Chapter 201 – Ocular Myopathies
RICHARD M. RUBIN
ALFREDO A. SADUN
• Pathology of the extraocular muscles that results in ophthalmoplegia and other disorders of ocular motility.
• Limitations of motility.
• Acquired and of known mechanism (Graves’ disease).
• Acquired and consequent to other processes (certain forms of myositis).
• Congenital but may not manifest until late adulthood (mitochondrial).
Diseases that involve metabolic abnormalities, atrophy, infiltration, or inflammation of the ocular muscles may appear as weakness or restriction. Except for Graves’ dysthyroid ophthalmopathy, most of these conditions are uncommon or rare. Graves’ dysthyroid ophthalmopathy, orbital myositis, and infiltrative myopathies are covered in Part 11 , and other orbital diseases and trauma that may cause restrictive eye syndromes are discussed in Chapters 95 and 96 . The four sections of this chapter independently cover mitochondrial myopathies, dystrophic myopathies, Graves’ dysthyroid ophthalmopathy, and other inflammatory and infiltrative myopathies.
EPIDEMIOLOGY AND PATHOGENESIS
Mitochondria are cytoplasmic organelles that produce energy for cell functions, maintenance, repair, and growth through the enzymatic processes of oxidative phosphorylation. A group of neurodegenerative and myopathic syndromes result from disorders of mitochondrial metabolism that cause defects in the energy cycle of susceptible tissues. For reasons that remain unclear, the tissues most reliant on mitochondrial energy are those of the central nervous system, heart, muscles, kidneys, and endocrine organs. Hence, these tissues are most likely to show various clinical manifestations of mitochondrial dysfunction.
Each mitochondrion possesses 2–10 mitochondrial DNA genomes made up of a closed circle of 16,569 nucleotide base pairs. The mitochondrial DNA encodes for 13 polypeptides essential in oxidative phosphorylation and for ribosomal and transfer ribonucleic acids essential in the production of mitochondrial proteins. Nuclear DNA encodes for an additional 56 subunits of the electron transport chain and for genes required for replication, transcription, and translation of the mitochondrial genes.
Mitochondrial DNA has unique genetics for several reasons, which include its cytoplasmic location and the multiple DNA copies that exist in each cell. Mitochondrial DNA is inherited maternally because it is transmitted via oocyte cytoplasm. In addition, new mutations often result in heteroplasmy, a mixed intracellular population of normal and mutant DNA molecules. Also, multiple random and asymmetrical mitochondrial divisions lead to replicative segregation and eventually homoplasmy, such that each cell possesses only pure mutant mitochondrial DNA. Thus, the relative proportion of normal and mutant mitochondrial DNA may vary from cell to cell and from individual to individual.
The variable phenotypic expressions of mitochondrial dysfunction likely arise from interplay of the unique features of mitochondrial inheritance that cause heteroplasmy and homoplasmy, the modifying contribution of nuclear DNA under the influence of mendelian genetics, the deterioration of mitochondrial function with aging, and the different energy requirements of specific tissues.
The most common mitochondrial disorder to affect muscles is chronic progressive external ophthalmoplegia (CPEO) and its best known subtype, Kearns–Sayre syndrome. Less common mitochondrial myopathies of ophthalmic importance include mitochondrial encephalopathy with lactic acidosis and stroke-like syndrome (MELAS), myoclonic epilepsy with ragged red fibers (MERRF, Fukuhara’s syndrome), and mitochondrial neurogastrointestinal encephalopathy. 
Mitochondrial disorders that affect tissues other than muscle during early childhood include Alpers’ disease, Menkes’ disease, and Leigh’s disease; one that manifests later in life is Leber’s hereditary optic neuropathy (LHON).
Patients who have CPEO often exhibit initial bilateral ptosis followed by limitation of ductions in all directions and marked delay of saccades. Downward gaze may be spared until late in the disease course. Curiously, despite ocular misalignment, these patients rarely complain of diplopia. Weakness of the orbicularis oculi and facial muscles is found commonly, and pigmentary retinopathy may be associated.
Kearns–Sayre syndrome, in particular, is characterized by the triad of external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction block during the first or second decade of life (early-onset CPEO). Peripapillary pigment atrophy and salt-and-pepper retinal pigment epithelial changes are most striking in the macula. True bone spicule pigmentary retinopathy as seen in retinitis pigmentosa is not typical in Kearns–Sayre syndrome.
The MELAS syndrome manifests with ptosis and external ophthalmoplegia, in addition to the commonly associated visual disturbances, which may include hemianopia or cortical blindness. Eventually, MERRF develops into progressive optic atrophy.
The possibility of muscle disease should be considered whenever ophthalmoplegia does not correspond to the pattern of a cranial nerve palsy and when there is acquired ptosis. Most diagnoses are made through a process of exclusion and imaging studies.
Diagnoses of mitochondrial disorders often are supported by histopathological and biochemical evidence of mitochondrial dysfunction. Specific identification of an enzyme defect may confirm the diagnosis. Generally, to show abnormalities in patients who have mitochondrial cytopathies, substrates of oxidative phosphorylation from serum and cerebrospinal fluid (CSF), which include glucose, lactate, and pyruvate, and the pH of venous blood during fasting all are measured. Elevation of CSF protein levels also may help in the diagnosis of CPEO and MELAS syndrome.
