Ocular Manifestations of Acquired Muscle Disease



Ocular Manifestations of Acquired Muscle Disease


Curtis E. Margo

Don B. Smith



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.


MYOTONIC DYSTROPHY

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

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.


MUSCULAR DYSTROPHIES

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


OCULOPHARYNGEAL MUSCULAR DYSTROPHY

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.


DISORDER OF MEMBRANE CHANNELS

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

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

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Jul 11, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on Ocular Manifestations of Acquired Muscle Disease

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