BILATERAL CENTRAL RETINAL VEIN OCCLUSION IN A YOUNG PERSON WITH STORM SYNDROME Srinivas R. Sadda, MD, Pearse A. Keane, MRCOphth, MSc
Purpose: To report the presence of previously undescribed retinal abnormalities in patients with Storm and other progeric syndromes. Methods: Review of the clinical and photographic records of a patient with Storm syndrome who developed bilateral central retinal vein occlusion. Results: A 43-year-old woman with a diagnosis of Storm (Werner-like) syndrome, a connective tissue disease characterized by premature aging, presented with bilateral nonsimultaneous central retinal vein occlusion. The patient was also observed to have bilateral peripheral retinal pigment epithelial alterations. Conclusion: Retinal abnormalities can be observed in patients with premature aging syndromes. These abnormalities include the development of venous occlusive disease and peripheral retinal pigment epithelial alterations at a relatively young age and may be related to the underlying genetic mutation. RETINAL CASES & BRIEF REPORTS 3:313–315, 2009
From the Doheny Retina Institute, Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California.
Case Report A 43-year-old woman, with no ocular history, presented with a 1-week history of blurred vision in her left eye. Ten years earlier, she had been diagnosed with Storm syndrome by her rheumatologist on the basis of a constellation of findings, including premature aging (with tautening of the face and hands), alopecia and graying of scalp hair, calcific disease of the aortic and mitral valves (status postaortic and mitral mechanical valve replacements), intestinal fat malabsorption, and chronic renal insufficiency (on peritoneal dialysis). Given the prosthetic cardiac valves, the patient was maintained on warfarin sodium, and her anticoagulation was felt to be therapeutic at the time of her presentation with an international normalized ratio of 2.9. As a result of her chronic renal insufficiency, the patient had a history of anemia for which she was treated with erythropoietin. Her other medications included labetalol and calcitriol. Her hemoglobin level at the time of presentation was 10 g/dL (lower limit of normal being 12). The patient’s medical history was also notable for mild hypertension of 5 years in duration (subsequent to the development of renal disease). Her blood pressure was well controlled with an average pressure of 120/80 mmHg; of note, no severe blood pressure elevations (i.e., ⬎180 mmHg systolic or ⬎100 mmHg diastolic) were documented during this time. Ophthalmic examination at the time of presentation revealed a best-corrected Snellen visual acuity of 20/20 in the right eye and 20/50 in the left. Color vision testing was normal with the patient able to identify all 10 Ishihara plate correctly in both eyes. Ocular motility and confrontation visual fields were normal in both eyes. Pupillary examination revealed equal, round, and briskly reactive pupils bilaterally without evidence of a definite relative afferent pupillary defect. Anterior segment examination was normal with clear corneas and lenses, no inflammation, and no iris or angle neovascularization.
S
torm syndrome was a designation first applied by Weisman et al to describe an autosomal-dominantly inherited connective tissue disorder that affected five generations of a family of German extraction with the name Storm.1 Because of similarities to Werner syndrome (except for the absence of cataracts), some have termed the condition Werner-like syndrome.2 The syndrome is characterized by a premature aged appearance (as a result of thinning and graying of scalp hair in adolescence, tautening of the skin of the hands and face, excessive wrinkling of the palmar skin, and loss of eyebrows and lashes), early progressive calcific cardiac valvular disease, and, in some cases polyarticular arthropathy, fat malabsorption, and renal failure (resulting from arteriolar hypoplasia).1 Ocular abnormalities have not been previously reported. This report describes a young patient with Storm syndrome who developed bilateral nonsimultaneous central retinal vein occlusion (CRVO). The authors have no proprietary or financial interest in this report. Reprint requests: Srinivas R. Sadda, MD, Doheny Eye Institute, DEI 3623, 1450 San Pablo Street, Los Angeles, CA 90033; e-mail: [email protected]
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NUMBER 3
Fig. 1. Montage of fundus photographs obtained at initial presentation. A, The right eye did not show any evidence of venous occlusive disease. B, The left eye showed evidence of mild venous tortuousity, congestion of the optic nerve with blurring of disk margins, mild macular edema (as evidenced by blunted foveal reflex), and intraretinal hemorrhages in all four quadrants (although concentrated in the posterior pole). The venous system of the left eye could not be collapsed even with moderate pressure (spontaneous pulsations were present in the right eye). Granular pigment mottling and atrophy were observed in the retinal periphery in both eyes (left ⬎ right), most prominent inferonasally. Changes were more peripheral (mostly beyond the field of view) and subtle in the right eye.
