- Email: [email protected]
Kayser-Fleischer ring as the presenting sign of Wilson disease
Kayser–Fleischer Ring as the Presenting Sign of Wilson Disease Mimi Liu, MD, Elisabeth J. Cohen, George J. Brewer, MD, and Peter R. Laibson, MD PURPOSE:
To describe a case in which the recognition by the ophthalmologist of Kayser–Fleischer rings played a crucial role in the diagnosis of Wilson disease (hepatolenticular degeneration). DESIGN: Interventional case report. METHODS: An 18-year-old woman was found to have bilateral peripheral golden brown pigment deposits at the level of the Descemet membrane consistent with Kayser– Fleischer rings. She initially denied systemic symptoms. RESULTS: The serum cerumoplasmin level of the patient was normal. Liver function tests were also normal. Further evaluations with 24-hour urine copper assay and liver biopsy were positive for Wilson disease. She underwent anticopper therapy and, 6 months later, reported improved concentration and balance. No appreciable change occurred in the Kayser–Fleischer rings. CONCLUSION: Wilson disease occurs when a defective copper-transporting enzyme in the liver results in toxic copper accumulation in multiple organs. Because of the insidious nature of the disease, patients may not seek medical attention until severe irreversible damage has occurred. By diagnosis of Kayser–Fleischer rings, ophthalmologists may play a critical role in the early recognition and proper evaluation of such patients. (Am J Ophthalmol 2002;133:832– 834. © 2002 by Elsevier Science Inc. All rights reserved.)
FIGURE 2. (Top) Sequence analysis of M1S1 near codon 118 in the younger brother. The arrow indicates the homozygous mutation Glu118Stop. No mutation was detected in a healthy control (Bottom). The result in the elder brother was exactly the same as in the younger brother (data not shown).
A ular diagnosis may be useful, especially in sporadic cases of gelatinous drop-like corneal dystrophy without a gelatinous drop-like region. REFERENCES
1. Kanai A, Kaufman HE. Electron microscopic studies of primary band-shaped keratopathy and gelatinous, drop-like corneal dystrophy in two brothers. Ann Ophthalmol 1982;14: 535–539. 2. Akiya S, Takahashi H, Furukawa H, et al. A case of one eye with gelatinous drop-like corneal dystrophy and the other eye with band-shaped spheroidal corneal degeneration. Ophthalmologica 1995;209:96 –100. 3. Tsujikawa M, Kurahashi H, Tanaka T, et al. Identification of the gene responsible for gelatinous drop-like corneal dystrophy. Nat Genet 1999;21:420 – 423. 4. Nakamura T, Nishida K, Dota A, et al. Gelatino-lattice corneal dystrophy: clinical features and mutational analysis. Am J Ophthalmol 2000;129:665– 666.
832
AMERICAN JOURNAL
N 18-YEAR-OLD WOMAN PRESENTED TO A GENERAL
ophthalmologist for a routine examination. She was found to have attention deficit disorder at age 15 and took ritalin. Kayser–Fleischer rings were observed, but the initial examination of the patient showed normal liver function tests, and a cerumoplasmin (Cp) level of 25.1 mg/dl (normal, 25 to 63 mg/dl). She denied neurologic or systemic symptoms, and her family history was unremarkable. She was referred to the Wills Eye Hospital Cornea Service for a second opinion. The best-corrected acuity of the patient was 20/20 in both eyes. Deep brown peripheral corneal deposits consistent with Kayser–Fleischer rings were seen on slit-lamp examination (Figures 1 and 2). On review of systems, she Accepted for publication Jan 22, 2002. From the Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania (M.L., E.J.C., P.R.L.), and the Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, Michigan (G.J.B.). Inquiries to Mimi Liu, MD, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107; fax: (215) 928-3854; e-mail: mimiliu@ hotmail.com
OF
OPHTHALMOLOGY
JUNE 2002
FIGURE 1. Slit-lamp biomicroscopy shows peripheral golden brown deposits measuring 1.5 mm superiorly and 1.0 mm inferiorly.