Electrocardiograms should be obtained for all patients suspected of mitochondrial cytopathies, to detect any life-threatening cardiac conduction abnormalities. Neuroimaging may help in the assessment for other causes of neurological deficits. In CPEO, magnetic resonance imaging (MRI) of the brain often shows hyperintensity in the thalamus and globus pallidus on T2-weighted images. Kearns–Sayre syndrome was shown in one case to have MRI findings indistinguishable from those of multiple sclerosis. Posterior cerebral cortical abnormalities that correspond to focal neurological deficits commonly are found on neuroimaging in MELAS syndrome.
Genetic analysis for mitochondrial DNA mutations from blood leukocytes or muscle biopsy may show a characteristic mutation in MELAS syndrome. Poor correlation exists between specific mitochondrial DNA mutations and CPEO, because CPEO may exhibit a clinical picture related to a final common pathway of impaired mitochondrial energy production in muscle from a variety of mutations. Diseases of glycolipid metabolism, lysosomal or glycogen storage, peroxisome dysfunction, and acquired viral, toxic, and endocrine myopathies and encephalopathies also must be ruled out. Electromyography helps to differentiate myopathic from neuropathic causes of muscle weakness.
Systemic findings of CPEO include short stature, peripheral neuropathy, ataxia, spasticity, somatic muscle weakness, vestibular dysfunction, and deafness.  Lactic acidosis is found often because of defective aerobic metabolism. Abnormalities of cardiac conduction and of the central nervous system, which include cerebellar dysfunction and elevated CSF protein exceeding 100?mg/dl, are associated with Kearns–Sayre syndrome. The cardiac conduction disturbances have an onset typically 10 years after ptosis appears and may result in sudden death. Endocrine dysfunction may include hypoparathyroidism, diabetes mellitus, hypogonadism, or growth hormone deficiency. In CPEO and Kearns–Sayre syndrome, the brain eventually may undergo spongiform degeneration, with the clinical picture of dementia. Basal ganglia calcifications may occur.
The association of progressive ophthalmoplegia with peripheral neuropathy, leukoencephalopathy, and gastrointestinal dysmotility in mitochondrial disease has been reported. It is likely that additional multiorgan system, mitochondrial syndromes will be elucidated.
Seizures, vomiting, lactic acidosis, episodes of hemiparesis, and stroke-like events during childhood or early adulthood characterize MELAS. Although partial recovery from these stroke-like episodes is the rule, severe neurological damage eventually results. Typically, MERRF occurs during the second decade of life with myoclonus, followed by ataxia, weakness, and seizures.
Biopsy of skeletal muscle reveals “ragged red fibers” that stain red or purple using a modified Gomori trichrome stain ( Fig. 201-1 ). The mitochondria of the involved muscle fibers are concentrated peripherally and may show increased staining for the mitochondrial enzyme succinate dehydrogenase. Biochemical abnormalities of oxidative phosphorylation, such as patchy cytochrome-c oxidase deficiency, may be detected by muscle biopsies, as well.
The ultrastructural appearances of skeletal muscle mitochondria are varied and may show enlarged mitochondria that contain crystal-like inclusions; changes in the number, shape, or regularity of cristae; or emptiness, vacuolization, or triglyceride accumulation within mitochondria ( Fig. 201-2 ). The mitochondria often are increased in number and size. Such morphological changes are not necessarily unique and may be found in other muscle disorders, such as the muscular dystrophies or polymyositis. Histopathologically, the retinal findings in Kearns–Sayre syndrome suggest retinal pigment epithelial dysfunction rather than photoreceptor disease.
Coenzyme Q10, essential for normal mitochondrial function and deficient in a proportion of patients who have CPEO and Kearns–Sayre syndrome, administration has been associated with improved exercise tolerance, cardiac function, and ataxia in some patients with Kearns–Sayre syndrome. Other treatments, such as thiamine, also aim to bypass or enhance oxidative phosphorylation
Figure 201-1 MELAS syndrome. A, Complete external ophthalmoplegia in a 20-year-old woman. B, Microscopic section of degenerated extraocular muscles stained with trichrome shows “ragged red fibers.” (Case presented by Dr. R. Folberg, Verhoeff Society, 1993, and reported by Rummelt V, et al. Ophthalmology. 1993;100:1757.)
Figure 201-2 Viewed with an electron microscope, the abnormal mitochondria in a case of chronic progressive external ophthalmoplegia shown as electron dense and globular. The normal arrangement of cristae is not seen.
but only occasionally have been shown to improve exercise tolerance, cardiac conduction, or lactic acidosis. However, coenzyme Q10 and these other treatments do not improve the ophthalmoplegia, retinopathy, or ptosis in patients who have CPEO or Kearns–Sayre syndrome.
Complaints that arise from ptosis often are handled by ptosis crutches or a careful surgical approach, in which the lid is raised minimally by addressing the visual obstruction rather than the cosmetic appearance. Overly aggressive attempts to treat the ptosis may result in exposure keratopathy and corneal ulceration because of weak orbicularis oculi muscles and a poor Bell’s reflex. Symptomatic ocular deviations may be treated successfully with strabismus surgery.
