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Low Intraocular Pressure Resulting from Ciliary Body Detachment in Patients with Myotonic Dystrophy
Low Intraocular Pressure Resulting from Ciliary Body Detachment in Patients with Myotonic Dystrophy Nicola Rosa, MD,1,2 Michele Lanza, MD,1,2 Maria Borrelli, MD,1,2 Maddalena De Bernardo, MD,1,2 Alberto Palladino, MD,3 Maria Grazia Di Gregorio, MD,3 Fabrizia Pascotto, MD,1,2 Luisa Politano, MD3 Purpose: To investigate why myotonic dystrophy type 1 (DM1) patients have low intraocular pressure (IOP). Design: Prospective, comparative case series. Participants: One hundred two eyes of 51 patients with DM1 (age range, 21– 64 years) and 44 eyes of 22 healthy subjects of similar age (21– 64 years). Methods: All participants underwent IOP measurement with Goldmann applanation tonometry and an in vivo examination of the ciliary body with a 35-MHz high-resolution B-scan. The findings were compared between the 2 groups. In both groups, only patients with no history of ocular trauma or surgery were included. The differences were evaluated using the unpaired Student t test. Main Outcome Measurements: Intraocular pressure, central corneal thickness (CCT), and echographic evidence of ciliary body detachment. Results: The mean⫾standard deviation (SD) IOP in patients with DM1 was 10.9⫾3.1 mmHg and that in the control patients was 15.4⫾2.2 mmHg, a difference that reached significance (P⬍0.01). The mean⫾SD CCT (measured at the pupillary center) was 574.4⫾37.9 m in the patients with DM1 and 557.8⫾39.2 m in the controls (P ⫽ 0.02). Detachment of the ciliary body was identified in all DM1 subjects. Size was variable and the detachment involved 1 or more quadrants. The number of quadrants affected by the detachment was not correlated with the IOP (R2 ⫽ 0.088) or the size of the CTG expansion. No detachments were found in the healthy controls. Conclusions: Detachment of the ciliary body may explain the low IOP values in patients with DM1. The finding of a ciliary body detachment in an individual who has not had recent eye surgery or trauma raises the possibility of a DM1 diagnosis. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2011;118:260 –264 © 2011 by the American Academy of Ophthalmology.
Myotonic dystrophy type 1 (DM1) is a muscle disease with an autosomal dominant mode of inheritance that affects approximately 1 in 8000 white persons. The genetic defect associated with DM1 is abnormal expansion of a CTG trinucleotide repeat in the 3= end of the DMPK gene on chromosome 19q13.3. Normal alleles have from 5 to 34 CTG repeats, whereas DM1 alleles contain from 50 to 2000 or more CTG repeats.1–3 In DM1, the muscle involvement is characterized by myotonia and muscular weakness involving the facial, axial, semidistal, and distal compartments. Symptoms generally develop between the second and the fourth decades of life and progress slowly over time. Besides muscles, DM1 affects other organs, including endocrine function (diabetes, thyroid dysfunction, hypogonadism), the nervous system (mental retardation), the gastrointestinal tract (dysphagia, pseudo-obstruction), and the heart. Cardiac involvement poses a major problem in clinical management; cardiac complications are the primary cause of premature death in DM1. In particular, there is a high
260
© 2011 by the American Academy of Ophthalmology Published by Elsevier Inc.