FIGURE 2. Slit-lamp biomicroscopy demonstrates granular corneal pigment deposits located at the level of the Descemet membrane.
reported leg cramps and imbalance. Her 24-hour urine copper level was 841 g (normal, 20 to 50 g). Liver biopsy showed diagnostically increased copper content. Wilson disease was diagnosed. On further questioning, she recalled a 6-month history of progressive hand tremors, slurred speech, micrographia, and drooling. She underwent induction treatment with oral tetrathiomolybdate for 8 weeks, followed by maintenance with oral zinc acetate. All of her symptoms decreased after 6 months and are expected to continue to improve over the next 2 years. No appreciable change occurred in the Kayser–Fleischer rings at the 9-month follow-up. Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder in which a defect in copper transporting enzyme (ATP7B) in the liver results in a failure of biliary excretion of copper and toxic accumulation in multiple organs. ATP7B is involved in the incorporation of copper into Cp so that a defect in ATP7B not only results in increased copper levels, but also in low Cp levels. Patients present in their teens and twenties with hepatic dysfunction or movement disorder symptoms such as tremor, dystonia, incoordination, slurred speech, and behavioral changes. Although rarely seen in patients with other forms of hepatic disease, Kayser–Fleischer rings are
found in over 99% of Wilson patients who are affected neurologically.2 Kayser–Fleischer rings are copper deposits in the Descemet membrane and may be golden brown, ruby red, or blue-green. They first appear superiorly and spread circumferentially. Gonioscopy may assist the visualization of early deposits in the angle that may precede corneal deposits visible by slit-lamp examination. The presence of Kayser–Fleischer rings should be considered as indicative of Wilson disease until proven otherwise, because almost always this will be the diagnosis. However, these rings are rarely observed in other conditions associated with obstructive liver diseases, chalcosis, multiple myeloma, and pulmonary carcinoma.3,4 Twentyfour– hour urine copper is a more sensitive screening test than is serum Cp. Liver biopsy for quantitative copper assay with a copper-free needle is the gold standard for the diagnosis of Wilson disease. Kayser–Fleischer rings have been reported to fade with anticopper therapy,5 but a recent study failed to show a correlation between reduced ring size and improved neurologic function.1 Penicillamine was the first orally effective anticopper therapy. However, it is associated with hypersensitivity reactions and worsening of neurologic symptoms in 25% to 30% of patients.2 Tetrathiomolybdate forms a stable com-
VOL. 133, NO. 6
BRIEF REPORTS
833
plex with protein and copper and prevents copper absorption. Zinc induces intestinal metallothionein that binds copper and prevents its transfer to the circulation.2 Recovery of neurologic and hepatic function may be dramatic during the first 2 years of therapy and depends on the disease severity at presentation. This underscores the importance of early recognition of the disease by ophthalmologists.
RESULTS:
In both patients, bleb leaks were closed successfully with amniotic membrane graft, and bleb function was maintained during the follow-up period of 34 and 14 months, respectively. CONCLUSION: Amniotic membrane graft may be considered an alternative method for treating late-onset filtering bleb leaks while maintaining bleb function. As the number of cases was small, more cases need to be accumulated to verify the usefulness of this technique. (Am J Ophthalmol 2002;133:834 – 835. © 2002 by Elsevier Science Inc. All rights reserved.)
REFERENCES
1. Rodman R, Burnstine M, et al. Wilson’s disease: presymptomatic patients and Kayser-Fleischer rings. Ophthalmic Genetics 1997;18:79 – 85. 2. Brewer G. Recognition, diagnosis, and management of Wilson’s disease. Proc Soc Exp Bio Med 2000;223:39 – 46. 3. Lipman RM, Deutsch TA. Yellow-green posterior limbal ring in a patient who does not have Wilson’s disease. Arch Ophthalmol 1990;108:1385. 4. Martin NF, Kincaid MC, Stark WJ, et al. Ocular copper deposition associated with pulmonary carcinoma, IgG monoclonal gammopathy and hypercupremia. Ophthalmology 1983;90:110 –116. 5. Esmaeli B, Burnstine M, Martyonyi C, Sugar A, Johnson V, Brewer G. Regression of Kayser-Fleischer rings during oral zinc therapy: correlation with systemic manifestations of Wilson’s disease. Cornea 1996;15:582–588.