Periodic evaluation by a cardiologist is indicated in Kearns–Sayre syndrome. In some instances, placement of a pacemaker for prophylactic pacing or for treatment of symptomatic cardiac block is necessary to prevent sudden death. The systemic use of corticosteroids is contraindicated in Kearns–Sayre syndrome because of the possible precipitation of coma and death from hyperglycemic acidosis.  Genetic counseling should be offered to all patients who have mitochondrial cytopathies.
COURSE AND OUTCOMES
Chronic progressive external ophthalmoplegia is a slowly progressive loss of lid and extraocular motor function. The diplopia may or may not worsen, because the symmetry of the ophthalmoplegia may prevent strabismus. However, small ptosis correction may be required as described above. In severe cases that have more generalized manifestations, such as in Kearns–Sayre syndrome, retinopathy and cardiac problems may develop. Patients who have MELAS and MERRF may develop several neurological deficits, which include ataxia, weakness, and seizures.
EPIDEMIOLOGY AND PATHOGENESIS
Three forms of muscular dystrophy of ophthalmologic importance exist, all of which involve progressive weakness of the skeletal muscles. Myotonic dystrophy, like the other three forms, involves difficulties with relaxation of skeletal muscles after contraction. Myotonic dystrophy is an autosomal dominant condition in which the first symptoms usually appear during the teenage years or in young adulthood. Several large pedigrees have been identified.
Oculopharyngeal dystrophy usually develops a little later, in young or middle-aged adults. The first symptoms often are difficulty
Figure 201-3 Slit-lamp view of a “Christmas tree” cataract in myotonic dystrophy. Note the iridescent or colored refractile flecks (arrow).
in swallowing, with ptosis later. A large French Canadian autosomal dominant pedigree has been identified, in which the original ancestor immigrated to Quebec in 1634.  Autosomal recessive and sporadic inheritances also have been reported.
Fukuyama’s syndrome (MERRF) is an autosomal recessive condition most often found in people of Japanese descent. Unlike the other two forms above, in Fukuyama’s syndrome the manifestations and death occur in early childhood.
In myotonic dystrophy, abnormalities in the extraocular muscles are accompanied by involvement of other muscles, which include the levator, and result in slowly progressive bilateral ptosis. Other ocular findings include cataracts, described as Christmas tree cataracts ( Fig. 201-3 ) for their multiple refractile colors.
In oculopharyngeal dystrophy, dysphagia is followed soon by bilateral ptosis which, over a period of years, is followed by external ophthalmoplegia and weakness of the orbicularis. The patient, despite a remarkable lack of ocular motility, may not complain of diplopia, because often the limitations of eye movement are very symmetrical so that no strabismus occurs.
In Fukuyama’s syndrome, in addition to the weakness of the orbicularis and a strabismus, nystagmus, anterior polar cataracts, optic nerve atrophy, and a chorioretinal degeneration with retinoschisis or detachment occur, also.
The electromyogram, with characteristic spontaneous, high-frequency bursts, is diagnostic for all forms of dystrophic myotonias. Furthermore, all dystrophic myotonias are evident clinically by blepharospasm or the inability of the patient to open the eyes after they have been forcibly closed for some time. Only myotonic dystrophy has intraocular findings such as the Christmas tree cataract (see Fig. 201-3 ). Both myotonic dystrophy and oculopharyngeal dystrophy have external ophthalmoplegia, but Fukuyama’s syndrome does not. In all three dystrophies, biopsy reveals characteristic histopathology.
In myotonic dystrophy, involvement of the muscles of the head and neck gives the characteristic narrow, drawn facial appearance or “hatchet facies” ( Fig. 201-4 ). Involvement of the cardiac muscles may result in congestive heart failure. Dysphagia, constipation, and incontinence are not uncommon. In some cases mental retardation occurs, and in males testicular atrophy and premature baldness are frequent. In oculopharyngeal dystrophy,
Figure 201-4 Front view of a patient who has myotonic dystrophy. The muscle wasting gives the characteristic drawn appearance of “hatchet facies.”
the bulbar musculature is affected frequently and temporalis wasting occurs. Patients have difficulty swallowing without aspirating. Other bulbar and limb girdle muscles become involved later. In Fukuyama’s syndrome, the proximal muscle groups are involved most. Mental retardation, seizures, severe motor development delay, and cortical blindness are common.
In myotonic dystrophy, findings from histopathological examination of the extraocular muscles are similar to those seen in the skeletal muscles. Down the centers of muscle fibers run rows of nuclei. The myofilaments and sarcoplasmic reticulum are disrupted, and accumulations of impaired mitochondria may be found. In oculopharyngeal dystrophy, tubulofilamentous intranuclear inclusion bodies are seen on ultrastructural examination of muscle biopsies. In Fukuyama’s syndrome, the same changes are seen, confined largely to the proximal muscle groups.
For all three muscular dystrophies, treatment consists of symptomatic support. The cataracts of myotonic dystrophy may be removed. Foot braces and other devices are available to help support footdrop or other skeletal muscle weakness. All patients affected by dystrophic myopathies need to be referred to neurologists.
COURSE AND OUTCOMES
Progressive atrophy of the skeletal muscles leads to a variety of systemic difficulties. In myotonic dystrophy the patient develops difficulty climbing stairs and, eventually, even with walking and holding the head up. Vision may be maintained after cataract surgery. In oculopharyngeal dystrophy, dysphagia is most problematic.