Intraocular pressures were 10 and 11 in the 2 eyes, respectively, using applanation tonometry. Ophthalmoscopic and contact lens biomicroscopic examination of the fundus was notable for a mildly syneretic vitreous, narrowed arterioles, and midperipheral retinal pigment epithelial (RPE) changes in both eyes (left eye ⬎ right eye). These RPE abnormalities consisted of large zones of granular change with RPE atrophy as well as punctuate areas of hyperpigmentation extending anteriorly from outside the vascular arcades to just anterior to the equator. In addition, in the symptomatic left eye, a few intraretinal hemorrhages (blot and flame-shaped) were noted in all retinal layers, in all retinal quadrants, with mild associated vascular tortuousity (Figure 1). Mild cystoid macular edema was present. The retinal venous system of the left eye could not be collapsed or made to pulsate even with moderate pressure applied by the fundus contact lens, suggestive of venous outflow obstruction as opposed to a venous stasis picture. In contrast, spontaneous venous pulsations were observed in the right eye. The patient declined fluorescein angiography, although based on the clinical appearance, she was determined to have a perfused CRVO. The patient was observed monthly over a 6-month period to monitor for neovascularization and was noted to have progressive worsening in vision (to 20/125) associated with a progressive increase in macular edema. She then presented with new blurring of vision in her
right eye. There was no significant change in her medical history with relatively stable laboratory hematologic values. Examination of the left eye was unchanged. The right eye demonstrated reduction in vision to 20/63, new intraretinal hemorrhages in all four quadrants (Figure 2A) with venous tortuousity (including no venous pulsations despite pressure), and mild foveal cystoid macular edema. The RPE alterations nasal to the optic disk were more pronounced. The patient again declined fluorescein angiography. When seen 2 months later, the patient’s clinical picture had worsened with a decrease in vision to 20/200 and a dramatic increase in hemorrhages and macular edema (Figure 2B). Radiologic and laboratory investigations performed by the patient’s internist at the time of the second venous occlusion were unrevealing; these included a normal carotid ultrasound, echocardiography negative for a cardiac embolic source, normal blood levels of homocysteine, protein C, protein S, antithrombin III, factor V Leiden, no activated protein C resistance, and negative antiphospholipid/anticardiolipin antibodies. Intravitreal steroids and antivascular endothelial growth factor therapies were not well established as potential options for patients with venous occlusive disease at the time of the patient’s initial presentation (2001). Thus, continued observation at monthly intervals was recommended.
Fig. 2. A, Montage of color fundus photographs of the right eye 6 months after initial presentation. Intraretinal hemorrhages were now evident in all four quadrants associated with venous tortuousity and blurring of the nasal disk margin. Peripheral granular RPE alterations were now more prominent and evident more posteriorly, nasal to the optic nerve. B, By 2 months later (8 months after initial presentation), there was a dramatic increase in the amount of hemorrhage and macular edema in the right eye.