incidence of sudden death, ranging from 2% to 30% of cases, that is related primarily to the development of conduction block. A second form of myotonic dystrophy, proximal myotonic myopathy, or myotonic dystrophy type 2, which has been described previously,4 results from CTG expansion on chromosome 3. The similarities of and differences between DM1 and myotonic dystrophy type 2 are shown in Table 1.5 The most common ocular abnormalities in DM1 include cataract, ptosis, exposure keratitis, pigmentary abnormalities, abnormal electroretinography results, abnormal dark adaptation, and weakness of the orbicularis ocular muscles.6 It also has been reported that patients with DM1 can have low intraocular pressure (IOP).7,8 In a previously published study, we found this hypotony to be real and unrelated to different corneal biomechanical properties or endothelium abnormalities.9,10 Although it has been suggested that the hypotony in DM1 could be related to increased outflow ISSN 0161-6420/11/$–see front matter doi:10.1016/j.ophtha.2010.06.020
Rosa et al 䡠 Ciliary Body and Myotonic Dystrophy Table 1. Similarities and Differences in Myotonic Dystrophy Type 1 and Myotonic Dystrophy Type 2 Myotonic Dystrophy Type 1-Specific Features Prominent distal muscle weakness at onset Distal muscle atrophy at onset Congenital DM1 Gastrointestinal tract problems
Shared Features Myotonia* Muscle weakness and atrophy Cataract Cardiac conduction defects* Cognitive dysfunction* Hypersomnia* Insulin resistance Testicular atrophy Frontal balding in men Hypogammaglobulinemia Muscle pain
Myotonic Dystrophy Type 2-Specific Features Prominent proximal muscle weakness at onset Proximal muscle atrophy at onset Hypertrophic calf muscles
DM1 ⫽ myotonic dystrophy type 1. *Present in myotonic dystrophy type 2, but more prominent in myotonic dystrophy type 1.5
facility or decreased aqueous secretion, the pathophysiologic mechanism responsible for low IOP remains unclear.11,12 Some authors attributed the hyposecretion of aqueous humor to ciliary body atrophy.13 To determine the mechanism of the low IOP in DM1, the authors performed an in vivo study of the ciliary body in these patients.
Patients and Methods A total of 102 eyes of 51 patients (28 men, 23 women) with DM1 who were followed up at the Department of Cardiomyology and Medical Genetics, Second University Medical School, Naples, Italy, were enrolled consecutively in this study. The patients ranged in age from 21 to 64 years (mean⫾standard deviation [SD], 37.1⫾11 years). The diagnosis of DM1 was based on family history, typical muscular findings, and electromyography results and was confirmed by genetic analysis showing pathologic CTG repeats of different sizes (mean number, 785; range, 68 –2900) in all patients. The control group consisted of 44 eyes (22 healthy subjects) who were similar in age (range, 21– 64 years; mean⫾SD, 40.6⫾12.5 years). The inclusion criterion was a definitive diagnosis of DM1 obtained by molecular analysis. The exclusion criteria were the presence of cataract, previous ocular surgery, use of systemic or topical drugs that alter the aqueous humor flow or IOP, or contact lens wear. Each patient provided informed consent according to the guidelines of the Declaration of Helsinki, and the institutional review board approved the study protocol. All patients underwent a complete ophthalmic examination including measurement of the IOP by Goldmann applanation tonometry, measurement of the central corneal thickness with the Pentacam camera (Oculus, Wetzlar, Germany), and an examination with Hi Scan ultrasound biomicroscopy (Optikon 2000, Rome, Italy). This device has a 35-MHz probe and achieves a tissue resolution of approximately 50 m. Scanning was performed with the patients supine in standard room light. A fixation target was used for the unaffected eye. After topical anesthesia was instilled, an eye cup was placed on the eye and was filled with saline solution, which serves as a coupling medium.14 The ultrasound probe was placed in the coupling medium approximately 7 to 8 mm from the ocular surface. Fine transverse and longitudinal movements of the probe were performed manually to capture multiple scans of the ciliary body over 360° in each eye.
Results In patients with DM1, the IOP values ranged from 3 to 19 mmHg (mean⫾SD, 10.9⫾3.1 mmHg). In the control group, the IOP values ranged from 11 to 19 mmHg (mean⫾SD, 15.4⫾2.2 mmHg). The difference between the groups reached significance (P⬍0.01). In the patients with DM1, the central corneal thickness ranged from 502 to 678 m (mean⫾SD, 574.4⫾37.9 m), and in the control group, the central corneal thickness ranged from 503 to 660 m (mean⫾SD, 557.8⫾39.2 m; P ⫽ 0.02). The echographic examination in patients with DM1 showed the presence of an area of lower refraction below the ciliary body (Fig 1) that is consistent with the presence of fluid behind the ciliary body. This finding was not present over 360°, and the extent differed in each patient (Table 2, available at http://aaojournal. org). In 48 patients, this finding was present bilaterally, and the number of involved quadrants was the same in 25 patients (1 quadrant in 1 patient, 2 quadrants in 8 patients, 3 quadrants in 7 patients, and 4 quadrants in 9 patients). Considering both eyes, the inferior quadrant was affected most often (75 eyes), whereas the quadrant that was most often involved
Figure 1. Echographic image showing the presence of a ciliary body detachment in a myotonic dystrophy (DM1) patient. dB ⫽ decibels.