GRAVES’ DYSTHYROID OPHTHALMOPATHY
EPIDEMIOLOGY AND PATHOGENESIS
Graves’ dysthyroid ophthalmopathy is the most common cause of exophthalmos—it probably accounts for more than 50% of cases. Prevalence, although uncertain, has been estimated in studies in the United States at 0.4% and in the United Kingdom at 1.1–1.6%. Women are affected 3–10 times more frequently than men. The mean age of appearance for Graves’ thyroid disease is 41 years, and the orbital disease occurs an average of 2.5 years afterward. Even though the disease is more common in women, the severity of disease tends to be greater in men and in patients above 50 years of age.
Graves’ ophthalmopathy is presumed to result from autoimmune processes that include extraocular muscle myositis, fibroblast proliferation, glycosaminoglycan overproduction, and orbital congestion. Both humoral and cell-mediated immune mechanisms have been implicated. The hyperthyroidism in Graves’ disease may run an independent course and has been attributed to stimulation of thyrotropin receptors on the thyroid cell plasma membrane by immunoglobulin. These thyroid-stimulating immunoglobulins (previously called long-acting thyroid stimulator proteins) are demonstrable in 50% of patients who have active Graves’ disease. However, orbital changes have not been found to occur directly in response to these thyroid-stimulating antibodies. Other immunoglobulins have been identified in the stimulation of collagen synthesis by fibroblasts and myoblast proliferation, although it remains uncertain whether these antibodies are primarily pathogenic or occur secondarily because of local inflammatory processes.
Immunohistochemical analysis and histological findings have shown orbital infiltration with mononuclear cells sensitized to retro-orbital antigens. Abnormal helper-to-suppressor T-cell ratios and reductions in the number of T-suppressor cells are thought to be associated with a proliferation of B lymphocytes that produce autoantibodies directed against the orbital tissues. The expression of immunomodulatory proteins, such as histocompatibility antigen molecules, intercellular adhesion molecules, and heat-shock proteins, may play a role in the presentation and recognition of antigenic epitopes specific to orbital and thyroid tissues. Cytokines released by the infiltrating monocytes may stimulate immunomodulatory protein expression, glycosaminoglycan production, and proliferative activity from orbital fibroblasts. Site-specific differences between orbital and pretibial fibroblasts from fibroblasts in other locations may explain why connective tissue involvement in Graves’ disease is limited largely to the orbital and pretibial regions. Orbital venous congestion also has been suggested to contribute significantly to the pathogenesis of many of the clinical findings of Graves’ ophthalmopathy.
Both genetic and environmental risk factors have been identified, which may predispose toward or act as triggers for the abnormal autoimmune disturbance in Graves’ disease. Population studies show linkage to certain histocompatibility antigens, which include HLA-B8 and HLA-DR3 in Caucasian, HLA-BW46 in Chinese, and HLA-BW35 in Japanese patients. Environmental factors such as stress, smoking, and infection with certain gram-negative organisms (e.g., Yersinia enterocolitica) may increase the risk or severity of Graves’ ophthalmopathy.
The eye manifestations of Graves’ ophthalmopathy typically are self-limited. An active phase of inflammation and progression tends to stabilize spontaneously 8–36 months after onset. Initial symptoms of Graves’ ophthalmopathy may be complaints of foreign-body sensation, tearing, or photophobia, often accompanied by signs that include lid retraction, lid lag, lagophthalmos, prominence of the episcleral vessels over the horizontal rectus muscles, and lid edema ( Fig. 201-5 , A). Exophthalmos reflects an increase in soft tissue mass within the bony orbit and may result from enlargement of the extraocular muscles or increased orbital fat volume ( Fig. 201-5 , B). Exophthalmos is almost always bilateral and usually relatively symmetrical. Attempts to push the globe back into the orbit (retropulsion) typically are met with firm resistance because of the inflammatory orbital changes that preclude displacement of the fat.
Figure 201-5 Graves’ disease. A, In Graves’ disease, exophthalmos often looks more pronounced than it actually is because of the extreme lid retraction that may occur. This patient, for instance, had minimal proptosis of the left eye but marked lid retraction. B, A histological section shows both fluid and inflammatory cells separating the muscle bundles. The inflammatory cells are predominantly lymphocytes, plus plasma cells. (A, Courtesy of Shaffer DB. In Yanoff M, Fine BS. Ocular Pathology, 4th ed. London, Mosby, 1996.)
Limitation of ocular motility is the direct consequence of pathological changes that affect the extraocular muscles. The inferior rectus muscle is involved most commonly, followed by the medial rectus and the superior rectus. Clinical complaints associated most frequently with muscle restriction are nontorsional, vertical, or oblique diplopia, which may be noticed only on awakening. Patients often are bothered by the feeling of orbital fullness and the pulling sensation experienced on gaze away from a restricted muscle. Also, increased intraocular pressure may occur on gaze in the opposite direction of the restricted muscle. In particular, this is seen on upgaze with inferior rectus restriction.
