvement are not understood, certain clinical syndromes are well established.30 In some disorders, the inborn error in mitochondrial metabolism results in the accumulation of abnormal protein within the mitochondria. The accumulation of protein can lead to identifiable alterations in mitochondrial structure by light microscopy. With special histologic stains (e.g., modified trichrome), mitochondria appear as clumps of red dots or so-called ragged red fibers. Ultrastructural studies show that these mitochondria are filled with protein crystals and other electron-dense deposits. The utility of muscle biopsy in mitochondrial cytopathies is limited primarily by the low sensitivity of the test.


Chronic progressive external ophthalmoplegia (CPEO) is characterized by slowly progressive limitation in ocular motility. The disease progresses with such symmetry that diplopia is rarely noticed. Slowed saccades are an early sign of this motility disturbance.31 Ptosis is an almost universal finding and can precede the onset of ophthalmoplegia. Pupils are spared. As the disease progresses, eyes are fixed in a primary position and the lids become severely ptotic. Neither oculocephalic maneuvers nor caloric stimulation can move the eyes. The disease has an insidious onset usually beginning in young to middle-aged adults but ranges from infancy to older adults.

Several other ocular conditions have been associated with CPEO including optic atrophy, pigmentary retinopathy, and corneal abnormalities. Systemic manifestations have included facial and peripheral myopathies, spasticity, deafness, vestibular dysfunction, dementia, and ataxia.31 Various endocrine; skin; and cardiac disorders, particularly conduction block, have been reported.

In 1958, Kearns and Sayre32 reported a series of patients with external ophthalmoplegia, pigmentary degeneration, and cardiomyopathy. This constellation of findings is now regarded as a subset of CPEO and includes minor findings of elevated cerebrospinal fluid protein and cerebellar dysfunction. Patients with the Kearns-Sayre syndrome are usually younger than 20 years and are likely to have abnormalities of cardiac conduction and other systemic abnormalities.

Approximately half of patients with CPEO have demonstrable mtDNA deletions on skeletal muscle biopsy compared with nearly 90% with the Kearns-Sayre syndrome.33,34 The fact that mtDNA deletions occur in different proportions to normal in various tissues probably reflects the fact that mitotic segregation of organelles is not a uniform processes in primitive stem cells and that there is a certain variability of postmitotic cell division after gestation. It is probable that as yet undetected point mutations in mtDNA or other nuclear genes exists in patients with CPEO who do not have any demonstrable mtDNA deletions.

There is no known effective treatment for mitochondrial cytopathies. No benefit has been demonstrated from coenzyme Q10, riboflavin, or vitamin C. The avoidance of substances that theoretically stress mitochondrial function such as tobacco and alcohol is a reasonable recommendation, and patients should be provided with genetic counseling. Severe ptosis can be managed with lid crutches or surgery.


Leber's hereditary optic neuropathy has a variable clinical phenotype but rarely includes muscle dysfunction. Myoclonic epilepsy and ragged red fibers (MERRF); mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); and Leigh's disease are known mitochondrial cytopathies that may have variable proportions of ocular and muscle involvement.35

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Visceral myopathies are rare inherited diseases characterized by problems with intestinal motility, bladder dysfunction, and peripheral neuropathy.36–38 Most are transmitted as autosomal recessive traits, but an occasional sporadic case has been reported. Ocular manifestations have been reported including ptosis and external ophthalmoplegia.37,38
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Polymyalgia rheumatica (PMR) is a disorder of persons older than 50 years characterized by muscular aches and stiffness of the neck, shoulders, and pelvis. The discomfort is generally worse in the morning or after prolonged inactivity. The condition is relatively common with an annual incidence of 54 per 100,000 in people older than 50.39 Women are affected twice as often as men. Although PMR has no known ocular complications, its association, and clinical overlap, with giant cell arteritis makes it an important disease for ophthalmologists to understand.

Since 1960, when the association between PMR and giant cell arteritis was first described, there has been controversy about the relationship of the two conditions. Approximately 10% to 15% of people with PMR and no signs or symptoms of giant cell arteritis have positive temporal artery biopsies.40 People with giant cell arteritis are approximately 10 years older than those with PMN, which suggests that PMN may be an earlier phase along a spectrum of disease. A substantial proportion of patients with giant cell arteritis, however, have no symptoms of PMN. People with PMR and giant cell arteritis may have similar nonspecific constitutional features, including low-grade fever, weight loss, and fatigue. The myalgias of PMR and the headache of giant cell arteritis respond dramatically to corticosteroids. The ocular manifestations of giant cell arteritis include anterior ischemic optic neuropathy, central retinal artery occlusion, and disturbances in ocular motility. The clinical manifestations of giant cell arteritis are described thoroughly in other chapters.