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Figure 2. Scatterplot between intraocular pressure (IOP; x-axis) and number of involved quadrants (y-axis) showing a poor correlation (R2 ⫽ 0.088). dB ⫽ decibels.
in the right eyes was the temporal quadrant (39 eyes) and in the left eyes was the inferior quadrant (44 eyes). The number of involved quadrants was unrelated to the IOP (Fig 2). This clinical picture was not present in any control patients (Fig 3).
Discussion Ocular hypotony has been reported to be among the most frequent ocular anomalies associated with DM1. Several causes of ocular hypotony have been described, such as the combined use of topical timolol and dorzolamide,15 intraocular surgery,16,17 or trauma.18 None of these is responsible for the DM1 in the current study, because patients who had undergone a previous intraocular surgery, had sustained ocular trauma, or had been treated with an ocular medication were excluded. Hypotony also can result from either increased outflow (abnormally low episcleral venous pressure, abnormally high outflow facility, slow rate of aqueous flow through the anterior chamber, abnormally high rate of uveoscleral outflow) or decreased aqueous production (hyalinization and/or atrophy of the ciliary processes). Our in vivo high-frequency ultrasound findings in the patients with DM1 in the current study support the hypothesis of Khan and Brubaker.19 In fact, the atrophy of the ciliary muscle could increase the uveoscleral outflow, leading to ciliary body detachment (shown by echography). This condition causes a decrease in the ciliary body blood supply and a consequent decrease in the aqueous production and ocular hypotonia. This also may explain the findings of Burian and Burns,11 who examined 45 eyes of 23 patients with DM1 who had a mean IOP of 10 mmHg (range, 4 –17 mmHg). When the patients were divided into age groups, the investigators found a decrease in IOP with advancing age, which also can explain why the ciliary body detachment is not always related to low IOP. Ocular hypotony can be defined in several ways. Some authors have described ocular hypotony as the presence of IOP of less than 5 mmHg,20 whereas others have defined it as an IOP of less than the level that causes
262
structural and functional changes that disallow normal ocular functions.21 Pederson22 divided hypotony into 2 categories: statistical and clinical. Statistical hypotony was defined is an IOP of less than 6.5 mmHg, which is more than 3 SDs less than the mean. Clinical hypotony was defined as low IOP that can result in visual loss, which occurs with an IOP of less than 4 mmHg. Schubert23 defined hypotony as low IOP in an individual eye leading to functional and structural changes. Several authors have investigated the reason for low IOP in patients with myotonic dystrophy; however, the results remain controversial. Junge24 suggested that increased outflow facility may account for the hypotony, but other researchers7,13 found tonographic outflow facility to be normal and insufficient to explain the hypotony, and for these reasons, they attributed the hypotony to either decreased aqueous formation or abnormal uveoscleral outflow. Unfortunately, tonographic data are questionable in eyes with very low IOP; for this reason, Walker et al25 measured the rate of clearance of fluorescein from the anterior chamber and the endothelial permeability to fluorescein in patients with myotonic dystrophy and found the measurements to be the same as in normal subjects. Moreover, the investigators found the blood–aqueous barrier to be more permeable to fluorescein than normal, a finding that Blanksma et al26 confirmed. They concluded that aqueous flow cannot be monitored based on the rate of clearance of topically instilled fluorescein in subjects with myotonia, because the clearance resulting from diffusion may represent a significantly large fraction of the total clearance. Aqueous hyposecretion has been attributed to atrophy of the ciliary body13 or to elevated plasma concentrations of gonadotropins.26 The hypothesis of decreased aqueous formation is supported by histologic findings that indicated that the stroma of the ciliary processes is hyalinized27 and by cycloscopic findings that showed that the ciliary processes in this condition are small.28 In contrast, Khan and Brubaker19 reported increased gonadotropin follicle-stimulating and luteinizing hormones
Figure 3. Echographic image of the ciliary body in a healthy subject.