Patients with Graves’ disease may have sore eyes from exposure keratopathy or superior limbic keratitis. Dry eye is common because of disturbances in tear quantity and, especially, tear film constitution, as well as because of the increased exposure. Acute disease is associated with conjunctival and periorbital edema. With quiescence of the disease, the swelling may reduce, although motility disturbances and exophthalmos tend to remain. Optic nerve involvement also may occur because of compression of the optic nerve at the orbital apex by the enlarged muscles ( Fig. 201-6 ). This is more likely to be associated with superior rectus enlargement and no gross exophthalmos (which is a form of self-decompression). Optic nerve compression may be associated with decreasing visual acuity, color loss, afferent pupillary defect, and visual field loss. On examination, the optic disc may be swollen, normal, or atrophic.
In 1969, Werner proposed the “NO SPECS” classification for signs of Graves’ ophthalmopathy. In 1981, Van Dyke refined the class 2 NO SPECS soft tissue findings with the mnemonic RELIEF ( Table 201-1 ). Although the mnemonics help to remember the manifestations of Graves’ disease, not uncommonly, the order of signs and symptoms does not follow the order
Figure 201-6 Fundus view of a case of Graves’ ophthalmopathy. The patient was losing vision as a consequence of optic neuropathy. Note the congested appearance of the optic nerve head. (Courtesy of Dr. S. Feldon.)
TABLE 201-1 — “NO SPECS” AND “RELIEF” CATEGORIZATION OF GRAVES’ DISEASE
No signs nor symptoms
Only signs are upper eyelid retraction, lid lag, stare
Soft tissue signs and symptoms:
• Resistance to retropulsion
• Edema of conjunctiva and caruncle
• Lacrimal gland enlargement
• Injection over the horizontal rectus muscle insertions
• Edema of the eyelids
• Fullness of the eyelids
Extraocular muscle involvement
Corneal involvement secondary to exposure
Sight loss secondary to optic nerve compression
of the classification but consists of combinations of findings from various classes.
In 1995, Bartley and Gorman proposed diagnostic criteria for Graves’ ophthalmopathy as eyelid retraction with objective thyroid dysfunction, or either eyelid retraction or objective thyroid dysfunction in association with exophthalmos, optic neuropathy, or extraocular muscle involvement. The clinical signs must not be attributable to other causes.
In Graves’ ophthalmopathy, muscle tendons are relatively spared on computed tomography (CT) scan ( Fig. 201-7 ; see Fig. 193-2 ).  The non–contrast-enhanced coronal orbital CT scan is most helpful in the assessment of the size of the extraocular muscles. Bilateral enlargement is strongly suggestive of thyroid ophthalmopathy, even when the thyroid function study results are normal.
The differential diagnosis includes orbital tumors, which may be primary (hemangioma, meningioma, glioma, lymphoma) or metastatic (breast, lung, colon, prostate), as discussed in Chapter 206 . The distinction from Graves’ ophthalmopathy usually is apparent, both by the lid findings (such as lid lag) characteristic of Graves’ ophthalmopathy and by the distinct neuroimages
Figure 201-7 Computed tomography scan of the orbit in a case of Graves’ ophthalmopathy. Note the enlarged muscles (medial recti more than lateral recti). (Courtesy of Dr. M. Yanoff.)
Figure 201-8 Ultrasonographic image (“B” scan) of the orbit in a case of Graves’ ophthalmopathy. Two enlarged muscles (dark shadows) are seen behind the globe. (Courtesy of Dr. S. Feldon.)
of orbital tumors. One exception may be lymphoma, which may be differentiated by its propensity to involve the lacrimal gland and by its lack of clinical manifestations.
Orbital inflammations, such as orbital pseudotumor, may be more difficult to differentiate. However, ultrasonography ( Fig. 201-8 ) and CT may be used to note the sparing of the muscle tendons seen only in Graves’ ophthalmopathy. Furthermore, ultrasonography may be used to distinguish the characteristic, widely separated, and fairly high-amplitude spikes seen in Graves’ ophthalmopathy ( FIG. 201-9 ) from those found in diseases such as orbital myositis. Neuroimaging and possibly biopsy of nasal mucosa may help to exclude diseases such as Wegener’s granulomatosis. Scanning also helps to differentiate orbital infections, such as preseptal or orbital cellulitis; however, the classic clinical characteristics of infections must be recognized ( Chapter 206 ). The orbital congestion consequent to carotid–cavernous sinus or dural shunt fistulae also may be differentiated clinically (they do not produce an increase in orbital resistance to retropositus nor lid lag) and particularly by MRI.
Ophthalmopathy is clinically evident in 25–50% of patients with Graves’ hyperthyroidism. Occasionally, Graves’ ophthalmopathy occurs in patients affected by Hashimoto’s thyroiditis
Figure 201-9 Ultrasonographic image (“A” scan) of the orbit in a case of Graves’ ophthalmopathy. Note the high-amplitude spikes characteristic of such muscles. (Courtesy of Dr. S. Feldon.)
or in patients who have no evidence of thyroid disease. Thyroid hormone levels may be elevated, normal, or even low. Although unnecessary to confirm a diagnosis of Graves’ ophthalmopathy, measurements of tri-iodothyronine, thyroxine, and thyroid-stimulating hormone levels are performed.
Systemic manifestations of Graves’ disease may include nervousness, emotional lability, tremor, weakness, fatigue, heat intolerance, sweating, dyspnea, palpitations, goiter, leg swelling, increased appetite, weight loss, and hair thinning.