L
ATE-ONSET BLEB LEAK IS A WELL-DOCUMENTED COM-
plication of filtration surgery.1 The treatment of bleb leaks is difficult, and the results have not proved satisfactory.1,2 Various surgical treatments, including direct suturing of the conjunctival buttonhole or surgical revision with advancement of fornix conjunctival flap, have been utilized.2 However, these surgical modalities share the risk of loss of bleb function. In the field of ophthalmology, amniotic membrane graft has been proved effective for the ocular surface reconstruction.3 Because of these encouraging results, we performed amniotic membrane graft in patients with bleb leaks after trabeculectomy with mitomycin C. We report here the preliminary results of surgical treatment of two eyes of two patients with late-onset bleb leaks. ● CASE 1:
A 23-year-old Asian man underwent a trabeculectomy with adjunctive mitomycin C in the left eye on December 5, 1997. Eight months after trabeculectomy, the patient developed bleb leaks at two different sites on the filtering bleb. Small localized leaks were found in a transparent area on a larger thin and translucent avascular bleb (Figure 1, left side). Intraocular pressure was 20 mm Hg without the use of antiglaucoma medications, and the anterior chamber was deep and clear. Amniotic membrane was prepared as previously described.3 Under topical anesthesia, the fashioned membrane with the basement membrane on the conjunctival side was then secured to the conjunctiva by interrupted 10 – 0 nylon sutures. The entire bleb was covered, and the sutures were placed away from the edge of the bleb (Figure 2). After surgery, 0.3% ofloxacin and 0.1% fluorometholone were instilled four times daily for 2 weeks. Three weeks postoperatively, the amniotic membrane was removed spontaneously by the weakening of the sutured area of the amniotic membrane graft, and a well-functioning bleb with no signs of leakage was observed (Figure 1, right side). Sutures were removed without any signs of leakage at postoperative 3 weeks. Thirty-four months postoperatively, a well-functioning bleb without any leakage was observed and intraocular pressure was 18 mm Hg without the use of antiglaucoma medications.
Amniotic Membrane Graft for Lateonset Glaucoma Filtering Leaks Changwon Kee, MD, and Jeong-Min Hwang, MD PURPOSE:
To evaluate the effectiveness and safety of amniotic membrane graft in the management of late-onset filtering bleb leaks after trabeculectomy with mitomycin C. DESIGN: Prospective, noncomparative, interventional case reports. METHODS: Two eyes of two patients with late-onset filtering bleb leak received an amniotic membrane graft.
Accepted for publication Jan 16, 2002. From the Department of Ophthalmology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Korea (C.K.), and the Department of Ophthalmology, Seoul Municipal Boramae Hospital, School of Medicine, Seoul National University, Seoul, Korea (J.-M.H.). Inquires to Changwon Kee, MD, Department of Ophthalmology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul 135-710, Korea; fax: (⫹82) 2-3410-0074; e-mail: cwkee@ ophthalmology.org
834
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
JUNE 2002
To describe a case in which the recognition by the ophthalmologist of Kayser–Fleischer rings played a crucial role in the diagnosis of Wilson disease (hepatolenticular degeneration). DESIGN: Interventional case report. METHODS: An 18-year-old woman was found to have bilateral peripheral golden brown pigment deposits at the level of the Descemet membrane consistent with Kayser– Fleischer rings. She initially denied systemic symptoms. RESULTS: The serum cerumoplasmin level of the patient was normal. Liver function tests were also normal. Further evaluations with 24-hour urine copper assay and liver biopsy were positive for Wilson disease. She underwent anticopper therapy and, 6 months later, reported improved concentration and balance. No appreciable change occurred in the Kayser–Fleischer rings. CONCLUSION: Wilson disease occurs when a defective copper-transporting enzyme in the liver results in toxic copper accumulation in multiple organs. Because of the insidious nature of the disease, patients may not seek medical attention until severe irreversible damage has occurred. By diagnosis of Kayser–Fleischer rings, ophthalmologists may play a critical role in the early recognition and proper evaluation of such patients. (Am J Ophthalmol 2002;133:832– 834. © 2002 by Elsevier Science Inc. All rights reserved.)
FIGURE 2. (Top) Sequence analysis of M1S1 near codon 118 in the younger brother. The arrow indicates the homozygous mutation Glu118Stop. No mutation was detected in a healthy control (Bottom). The result in the elder brother was exactly the same as in the younger brother (data not shown).
A ular diagnosis may be useful, especially in sporadic cases of gelatinous drop-like corneal dystrophy without a gelatinous drop-like region. REFERENCES
1. Kanai A, Kaufman HE. Electron microscopic studies of primary band-shaped keratopathy and gelatinous, drop-like corneal dystrophy in two brothers. Ann Ophthalmol 1982;14: 535–539. 2. Akiya S, Takahashi H, Furukawa H, et al. A case of one eye with gelatinous drop-like corneal dystrophy and the other eye with band-shaped spheroidal corneal degeneration. Ophthalmologica 1995;209:96 –100. 3. Tsujikawa M, Kurahashi H, Tanaka T, et al. Identification of the gene responsible for gelatinous drop-like corneal dystrophy. Nat Genet 1999;21:420 – 423. 4. Nakamura T, Nishida K, Dota A, et al. Gelatino-lattice corneal dystrophy: clinical features and mutational analysis. Am J Ophthalmol 2000;129:665– 666.