Rosa et al 䡠 Ciliary Body and Myotonic Dystrophy in patients with myotonia, but stated that a cause-and-effect relationship with aqueous dynamics could not be demonstrated. Based on anatomic studies that showed that the ciliary muscle and the iris sphincter show signs of atrophy,12,28 the investigators hypothesized that the hypotony primarily is the result of atrophy of the ciliary muscle, which increases fluid exchange between the anterior chamber and the anterior uvea, with consequent enhanced uveoscleral outflow. There are 3 mechanisms by which CTG expansion can result in DM1. First, repeat expansion may alter the processing or transport of the mutant dystrophia miotonica proteine kinase (DMPK) mRNA and consequently may reduce DMPK levels. Second, CTG expansion may establish a region of heterochromatin 3= of the repeat sequence and decrease SIX5 transcription. Third, toxic effects of the repeat expansion may be intrinsic to the repeated elements at the level of the DNA or RNA. Previous studies have reported that a dose-dependent loss of murine Dm15 (the mouse DMPK homolog) produces a partial myotonic dystrophy phenotype characterized by decreased development of skeletal muscle force and cardiac conduction disorders. Klesert et al29 analyzed a mouse strain in which Six5 was deleted to test the role of Six5 loss in myotonic dystrophy. The authors reported that the rate and severity of cataract formation was inversely related to the Six5 dosage and was temporally progressive. Six5⫹/– and Six5–/– mice showed increased steady-state levels of the Na⫹/K⫹-ATPase ␣-1 subunit and decreased Dm15 mRNA levels. Thus, altered ion homeostasis may contribute to detachment of the ciliary body, hypotonia, and cataract formation. The authors propose that a ciliary body detachment in an individual who had not undergone an ocular surgery or sustained a trauma could be considered a marker of suspected DM1 diagnosis, because such a detachment does not occur in normal individuals.
References 1. Mahadevan M, Tsilfidis C, Sabourin L, et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3= untranslated region of the gene. Science 1992;255:1253–5. 2. Fu YH, Pizzuti A, Fenwick RG Jr, et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 1992;255:1256 – 8. 3. Brook JD, McCurrach ME, Harley HG, et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3= end of transcript encoding a protein kinase family member. Cell 1992;68:799 – 808. 4. Liquori CL, Ricker K, Moseley ML, et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 2001;293:864 –7. 5. Cho DH, Tapscott SJ. Myotonic dystrophy: emerging mechanisms for DM1 and DM2. Biochim Biophys Acta 2007;1772: 195–204. 6. Harper PS. Myotonic dystrophy. In: Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. Emery and Rimoin’s Principles and Practice of Medical Genetics, 4th ed. London: ChurchillLivingstone, 2002;3393– 418.
7. Dreyer RF. Ocular hypotony in myotonic dystrophy. Int Ophthalmology 1983;6:221–3. 8. Kuhn E, Piesbergen HJ. 5Hypotension des Bulbus und Katarakt bei myotonischer Dystrophie [in German]. Klin Monbl Augenheilkd Augenarztl Fortbild 1957;2130:329 –35. 9. Rosa N, Lanza M, Borrelli M, et al. intraocular pressure and corneal biomechanical properties in patients with myotonic dystrophy. Ophthalmology 2009;116:231– 4. 10. Rosa N, Lanza M, Borrelli M, et al. Corneal thickness and endothelial cell characteristics in patients with myotonic dystrophy. Ophthalmology1 2010;117:223–5. 11. Burian HM, Burns CA. Ocular changes in myotonic dystrophy. Trans Am Ophthalmol Soc 1966;64:250 –73. 12. Houber JP, Babel J. Uveo-retinal lesions in myotonic dystrophy: histological study [in French]. Ann Ocul (Paris) 1970;203:1067–76. 13. Nappi G, Savoldi F, Sandrini G, Poloni M. Tonographic evaluation of intraocular pressure in myotonic dystrophy. Boll Soc Ital Biol Sper 1978;54:180 –3. 14. Tello C, Liebmann J, Ritch R. An improved coupling medium for ultrasound biomicroscopy. Ophthalmic Surg 1994;25:410–1. 