Fundus photograph showing (A) a well-circumscribed yellow placoid area of sclerochoroidal calcification along the temporal vascular arcade, (B) a large yellowish elevated dome-shaped mound of sclerochoroidal calcification, (C) a patient with Gitelman syndrome exhibiting multifocal geographic sclerochoroidal calcification in the postequatorial location, and (D) a patient with Gitelman syndrome demonstrating a wide area of choroidal heterochromia and retinal pigment epithelial atrophy over and around a focus of sclerochoroidal calcification.
Fluorescein angiogram of a patient with sclerochoroidal calcification. Characteristically, the lesion showed autofluorescence with red-free filter, mild-to-moderate hypofluorescence (arrowhead) in the arterial phase (A), mild-to-moderate hyperfluorescence in the venous phase (B) that intensified over time (C), with persistent late staining (D). Note mottled hyperfluorescence around the lesion corresponding to areas of retinal pigment epithelial atrophy.
Indocyanine green angiogram of a patient with sclerochoroidal calcification. The lesion showed autofluorescence with red-free filter (A) and hypofluorescence (arrow) (B) at the early, middle, and late phases.
Ultrasonogram of a patient with sclerochoroidal calcification. (A) B-scan ultrasonogram showing an elevated echodense focus of sclerochoroidal calcification with orbital shadowing and(B) a corresponding A-scan ultrasonogram demonstrating high reflectivity.
Axial computed tomographic scan showing calcified areas in the sclerochoroidal interface of both eyes.
Honavar SG, Shields CL, Demirci H, Shields JA. Sclerochoroidal CalcificationClinical Manifestations and Systemic Associations. Arch Ophthalmol. 2001;119(6):833-840. doi:10.1001/archopht.119.6.833
Sclerochoroidal calcification is an unusual ocular condition that is believed to be idiopathic in most cases.
To describe the clinical manifestations of sclerochoroidal calcification and to investigate its possible systemic associations.
This noncomparative consecutive case series included patients diagnosed as having sclerochoroidal calcification based on clinical characteristics and diagnostic test findings. We analyzed the demographic, systemic, and ocular features of 27 such patients. Systemic evaluation included tests for calcium-phosphorus metabolism in 19 patients and renal tubular hypokalemic metabolic alkalosis syndromes (Bartter or Gitelman syndrome) in 13.
All the patients were asymptomatic older (mean age, 70 years) white individuals, incidentally noted as having a choroidal lesion on routine examination. Among 38 eyes, the main referral diagnoses were choroidal metastasis in 10 eyes (26%), choroidal melanoma in 8 (21%), and choroidal nevus in 4 (11%). Sixteen patients (59%) had unilateral clinical findings, while 11 (41%) had bilateral. The Snellen visual acuity was 20/50 or better in 37 eyes (97%). Cogan scleral plaque was visible anterior to the insertion of horizontal rectus muscles in 10 eyes (26%). Among 77 foci, there were a mean of 2 foci of sclerochoroidal calcification in each eye, 41 yellow (53%), 32 yellow-white (42%), 2 white(3%), and 2 orange (3%), measuring a mean 2.6 mm in diameter and 1.1 mm in thickness. The most common locations were postequatorial in 45 (58%), along the temporal vascular arcades in 30 (39%), and in the superotemporal quadrant in 43 (56%). A-scan and B-scan ultrasonography revealed dense echoes compatible with calcium, with orbital shadowing. All the lesions remained stable in size and configuration during a mean follow-up of 38 months. One patient developed a choroidal neovascular membrane over the area of sclerochoroidal calcification. Investigations for abnormal calcium-phosphorus metabolism in 19 patients revealed primary hyperparathyroidism in 1 patient (5%). Clinical and biochemical evaluation of 13 patients demonstrated hypomagnesemia in 6 (46%). Four patients (31%) met the criteria for the diagnosis of Gitelman syndrome.
Sclerochoroidal calcification usually manifests as multiple discrete yellow placoid lesions in the midperipheral fundus of asymptomatic older white individuals. Although most cases may be idiopathic in nature, some patients may have underlying systemic disorders involving abnormal calcium-phosphorus metabolism or renal tubular hypokalemic metabolic alkalosis syndromes. All patients with sclerochoroidal calcification should be tested for these treatable systemic associations.