832
AMERICAN JOURNAL
N 18-YEAR-OLD WOMAN PRESENTED TO A GENERAL
ophthalmologist for a routine examination. She was found to have attention deficit disorder at age 15 and took ritalin. Kayser–Fleischer rings were observed, but the initial examination of the patient showed normal liver function tests, and a cerumoplasmin (Cp) level of 25.1 mg/dl (normal, 25 to 63 mg/dl). She denied neurologic or systemic symptoms, and her family history was unremarkable. She was referred to the Wills Eye Hospital Cornea Service for a second opinion. The best-corrected acuity of the patient was 20/20 in both eyes. Deep brown peripheral corneal deposits consistent with Kayser–Fleischer rings were seen on slit-lamp examination (Figures 1 and 2). On review of systems, she Accepted for publication Jan 22, 2002. From the Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania (M.L., E.J.C., P.R.L.), and the Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, Michigan (G.J.B.). Inquiries to Mimi Liu, MD, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107; fax: (215) 928-3854; e-mail: mimiliu@ hotmail.com
OF
OPHTHALMOLOGY
JUNE 2002
FIGURE 1. Slit-lamp biomicroscopy shows peripheral golden brown deposits measuring 1.5 mm superiorly and 1.0 mm inferiorly.
FIGURE 2. Slit-lamp biomicroscopy demonstrates granular corneal pigment deposits located at the level of the Descemet membrane.
reported leg cramps and imbalance. Her 24-hour urine copper level was 841 g (normal, 20 to 50 g). Liver biopsy showed diagnostically increased copper content. Wilson disease was diagnosed. On further questioning, she recalled a 6-month history of progressive hand tremors, slurred speech, micrographia, and drooling. She underwent induction treatment with oral tetrathiomolybdate for 8 weeks, followed by maintenance with oral zinc acetate. All of her symptoms decreased after 6 months and are expected to continue to improve over the next 2 years. No appreciable change occurred in the Kayser–Fleischer rings at the 9-month follow-up. Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder in which a defect in copper transporting enzyme (ATP7B) in the liver results in a failure of biliary excretion of copper and toxic accumulation in multiple organs. ATP7B is involved in the incorporation of copper into Cp so that a defect in ATP7B not only results in increased copper levels, but also in low Cp levels. Patients present in their teens and twenties with hepatic dysfunction or movement disorder symptoms such as tremor, dystonia, incoordination, slurred speech, and behavioral changes. Although rarely seen in patients with other forms of hepatic disease, Kayser–Fleischer rings are
found in over 99% of Wilson patients who are affected neurologically.2 Kayser–Fleischer rings are copper deposits in the Descemet membrane and may be golden brown, ruby red, or blue-green. They first appear superiorly and spread circumferentially. Gonioscopy may assist the visualization of early deposits in the angle that may precede corneal deposits visible by slit-lamp examination. The presence of Kayser–Fleischer rings should be considered as indicative of Wilson disease until proven otherwise, because almost always this will be the diagnosis. However, these rings are rarely observed in other conditions associated with obstructive liver diseases, chalcosis, multiple myeloma, and pulmonary carcinoma.3,4 Twentyfour– hour urine copper is a more sensitive screening test than is serum Cp. Liver biopsy for quantitative copper assay with a copper-free needle is the gold standard for the diagnosis of Wilson disease. Kayser–Fleischer rings have been reported to fade with anticopper therapy,5 but a recent study failed to show a correlation between reduced ring size and improved neurologic function.1 Penicillamine was the first orally effective anticopper therapy. However, it is associated with hypersensitivity reactions and worsening of neurologic symptoms in 25% to 30% of patients.2 Tetrathiomolybdate forms a stable com-
VOL. 133, NO. 6
BRIEF REPORTS
833
plex with protein and copper and prevents copper absorption. Zinc induces intestinal metallothionein that binds copper and prevents its transfer to the circulation.2 Recovery of neurologic and hepatic function may be dramatic during the first 2 years of therapy and depends on the disease severity at presentation. This underscores the importance of early recognition of the disease by ophthalmologists.
