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Spider dystrophy as an ocular manifestation of myotonic dystrophy
Optometry (2010) 81, 188-193
Spider dystrophy as an ocular manifestation of myotonic dystrophy Amber C. Louprasong, O.D., Dennis J. Light, O.D., and Rebecca S. Diller, O.D. Dayton Veterans Affairs Medical Center, Dayton, Ohio.
KEYWORDS Myotonic dystrophy; Cataract; Hypotony; Extraocular muscle; Pigment pattern dystrophy; Spider dystrophy
Abstract BACKGROUND: Myotonic dystrophy is the most common adult-onset muscular dystrophy. It is an autosomal dominant inherited neuromuscular disease that is characterized by myotonia, muscle weakness, and atrophy. It affects multiple systems including skeletal muscular, gastrointestinal, cardiac, respiratory, central nervous, endocrine, and ocular. Ocular manifestations of myotonic dystrophy include cataract, ocular muscle changes, hypotony, and retinal pigmentary changes in the periphery or in the macula (known as pigment pattern dystrophy). This report presents and discusses the case of a pigmented pattern dystrophy known as spider dystrophy as an ocular manifestation of myotonic dystrophy. CASE REPORT: A 44-year-old man with myotonic dystrophy presented to the eye clinic for routine examination. Ocular history included previous bilateral cataract surgery and mild bilateral ptosis for the last ‘‘few years.’’ Dilated fundus examination was remarkable for bilateral macular pigmentary changes in an irregular ‘‘spider’’-shaped pattern. The patient was asymptomatic without decrease in vision or Amsler grid defects. Optical coherence tomography was normal. A retinal consult concurred with the diagnosis of spider dystrophy. Photo documentation was obtained, and the patient is being monitored annually. CONCLUSION: Pigmented pattern dystrophies, including spider dystrophy, have been associated with myotonic dystrophy. They are set apart from other retinal dystrophies because they rarely affect visual acuity, and the majority of patients are asymptomatic. Progression may lead to reduced vision and in rare cases choroidal neovascularization. Annual dilated examinations, photo documentation, optical coherence tomography, and home Amsler grid monitoring are recommended for follow-up care. Optometry 2010;81:188-193
Myotonic dystrophy, or dystrophia myotonica (DM), is an autosomal dominant genetic neuromuscular disease with variable penetrance.1 The prevalence is approximately 2.5 to 5.5 per 100,000, and the annual incidence is 1 in 8,000.2 Typical onset occurs in the second decade. Earlier diagnosis is associated with a more severe course.3 It affects multiple systems including skeletal muscular,
Corresponding author: Amber C. Louprasong, O.D., Dayton Veterans Affairs Medical Center, Optometry, 4100 West Third St., Dayton, Ohio 45428. E-mail: [email protected]
gastrointestinal, cardiac, respiratory, central nervous, endocrine, reproductive, and ocular.4 Ocular manifestations may be the initial presentation of myotonic dystrophy without other systemic involvement. The hallmark ocular finding is bilateral iridescent cataract affecting nearly 100% of all patients.1 Ocular muscle changes, hypotony, and peripheral retinal pigmentary changes have also been noted.1,5,6 A final presentation that may be overlooked is macular retinal pigmentary change known as pigmented pattern dystrophy. Pattern dystrophies are divided into subsets based on different unique clinical presentations. Their appearance separates them, but they share the same disease process.
1529-1839/10/$ -see front matter This is a U.S. government work. There are no restrictions on its use. Published by Elsevier Inc. on behalf of the American Optometric Association.
doi:10.1016/j.optm.2009.08.013
Louprasong et al
Figure 1
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189
Irregular ‘‘spider’’-shaped macular pigmentary changes in the
right eye.
Case report A 44-year-old white man presented for routine examination in March 2008 without ocular or visual complaints. His medical history was positive for myotonic dystrophy, type 2 diabetes mellitus for the past 6 years, hypercholesterolemia, classic migraines, gastroesophageal reflux disease, hypersomnia with sleep apnea, and impotence. His ocular history included cataract surgery in both eyes (OU) in 2005, neodymium-doped yttrium aluminum garnet capsulotomy OU in 2006, and a mild ‘‘lid droop’’ OU for the last ‘‘few years.’’ His familial history was positive for myotonic dystrophy in his 2 brothers and 1 sister. Each sibling had undergone cataract surgery. His current medications included acetaminophen, insulin, propanolol, tramadol, omeprazole, vardenafil, and a multivitamin with lutein. Examination found visual acuity of 20/20 OU at distance and near with his current spectacle correction. Amsler grid testing was negative for metamorphopsia OU. Pupillary reactions were equal and normal without afferent defects. Ocular motility was full without asthenopia or diplopia. Cover testing at distance was orthophoric in primary gaze through his current spectacle correction. Confrontation visual fields were full in all quadrants. Slit lamp examination found a mild ptosis OU. Anterior segment was remarkable for posterior chamber intraocular lens with an open posterior capsule OU. Intraocular pressures by applanation tonometry were 12 mmHg in the right eye (O.D.) and 13 mmHg in the left eye (O.S.). Dilated fundus examination found healthy optic nerve rim tissue with a cupto-disc ratio of 0.50 vertical/horizontal OU. The macula and posterior pole had pigmented changes in an irregular ‘‘spider’’-shaped pattern with questionable elevation (see Figures 1-4). Peripheral fundus examination found a small choroidal nevus superior O.S. Further examination was unremarkable. A diagnosis was made of type 2 diabetes mellitus without retinopathy OU and myotonic dystrophy with
Figure 2
Similar presentation in the left eye. Note pattern is contained within posterior pole.
ocular manifestations of cataract (removed) OU, ptosis, and questionable pigmented pattern dystrophy (spider dystrophy) versus macular degeneration. He was asked to return to the clinic for retinal photos, optical coherence tomography (OCT) of the macula, and a consultation with a retinal specialist in 8 weeks. He was also given an Amsler grid to monitor at home 3 times per week and advised to continue taking multivitamin with lutein. The Age-Related Eye Disease Study (AREDS) was discussed, and it was acknowledged that the effect of vitamin supplements on pigment pattern dystrophy is unclear. The patient returned to the clinic in 8 weeks with no reported change in vision. An OCTof the macula was unremarkable and showed normal thickness OU. Fundus photos were taken. The examining vitreoretinal surgeon concurred with the diagnosis of spider dystrophy. The patient was advised to continue the multivitamin with lutein and home monitoring with an Amsler grid. He was asked to return in 1 year for follow-up or sooner if changes in his vision developed.