SCLEROCHOROIDAL calcification is an uncommon condition that classically manifests as multiple discrete yellow placoid lesions, often discovered as an incidental finding in asymptomatic older white individuals.1- 8 Despite several cases of sclerochoroidal calcification reported in the literature,1- 8 this entity remains poorly recognized and is most often misdiagnosed as a malignant tumor, resulting in unwarranted intervention.1,4,8
Sclerochoroidal calcification is ordinarily believed to be idiopathic, based on published reports1,3,4 in which patients generally showed normal calcium-phosphorus metabolism and no associated systemic or ocular causes for metastatic or dystrophic calcification. However, several conditions associated with abnormal calcium-phosphorus metabolism(hyperparathyroidism, pseudohypoparathyroidism, vitamin D intoxication, sarcoidosis, hypophosphatemia, and chronic renal failure) have been reported to result in metastatic sclerochoroidal calcification.2,9- 11 It has recently been recognized that sclerochoroidal calcification can occur in association with primary renal tubular hypokalemic metabolic alkalosis syndromes, such as the Bartter12 and Gitelman13 syndromes. Such patients may be asymptomatic, have normal calcium-phosphorus metabolism, and possibly remain undetected unless specific tests for renal tubular function are performed.14 It is important that these patients be identified because of the possible systemic implications and the treatable nature of these disorders.14,15
Although there are isolated case reports2,9- 13 identifying systemic associations of sclerochoroidal calcification, the magnitude of the problem has not been established in a large cohort of patients with a standard evaluation protocol. We have attempted to address this issue by evaluating a series of patients with sclerochoroidal calcification using a clinical and biochemical protocol designed to investigate for abnormal calcium-phosphorus metabolism and primary renal tubular hypokalemic metabolic alkalosis syndromes. Herein, we report our results, emphasizing the diagnostic clinical features and the systemic associations.
The computerized patient database at the Oncology Service, Wills Eye Hospital, Philadelphia, Pa, was searched for patients with sclerochoroidal calcification treated between January 1983 and February 2000. Twenty-seven consecutive patients were identified for a detailed review. The collected data included age at presentation, ethnicity (African American, Asian, white, or Hispanic), sex (male or female), and laterality (unilateral or bilateral). The details of symptoms, the initial diagnosis, and treatment before referral were recorded. Associated relevant systemic disease (hyperparathyroidism, pseudohypoparathyroidism, gout, pseudogout, chronic renal failure, nephrocalcinosis, arthritis, chondrocalcinosis, hypophosphatemia, hypercalcemia, and sarcoidosis) and systemic medications (diuretics, calcium, magnesium, and vitamin D) were noted. Ocular features, including Snellen visual acuity, Cogan scleral plaque, or any atypical intrascleral calcification (number and location), were recorded. Detailed information on each lesion, including color (yellow, white, or orange), shape (circular, elliptical, annular [ring-shaped], or geographic), margin(regular or irregular), contour (flat, placoid, or dome-shaped), diameter, thickness, anteroposterior location (between the vascular arcades, along the vascular arcades, vascular arcades to the equator, or equator to the ora), quadrant location (superotemporal, inferotemporal, inferonasal, superonasal, or macula), proximity to the optic disc, proximity to the foveola, and secondary changes (retinal pigment epithelial atrophy, retinal pigment epithelial hyperplasia, retinal pigment epithelial detachment, subretinal fluid, or subretinal neovascular membrane), was collected. Results of A-scan and B-scan ultrasonography, fluorescein angiography, indocyanine green angiography, and computed tomography were analyzed. Duration of follow-up of each patient; Snellen visual acuity; alteration in shape, size, and configuration of sclerochoroidal calcification; occurrence of ocular complications; and manifestation of new systemic disease during the follow-up were noted. Results of systemic investigations (serum calcium, phosphorus, parathyroid hormone, and calcitonin) were recorded. The patients were evaluated using a clinical and laboratory protocol designed to diagnose primary renal tubular hypokalemic metabolic alkalosis syndromes. The diagnosis of Bartter or Gitelman syndrome was made based on the established criteria.14 Bartter syndrome was diagnosed in patients with hypokalemia, metabolic alkalosis, hyperreninism and hyperaldosteronism, impaired urine concentrating ability, increased urine sodium and chloride excretion, and hypercalciuria.14 Gitelman syndrome was diagnosed in the presence of hypokalemia, metabolic alkalosis, hypomagnesemia, normal urine concentrating ability, and hypocalciuria.14
Twenty-seven consecutive patients (38 eyes) with sclerochoroidal calcification seen on the oncology service between January 1983 and February 2000 were included in this study. Sixteen patients (59%) had unilateral sclerochoroidal calcification, while 11 (41%) had bilateral. There were 12 male (44%) and 15 female (56%) patients, all white, with a median age of 70 years (range, 42-95 years). All the patients were asymptomatic and were detected as having a fundus lesion on the most recent routine ophthalmic examination. The main referral diagnoses(Table 1) were choroidal metastasis in 10 eyes (26%) and choroidal melanoma in 8 (21%).