15. Sharma T, Salmon JF. Hypotony and choroidal detachment as a complication of topical combined timolol and dorzolamide. J Ocul Pharmacol Ther 2007;23:202–5. 16. Callahan C, Ayyala RS. Hypotony and choroidal effusion induced by topical timolol and dorzolamide in patients with previous glaucoma drainage device implantation. Ophthalmic Surg Lasers Imaging 2003;34:467–9. 17. Salzmann J, Khaw PT, Laidlaw A. Choroidal effusions and hypotony caused by severe anterior lens capsule contraction after cataract surgery. Am J Ophthalmol 2000;129:253– 4. 18. Gentile RC, Pavlin CJ, Liebmann JM, et al. Diagnosis of traumatic cyclodialysis by ultrasound biomicroscopy. Ophthalmic Surg Lasers 1996;27:97–105. 19. Khan AR, Brubaker RF. Aqueous humor flow and flare in patients with myotonic dystrophy. Invest Ophthalmol Vis Sci 1993;34:3131–9. 20. Fannin LA, Schiffman JC, Budenz DL. Risk factor for hypotony maculopathy. Ophthalmology 2003;110:1185–91. 21. Bojadós S, Vela JI, Roselló N, et al. Choroidal detachment associated with delayed spontaneous ocular hypotony. Arch Soc Esp Oftalmol 2007;82:381– 4. 22. Pederson JE. Ocular hypotony. Trans Ophthalmol Soc UK 1986;105:220 – 6. 23. Schubert HD. Postsurgical hypotony: relationship to fistulization, inflammation, chorioretinal lesions, and the vitreous. Surv Ophthalmol 1996;41:97–125. 24. Junge J. Ocular changes in dystrophia myotonica. Ophthalmologica 1968;155:291–2. 25. Walker SD, Brubaker RF, Nagataki S. Hypotony and aqueous humor dynamics in myotonic dystrophy. Invest Ophthalmol Vis Sci 1982;22:744 –51. 26. Blanksma LJ, Kooijman AC, Siertsema JV, Roze JH. Fluorophotometry in myotonic dystrophy. Doc Ophthalmol 1983;56: 111– 4. 27. Burns CA. Ocular histopathology of myotonic dystrophy. A clinicopathologic case report. Am J Ophthalmol 1969;68: 416 –22. 28. Meyer E, Navon D, Auslender L, Zonis S. Myotonic dystrophy: pathological study of the eyes. Ophthalmologica 1980;181:215–20. 29. Klesert TR, Cho DH, Clark JI, et al. Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy. Nat Genet 2000;25:105–9.
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Footnotes and Financial Disclosures Originally received: January 13, 2010. Final revision: June 8, 2010. Accepted: June 15, 2010. Available online: August 30, 2010.
Manuscript no. 2010-67.
1
Centro Grandi Apparecchiature, Second University of Naples, Naples, Italy.
2
Eye Department, Second University of Naples, Naples, Italy.
3
Department of Experimental Medicine, Cardiomyology and Medical Genetics, Second University of Naples, Naples, Italy.
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Presented at: American Academy of Ophthalmology Joint Meeting with the Pan-American Association of Ophthalmology, October 2009, San Francisco, California. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Correspondence: Nicola Rosa, MD, Centro Grandi Apparecchiature, Second University of Naples, Via De Crecchio 16, 80100 Naples, Italy. E-mail: nicola. [email protected].
Myotonic dystrophy type 1 (DM1) is a muscle disease with an autosomal dominant mode of inheritance that affects approximately 1 in 8000 white persons. The genetic defect associated with DM1 is abnormal expansion of a CTG trinucleotide repeat in the 3= end of the DMPK gene on chromosome 19q13.3. Normal alleles have from 5 to 34 CTG repeats, whereas DM1 alleles contain from 50 to 2000 or more CTG repeats.1–3 In DM1, the muscle involvement is characterized by myotonia and muscular weakness involving the facial, axial, semidistal, and distal compartments. Symptoms generally develop between the second and the fourth decades of life and progress slowly over time. Besides muscles, DM1 affects other organs, including endocrine function (diabetes, thyroid dysfunction, hypogonadism), the nervous system (mental retardation), the gastrointestinal tract (dysphagia, pseudo-obstruction), and the heart. Cardiac involvement poses a major problem in clinical management; cardiac complications are the primary cause of premature death in DM1. In particular, there is a high
260
© 2011 by the American Academy of Ophthalmology Published by Elsevier Inc.