Discussion Myotonic dystrophy is a rare genetic neuromuscular disease that is characterized by myotonia, muscle weakness, and atrophy. Progression and presentation can vary greatly, although typically it is a slowly progressive disorder.4 Initial onset of symptoms is most commonly seen in the second decade, although presentation may be seen from before birth to later ages.1 Multiple organ degeneration leads to premature aging in myotonic dystrophy patients. The most frequent primary causes of death are pneumonia in 31% and cardiac arrhythmias in 29%. There is no current cure for myotonic dystrophy or treatment to delay its progression.7 Myotonic dystrophy is divided into 2 clinical disorders with overlapping phenotypes and distinct molecular genetic
190
Figure 3
Optometry, Vol 81, No 4, April 2010
Irregular pigmentation disappears with red-free presentation,
right eye.
Figure 4
defects: myotonic dystrophy type 1 (DM1), the classic disease described by Steinert, and myotonic dystrophy type 2 (DM2), formerly known as proximal myotonic myopathy (PROMM).8 The underlying genetic defect expressed as classic DM1 is an unstable expansion of a cytosine-thymine-guanine (CTG) trinucleotide repeat in the serine-threonine protein kinase (named dystrophia myotonica-protein kinase) on chromosome 19q13.3.8,9 This unstable repeating trinucleotide lengthens with each successive generation in a process known as anticipation. Thus, from affected parent to child the disease symptoms occur earlier and are more severe in presentation.8 A congenital form of DM1 occurs almost exclusively in infants born to affected mothers.8 DM2 was named in the late 1990s after reports of patients with clinical presentations similar to DM1 who lacked the expansion of the CTG triplet repeat, and who presented with limb weakness that was more proximal than distal and with less atrophy.9 The genetic basis for DM2 was discovered to be secondary to an unstable cytosine-cytosinethymine-guanine (CCTG) tetra-repeat expansion in intron 1 of the zinc finger protein 9 gene on chromosome 3.9 The exact pathogenesis is unknown.1 DM1 is the more common form of myotonic dystrophy, accounting for 95% across most of the world.4 The 2 forms share clinical similarities yet differ in severity. DM2 has a less severe presentation and is less likely to affect multiple organs. Patients may even be asymptomatic and never diagnosed.10 Both, however, may affect multiple systems with varying manifestations including skeletal, gastrointestinal, cardiac, respiratory, endocrine, reproductive, and ocular.10,11 Skeletal muscle impairments usually present as myotonia, muscle weakness, atrophy, and fatigue. The muscles most frequently affected are the facial muscles, levator, palpebrae superficialis, temporalis, sternomastoids, the distal muscles of the forearm, and the ankle dorsiflexors. Less commonly involved are the quadriceps, respiratory
muscles, intrinsic muscles of the hands and feet, palatal and pharyngeal muscles, and tongue.12 Myotonia typically affects voluntary muscles and is the trademark of myotonic dystrophy. It is characterized by slowed muscle relaxation in response to continuous spontaneous activity.13 Patients’ symptoms may vary, and they are often more likely to complain of hand weakness versus myotonia. If patients are aware of myotonia they often will report difficulty releasing their grasp on objects.12 Symptoms may be exacerbated by cold, emotional excitement, and menstruation, and although the symptoms may vary throughout the day, they usually are more evident in the morning.1 Muscle weakness is most commonly found to be slowly progressive, but it is difficult to predict rate or prognosis. Limited mobility is typically preserved even in late stages.14 Patients may undergo physical therapy and might need special devices to support their therapy. The gastrointestinal system may also be affected in myotonic patients. The most common manifestations of the upper digestive tract include dysphagia caused by difficulties chewing, gastroesophageal reflux, regurgitation, and dyspepsia. The major complication of dysphagia is aspiration, which can lead to pneumonia. Lower digestive tract involvement includes abdominal pains, constipation, or irritable bowel syndrome.15 Treatments include prokinetic, antidyspeptic drugs, and laxatives to help with motility disorders.16 Cardiac involvement is a well-known complication of myotonic dystrophy and presents as conduction disturbances and tachyarrhythmias.17 Histologic studies have found fibrosis and fatty infiltration affecting the myocardium, including the conducting tissue.4 The most common abnormalities are atrioventricular and intraventricular conduction problems as well as atrial fibrillation and flutter, enlarged heart, hypotension, and electrocardiographic abnormalities.11,18 Patients may be asymptomatic or report syncope, presyncope, dizziness, palpitations, or tachycardia. Cardiac abnormalities
Absence of pigmentation with black and white presentation,
left eye.