315
RETINAL VEIN OCCLUSION IN STORM SYNDROME
Discussion The patient described in this report presented with the classic features of Storm syndrome, including a prematurely aged appearance, early calcific disease of the aortic and mitral valves, arteriolar narrowing, history of intestinal fat malabsorption, and renal failure. The only aspect of the patient’s presentation that departed from the prototypical features of the disorder was the female gender (previous cases were male).1 Storm syndrome is distinguished from Werner syndrome by the absence of cataracts.2 As a result of its rarity and its similarity to Werner syndrome, some have used the term Werner-like syndrome. Werner syndrome has been extensively characterized and the genetic defect (in the WRN gene, also known as the RECQL2 gene—mapping to 8p12-p11.2) has been identified.3 The WRN gene encodes a DNA helicase that, in its mutant form, appears to trigger a sequence of premature expression of inhibitors of DNA synthesis and other genes, resulting in early cellular senescence; effectively, cells lose their replicative ability at an earlier point in time. This defect appears to have a profound impact on fibroblast function and may explain the high frequency of wound dehiscence in these patients after cataract surgery.4 Although cystoid macular edema has been described in patients with Werner syndrome after cataract surgery,4 and a case of macular coloboma has been reported in a patient with features similar to Werner’s,5 CRVO and RPE alterations, as noted in this patient, have not been previously described in Werner or Storm syndrome. A causal relationship between Storm syndrome and retinal venous occlusive disease, however, cannot be established on the basis of this case report. First, in contrast to Werner syndrome, the underlying genetic defect and pathogenic mechanism of Storm syndrome is unknown. Second, this patient has a number of other risk factors likely to increase her risk of developing venous occlusive disease. For example, this patient has hypertension (albeit well-controlled), which is a well-established risk factor for the development of retinal venous occlusive disease.6 In addition, this patient had significant anemia resulting from her chronic renal insufficiency, and anemia alone (in the absence of other blood dyscrasias or coagulopathies) has been associated with the development of CRVO.7 Moreover, kidney disease has been suggested as a risk factor for CRVO.6 In the published literature, however, there is no description of a patient in this age group developing bilateral CRVO on the basis of hypertension or anemia alone, and if it occurs, it is probably rare. One could hypothesize that the progeric process associated with Storm syndrome may effectively create a situation in which the retinal vessels also behave in a similar manner to those of an
older patient. Nonetheless, given the patient’s young age, we performed an extensive laboratory workup for other known hematologic risk factors for retinal vein occlusion in young patients,8 but this evaluation was unrevealing. The etiology of the peripheral RPE changes in this patient is also uncertain. One could hypothesize that they occur secondary to hypertensive damage to the choriocapillaris with secondary degeneration of the RPE. However, these RPE alterations may also be a manifestation of the premature aging process and may be akin to the peripheral reticular pigmentary alterations that are commonly observed in elderly patients.9 Miceli and Jazwinski have recently described the upregulation of WRN (Werner syndrome helicase) gene expression in an RPE cell line (ARPE 19) in the setting of mitochondrial dysfunction that may be a characteristic of the aging processes.10 It is possible that this phenomenon could be involved in the development of senile reticular pigmentary degeneration as well as the RPE alterations observed in the patient described in this report. In summary, we report a patient with Storm (Wernerlike) syndrome who developed bilateral nonsimultaneous CRVO associated with peripheral RPE abnormalities. Premature aging syndromes, although not common, are of considerable importance because they provide insight into the sequence of events that occur in the normal aging process. Key words: central retinal vein occlusion, retinal pigment epithelium, Storm syndrome, Werner syndrome. References 1.
Weisman HF, Gaither NS, Moore J, et al. The Storm syndrome: a new pleiotropic, autosomal dominant disorder affecting connective tissue. Am J Hum Genet 1989;45:A67. 2. Goto M, Takeuchi F, Tanimoto K, Miyamoto T. Clinical, demographic, and genetic aspects of the Werner syndrome in Japan. Adv Exp Med Biol 1985;190:245–261. 3. Gray MD, Shen JC, Kamath-Loeb AS, et al. The Werner syndrome protein is a DNA helicase. Nat Genet 1997;17:100 –103. 4. Jonas JB, Ruprecht KW, Schmitz-Valckenberg P, et al. Ophthalmic surgical complications in Werner’s syndrome: report on 18 eyes of nine patients. Ophthalmic Surg 1987;18:760 –764. 5. Loh RC, Tan DS. An unusual case of progeria-like dwarfism with bilateral macular coloboma. Am J Ophthalmol 1970;70:968–974. 6. Hayreh SS, Zimmerman B, McCarthy MJ, Podhajsky P. Systemic diseases associated with various types of retinal vein occlusion. Am J Ophthalmol 2001;131:61–77. 7. Kirkham TH, Wrigley PF, Holt JM. Central retinal vein occlusion complicating iron deficiency anaemia. Br J Ophthalmol 1971;55:777–780. 8. Fegan CD. Central retinal vein occlusion and thrombophilia. Eye 2002;16:98 –106. 9. Humphrey WT, Carlson RE, Valone JA Jr. Senile reticular pigmentary degeneration. Am J Ophthalmol 1984;98:717–722. 10. Miceli MV, Jazwinski SM. Common and cell type-specific responses of human cells to mitochondrial dysfunction. Exp Cell Res 2005;302:270 –280.