RESULTS:
In both patients, bleb leaks were closed successfully with amniotic membrane graft, and bleb function was maintained during the follow-up period of 34 and 14 months, respectively. CONCLUSION: Amniotic membrane graft may be considered an alternative method for treating late-onset filtering bleb leaks while maintaining bleb function. As the number of cases was small, more cases need to be accumulated to verify the usefulness of this technique. (Am J Ophthalmol 2002;133:834 – 835. © 2002 by Elsevier Science Inc. All rights reserved.)
REFERENCES
1. Rodman R, Burnstine M, et al. Wilson’s disease: presymptomatic patients and Kayser-Fleischer rings. Ophthalmic Genetics 1997;18:79 – 85. 2. Brewer G. Recognition, diagnosis, and management of Wilson’s disease. Proc Soc Exp Bio Med 2000;223:39 – 46. 3. Lipman RM, Deutsch TA. Yellow-green posterior limbal ring in a patient who does not have Wilson’s disease. Arch Ophthalmol 1990;108:1385. 4. Martin NF, Kincaid MC, Stark WJ, et al. Ocular copper deposition associated with pulmonary carcinoma, IgG monoclonal gammopathy and hypercupremia. Ophthalmology 1983;90:110 –116. 5. Esmaeli B, Burnstine M, Martyonyi C, Sugar A, Johnson V, Brewer G. Regression of Kayser-Fleischer rings during oral zinc therapy: correlation with systemic manifestations of Wilson’s disease. Cornea 1996;15:582–588.
L
ATE-ONSET BLEB LEAK IS A WELL-DOCUMENTED COM-
plication of filtration surgery.1 The treatment of bleb leaks is difficult, and the results have not proved satisfactory.1,2 Various surgical treatments, including direct suturing of the conjunctival buttonhole or surgical revision with advancement of fornix conjunctival flap, have been utilized.2 However, these surgical modalities share the risk of loss of bleb function. In the field of ophthalmology, amniotic membrane graft has been proved effective for the ocular surface reconstruction.3 Because of these encouraging results, we performed amniotic membrane graft in patients with bleb leaks after trabeculectomy with mitomycin C. We report here the preliminary results of surgical treatment of two eyes of two patients with late-onset bleb leaks. ● CASE 1:
A 23-year-old Asian man underwent a trabeculectomy with adjunctive mitomycin C in the left eye on December 5, 1997. Eight months after trabeculectomy, the patient developed bleb leaks at two different sites on the filtering bleb. Small localized leaks were found in a transparent area on a larger thin and translucent avascular bleb (Figure 1, left side). Intraocular pressure was 20 mm Hg without the use of antiglaucoma medications, and the anterior chamber was deep and clear. Amniotic membrane was prepared as previously described.3 Under topical anesthesia, the fashioned membrane with the basement membrane on the conjunctival side was then secured to the conjunctiva by interrupted 10 – 0 nylon sutures. The entire bleb was covered, and the sutures were placed away from the edge of the bleb (Figure 2). After surgery, 0.3% ofloxacin and 0.1% fluorometholone were instilled four times daily for 2 weeks. Three weeks postoperatively, the amniotic membrane was removed spontaneously by the weakening of the sutured area of the amniotic membrane graft, and a well-functioning bleb with no signs of leakage was observed (Figure 1, right side). Sutures were removed without any signs of leakage at postoperative 3 weeks. Thirty-four months postoperatively, a well-functioning bleb without any leakage was observed and intraocular pressure was 18 mm Hg without the use of antiglaucoma medications.
Amniotic Membrane Graft for Lateonset Glaucoma Filtering Leaks Changwon Kee, MD, and Jeong-Min Hwang, MD PURPOSE:
To evaluate the effectiveness and safety of amniotic membrane graft in the management of late-onset filtering bleb leaks after trabeculectomy with mitomycin C. DESIGN: Prospective, noncomparative, interventional case reports. METHODS: Two eyes of two patients with late-onset filtering bleb leak received an amniotic membrane graft.
Accepted for publication Jan 16, 2002. From the Department of Ophthalmology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Korea (C.K.), and the Department of Ophthalmology, Seoul Municipal Boramae Hospital, School of Medicine, Seoul National University, Seoul, Korea (J.-M.H.). Inquires to Changwon Kee, MD, Department of Ophthalmology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul 135-710, Korea; fax: (⫹82) 2-3410-0074; e-mail: cwkee@ ophthalmology.org
834
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
JUNE 2002