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may evolve over months, and it is recommended that patients receive a standard 12-lead electrocardiogram (ECG) annually.18 The American College of Cardiology recommends pacemakers to patients with third-, second-, and first-degree heart blocks and patients with His-ventricular interval .100 ms, regardless if the patient is asymptomatic.18 The respiratory system is affected by weakening of the muscles in the chest, diaphragm, pharynx, and larynx.19,20 Alveolar hypoventilation and retention of carbon dioxide results in hypoxemia, which may manifest as excessive daytime sleepiness, sleep apnea, difficulty waking in the morning, headaches, or even nausea.14,20 Myotonic patients may also experience bronchopulmonary infection secondary to a diminished cough reflex leading to increased mucus accumulation in the lungs and/or from repeated food aspiration.21 Central nervous system involvement also plays a role in excessive daytime sleepiness disorder and fatigue that is present in more than 50% of myotonic patients.22 Overall intelligence usually is not impaired, as mental retardation is typically only seen in the congenital form. Patients may lack initiative, be inactive, experience memory deficits, and have visual-spatial abnormalities. The pathogenesis of this is controversial.23 The endocrine and reproductive systems may also be affected leading to insulin resistance; frontal baldness; and pituitary, adrenal, and thyroid involvement.24 When hypothyroid and diabetes coexist with excessive muscle stiffness or weakness, myotonic dystrophy should be considered. Muscle pain, myotonia, and muscle cramps may be exacerbated by pregnancy and menses. Infertility, irregular menstrual cycle, and testicular atrophy have also been noted.10 Ocular complications are typically present in all myotonic dystrophy patients and may be the first clinical sign. Cataracts, ocular muscle changes, hypotony, and retinal pigmentary changes, including pigmented pattern dystrophies, have all been noted. Nearly 100% of all myotonic dystrophy patients will have bilateral iridescent cortical and subcapsular cataract formation that appears before the age of 50; 33% will become clinically significant.1 The cataracts may remain stable or progress. Patients may or may not appreciate a decrease in vision depending on the stage of the cataract. It is postulated that mitotic instability of the dystrophy gene in the lens epithelial cells influences cell density and function leading to opacity.25 These epithelial cell changes may also lead to an increased risk for the development of intraocular fibrosis after cataract surgery and recurrences of secondary capsule opacification.26 The ocular muscles experience the same degradation as other skeletal muscles resulting in external ophthalmoplegia, bilateral motility disturbance, orbicularis oculi and levator muscle weakness, and ptosis.1 Patients may experience infrequent blinking and require lubrication to prevent corneal compromise. Lids may need to be taped at night to prevent exposure keratitis. If ptosis interferes with visual field, it is appropriate to consider use of lid crutches or
191 referral to an oculoplastic surgeon for potential blepharoplasty.27 Hypotony may also be present in patients with myotonic dystrophy, although the exact pathophysiology is unknown. The decreased intraocular pressure may be caused by changes in the ciliary processes or increased facility of outflow.28 One study found a range of intraocular pressure of 4 to 17 mmHg in myotonic patients, with an average of 10 mmHg.1 Retinal pigment epithelium (RPE) changes can occur in the peripheral retina mimicking retinitis pigmentosa or in the macula where they are known as pigment pattern dystrophy. Macular pigment changes occur in 20% of patients and have been attributed to pattern dystrophies, premature aging, quinine toxicity, or other etiologies contributing to macular changes.1 Pigmented pattern dystrophies are a family of slow progressive macular changes appearing as yellow flecks or granular or reticular pigment deposits at the level of retinal pigment epithelium. Presentation of pattern dystrophies typically manifest in the second to fifth decade of life, although there have been reports of visible macular changes at age 5.29 Pattern dystrophies typically are bilateral and symmetric; however, they may be unilateral or bilateral with phenotypic variations.30 Pattern dystrophy is set apart from other maculopathies, because it is less devastating to visual function. Patients may report a decrease in vision, metamorphopsia, difficulty with dark adaptation, or central scotoma.5 The majority of patients, however, are asymptomatic with minimal decline in visual acuity early in life. As the disease progresses and the RPE begins to atrophy, the patient may begin to lose central vision. Vision loss is not typically seen until the patient is 70 years or older, but some reports show vision loss as early as age 50.31 Although the exact etiology of pattern dystrophies is unknown, research has associated these with mutations in the human peripherin/RDS (retinal degeneration slow) gene.5,32 The peripherin gene is a component of the outer segment discs of rods and cones in which phototransduction is initiated. It encodes the peripherin/RDS protein, which plays a pivotal role in the formation, maintenance, and renewal of the photoreceptor outer segments.32,33 A mutation in the peripherin gene disrupts the metabolism of the discs, ultimately leading to the breakdown of the RPE and the accumulation of lipofuscin within the cells, typically sparing the choriocapillaris. There have been rare reports of choroidal neovascularization in advanced cases.34,35 Pattern dystrophies also have been observed in other systemic diseases including Crohn’s disease, pseudoxanthoma elasticum, Kiellin’s syndrome, McArdle’s disease, and maternally inherited deafness and diabetes.5,6 Pigmented pattern dystrophies have been subdivided into 5 different groups based on the pattern formed by the pigment distribution. The first group is known as adultonset foveomacular vitelliform, with an autosomal dominant inheritance pattern. It appears bilaterally as a slightly raised yellow oval lesion at the macula. Typically, the size
192 is one third to one disc diameter, although occasionally it may be larger, and can be misdiagnosed as Best’s vitelliform macular dystrophy or bilateral serous retinal detachment. In later stages, the lesions may fade and leave an irregular area with a depigmented oval shape.5,34 Group 2 is butterfly dystrophy also with an autosomal dominant inheritance pattern. It appears with the focal point being reticular pigmentation within the macula forming a butterfly shape. The pigmentation initially increases, and later slow depigmentation occurs, with atrophic changes.2 Group 3 is reticular dystrophy with autosomal dominant and recessive inheritance patterns. In this group, the initial lesion presents within the central macula as a darkly pigmented spot approximately 1 disc diameter in size. Eventually, fine networks of pigment granules radiate from the central point and appear as a fishnet not extending beyond the posterior pole.5,36 Another variation of this group, and the one highlighted in this case report, is spider dystrophy. This presentation, also known as macroreticular dystrophy, presents later in life compared with reticular dystrophy. It appears as a linear spider or propellerlike shape and is wider and larger than reticular dystrophy. It also