Purpose: To report the presence of previously undescribed retinal abnormalities in patients with Storm and other progeric syndromes. Methods: Review of the clinical and photographic records of a patient with Storm syndrome who developed bilateral central retinal vein occlusion. Results: A 43-year-old woman with a diagnosis of Storm (Werner-like) syndrome, a connective tissue disease characterized by premature aging, presented with bilateral nonsimultaneous central retinal vein occlusion. The patient was also observed to have bilateral peripheral retinal pigment epithelial alterations. Conclusion: Retinal abnormalities can be observed in patients with premature aging syndromes. These abnormalities include the development of venous occlusive disease and peripheral retinal pigment epithelial alterations at a relatively young age and may be related to the underlying genetic mutation. RETINAL CASES & BRIEF REPORTS 3:313–315, 2009
From the Doheny Retina Institute, Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California.
Case Report A 43-year-old woman, with no ocular history, presented with a 1-week history of blurred vision in her left eye. Ten years earlier, she had been diagnosed with Storm syndrome by her rheumatologist on the basis of a constellation of findings, including premature aging (with tautening of the face and hands), alopecia and graying of scalp hair, calcific disease of the aortic and mitral valves (status postaortic and mitral mechanical valve replacements), intestinal fat malabsorption, and chronic renal insufficiency (on peritoneal dialysis). Given the prosthetic cardiac valves, the patient was maintained on warfarin sodium, and her anticoagulation was felt to be therapeutic at the time of her presentation with an international normalized ratio of 2.9. As a result of her chronic renal insufficiency, the patient had a history of anemia for which she was treated with erythropoietin. Her other medications included labetalol and calcitriol. Her hemoglobin level at the time of presentation was 10 g/dL (lower limit of normal being 12). The patient’s medical history was also notable for mild hypertension of 5 years in duration (subsequent to the development of renal disease). Her blood pressure was well controlled with an average pressure of 120/80 mmHg; of note, no severe blood pressure elevations (i.e., ⬎180 mmHg systolic or ⬎100 mmHg diastolic) were documented during this time. Ophthalmic examination at the time of presentation revealed a best-corrected Snellen visual acuity of 20/20 in the right eye and 20/50 in the left. Color vision testing was normal with the patient able to identify all 10 Ishihara plate correctly in both eyes. Ocular motility and confrontation visual fields were normal in both eyes. Pupillary examination revealed equal, round, and briskly reactive pupils bilaterally without evidence of a definite relative afferent pupillary defect. Anterior segment examination was normal with clear corneas and lenses, no inflammation, and no iris or angle neovascularization.
S
torm syndrome was a designation first applied by Weisman et al to describe an autosomal-dominantly inherited connective tissue disorder that affected five generations of a family of German extraction with the name Storm.1 Because of similarities to Werner syndrome (except for the absence of cataracts), some have termed the condition Werner-like syndrome.2 The syndrome is characterized by a premature aged appearance (as a result of thinning and graying of scalp hair in adolescence, tautening of the skin of the hands and face, excessive wrinkling of the palmar skin, and loss of eyebrows and lashes), early progressive calcific cardiac valvular disease, and, in some cases polyarticular arthropathy, fat malabsorption, and renal failure (resulting from arteriolar hypoplasia).1 Ocular abnormalities have not been previously reported. This report describes a young patient with Storm syndrome who developed bilateral nonsimultaneous central retinal vein occlusion (CRVO). The authors have no proprietary or financial interest in this report. Reprint requests: Srinivas R. Sadda, MD, Doheny Eye Institute, DEI 3623, 1450 San Pablo Street, Los Angeles, CA 90033; e-mail: [email protected]
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2009
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VOLUME 3
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NUMBER 3
Fig. 1. Montage of fundus photographs obtained at initial presentation. A, The right eye did not show any evidence of venous occlusive disease. B, The left eye showed evidence of mild venous tortuousity, congestion of the optic nerve with blurring of disk margins, mild macular edema (as evidenced by blunted foveal reflex), and intraretinal hemorrhages in all four quadrants (although concentrated in the posterior pole). The venous system of the left eye could not be collapsed even with moderate pressure (spontaneous pulsations were present in the right eye). Granular pigment mottling and atrophy were observed in the retinal periphery in both eyes (left ⬎ right), most prominent inferonasally. Changes were more peripheral (mostly beyond the field of view) and subtle in the right eye.