Generally, as in other forms of inflammatory myositis, the early histopathology in Graves’ ophthalmopathy consists of inflammatory cell infiltration, mucopolysaccharide deposition, and increased water content. In the later stages, the muscles undergo atrophy and fibrosis (see Fig. 201-5 , B). These changes are associated with enlargement of the extraocular muscles and relative sparing of the tendinous insertions. More particularly, the cellular infiltrate is hypocellular and polymorphous, and consists primarily of mature lymphocytes, plasma cells, and macrophages.
The management of Graves’ ophthalmopathy is largely independent of the management of the concomitant endocrinopathy. Such patients require at least two specialists to manage both aspects of the disease. The short-term goal of therapy in Graves’ ophthalmopathy is to conserve useful vision, which may mean the provision of artificial tears or improvement of lid coverage for an exposed cornea. In rare cases, it may mean the treatment of Graves’ optic neuropathy (see Fig. 201-6 ). The long-term goal of therapy is restoration of the orbital anatomy. If possible, this should entail postponement of reconstructive surgery until lack of progression has been established. In general, several tools exist in the management of Graves’ ophthalmopathy.
The use of corticosteroids in Graves’ ophthalmopathy is controversial. Without question, an immediate benefit occurs, but this seems to decay with time.  Hence, many investigators believe that corticosteroids should be reserved for use in patients who have optic neuropathy, and in such cases are given in large dosages (over 100?mg prednisone per day).
Radiation as a nonspecific immunosuppressant does lead to improvement in Graves’ ophthalmopathy. However, the effect may take a few months to maximize, and in the interim visual loss from an optic neuropathy may become permanent. Complications (short and very long term) arise from radiation
therapy that suggest it should not be employed except in cases of optic neuropathy. Some investigators use radiation therapy in cases of severe visual loss from an optic neuropathy in conjunction with corticosteroids.
Immunosuppressant agents such as azathioprine or cyclophosphamide have been advocated. The combined use of prednisone and cyclosporine has been suggested as well.
The common surface problems of ocular irritation, foreign-body sensation, and tearing usually are treated best with artificial tears and other lubricants. However, eyelid surgery for severe lid retraction is also of benefit.
Diplopia may be managed early with spectacle prisms. However, the variable nature of Graves’ ophthalmopathy-induced diplopia and its noncomitance make prism use, Fresnel as well as standard, ineffectual. Eventually, most patients who have diplopia require strabismus surgery. The most frequent procedure is a recession of the inferior rectus muscle to compensate for restriction.
Surgery also is an option to address the common problems of exophthalmos and lid retraction. Some investigators, however, argue that orbital decompression surgery be reserved for cases that involve optic neuropathy, because this type of surgery carries a higher risk than the strabismus or lid surgeries described above, and the cosmetic problem can be addressed, at least partly, with combined upper and lower lid and lateral canthoplasty procedures. Orbital decompression may be performed from lateral, medial, and floor approaches (or combinations). Surgical decompression is reserved for when the patient does not respond to medical treatment. However, the optic neuropathy of Graves’ ophthalmopathy can be serious, and the clinician must be prepared to identify the problem at the earliest stage and approach it by medical, surgical, or radiation therapy.
COURSE AND OUTCOMES
As described above, most cases of Graves’ ophthalmopathy stabilize or even regress partially within 8–36 months. Once stable, the condition is reviewed for the need for additional surgery. Most patients do well, but may continue to complain of dry eye symptoms and require the continued use of artificial tears.
OTHER INFLAMMATORY AND INFILTRATIVE MYOPATHIES
EPIDEMIOLOGY AND PATHOGENESIS
The most common cause of primary muscle dysfunction is inflammation. Inflammation or secondary ischemia related to swelling (tissue compartment syndrome) may lead to fibrosis and scarring within an extraocular muscle. Orbital congestion may cause a restrictive component. Such orbital inflammation, or orbital pseudotumor, is usually idiopathic, although the cause may sometimes be determined.
Idiopathic orbital myositis refers to nonspecific orbital inflammation. However, a variety of conditions, such as Crohn’s disease, or more localized diseases, such as sinusitis and asthma, have been reported to incite an attack of orbital myositis. This orbital inflammation may extend anteriorly to involve the posterior globe (posterior scleritis) or lacrimal gland (dacryoadenitis), or posteriorly as an orbital apex syndrome. When orbital pseudotumor involves primarily the muscles (myositis), it tends to occur unilaterally (although bilateral involvement may occur up to 25% of the time) in young adults, with women involved more frequently than men. A variety of granulomatous, infectious, neoplastic, and vasculitic disorders may masquerade as myositis, also.
Infectious myositis may result from trichinosis, but more commonly the cause is never determined. Orbital cellulitis may be bacterial and originate from the paranasal sinuses, or fungal in association with metabolic acidosis or diabetes mellitus.
Myositis may be associated with systemic or distant inflammatory disease such as Crohn’s disease. Other inflammatory syndromes, such as Wegener’s granulomatosis and giant cell arteritis, also may affect the extraocular muscles directly.