does not typically extend into the periphery, although peripheral stippling may be seen in some patients.35 Group 4 is multifocal pattern dystrophy simulating fundus flavimaculatus with an autosomal dominance inheritance pattern. Presentation includes multiple yellow irregular lesions that can be found central or peripheral. These lesions may connect in a triradiate pattern appearing similar to fundus flavimaculatus, also known as Stargardt’s disease.5,6 Group 5 is fundus pulverulentus with an autosomal dominance inheritance pattern. On fundus examination it will appear as coarse pigment mottling in the macula and the RPE changes may be interpreted as a salt and pepper appearance. Pigment changes may be seen in the posterior pole and midperiphery.5,29 The pattern dystrophies have been divided conveniently into these 5 groups based on appearance, but it is important to realize that their presentation may fall in between groups. On examination, it may be documented as pattern dystrophy in general because it may be too difficult to distinguish a specific group. The mechanism that leads to these different phenotypes is unknown. It has been proposed that the different phenotypes are caused by interactions of the peripherin gene and other proteins in the rods or cones.30 Mutation in the peripherin gene has also been associated with other retinal disorders including retinitis pigmentosa, fundus flavimaculatus, and Stargardt’s-like disease. 37,38 There are reports showing pattern dystrophies to be progressive and morphing from one phenotype to another over years.39 Other studies have found evidence of an agedependent pattern. Macular changes were less pronounced, and visual acuity was less affected in patients 50 years old or younger. Over the age of 50, macular changes were more extensive, and visual loss was common in at least 1 eye. More advanced stages showed significant vision loss with geographic atrophy or neovascularization and may be
Optometry, Vol 81, No 4, April 2010 difficult to differentiate from age related macular degeneration.31,35 Diagnosis of pattern dystrophy is typically made after unique fundus findings are found on ophthalmoscopy. Other testing can be useful to help make the diagnosis. OCT may show thickening of the RPE and hyperreflective deposits under the neurosensory retina.40 Electro-oculogram is abnormal in one third of patients. Electroretinogram is typically normal, but can be subnormal in the elderly population. Color vision and visual fields are typically unremarkable until there is a decrease in visual acuity. Fluorescein angiography will show hypofluorescence in areas of increased pigmentation and hyperfluorescence in areas of RPE atrophy.34 Management consists of observation when visual acuity is minimally affected. Patients should receive genetic counseling, and photo documentation should be obtained. Home Amsler grid testing may be used to monitor for vision changes. In the rare event of visual decline, fluorescein angiography should be performed to rule out neovascularization. There have been no formal studies examining the role of multivitamin therapy in patients with pigmented pattern dystrophy, so the effect is unknown. The AREDS was based on patients with age-related macular degeneration, a degenerative process of multiple factors including genetics, smoking, free radicals, and oxidative stress leading to retinal damage. Nutritional supplementation boosts antioxidant and anti-inflammatory potential to aid in the prevention of retinal damage.41 The underlying pathogenesis of pigment pattern dystrophies is genetic mutation so the benefit of multivitamin therapy remains unclear. Patients may be placed on a vitamin supplement prophylactically.
Conclusion Pattern dystrophies, including spider dystrophy, have been associated with systemic diseases, including an ocular manifestation of myotonic dystrophy. Patients should be educated on the potential for progression and monitored annually. The patient can monitor changes with home Amsler grid testing and may wish to consider a vitamin supplement with lutein as a precaution. Management should include photo documentation, OCT, genetic counseling, and fluorescein angiography when indicated to rule out neovascular membranes.
Acknowledgment The authors thank Gregory A. Kiracofe, O.D., for his contributions to this article.
References 1. Adamczyk DT. Myotonic dystrophy. In: Marks ES, Adamczyk DT, Thomann KH, eds. Primary eyecare in systemic disease. Norwalk: Appleton and Lange; 2005:134-8.
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2. Ranum LP, Day J. Myotonic dystrophy: RNA pathogenesis comes into focus. Am Hum Genet 2004;74:793-804. 3. Borchert MS. Diseases of the ocular muscles. In: Albert, Jakobiec, eds. Principles and practice of ophthalmology. 2nd ed. Philadelphia: Saunders Elsevier; 2008:4069-70. 4. Harper PS. Myotonic dystrophy: A multisystemic disorder. In: Harper PS, Engelen BV, Eymard W, et al., eds. Myotonic dystrophy present management future therapy. New York: Oxford University Press; 2004:3-11. 5. Gass JD. Stereoscopic atlas of macular diseases diagnosis and treatment, 4th edition. St. Louis: Mosby; 1997:314-24. 6. Swann PG, Collin HB, Livanes A. Pattern dystrophies of the retinal pigment epithelium. Clin Exp Optom 2000;83:274-8. 7. de Die-Smulders CE, Howeler CJ, Thijs C, et al. Age and causes of death in adult-onset myotonic dystrophy. Brain 1998;121:1557-63. 8. Brown RH, Mendell JR Jr. Muscular dystrophies and other muscle diseases. In: Kasper DL, Braunwald E, Fauci AS, et al., eds. Harrison’s principles of internal medicine 16th edition-Volume II. New York: McGraw-Hill, Medical Pub. Division; 2005:2530-1. 9. Logigian EL, Ciafaloni E, Quinn LC, et al. Type and distribution of myotonic discharges are different in type 1 and type 2 myotonic dystrophy. Muscle Nerve 2007;35:479-85. 10. Meola G, Moxley RT 3rd. Myotonic dystrophy type 2 and related myotonic disorders. J Neurol 2004;251:1173-82. 11. Pelargonio G, Dello Russo A, Sanna T, et al. Myotonic dystrophy and the heart. Heart 2002;88:665-70. 12. Hilton-Jone D, Myotonia. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford textbook of medicine 4th ed., Vol. 3. New York: Oxford University Press; 1983:1235-9. 13. Finsterer J. Myotonic dystrophy type 2. Eur J Neurol 2002;9:441-7. 14. Longman C. Myotonic dystrophy. J R Coll Physicians of Edinb 2006; 36:51-5. 15. Tieleman AA, van Vliet J, Jansen J, et al. Gastrointestinal involvement is frequent in myotonic dystrophy type 2. Neuromuscul Disord 2008; 18:647-9. 16. Bellini M, Biagi S, Stasi C, et al. Gastrointestinal manifestations in myotonic muscular dystrophy. World J Gastroenterol 2006;12:1821-8. 17. Phillips MF, Harper PS. Cardiac disease in myotonic dystrophy. Cardiovasc Res 1997;33:13-21. 18. Benatar M. Neuromuscular disease: evidence and analysis in clinical neurology. New Jersey: Human Press, 2006:433-49. 19. Cirignotta F, Mondini S, Zucconi M, et al. Sleep related breathing impairment in myotonic dystrophy. J Neurol 1987;235:80-5. 20. Calabrese P, Gryspeert N, Auriant I, et al. Postural breathing pattern changes in patients with myotonic dystrophy. Respir Physio 2000; 122:1-13. 21. de Backer M, Bergmann P, Perissino A, et al. Respiratory failure and cardiac disturbances in myotonic dystrophy. Eur J Intensive Care Med 1976;2:63-7. 22. Meola G, Sansone V. Cerebral involvement in myotonic dystrophies. Muscle Nerve 2007;36:294-306. 23. Abe K, Fujimura H, Toyooka K, et al. Involvement of central nervous system in myotonic dystrophy. J Neurol Sci 1994;127:179-85.