Intraocular pressures were 10 and 11 in the 2 eyes, respectively, using applanation tonometry. Ophthalmoscopic and contact lens biomicroscopic examination of the fundus was notable for a mildly syneretic vitreous, narrowed arterioles, and midperipheral retinal pigment epithelial (RPE) changes in both eyes (left eye ⬎ right eye). These RPE abnormalities consisted of large zones of granular change with RPE atrophy as well as punctuate areas of hyperpigmentation extending anteriorly from outside the vascular arcades to just anterior to the equator. In addition, in the symptomatic left eye, a few intraretinal hemorrhages (blot and flame-shaped) were noted in all retinal layers, in all retinal quadrants, with mild associated vascular tortuousity (Figure 1). Mild cystoid macular edema was present. The retinal venous system of the left eye could not be collapsed or made to pulsate even with moderate pressure applied by the fundus contact lens, suggestive of venous outflow obstruction as opposed to a venous stasis picture. In contrast, spontaneous venous pulsations were observed in the right eye. The patient declined fluorescein angiography, although based on the clinical appearance, she was determined to have a perfused CRVO. The patient was observed monthly over a 6-month period to monitor for neovascularization and was noted to have progressive worsening in vision (to 20/125) associated with a progressive increase in macular edema. She then presented with new blurring of vision in her
right eye. There was no significant change in her medical history with relatively stable laboratory hematologic values. Examination of the left eye was unchanged. The right eye demonstrated reduction in vision to 20/63, new intraretinal hemorrhages in all four quadrants (Figure 2A) with venous tortuousity (including no venous pulsations despite pressure), and mild foveal cystoid macular edema. The RPE alterations nasal to the optic disk were more pronounced. The patient again declined fluorescein angiography. When seen 2 months later, the patient’s clinical picture had worsened with a decrease in vision to 20/200 and a dramatic increase in hemorrhages and macular edema (Figure 2B). Radiologic and laboratory investigations performed by the patient’s internist at the time of the second venous occlusion were unrevealing; these included a normal carotid ultrasound, echocardiography negative for a cardiac embolic source, normal blood levels of homocysteine, protein C, protein S, antithrombin III, factor V Leiden, no activated protein C resistance, and negative antiphospholipid/anticardiolipin antibodies. Intravitreal steroids and antivascular endothelial growth factor therapies were not well established as potential options for patients with venous occlusive disease at the time of the patient’s initial presentation (2001). Thus, continued observation at monthly intervals was recommended.
Fig. 2. A, Montage of color fundus photographs of the right eye 6 months after initial presentation. Intraretinal hemorrhages were now evident in all four quadrants associated with venous tortuousity and blurring of the nasal disk margin. Peripheral granular RPE alterations were now more prominent and evident more posteriorly, nasal to the optic nerve. B, By 2 months later (8 months after initial presentation), there was a dramatic increase in the amount of hemorrhage and macular edema in the right eye.