Amyloidosis and Infiltrative Myopathies
Other infiltrative processes (amyloidosis and lymphoma) may limit extraocular muscle relaxation. Neoplasms may extend locally into or metastasize directly to a muscle.
Idiopathic and other forms of orbital inflammatory disease or orbital pseudotumor (orbital myositis) are associated with significant extraocular muscle involvement.  The myositis may be isolated to a single muscle, but most often it affects several. Even though the disease process often is bilateral, most often symptoms are reported as unilateral and typically include some degree of discomfort in almost all patients. The pain often is most severe when ductions away from the most affected muscle are attempted. Patients also frequently experience gaze-evoked diplopia. Local orbital signs such as exophthalmos and injection are common. Children are more apt to have bilateral orbital involvement, may develop spontaneous orbital hemorrhage, and are less likely to have an associated systemic disease.
In orbital myositis, the involved extraocular muscle usually is enlarged on orbital imaging. Enhancement of the muscle, and particularly its insertion into the globe, may help to separate myositis from thyroid ophthalmopathy. Crohn’s disease, vasculitis, serum sickness, herpes zoster, sarcoidosis, Lyme’s disease, and trichinosis all are considered part of the review of systems and investigated by special studies. The diagnosis of orbital pseudotumor or idiopathic orbital myositis is one of exclusion and can be made only after the appropriate investigations have been carried out, as described above. If a meticulous history and physical examination are followed by appropriate studies, which include orbital imaging, and no diagnosis can be confirmed, tissue biopsy is usually considered. In many cases, the clinical picture is sufficiently clear and a trial of glucocorticoids may be initiated, but often an orbital biopsy is indicated, especially if the orbital inflammation is refractory to glucocorticoids or returns after the glucocorticoids have been tapered.
An unclear relationship exists between idiopathic orbital pseudotumor, or orbital myositis, and paranasal sinus disease, sinusitis, or even a concomitant upper respiratory infection. Systemic conditions associated with myositis include trichinosis, tuberculosis, aspergillosis, Lyme’s disease, and other infections, distant inflammatory disease such as Crohn’s disease, sarcoidosis, amyloidosis, acromegaly, POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome, and lithium therapy.
In addition to the general changes described above, various specific causes of myositis have their own characteristic histopathological features. For example, in cases of foreign bodies, granulomatous inflammation with multinucleated giant cells are found. Polymorphonuclear leukocytes are seen in association with various infections. Eosinophilic infiltration is seen in trichinosis.
In idiopathic orbital myositis, nonspecific and non-neoplastic inflammatory lesions occur in the orbit with diverse pathological appearances—most often they display a polymorphous,
chronic inflammatory infiltration. In chronic forms of idiopathic pseudotumor, large amounts of fibrovascular stroma also may be seen. The pathological differentiation between orbital pseudotumor, benign lymphoid hyperplasia, monomorphous lymphoid lesions, and malignant lymphoma may be difficult. Immunological cell markers and gene rearrangement studies can help in the differentiation of these entities. However, 15–20% of patients who have polyclonal cell markers eventually may develop a monoclonal malignant lymphoma.
In orbital myositis with plasma cell or lymphoproliferative infiltration an associated amyloidosis may occur. This amyloid shows on hematoxylin and eosin staining as an eosinophilic hyaline accumulation that often surrounds the blood vessels. It also may accumulate in round globules within the extraocular muscles.
In myositis, the issue often comes down to whether to treat with glucocorticoids. High-dose, daily glucocorticoids usually reverse the disease process effectively and eliminate the pain. Inadequate treatment may result in recurrence, but once the desired effect occurs, the glucocorticoids must be tapered slowly over several weeks or months and discontinued. Nonsteroidal anti-inflammatory drugs are less effective than glucocorticoids but have fewer side effects. In those patients who do not respond or who become glucocorticoid dependent, low-dose radiation therapy (2000?cGy) may induce a remission effectively. However, many inflammatory and infiltrative myopathies initially respond to such treatment, only to recur. Furthermore, treatment may not only obfuscate the natural history of the disease, but may make the diagnosis by biopsy more difficult. Hence, it often is prudent to complete the diagnostic workup, which includes orbital biopsy, prior to anti-inflammatory treatment.
COURSE AND OUTCOMES
Idiopathic orbital myositis usually responds very well to systemic glucocorticoids. In most cases, the diagnostic workup does not yield any causative factor and recurrences are not very common. Such patients do well and show no evidence of any ophthalmologic sequelae.
1. DiMauro S, Moraes CT. Mitochondrial encephalopathies. Arch Neurol. 1993; 50:1197–207.
2. Moraes CT, DiMauro S, Zeviani M, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns–Sayre syndrome. N Engl J Med. 1989;320:1293–9.
3. Holt IJ, Harding AE, Cooper JM, et al. Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. Ann Neurol. 1989;26:699–708.
4. Hirano M, Silvestri G, Blake DM, et al. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology. 1994;44:721–7.
5. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science. 1992;242:1427–30.
6. Fang W, Huang CC, Lee CC, et al. Ophthalmologic manifestation in MELAS syndrome. Arch Neurol. 1993;50:977–80.
7. Crisi G, Ferrari G, Merelli E, Cocconcelli P. Magnetic resonance imaging in a case of Kearns–Sayre syndrome confirmed by molecular analysis. Neuroradiology. 1994;36:37–8.