193 24. Johansson A, Olsson T. Endocrine changes in myotonic dystrophy. In: Harper PS, Engelen BV, Eymard W, et al., eds. Myotonic dystrophy present management future therapy. New York: Oxford University Press; 2004:3-11. 25. Abe T, Sato M, Kuboki J, et al. Lens epithelial changes and mutated gene expression in patients with myotonic dystrophy. Br J Ophthalmol 1999;83:452-7. 26. Gjertsen IK, Sandvig KU, Eide N, et al. Recurrence of secondary opacification and development of a dense posterior vitreous membrane in patients with myotonic dystrophy. J Cataract Refract Surg 2003;29: 213-6. 27. Wong VA, Beckingsale PS, Oley CA, et al. Management of myogenic ptosis. Ophthalmology 2002;109:1023-31. 28. Dreyer RF. Ocular hypotony in myotonic dystrophy. Int Ophthalmol 1983;6:221-3. 29. Jimn˜ez-Sierra JM, Ogden TE, Van Boemel GB. Inherited retinal disease: a diagnostic guide. St. Louis: Mosby; 1989:59-73. 30. Grover S, Fishman GA, Stone EM. Atypical presentation of pattern dystrophy in two families with peripherin/RDS mutations. Ophthalmology 2002;109:1110-17. 31. Francis PJ, Schultz DW, Gregory AM, et al. Genetic and phenotypic heterogeneity in pattern dystrophy. Br J Ophthalmol 2005;89: 1115-9. 32. Boon CJ, den Hollander AI, Hoyng CB, et al. The spectrum of retinal dystrophies caused by mutations in the peripherin/RDS gene. Prog Retin Eye Res 2008;27:213-35. 33. Marmor MF, Small KW. Dystrophies of the retinal pigment epithelium. In: Marmor MF, Wolfensberger TJ, eds. The retinal pigment epithelium. New York: Oxford University Press; 1998:334-6. 34. Reed KK. Differential diagnosis of hereditary pigmentary maculopathies. Clin Eye Vis Care 2000;12:3-14. 35. Battaglia Parodia M, Da Pozzo S, Ravalico G. Photodynamic therapy for choroidal neovascularization associated with pattern dystrophy. Retina 2003;23:171-6. 36. Merin S, Zlotogora J, Sharon D. Inherited eye diseases: diagnosis and management. Boca Raton: Taylor & Francis; 2005:218-21. 37. Zhang K, Garibaldi DC, Li Y, et al. Butterfly-shaped pattern dystrophy: a genetic, clinical, and histopathological report. Arch Ophthalmol 2002;120:485-90. 38. Boon CJ, van Schooneveld MJ, den Hollander AI, et al. Mutations in the peripherin/RDS gene are an important cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus. Br J Ophthalmol 2007;91:1504-11. 39. Cardillo Piccolino F, Zingirian M. Pattern dystrophy of the retinal pigment epithelium with vitelliform macular lesion: evolution in ten years. Int Ophthalmol 1998;11:207-17. 40. Cruz-Villegras Rosenfeld PJ. Puliafito CA. Retinal dystrophies. In: Schuman JS, Puliafito CA, Fujimoto JG, eds. Optical coherence tomography of ocular diseases. 2nd ed. Thorofare, NJ: SLACK Inc., 1996:414. 41. Bartlett H, Eperjesi F. Age-related macular degeneration and nutritional supplementation: a review of randomized controlled trials. Ophtham Physiol Opt 2003;23:383-99.
Spider dystrophy as an ocular manifestation of myotonic dystrophy Amber C. Louprasong, O.D., Dennis J. Light, O.D., and Rebecca S. Diller, O.D. Dayton Veterans Affairs Medical Center, Dayton, Ohio.
KEYWORDS Myotonic dystrophy; Cataract; Hypotony; Extraocular muscle; Pigment pattern dystrophy; Spider dystrophy
Abstract BACKGROUND: Myotonic dystrophy is the most common adult-onset muscular dystrophy. It is an autosomal dominant inherited neuromuscular disease that is characterized by myotonia, muscle weakness, and atrophy. It affects multiple systems including skeletal muscular, gastrointestinal, cardiac, respiratory, central nervous, endocrine, and ocular. Ocular manifestations of myotonic dystrophy include cataract, ocular muscle changes, hypotony, and retinal pigmentary changes in the periphery or in the macula (known as pigment pattern dystrophy). This report presents and discusses the case of a pigmented pattern dystrophy known as spider dystrophy as an ocular manifestation of myotonic dystrophy. CASE REPORT: A 44-year-old man with myotonic dystrophy presented to the eye clinic for routine examination. Ocular history included previous bilateral cataract surgery and mild bilateral ptosis for the last ‘‘few years.’’ Dilated fundus examination was remarkable for bilateral macular pigmentary changes in an irregular ‘‘spider’’-shaped pattern. The patient was asymptomatic without decrease in vision or Amsler grid defects. Optical coherence tomography was normal. A retinal consult concurred with the diagnosis of spider dystrophy. Photo documentation was obtained, and the patient is being monitored annually. CONCLUSION: Pigmented pattern dystrophies, including spider dystrophy, have been associated with myotonic dystrophy. They are set apart from other retinal dystrophies because they rarely affect visual acuity, and the majority of patients are asymptomatic. Progression may lead to reduced vision and in rare cases choroidal neovascularization. Annual dilated examinations, photo documentation, optical coherence tomography, and home Amsler grid monitoring are recommended for follow-up care. Optometry 2010;81:188-193
Myotonic dystrophy, or dystrophia myotonica (DM), is an autosomal dominant genetic neuromuscular disease with variable penetrance.1 The prevalence is approximately 2.5 to 5.5 per 100,000, and the annual incidence is 1 in 8,000.2 Typical onset occurs in the second decade. Earlier diagnosis is associated with a more severe course.3 It affects multiple systems including skeletal muscular,
Corresponding author: Amber C. Louprasong, O.D., Dayton Veterans Affairs Medical Center, Optometry, 4100 West Third St., Dayton, Ohio 45428. E-mail: [email protected]
gastrointestinal, cardiac, respiratory, central nervous, endocrine, reproductive, and ocular.4 Ocular manifestations may be the initial presentation of myotonic dystrophy without other systemic involvement. The hallmark ocular finding is bilateral iridescent cataract affecting nearly 100% of all patients.1 Ocular muscle changes, hypotony, and peripheral retinal pigmentary changes have also been noted.1,5,6 A final presentation that may be overlooked is macular retinal pigmentary change known as pigmented pattern dystrophy. Pattern dystrophies are divided into subsets based on different unique clinical presentations. Their appearance separates them, but they share the same disease process.