incidence of sudden death, ranging from 2% to 30% of cases, that is related primarily to the development of conduction block. A second form of myotonic dystrophy, proximal myotonic myopathy, or myotonic dystrophy type 2, which has been described previously,4 results from CTG expansion on chromosome 3. The similarities of and differences between DM1 and myotonic dystrophy type 2 are shown in Table 1.5 The most common ocular abnormalities in DM1 include cataract, ptosis, exposure keratitis, pigmentary abnormalities, abnormal electroretinography results, abnormal dark adaptation, and weakness of the orbicularis ocular muscles.6 It also has been reported that patients with DM1 can have low intraocular pressure (IOP).7,8 In a previously published study, we found this hypotony to be real and unrelated to different corneal biomechanical properties or endothelium abnormalities.9,10 Although it has been suggested that the hypotony in DM1 could be related to increased outflow ISSN 0161-6420/11/$–see front matter doi:10.1016/j.ophtha.2010.06.020
Rosa et al 䡠 Ciliary Body and Myotonic Dystrophy Table 1. Similarities and Differences in Myotonic Dystrophy Type 1 and Myotonic Dystrophy Type 2 Myotonic Dystrophy Type 1-Specific Features Prominent distal muscle weakness at onset Distal muscle atrophy at onset Congenital DM1 Gastrointestinal tract problems
Shared Features Myotonia* Muscle weakness and atrophy Cataract Cardiac conduction defects* Cognitive dysfunction* Hypersomnia* Insulin resistance Testicular atrophy Frontal balding in men Hypogammaglobulinemia Muscle pain
Myotonic Dystrophy Type 2-Specific Features Prominent proximal muscle weakness at onset Proximal muscle atrophy at onset Hypertrophic calf muscles
DM1 ⫽ myotonic dystrophy type 1. *Present in myotonic dystrophy type 2, but more prominent in myotonic dystrophy type 1.5
facility or decreased aqueous secretion, the pathophysiologic mechanism responsible for low IOP remains unclear.11,12 Some authors attributed the hyposecretion of aqueous humor to ciliary body atrophy.13 To determine the mechanism of the low IOP in DM1, the authors performed an in vivo study of the ciliary body in these patients.
Patients and Methods A total of 102 eyes of 51 patients (28 men, 23 women) with DM1 who were followed up at the Department of Cardiomyology and Medical Genetics, Second University Medical School, Naples, Italy, were enrolled consecutively in this study. The patients ranged in age from 21 to 64 years (mean⫾standard deviation [SD], 37.1⫾11 years). The diagnosis of DM1 was based on family history, typical muscular findings, and electromyography results and was confirmed by genetic analysis showing pathologic CTG repeats of different sizes (mean number, 785; range, 68 –2900) in all patients. The control group consisted of 44 eyes (22 healthy subjects) who were similar in age (range, 21– 64 years; mean⫾SD, 40.6⫾12.5 years). The inclusion criterion was a definitive diagnosis of DM1 obtained by molecular analysis. The exclusion criteria were the presence of cataract, previous ocular surgery, use of systemic or topical drugs that alter the aqueous humor flow or IOP, or contact lens wear. Each patient provided informed consent according to the guidelines of the Declaration of Helsinki, and the institutional review board approved the study protocol. All patients underwent a complete ophthalmic examination including measurement of the IOP by Goldmann applanation tonometry, measurement of the central corneal thickness with the Pentacam camera (Oculus, Wetzlar, Germany), and an examination with Hi Scan ultrasound biomicroscopy (Optikon 2000, Rome, Italy). This device has a 35-MHz probe and achieves a tissue resolution of approximately 50 m. Scanning was performed with the patients supine in standard room light. A fixation target was used for the unaffected eye. After topical anesthesia was instilled, an eye cup was placed on the eye and was filled with saline solution, which serves as a coupling medium.14 The ultrasound probe was placed in the coupling medium approximately 7 to 8 mm from the ocular surface. Fine transverse and longitudinal movements of the probe were performed manually to capture multiple scans of the ciliary body over 360° in each eye.