Of 38 eyes affected, Snellen visual acuity was equal to or better than 20/50 in 37 eyes (97%). One eye with an unrelated old superotemporal branch retinal vein obstruction had a visual acuity of 20/200. Cogan plaque was present in 10 (26%) of 38 eyes. It was located at the insertion of the medial rectus muscle in 3 eyes, the lateral rectus muscle in 2, and both the lateral and the medial rectus muscles in 5. The clinical characteristics of sclerochoroidal calcifications are listed in Table 2and demonstrated in Figure 1. The number of lesions in each eye ranged from 1 to 6 (mean, 2). The lesions were unifocal in 18 eyes (47%) and multifocal in 20 (53%). In all, there were 77 foci of sclerochoroidal calcification in 38 eyes. There were 41 yellow (53%), 32 yellow-white (42%), 2 white (3%), and 2 orange (3%) lesions. The diameter ranged from 0.5 to 8.0 mm (mean, 2.6 mm), and thickness as measured on ultrasonography ranged from 0.5 to 2.8 mm (mean, 1.1 mm). The shapes included 36 circular(47%), 22 elliptical (29%), 17 geographic (22%), and 2 annular (3%), with 58 regular (75%) and 19 irregular (25%) borders and 71 placoid (92%) and 6 dome-shaped (8%) configurations. Forty-five lesions (58%) were located between the temporal vascular arcades and the equator and 43 (56%) were in the superotemporal quadrant (Table 2). The proximity of the closest lesion to the optic disc ranged from 0 to 10 mm (mean, 4.4 mm) and from 1 to 8 mm (mean, 3.8 mm) to the foveola. Additional findings about the fundus are listed in Table 2.
The ocular clinical investigations performed in patients with sclerochoroidal calcification included fluorescein angiography (27 eyes), indocyanine green angiography (2 eyes), A-scan and B-scan ultrasonography (38 eyes), and computed tomography (5 eyes). Characteristically, the calcifications showed autofluorescence with red-free filter, mild-to-moderate hypofluorescence in the arterial phase, mild-to-moderate hyperfluorescence in the venous phase, and late staining(Figure 2). In addition, fluorescein angiography confirmed the presence of localized, sectoral, or diffuse retinal pigment epithelial atrophy. The indocyanine green angiography demonstrated normal large-caliber choroidal vessels external to the lesion and mild-to-moderate hypofluorescence of the lesion at all phases (Figure 3). The ultrasonogram typically showed surface-reflective and intensely echodense placoid lesions at the scleral-choroidal interface with orbital shadowing, characteristic of calcification (Figure 4). Although the calcification clearly involved the sclera and the choroid on ultrasonography in 33 eyes (87%), it seemed confined mostly to the choroid in 5 (13%). The dimensions of sclerochoroidal calcification measured larger on ultrasonography by a mean 1 mm in diameter and in thickness compared with the clinical estimate. Ultrasonography was also able to detect subtle lesions that were clinically not apparent. Four of 27 patients who were believed to have unilateral involvement on ophthalmoscopic examination were found to have sclerochoroidal calcification in the opposite eye on ultrasonography. Computed tomography showed sclerochoroidal plaques compatible with the presence of calcium (Figure 5) in the 5 patients in whom it was performed, but did not provide any additional information not seen on ultrasonography.