1529-1839/10/$ -see front matter This is a U.S. government work. There are no restrictions on its use. Published by Elsevier Inc. on behalf of the American Optometric Association.
doi:10.1016/j.optm.2009.08.013
Louprasong et al
Figure 1
Clinical Care
189
Irregular ‘‘spider’’-shaped macular pigmentary changes in the
right eye.
Case report A 44-year-old white man presented for routine examination in March 2008 without ocular or visual complaints. His medical history was positive for myotonic dystrophy, type 2 diabetes mellitus for the past 6 years, hypercholesterolemia, classic migraines, gastroesophageal reflux disease, hypersomnia with sleep apnea, and impotence. His ocular history included cataract surgery in both eyes (OU) in 2005, neodymium-doped yttrium aluminum garnet capsulotomy OU in 2006, and a mild ‘‘lid droop’’ OU for the last ‘‘few years.’’ His familial history was positive for myotonic dystrophy in his 2 brothers and 1 sister. Each sibling had undergone cataract surgery. His current medications included acetaminophen, insulin, propanolol, tramadol, omeprazole, vardenafil, and a multivitamin with lutein. Examination found visual acuity of 20/20 OU at distance and near with his current spectacle correction. Amsler grid testing was negative for metamorphopsia OU. Pupillary reactions were equal and normal without afferent defects. Ocular motility was full without asthenopia or diplopia. Cover testing at distance was orthophoric in primary gaze through his current spectacle correction. Confrontation visual fields were full in all quadrants. Slit lamp examination found a mild ptosis OU. Anterior segment was remarkable for posterior chamber intraocular lens with an open posterior capsule OU. Intraocular pressures by applanation tonometry were 12 mmHg in the right eye (O.D.) and 13 mmHg in the left eye (O.S.). Dilated fundus examination found healthy optic nerve rim tissue with a cupto-disc ratio of 0.50 vertical/horizontal OU. The macula and posterior pole had pigmented changes in an irregular ‘‘spider’’-shaped pattern with questionable elevation (see Figures 1-4). Peripheral fundus examination found a small choroidal nevus superior O.S. Further examination was unremarkable. A diagnosis was made of type 2 diabetes mellitus without retinopathy OU and myotonic dystrophy with
Figure 2
Similar presentation in the left eye. Note pattern is contained within posterior pole.
ocular manifestations of cataract (removed) OU, ptosis, and questionable pigmented pattern dystrophy (spider dystrophy) versus macular degeneration. He was asked to return to the clinic for retinal photos, optical coherence tomography (OCT) of the macula, and a consultation with a retinal specialist in 8 weeks. He was also given an Amsler grid to monitor at home 3 times per week and advised to continue taking multivitamin with lutein. The Age-Related Eye Disease Study (AREDS) was discussed, and it was acknowledged that the effect of vitamin supplements on pigment pattern dystrophy is unclear. The patient returned to the clinic in 8 weeks with no reported change in vision. An OCTof the macula was unremarkable and showed normal thickness OU. Fundus photos were taken. The examining vitreoretinal surgeon concurred with the diagnosis of spider dystrophy. The patient was advised to continue the multivitamin with lutein and home monitoring with an Amsler grid. He was asked to return in 1 year for follow-up or sooner if changes in his vision developed.
Discussion Myotonic dystrophy is a rare genetic neuromuscular disease that is characterized by myotonia, muscle weakness, and atrophy. Progression and presentation can vary greatly, although typically it is a slowly progressive disorder.4 Initial onset of symptoms is most commonly seen in the second decade, although presentation may be seen from before birth to later ages.1 Multiple organ degeneration leads to premature aging in myotonic dystrophy patients. The most frequent primary causes of death are pneumonia in 31% and cardiac arrhythmias in 29%. There is no current cure for myotonic dystrophy or treatment to delay its progression.7 Myotonic dystrophy is divided into 2 clinical disorders with overlapping phenotypes and distinct molecular genetic
190
Figure 3
Optometry, Vol 81, No 4, April 2010
Irregular pigmentation disappears with red-free presentation,
right eye.