Results In patients with DM1, the IOP values ranged from 3 to 19 mmHg (mean⫾SD, 10.9⫾3.1 mmHg). In the control group, the IOP values ranged from 11 to 19 mmHg (mean⫾SD, 15.4⫾2.2 mmHg). The difference between the groups reached significance (P⬍0.01). In the patients with DM1, the central corneal thickness ranged from 502 to 678 m (mean⫾SD, 574.4⫾37.9 m), and in the control group, the central corneal thickness ranged from 503 to 660 m (mean⫾SD, 557.8⫾39.2 m; P ⫽ 0.02). The echographic examination in patients with DM1 showed the presence of an area of lower refraction below the ciliary body (Fig 1) that is consistent with the presence of fluid behind the ciliary body. This finding was not present over 360°, and the extent differed in each patient (Table 2, available at http://aaojournal. org). In 48 patients, this finding was present bilaterally, and the number of involved quadrants was the same in 25 patients (1 quadrant in 1 patient, 2 quadrants in 8 patients, 3 quadrants in 7 patients, and 4 quadrants in 9 patients). Considering both eyes, the inferior quadrant was affected most often (75 eyes), whereas the quadrant that was most often involved
Figure 1. Echographic image showing the presence of a ciliary body detachment in a myotonic dystrophy (DM1) patient. dB ⫽ decibels.
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Figure 2. Scatterplot between intraocular pressure (IOP; x-axis) and number of involved quadrants (y-axis) showing a poor correlation (R2 ⫽ 0.088). dB ⫽ decibels.
in the right eyes was the temporal quadrant (39 eyes) and in the left eyes was the inferior quadrant (44 eyes). The number of involved quadrants was unrelated to the IOP (Fig 2). This clinical picture was not present in any control patients (Fig 3).
Discussion Ocular hypotony has been reported to be among the most frequent ocular anomalies associated with DM1. Several causes of ocular hypotony have been described, such as the combined use of topical timolol and dorzolamide,15 intraocular surgery,16,17 or trauma.18 None of these is responsible for the DM1 in the current study, because patients who had undergone a previous intraocular surgery, had sustained ocular trauma, or had been treated with an ocular medication were excluded. Hypotony also can result from either increased outflow (abnormally low episcleral venous pressure, abnormally high outflow facility, slow rate of aqueous flow through the anterior chamber, abnormally high rate of uveoscleral outflow) or decreased aqueous production (hyalinization and/or atrophy of the ciliary processes). Our in vivo high-frequency ultrasound findings in the patients with DM1 in the current study support the hypothesis of Khan and Brubaker.19 In fact, the atrophy of the ciliary muscle could increase the uveoscleral outflow, leading to ciliary body detachment (shown by echography). This condition causes a decrease in the ciliary body blood supply and a consequent decrease in the aqueous production and ocular hypotonia. This also may explain the findings of Burian and Burns,11 who examined 45 eyes of 23 patients with DM1 who had a mean IOP of 10 mmHg (range, 4 –17 mmHg). When the patients were divided into age groups, the investigators found a decrease in IOP with advancing age, which also can explain why the ciliary body detachment is not always related to low IOP. Ocular hypotony can be defined in several ways. Some authors have described ocular hypotony as the presence of IOP of less than 5 mmHg,20 whereas others have defined it as an IOP of less than the level that causes
262
structural and functional changes that disallow normal ocular functions.21 Pederson22 divided hypotony into 2 categories: statistical and clinical. Statistical hypotony was defined is an IOP of less than 6.5 mmHg, which is more than 3 SDs less than the mean. Clinical hypotony was defined as low IOP that can result in visual loss, which occurs with an IOP of less than 4 mmHg. Schubert23 defined hypotony as low IOP in an individual eye leading to functional and structural changes. Several authors have investigated the reason for low IOP in patients with myotonic dystrophy; however, the results remain controversial. Junge24 suggested that increased outflow facility may account for the hypotony, but other researchers7,13 found tonographic outflow facility to be normal and insufficient to explain the hypotony, and for