315
RETINAL VEIN OCCLUSION IN STORM SYNDROME
Discussion The patient described in this report presented with the classic features of Storm syndrome, including a prematurely aged appearance, early calcific disease of the aortic and mitral valves, arteriolar narrowing, history of intestinal fat malabsorption, and renal failure. The only aspect of the patient’s presentation that departed from the prototypical features of the disorder was the female gender (previous cases were male).1 Storm syndrome is distinguished from Werner syndrome by the absence of cataracts.2 As a result of its rarity and its similarity to Werner syndrome, some have used the term Werner-like syndrome. Werner syndrome has been extensively characterized and the genetic defect (in the WRN gene, also known as the RECQL2 gene—mapping to 8p12-p11.2) has been identified.3 The WRN gene encodes a DNA helicase that, in its mutant form, appears to trigger a sequence of premature expression of inhibitors of DNA synthesis and other genes, resulting in early cellular senescence; effectively, cells lose their replicative ability at an earlier point in time. This defect appears to have a profound impact on fibroblast function and may explain the high frequency of wound dehiscence in these patients after cataract surgery.4 Although cystoid macular edema has been described in patients with Werner syndrome after cataract surgery,4 and a case of macular coloboma has been reported in a patient with features similar to Werner’s,5 CRVO and RPE alterations, as noted in this patient, have not been previously described in Werner or Storm syndrome. A causal relationship between Storm syndrome and retinal venous occlusive disease, however, cannot be established on the basis of this case report. First, in contrast to Werner syndrome, the underlying genetic defect and pathogenic mechanism of Storm syndrome is unknown. Second, this patient has a number of other risk factors likely to increase her risk of developing venous occlusive disease. For example, this patient has hypertension (albeit well-controlled), which is a well-established risk factor for the development of retinal venous occlusive disease.6 In addition, this patient had significant anemia resulting from her chronic renal insufficiency, and anemia alone (in the absence of other blood dyscrasias or coagulopathies) has been associated with the development of CRVO.7 Moreover, kidney disease has been suggested as a risk factor for CRVO.6 In the published literature, however, there is no description of a patient in this age group developing bilateral CRVO on the basis of hypertension or anemia alone, and if it occurs, it is probably rare. One could hypothesize that the progeric process associated with Storm syndrome may effectively create a situation in which the retinal vessels also behave in a similar manner to those of an
older patient. Nonetheless, given the patient’s young age, we performed an extensive laboratory workup for other known hematologic risk factors for retinal vein occlusion in young patients,8 but this evaluation was unrevealing. The etiology of the peripheral RPE changes in this patient is also uncertain. One could hypothesize that they occur secondary to hypertensive damage to the choriocapillaris with secondary degeneration of the RPE. However, these RPE alterations may also be a manifestation of the premature aging process and may be akin to the peripheral reticular pigmentary alterations that are commonly observed in elderly patients.9 Miceli and Jazwinski have recently described the upregulation of WRN (Werner syndrome helicase) gene expression in an RPE cell line (ARPE 19) in the setting of mitochondrial dysfunction that may be a characteristic of the aging processes.10 It is possible that this phenomenon could be involved in the development of senile reticular pigmentary degeneration as well as the RPE alterations observed in the patient described in this report. In summary, we report a patient with Storm (Wernerlike) syndrome who developed bilateral nonsimultaneous CRVO associated with peripheral RPE abnormalities. Premature aging syndromes, although not common, are of considerable importance because they provide insight into the sequence of events that occur in the normal aging process. Key words: central retinal vein occlusion, retinal pigment epithelium, Storm syndrome, Werner syndrome. References 1.
Weisman HF, Gaither NS, Moore J, et al. The Storm syndrome: a new pleiotropic, autosomal dominant disorder affecting connective tissue. Am J Hum Genet 1989;45:A67. 2. Goto M, Takeuchi F, Tanimoto K, Miyamoto T. Clinical, demographic, and genetic aspects of the Werner syndrome in Japan. Adv Exp Med Biol 1985;190:245–261. 3. Gray MD, Shen JC, Kamath-Loeb AS, et al. The Werner syndrome protein is a DNA helicase. Nat Genet 1997;17:100 –103. 4. Jonas JB, Ruprecht KW, Schmitz-Valckenberg P, et al. Ophthalmic surgical complications in Werner’s syndrome: report on 18 eyes of nine patients. Ophthalmic Surg 1987;18:760 –764. 5. Loh RC, Tan DS. An unusual case of progeria-like dwarfism with bilateral macular coloboma. Am J Ophthalmol 1970;70:968–974. 6. Hayreh SS, Zimmerman B, McCarthy MJ, Podhajsky P. Systemic diseases associated with various types of retinal vein occlusion. Am J Ophthalmol 2001;131:61–77. 7. Kirkham TH, Wrigley PF, Holt JM. Central retinal vein occlusion complicating iron deficiency anaemia. Br J Ophthalmol 1971;55:777–780. 8. Fegan CD. Central retinal vein occlusion and thrombophilia. Eye 2002;16:98 –106. 9. Humphrey WT, Carlson RE, Valone JA Jr. Senile reticular pigmentary degeneration. Am J Ophthalmol 1984;98:717–722. 10. Miceli MV, Jazwinski SM. Common and cell type-specific responses of human cells to mitochondrial dysfunction. Exp Cell Res 2005;302:270 –280.