Figure 4
defects: myotonic dystrophy type 1 (DM1), the classic disease described by Steinert, and myotonic dystrophy type 2 (DM2), formerly known as proximal myotonic myopathy (PROMM).8 The underlying genetic defect expressed as classic DM1 is an unstable expansion of a cytosine-thymine-guanine (CTG) trinucleotide repeat in the serine-threonine protein kinase (named dystrophia myotonica-protein kinase) on chromosome 19q13.3.8,9 This unstable repeating trinucleotide lengthens with each successive generation in a process known as anticipation. Thus, from affected parent to child the disease symptoms occur earlier and are more severe in presentation.8 A congenital form of DM1 occurs almost exclusively in infants born to affected mothers.8 DM2 was named in the late 1990s after reports of patients with clinical presentations similar to DM1 who lacked the expansion of the CTG triplet repeat, and who presented with limb weakness that was more proximal than distal and with less atrophy.9 The genetic basis for DM2 was discovered to be secondary to an unstable cytosine-cytosinethymine-guanine (CCTG) tetra-repeat expansion in intron 1 of the zinc finger protein 9 gene on chromosome 3.9 The exact pathogenesis is unknown.1 DM1 is the more common form of myotonic dystrophy, accounting for 95% across most of the world.4 The 2 forms share clinical similarities yet differ in severity. DM2 has a less severe presentation and is less likely to affect multiple organs. Patients may even be asymptomatic and never diagnosed.10 Both, however, may affect multiple systems with varying manifestations including skeletal, gastrointestinal, cardiac, respiratory, endocrine, reproductive, and ocular.10,11 Skeletal muscle impairments usually present as myotonia, muscle weakness, atrophy, and fatigue. The muscles most frequently affected are the facial muscles, levator, palpebrae superficialis, temporalis, sternomastoids, the distal muscles of the forearm, and the ankle dorsiflexors. Less commonly involved are the quadriceps, respiratory
muscles, intrinsic muscles of the hands and feet, palatal and pharyngeal muscles, and tongue.12 Myotonia typically affects voluntary muscles and is the trademark of myotonic dystrophy. It is characterized by slowed muscle relaxation in response to continuous spontaneous activity.13 Patients’ symptoms may vary, and they are often more likely to complain of hand weakness versus myotonia. If patients are aware of myotonia they often will report difficulty releasing their grasp on objects.12 Symptoms may be exacerbated by cold, emotional excitement, and menstruation, and although the symptoms may vary throughout the day, they usually are more evident in the morning.1 Muscle weakness is most commonly found to be slowly progressive, but it is difficult to predict rate or prognosis. Limited mobility is typically preserved even in late stages.14 Patients may undergo physical therapy and might need special devices to support their therapy. The gastrointestinal system may also be affected in myotonic patients. The most common manifestations of the upper digestive tract include dysphagia caused by difficulties chewing, gastroesophageal reflux, regurgitation, and dyspepsia. The major complication of dysphagia is aspiration, which can lead to pneumonia. Lower digestive tract involvement includes abdominal pains, constipation, or irritable bowel syndrome.15 Treatments include prokinetic, antidyspeptic drugs, and laxatives to help with motility disorders.16 Cardiac involvement is a well-known complication of myotonic dystrophy and presents as conduction disturbances and tachyarrhythmias.17 Histologic studies have found fibrosis and fatty infiltration affecting the myocardium, including the conducting tissue.4 The most common abnormalities are atrioventricular and intraventricular conduction problems as well as atrial fibrillation and flutter, enlarged heart, hypotension, and electrocardiographic abnormalities.11,18 Patients may be asymptomatic or report syncope, presyncope, dizziness, palpitations, or tachycardia. Cardiac abnormalities
Absence of pigmentation with black and white presentation,
left eye.
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Clinical Care
may evolve over months, and it is recommended that patients receive a standard 12-lead electrocardiogram (ECG) annually.18 The American College of Cardiology recommends pacemakers to patients with third-, second-, and first-degree heart blocks and patients with His-ventricular interval .100 ms, regardless if the patient is asymptomatic.18 The respiratory system is affected by weakening of the muscles in the chest, diaphragm, pharynx, and larynx.19,20 Alveolar hypoventilation and retention of carbon dioxide results in hypoxemia, which may manifest as excessive daytime sleepiness, sleep apnea, difficulty waking in the morning, headaches, or even nausea.14,20 Myotonic patients may also experience bronchopulmonary infection secondary to a diminished cough reflex leading to increased mucus accumulation in the lungs and/or from repeated food aspiration.21 Central nervous system involvement also plays a role in excessive daytime sleepiness disorder and fatigue that is present in more than 50% of myotonic patients.22 Overall intelligence usually is not impaired, as mental retardation is typically only seen in the congenital form. Patients may lack initiative, be inactive, experience memory deficits, and have visual-spatial abnormalities. The pathogenesis of this is controversial.23 The endocrine and reproductive systems may also be affected leading to insulin resistance; frontal baldness; and pituitary, adrenal, and thyroid involvement.24 When hypothyroid and diabetes coexist with excessive muscle stiffness or weakness, myotonic dystrophy should be considered. Muscle pain, myotonia, and muscle cramps may be exacerbated by pregnancy and menses. Infertility, irregular menstrual cycle, and testicular atrophy have also been noted.10 Ocular complications are typically present in all myotonic dystrophy patients and may be the first clinical sign. Cataracts, ocular muscle changes, hypotony, and retinal pigmentary changes, including pigmented pattern dystrophies, have all been noted. Nearly 100% of all myotonic dystrophy patients will have bilateral iridescent cortical and subcapsular cataract formation that appears before the age of 50; 33% will become clinically significant.1 The cataracts may remain stable or progress. Patients may or may not appreciate a decrease in vision depending on the stage of the cataract. It is postulated that mitotic instability of the dystrophy gene in the lens epithelial cells influences cell density and function leading to opacity.25 These epithelial cell changes may also lead to an increased risk for the development of intraocular fibrosis after cataract surgery and recurrences of secondary capsule opacification.26 The ocular muscles experience the same degradation as other skeletal muscles resulting in external ophthalmoplegia, bilateral motility disturbance, orbicularis oculi and levator muscle weakness, and ptosis.1 Patients may experience infrequent blinking and require lubrication to prevent corneal compromise. Lids may need to be taped at night to prevent exposure keratitis. If ptosis interferes with visual field, it is appropriate to consider use of lid crutches or