these reasons, they attributed the hypotony to either decreased aqueous formation or abnormal uveoscleral outflow. Unfortunately, tonographic data are questionable in eyes with very low IOP; for this reason, Walker et al25 measured the rate of clearance of fluorescein from the anterior chamber and the endothelial permeability to fluorescein in patients with myotonic dystrophy and found the measurements to be the same as in normal subjects. Moreover, the investigators found the blood–aqueous barrier to be more permeable to fluorescein than normal, a finding that Blanksma et al26 confirmed. They concluded that aqueous flow cannot be monitored based on the rate of clearance of topically instilled fluorescein in subjects with myotonia, because the clearance resulting from diffusion may represent a significantly large fraction of the total clearance. Aqueous hyposecretion has been attributed to atrophy of the ciliary body13 or to elevated plasma concentrations of gonadotropins.26 The hypothesis of decreased aqueous formation is supported by histologic findings that indicated that the stroma of the ciliary processes is hyalinized27 and by cycloscopic findings that showed that the ciliary processes in this condition are small.28 In contrast, Khan and Brubaker19 reported increased gonadotropin follicle-stimulating and luteinizing hormones
Figure 3. Echographic image of the ciliary body in a healthy subject.
Rosa et al 䡠 Ciliary Body and Myotonic Dystrophy in patients with myotonia, but stated that a cause-and-effect relationship with aqueous dynamics could not be demonstrated. Based on anatomic studies that showed that the ciliary muscle and the iris sphincter show signs of atrophy,12,28 the investigators hypothesized that the hypotony primarily is the result of atrophy of the ciliary muscle, which increases fluid exchange between the anterior chamber and the anterior uvea, with consequent enhanced uveoscleral outflow. There are 3 mechanisms by which CTG expansion can result in DM1. First, repeat expansion may alter the processing or transport of the mutant dystrophia miotonica proteine kinase (DMPK) mRNA and consequently may reduce DMPK levels. Second, CTG expansion may establish a region of heterochromatin 3= of the repeat sequence and decrease SIX5 transcription. Third, toxic effects of the repeat expansion may be intrinsic to the repeated elements at the level of the DNA or RNA. Previous studies have reported that a dose-dependent loss of murine Dm15 (the mouse DMPK homolog) produces a partial myotonic dystrophy phenotype characterized by decreased development of skeletal muscle force and cardiac conduction disorders. Klesert et al29 analyzed a mouse strain in which Six5 was deleted to test the role of Six5 loss in myotonic dystrophy. The authors reported that the rate and severity of cataract formation was inversely related to the Six5 dosage and was temporally progressive. Six5⫹/– and Six5–/– mice showed increased steady-state levels of the Na⫹/K⫹-ATPase ␣-1 subunit and decreased Dm15 mRNA levels. Thus, altered ion homeostasis may contribute to detachment of the ciliary body, hypotonia, and cataract formation. The authors propose that a ciliary body detachment in an individual who had not undergone an ocular surgery or sustained a trauma could be considered a marker of suspected DM1 diagnosis, because such a detachment does not occur in normal individuals.
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Ophthalmology Volume 118, Number 2, February 2011
Footnotes and Financial Disclosures Originally received: January 13, 2010. Final revision: June 8, 2010. Accepted: June 15, 2010. Available online: August 30, 2010.
Manuscript no. 2010-67.
1
Centro Grandi Apparecchiature, Second University of Naples, Naples, Italy.
2
Eye Department, Second University of Naples, Naples, Italy.
3
Department of Experimental Medicine, Cardiomyology and Medical Genetics, Second University of Naples, Naples, Italy.
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Presented at: American Academy of Ophthalmology Joint Meeting with the Pan-American Association of Ophthalmology, October 2009, San Francisco, California. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Correspondence: Nicola Rosa, MD, Centro Grandi Apparecchiature, Second University of Naples, Via De Crecchio 16, 80100 Naples, Italy. E-mail: nicola. [email protected].