Nineteen of 27 patients were followed up for a mean of 38 months (range, 5 months to 9 years). All the patients continued to remain asymptomatic, with stable visual acuity, stable lesions, and no new lesions. Subretinal fluid spontaneously resolved in 1 patient and remained stable in 2. One patient developed a choroidal neovascular membrane over the area of sclerochoroidal calcification. The patient was carefully followed up for a year, and his central visual acuity remained stable at 20/30, with no change in the choroidal neovascular membrane.
Of 19 patients in whom investigations for serum calcium-phosphorus metabolism were available, 1 had evidence of primary hyperparathyroidism (serum parathyroid hormone, 80 ng/L, reference range, 10-65 ng/L; serum calcium, 11.4 mmol/L[45.6 mg/dL], reference range, 1.1-1.4 mmol/L [4.4-5.6 mg/dL]; serum phosphorus, 0.7 mmol/L [2.2 mg/dL], reference range, 1.0-1.4 mmol/L [3.1-4.3 mg/dL]). Thirteen patients underwent clinical and biochemical protocol to diagnose and differentiate primary renal tubular hypokalemic metabolic alkalosis syndromes(Bartter or Gitelman syndrome) based on the established criteria (Table 3).11 Four (31%) of the 13 patients had biochemical features diagnostic of Gitelman syndrome (Table 4), of whom only 1 was symptomatic (excessive muscle weakness, episodes of tetany, and arthritis) and manifested systemic signs (chondrocalcinosis). In addition, 2 others (15%) had hypomagnesemia but did not manifest all the features diagnostic of Gitelman syndrome. One of those with hypomagnesemia (0.5 mmol/L [1.2 mg/dL], reference range, 0.8-1.2 mmol/L [1.9-2.9 mg/dL]) was symptomatic (excessive muscle weakness, episodes of tetany, and arthritis) and had elevated serum bicarbonate (30 mmol/L, reference range, 21-28 mmol/L). Another patient showed only hypomagnesemia(0.5 mmol/L [1.2 mg/dL]). One (8%) of the 13 patients had hypercalciuria (12.9 mmol/d, reference range, 1.2-10 mmol/d) but manifested no other clinical or biochemical abnormality diagnostic of Bartter syndrome. Two of the 4 patients diagnosed as having Gitelman syndrome were treated with oral magnesium supplementation by their internists. They attained normal serum magnesium levels 3 to 6 months following the initiation of therapy.
Sclerochoroidal calcification is an uncommon clinical entity that can be dystrophic or metastatic but most commonly idiopathic.1- 11 Dystrophic calcification, the deposition of calcium in the presence of normal calcium-phosphorus metabolism, has been recognized with severe ocular trauma and chronic intraocular inflammation.1,2 Metastatic calcification, the deposition of calcium in normal tissues secondary to abnormal calcium-phosphorus metabolism, occurs with hyperparathyroidism, pseudohypoparathyroidism, vitamin D intoxication, sarcoidosis, hypophosphatemia, and chronic renal failure (Table 5).2,9- 11 The term idiopathic sclerochoroidal calcification is reserved for those cases with no detectable causes of metastatic or dystrophic calcification.