191 referral to an oculoplastic surgeon for potential blepharoplasty.27 Hypotony may also be present in patients with myotonic dystrophy, although the exact pathophysiology is unknown. The decreased intraocular pressure may be caused by changes in the ciliary processes or increased facility of outflow.28 One study found a range of intraocular pressure of 4 to 17 mmHg in myotonic patients, with an average of 10 mmHg.1 Retinal pigment epithelium (RPE) changes can occur in the peripheral retina mimicking retinitis pigmentosa or in the macula where they are known as pigment pattern dystrophy. Macular pigment changes occur in 20% of patients and have been attributed to pattern dystrophies, premature aging, quinine toxicity, or other etiologies contributing to macular changes.1 Pigmented pattern dystrophies are a family of slow progressive macular changes appearing as yellow flecks or granular or reticular pigment deposits at the level of retinal pigment epithelium. Presentation of pattern dystrophies typically manifest in the second to fifth decade of life, although there have been reports of visible macular changes at age 5.29 Pattern dystrophies typically are bilateral and symmetric; however, they may be unilateral or bilateral with phenotypic variations.30 Pattern dystrophy is set apart from other maculopathies, because it is less devastating to visual function. Patients may report a decrease in vision, metamorphopsia, difficulty with dark adaptation, or central scotoma.5 The majority of patients, however, are asymptomatic with minimal decline in visual acuity early in life. As the disease progresses and the RPE begins to atrophy, the patient may begin to lose central vision. Vision loss is not typically seen until the patient is 70 years or older, but some reports show vision loss as early as age 50.31 Although the exact etiology of pattern dystrophies is unknown, research has associated these with mutations in the human peripherin/RDS (retinal degeneration slow) gene.5,32 The peripherin gene is a component of the outer segment discs of rods and cones in which phototransduction is initiated. It encodes the peripherin/RDS protein, which plays a pivotal role in the formation, maintenance, and renewal of the photoreceptor outer segments.32,33 A mutation in the peripherin gene disrupts the metabolism of the discs, ultimately leading to the breakdown of the RPE and the accumulation of lipofuscin within the cells, typically sparing the choriocapillaris. There have been rare reports of choroidal neovascularization in advanced cases.34,35 Pattern dystrophies also have been observed in other systemic diseases including Crohn’s disease, pseudoxanthoma elasticum, Kiellin’s syndrome, McArdle’s disease, and maternally inherited deafness and diabetes.5,6 Pigmented pattern dystrophies have been subdivided into 5 different groups based on the pattern formed by the pigment distribution. The first group is known as adultonset foveomacular vitelliform, with an autosomal dominant inheritance pattern. It appears bilaterally as a slightly raised yellow oval lesion at the macula. Typically, the size
192 is one third to one disc diameter, although occasionally it may be larger, and can be misdiagnosed as Best’s vitelliform macular dystrophy or bilateral serous retinal detachment. In later stages, the lesions may fade and leave an irregular area with a depigmented oval shape.5,34 Group 2 is butterfly dystrophy also with an autosomal dominant inheritance pattern. It appears with the focal point being reticular pigmentation within the macula forming a butterfly shape. The pigmentation initially increases, and later slow depigmentation occurs, with atrophic changes.2 Group 3 is reticular dystrophy with autosomal dominant and recessive inheritance patterns. In this group, the initial lesion presents within the central macula as a darkly pigmented spot approximately 1 disc diameter in size. Eventually, fine networks of pigment granules radiate from the central point and appear as a fishnet not extending beyond the posterior pole.5,36 Another variation of this group, and the one highlighted in this case report, is spider dystrophy. This presentation, also known as macroreticular dystrophy, presents later in life compared with reticular dystrophy. It appears as a linear spider or propellerlike shape and is wider and larger than reticular dystrophy. It also does not typically extend into the periphery, although peripheral stippling may be seen in some patients.35 Group 4 is multifocal pattern dystrophy simulating fundus flavimaculatus with an autosomal dominance inheritance pattern. Presentation includes multiple yellow irregular lesions that can be found central or peripheral. These lesions may connect in a triradiate pattern appearing similar to fundus flavimaculatus, also known as Stargardt’s disease.5,6 Group 5 is fundus pulverulentus with an autosomal dominance inheritance pattern. On fundus examination it will appear as coarse pigment mottling in the macula and the RPE changes may be interpreted as a salt and pepper appearance. Pigment changes may be seen in the posterior pole and midperiphery.5,29 The pattern dystrophies have been divided conveniently into these 5 groups based on appearance, but it is important to realize that their presentation may fall in between groups. On examination, it may be documented as pattern dystrophy in general because it may be too difficult to distinguish a specific group. The mechanism that leads to these different phenotypes is unknown. It has been proposed that the different phenotypes are caused by interactions of the peripherin gene and other proteins in the rods or cones.30 Mutation in the peripherin gene has also been associated with other retinal disorders including retinitis pigmentosa, fundus flavimaculatus, and Stargardt’s-like disease. 37,38 There are reports showing pattern dystrophies to be progressive and morphing from one phenotype to another over years.39 Other studies have found evidence of an agedependent pattern. Macular changes were less pronounced, and visual acuity was less affected in patients 50 years old or younger. Over the age of 50, macular changes were more extensive, and visual loss was common in at least 1 eye. More advanced stages showed significant vision loss with geographic atrophy or neovascularization and may be
Optometry, Vol 81, No 4, April 2010 difficult to differentiate from age related macular degeneration.31,35 Diagnosis of pattern dystrophy is typically made after unique fundus findings are found on ophthalmoscopy. Other testing can be useful to help make the diagnosis. OCT may show thickening of the RPE and hyperreflective deposits under the neurosensory retina.40 Electro-oculogram is abnormal in one third of patients. Electroretinogram is typically normal, but can be subnormal in the elderly population. Color vision and visual fields are typically unremarkable until there is a decrease in visual acuity. Fluorescein angiography will show hypofluorescence in areas of increased pigmentation and hyperfluorescence in areas of RPE atrophy.34 Management consists of observation when visual acuity is minimally affected. Patients should receive genetic counseling, and photo documentation should be obtained. Home Amsler grid testing may be used to monitor for vision changes. In the rare event of visual decline, fluorescein angiography should be performed to rule out neovascularization. There have been no formal studies examining the role of multivitamin therapy in patients with pigmented pattern dystrophy, so the effect is unknown. The AREDS was based on patients with age-related macular degeneration, a degenerative process of multiple factors including genetics, smoking, free radicals, and oxidative stress leading to retinal damage. Nutritional supplementation boosts antioxidant and anti-inflammatory potential to aid in the prevention of retinal damage.41 The underlying pathogenesis of pigment pattern dystrophies is genetic mutation so the benefit of multivitamin therapy remains unclear. Patients may be placed on a vitamin supplement prophylactically.
Conclusion Pattern dystrophies, including spider dystrophy, have been associated with systemic diseases, including an ocular manifestation of myotonic dystrophy. Patients should be educated on the potential for progression and monitored annually. The patient can monitor changes with home Amsler grid testing and may wish to consider a vitamin supplement with lutein as a precaution. Management should include photo documentation, OCT, genetic counseling, and fluorescein angiography when indicated to rule out neovascular membranes.
Acknowledgment The authors thank Gregory A. Kiracofe, O.D., for his contributions to this article.
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