8. Drachman DA. Ophthalmoplegia plus. The neurodegenerative disorders associated with progressive external ophthalmoplegia. Arch Neurol. 1968;18:654–74.
9. Kearns TP. External ophthalmoplegia, pigmentary degeneration of the retina, and cardiomyopathy: a newly recognized syndrome. Trans Am Ophthalmol Soc. 1965;63:559–625.
10. Uncini A, Servidei, Silvestri G, et al. Ophthalmoplegia, demyelinating neuropathy, leukoencephalopathy, myopathy, and gastrointestinal dysfunction with multiple deletions of mitochondrial DNA: a mitochondrial multisystem disorder in search of a name. Muscle Nerve. 1994;17:667–74.
11. McKechnie NM, King M, Lee WR. Retinal pathology in the Kearns–Sayre syndrome. Br J Ophthalmol. 1985;69:63–9.
12. Goda S, Hamada T, Ishimoto S, et al. Clinical improvement after administration of coenzyme Q10 in a patient with mitochondrial encephalopathy. J Neurol. 1987;234:62–9.
13. Bachynski BN, Flynn JT, Rodrigues MM, et al. Hyperglycemic acidotic coma and death in Kearns–Sayre syndrome. Ophthalmology. 1986;93:391–6.
14. Johnson CC, Kuwabara T. Oculopharyngeal muscular dystrophy. Am J Ophthalmol. 1974;77:872–9.
15. Burian HM, Burns CA. Ocular changes in myotonic dystrophy. Am J Ophthalmol. 1967;63:22–34.
16. Tsutsumi A, Uchida Y, Osawa M, et al. Ocular findings in Fukuyama-type congenital muscular dystrophy. Brain Dev. 1989;11:413–9.
17. Kuwabara T, Lessell S. Electron microscopic study of extraocular muscles in myotonic dystrophy. Am J Ophthalmol. 1976;82:303–8.
18. Tumbridge WMG, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Wickham survey. Clin Endocrinol (Oxf). 1977;7:481–93.
19. Kendler DL, Lippa J, Rootman J. The initial clinical characteristics of Graves’ orbitopathy vary with age and sex. Arch Ophthalmol. 1993;111:197–201.
20. Bahn RS, Heufelder AE. Mechanisms of disease: pathogenesis of Graves’ ophthalmopathy. N Engl J Med. 1993;329:1468–75.
21. Saber E, McDonnell J, Zimmerman KM, et al. Extraocular muscle changes in experimental orbital venous stasis: some similarities to Graves’ orbitopathy. Graefes Arch Klin Exp Ophthalmol. 1996;234:331–6.
22. Levine MR, Tomsak RL, El-Toukhy E. Thyroid-related ophthalmopathy. Ophthalmol Clin North Am. 1996;9:645–58.
23. Prummel MF, Wiersinga WM. Smoking and risk of Graves’ disease. JAMA. 1993; 269:479–82.
24. Liu D, Feldon SE. Thyroid ophthalmopathy. Ophthalmol Clin North Am. 1992; 5:597–622.
25. Werner SC. Classification of the eye changes of Graves’ disease. Am J Ophthalmol. 1969;68:646–8.
26. Van Dyk HJ. Orbital Graves’ disease. A modification of the “NO SPECS” classification. Ophthalmology. 1981;88:479–83.
27. Bartley GB, Gorman CA. Diagnostic criteria for Graves’ ophthalmopathy. Am J Ophthalmol. 1995;119:792–5.
28. Trokel SL, Jakobiec FA. Correlation of CT scanning and pathologic features of ophthalmic Graves’ disease. Ophthalmology. 1981;88:553–64.
29. Kahaly G, Schrezenmeir J, Schweikert B, et al. Remission-maintaining effect of cyclosporin and endocrine ophthalmopathy. Transplant Proc. 1986;18:844–5.
30. Martinuzzi A, Sadun AA. Marginal myotomies of levator with lateral–tarsal canthoplasty in the treatment of Graves’ lid retraction. Ital J Ophthalmol. 1991;5: 23–9.
31. Bouree P, Bouvier JB, Passeron J, et al. Outbreak of trichinosis near Paris. BMJ. 1979;i:1047–9.
32. Pinchoff BS, Spahlinger DA, Bergstrom TJ, Sandall GS. Extraocular muscle involvement in Wegener’s granulomatosis. J Clin Neurol Ophthalmol. 1983; 3:163–8.
33. Katz B, Leja S, Melles RB, Press GA. Amyloid ophthalmoplegia: ophthalmoparesis secondary to primary systemic amyloidosis. J Clin Neurol Ophthalmol. 1988; 9:39–42.
34. Slamovits TL, Burde RM, Sedwick L, et al. Bumpy muscles. Surv Ophthalmol 1988; 33:189–99.
35. Kennerdell JS, Dresner SC. The nonspecific orbital inflammatory syndromes. Surv Ophthalmol. 1984;29:93–103.
36. Rootman J, Nugent R. The classification and management of acute orbital pseudotumors. Ophthalmology. 1982;89:1040–8.
37. Trokel SL, Hilal SK. Recognition and differential diagnosis of enlarged extraocular muscles in computed tomography. Am J Ophthalmol. 1979;87:503–12.