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Many of the disorders previous classified under the general rubric of metabolic myopathy have been reclassified as mitochondrial cytopathies or channelopathies. Inborn errors of carbohydrate and lipid metabolism that are not of mitochondrial or ion channel origin are uncommon.41 These diseases may present with exercise-induced weakness or pain or with signs or symptoms of rhabdomyolysis. Glycogen and lipid storage diseases rarely result in disturbances of ocular motility or ptosis.
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Polymyositis is an inflammatory disease of skeletal muscle. Its diagnosis is based on clinical history of muscle pain and weakness, elevated serum CK concentration, positive biopsy findings, and characteristic changes on electromyography.42 Dermatomyositis must be entertained when this same constellation of findings is associated with a localized or diffuse erythematous rash, eczematoid dermatitis, maculopapular eruption, or exfoliated dermatitis. Polymyositis also occurs in people with connective tissue diseases such as rheumatoid arthritis, scleroderma, and lupus erythematosus, which all have associated ocular manifestations. Approximately 10% of patients with polymyositis have an underlying malignancy. The diagnosis of polymyositis can precede the onset of malignancy by up to 2 years. Polymyositis typically spares the extraocular muscles and has no consistent ocular manifestations. Several cases of polymyositis with external ophthalmoplegia have been reported.43 Periocular skin and eyelids can be involved in dermatomyositis. The classic cutaneous lesions of dermatomyositis impart a lilac color to the skin, but nonspecific skin changes also occur with great regularity. Conjunctivitis, optic atrophy, retinitis, and pigmentary maculopathy are among the infrequent ocular complications of dermatomyositis.44–47

There is no pathophysiologic association between polymyositis and orbital myositis. These two conditions share a common descriptive name but are otherwise clinically distinct from one another. Orbital myositis is a form of inflammatory pseudotumor that selectively involves the extraocular muscles. Its pathogenesis is poorly understood and typically presents with orbital pain, limitation of ocular motility, and some degree of proptosis.

Inflammatory myopathy can also be a manifestation of scleroderma, Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease, and Behçet's disease.

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The mechanisms by which drugs lead to muscle dysfunction are diverse and often unknown.48,49 The drug-induced neuroleptic malignant syndrome is characterized by muscle rigidity, hyperthermia, altered mental status, and autonomic dysfunction.50 The neuroleptic malignant syndrome shares many features with MH, from which it must be distinguished. Disorders of ocular motility can occur in the neuroleptic malignant syndrome and usually consist of tonic deviation of the eyes in an upward direction. Oculogyric crisis of this nature can last from minutes to hours. The drug groups most commonly implicated with the neuroleptic malignant syndrome include phenothiazines, butyrophenones, and thioxanthenes. These drugs do not have to be taken in unusually high doses to trigger the syndrome; most cases develop in persons who are taking therapeutic doses. Overall mortality is nearly 20%.

Corticosteroids, ethanol, chloroquine, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are several of many drugs that are capable of causing myopathic injury and that can potentially affect the eye. The pathogenesis of drug-induced neuromuscular disease is diverse and beyond the scope of this review.48


On rare occasions, a systemic, blood-borne infection can secondarily involve an extraocular muscle leading to limitation of gaze, proptosis, or signs of orbital inflammation. Viral myopathies resulting from coxsackievirus A and B and influenza cause myopathies but usually do not affect extraocular muscles. The prototype infectious myopathy is caused by Trichinella spiralis, a nematode acquired from ingesting meat with encysted larvae. Cysts are ingested when raw or undercooked pork (or bear meat, in some areas) is eaten. Larvae liberated from the cyst migrate into the intestinal mucosa where they mature and reproduce. New larvae discharged from the female get into the vascular system and become disseminated throughout the body. The larvae enter skeletal muscle and encyst within 3 weeks and can exist in this stage for 5 to 10 years. The extraocular muscles are among the more common sites of involvement. Once in the muscle they cause degeneration of fibers. The severity and clinical findings depend on the burden of organisms and their muscular distribution. The disease is suspected by clinical findings and an eosinophilic leukocytosis, which is characteristic in the early stages of infection. Serologic conversion occurs after 3 or more weeks of infection. Biopsy of an involved muscle group or a random biopsy of the deltoid or gastrocnemius can demonstrate the organism. Old cysts become calcified. Ocular manifestations include conjunctival edema near the insertion of muscles, pain with eye movement, proptosis, and diplopia.51 Optic neuropathy and retinopathy can occur. Treatment consists of thiabendazole, once an infection has been verified.

Lyme disease may present with myositis. The disease is suspected based on potential exposure to the Ixodes tick vector and other findings such as erythema migrans, flu-like syndrome, and relapsing migratory arthritis. A variety of ocular abnormalities have been associated with Lyme disease from keratitis to optic neuropathy.52

A wide spectrum of infectious agents can cause myositis and also affect the eye and other parts of the visual pathway (Table 1). These microorganisms and their diverse ocular manifestations are covered in other chapters.


Table 1. Infectious Causes of Myositis


  Human immunodeficiency virus (HIV)
  Herpes simplex
  Hepatitis B and C
  Epstein-Barr Virus
  Respiratory syncytial virus






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Acquired systemic muscle disease affecting the eye consists of a variety of unrelated disorders, many of which have an inherited basis. Their ocular manifestations are diverse and include many findings besides disturbances in ocular motility. Although many patients have existent systemic disease when they are seen by ophthalmologists, some patients can initially present with symptoms referable to the eye or ocular adnexa. Surgeons need to be aware of MH and understand the role of preoperative screening for this disorder.
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