The finding of idiopathic sclerochoroidal calcification was initially attributed in the literature to choroidal osteomas in older patients,17 but it was later recognized to be sclerochoroidal calcification.1,4 Shields and associates,7 in their review of choroidal osteoma, illustrated a case of idiopathic sclerochoroidal calcification and discussed its differentiation from choroidal osteoma and other simulating lesions. Later, Lim and Goldberg8 reported a case of sclerochoroidal calcification that initially simulated choroidal metastasis. Investigators have described in smaller series the ophthalmoscopic, ultrasonographic, and fluorescein angiographic features diagnostic of this condition.2,4 The calcification was confirmed by histopathologic examination to be at the level of sclera and choroid.18
Sclerochoroidal calcification is generally considered to be predominantly bilateral.4 In our series of 27 patients, 16(59%) had unilateral calcification and 11 (41%) had bilateral calcification. The patients were older (median age, 70 years) and white. Sclerochoroidal calcification has rarely been reported in the young.19 The youngest patient in our series was 42 years. All the patients were asymptomatic, and most had excellent visual acuity. Cogan scleral plaque was found in 26% of eyes. The possible similar origin of Cogan plaque and sclerochoroidal calcification has been recognized.1 Scleral plaque as described by Cogan and Kuwabara20 represents calcification anterior to the horizontal rectus muscle insertions, and researchers have speculated that sclerochoroidal calcification represents calcification at the insertions of the inferior oblique and the superior oblique muscles.1 More than half the eyes with sclerochoroidal calcification manifested multiple lesions. Most of the lesions were yellow or yellow-white and measured a mean 2.6 mm in diameter and 1 mm in thickness. The classic location of sclerochoroidal calcification was postequatorial and superotemporal. Although the ophthalmoscopic and topographic appearance of sclerochoroidal calcification is characteristic, it is often unrecognized or misdiagnosed.1- 8 It is commonly mistaken for choroidal osteoma, choroidal metastasis, amelanotic choroidal nevus, or lymphoma.1,4,5,7 Ancillary investigations, such as fluorescein angiography, indocyanine green angiography, A-scan and B-scan ultrasonography, and computed tomography, may help confirm the diagnosis of sclerochoroidal calcification.
Systemic evaluation of a patient with sclerochoroidal calcification routinely includes screening tests for calcium-phosphorus metabolism.1,4 Of the 19 patients in our series who were investigated, 1 (5%) was found to have primary hyperparathyroidism. Prompted by an incidental discovery of hypomagnesemia in a patient with sclerochoroidal calcification, and the recent reports12,13 of its possible association with primary renal tubular hypokalemic metabolic alkalosis syndromes (Bartter and Gitelman syndromes), we reevaluated patients with a clinical and biochemical screening protocol. We found that 4 (31%) of 13 patients initially diagnosed as having idiopathic sclerochoroidal calcification indeed had features of Gitelman syndrome. In addition, 2 patients (15%) had hypomagnesemia, which is a component of the Gitelman syndrome, and 1 (8%) had hypercalciuria, a component of the Bartter syndrome.
The Bartter and Gitelman syndromes constitute an ensemble of closely related autosomal recessive renal tubular disorders of sodium-chloride transport, characterized by primary renal tubular hypokalemic metabolic alkalosis.14,21 In classic Bartter syndrome, the clinical presentation generally occurs in childhood, with polyuria, polydipsia, vomiting, a tendency for dehydration, and failure to thrive.14 Biochemically, these patients are distinguished by hypokalemic metabolic alkalosis, increased potassium excretion, and normal-to-elevated levels of urine calcium excretion.14 Hypomagnesemia is occasionally found.14 Clinical data demonstrating defective chloride transport in the distal nephron and decreased concentrating capacity suggest that the primary defect in classic Bartter syndrome involves the ascending limb of the loop of Henle.14 The molecular defect in Bartter syndrome is localized to the sodium-potassium-chloride cotransporter, the apical potassium channel, or the basolateral chloride channel in the ascending limb of the loop of Henle, with a genetic defect at chromosome 1p36.22
The Gitelman syndrome is characterized by a milder and later clinical presentation notable for fatigue, muscle weakness, and episodes of carpopedal spasm.14 Hypocalciuria and hypomagnesemia are the prominent features. Recently, it has been demonstrated that Gitelman syndrome results from mutations in the thiazide-sensitive sodium-chloride cotransporter of the distal nephron, with a genetic defect at chromosome 16q13.21,22 The features differentiating Bartter syndrome from Gitelman syndrome are summarized in Table 3.11
The mechanism of sclerochoroidal calcification in primary renal tubular hypokalemic metabolic alkalosis syndromes is not clear. Biologic evidence suggests a possible relationship between hypomagnesemia, calcium pyrophosphate dihydrate deposition, and sclerochoroidal calcification.13,23,24 Pathogenesis of sclerochoroidal calcification may be similar to that of chondrocalcinosis.16,23 Chondrocalcinosis results from deposition of calcium pyrophosphate dihydrate crystals in joints and is known to be associated with the Bartter and Gitelman syndromes.14 Pyrophosphatases, including alkaline phosphatase, are magnesium-dependent.24 Magnesium deficiency may result in increased production of inorganic pyrophosphates.23,24 Magnesium ions are known to increase the solubility of calcium pyrophosphate crystals.23,24 Hypomagnesemia may thus promote calcium pyrophosphate dihydrate formation and deposition in joints and sclera, resulting in chondrocalcinosis and sclerochoroidal calcification.23,24 A patient with sclerochoroidal calcification initially thought to be associated with persistent hypomagnesemia and pseudogout(calcium pyrophosphate dihydrate deposition disease)16 was later found to have characteristics of Gitelman syndrome and was included as such in this series.
Renal tubular hypokalemic metabolic alkalosis syndromes such as the Bartter and Gitelman syndromes carry systemic implications, including chronic muscle weakness, episodic tetany, carpopedal spasm, nephrocalcinosis, and chondrocalcinosis, in addition to direct consequences of hypokalemia and metabolic alkalosis.14 Patients with these syndromes are at high risk for cardiovascular instability with the use of anesthesia.14 It is thus important to recognize and treat these syndromes. The Bartter syndrome can be differentiated from the Gitelman syndrome by the described clinical and biochemical factors (Table 3).14 The recent developments in molecular biology have made genetic diagnosis of individual syndromes feasible.22 Both syndromes are treatable, and some of the systemic manifestations are entirely reversible. Treatment of Bartter syndrome is designed primarily to correct hypokalemia.14 It is treated by potassium supplementation and by prostaglandin synthetase inhibitors, such as indomethacin. Patients with Gitelman syndrome are best treated with oral magnesium pyrrolidone carboxylate supplementation alone.14,15 Two of the 4 patients diagnosed as having Gitelman syndrome in our series were successfully treated with oral magnesium supplementation. The long-term outcome of sclerochoroidal calcification in response to magnesium supplementation is yet unknown.
We do not know whether sclerochoroidal calcification that occurs in Bartter or Gitelman syndrome is clinically distinct from the common idiopathic variety.12,13 Although we did not note any specific differentiating features, the number of patients with a definitive diagnosis of primary renal tubular hypokalemic metabolic alkalosis syndromes is too small (4 of 13) to arrive at any inference. Description of ophthalmic features in patients with primary renal tubular hypokalemic metabolic alkalosis syndromes is conspicuously absent in the general medical literature.14,15,21,22 We also have no information on the temporal sequence of onset of sclerochoroidal calcification relative to other systemic manifestations of Bartter and Gitelman syndromes. These issues may be resolved only by a longitudinal study involving a large series of patients with primary renal tubular hypokalemic metabolic alkalosis syndromes and, conversely, by a long-term prospective study of a large group of patients with sclerochoroidal calcification. However, in the absence of any such information, our study is only indicative of a causal association of sclerochoroidal calcification with primary renal tubular hypokalemic metabolic alkalosis syndromes.
In conclusion, sclerochoroidal calcification is usually recognized as unilateral or bilateral multifocal yellowish placoid lesions in the superotemporal postequatorial area or along the temporal arcades in asymptomatic older white individuals. It can be mistaken for choroidal metastasis, amelanotic choroidal nevus or melanoma, or choroidal lymphoma. Fluorescein angiography and ultrasonography may help in confirming the diagnosis. Most cases of sclerochoroidal calcification may be idiopathic, but some patients may have associated renal tubular hypokalemic metabolic alkalosis syndromes or abnormal calcium-phosphorus metabolism. Considering the systemic implications and the treatable nature of these conditions, it may be worthwhile to screen all patients with sclerochoroidal calcification for the presence of systemic associations before categorizing and prognosticating the diagnosis as idiopathic.
Accepted for publication December 28, 2000.
This study was funded by the Hyderabad Eye Research Foundation, L.V. Prasad Eye Institute, Hyderabad, India (Dr Honavar); Orbis International (Dr Honavar) and Macula Foundation (Dr C. Shields), New York, NY; Eye Tumor Research Foundation, Philadelphia, Pa (Drs J. Shields and C. Shields); and Paul Kayser International Award of Merit in Retina Research, Houston, Tex (Dr J. Shields).
Corresponding author and reprints: Carol L. Shields, MD, Oncology Service, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107 (e-mail: email@example.com).