Diagnostic and

Therapeutic Challenges Edited by H. Richard McDonald Submitted by Lucy H.Y. Young; Commented by Jeffrey G. Gross, James C. Lai and Jeffrey L. Shakin, and John T. Thompson

his case was submitted by Dr. Lucy H.Y. Young was evaluated 2 years earlier by another physician. Tof the Massachusetts Eye and Ear Infirmary, Bos- His visual acuity at that time was 20/25 in both eyes ton, Massachusetts, for the Diagnostic and Therapeu- attributed to bilateral choroidal folds associated with tic Challenges Section of . short axial length (18.5 mm in each eye). On exami- nation his visual acuity is 20/40–2 right eye and 20/100 Case Report left eye. The refraction is not provided but assumed to A 23-year-old healthy white graduate student was referred to our be hyperopic (although emmetropia and even clinic because of decreased vision, left eye worse than right, for the may occur with short axial lengths). Physical exami- last 4 months. Two years earlier, the patient was seen by the nation disclosed a stature described as proportionately referring physician and was diagnosed with choroidal folds bilat- petite. His height was 4=11Љand he was accompanied erally associated with short axial length (18.5 mm bilaterally). Visual acuity was 20/25 bilaterally then. On our examination, by parents of normal stature. Intraocular pressures and visual acuity with correction was 20/40-2 in the right eye and anterior segment examination were normal. 20/100 in the left. External examination showed a proportionately The fundus photograph of both eyes shows crowded Љ petite man (4=11 tall) accompanied by parents who were taller optic nerves with no visible cupping. The major reti- (5=5Љ tall mother and 5=11Љ father). Intraocular pressures were measured to be 17 mmHg in the right eye and 18 mmHg in the left. nal vessels are mildly tortuous. The macula has Anterior segment examination was unremarkable. Fundus exami- clumps of RPE associated with chorioretinal folds. nation showed crowded optic nerves and multiple chorioretinal Although an is described by the folds through the macula with a component of epiretinal membrane author it is not clearly seen in the photographs and bilaterally (Figure 1). In addition, pigment clumpings at the retinal pigment epithelium (RPE) level with shallow serous detachment of there is no straightening of the perimacular vessels the macula were present, left worse than right. Fluorescein angiog- that are typically seen with a significant epiretinal raphy showed macular RPE disturbance with epiretinal membrane membrane. There is a horizontal macular abnormality and serous detachment, left Ͼ right (Figure 1). B-scan revealed that may represent a fold greater in the left eye. diffuse choroidal thickening and elevated and mac- ula bilaterally (Figure 2). OCT evaluation showed irregular Fluorescein angiography reveals punctate disturbance inner retinal surface, reflective RPE changes, and subretinal of the RPE in the papillomacular retina in the mid- fluid, left Ͼ right (Figure 3). The patient denied any dental or phase of the right eye. There is leakage noted in the skin abnormalities. papillomacular retina and central macula with pooling We asked several experts for their opinion. of dye surrounded by a mild disturbance of the RPE in the late phase of the left eye. The B-scan ultrasound Dr. Jeffrey G. Gross (Columbia, SC): images show a small with choroidal thickening Dr. Young describes a 23-year-old white man with best imaged with the gain reduced as noted in the left a 4-month history of decreased vision in both eyes. He eye. There is a normal posterior echo from the crys-

930 DIAGNOSTIC AND THERAPEUTIC CHALLENGES ● McDONALD 931

Fig. 1. Fundus photograph. Note chorioretinal folds and epiretinal membrane in addition to shallow serous detachment with pigment clumpings. Fluorescein angiography showed diffuse retinal pigment epithelium disturbance with multiple leakage sites, left Ͼ right. talline and the vitreous is clear. There is no retinal Fig. 2. B-scan ultrasounds show diffuse choroidal thickening and or choroidal detachment. OCT images reveal in the macular elevation bilaterally (top, right; bottom, left). right eye a significant distortion of the inner retina possibly associated with a thin epiretinal membrane, in the macula. This is demonstrated by the B-scan tiny amount of subretinal fluid, and possibly a tiny ultrasound images of this patient. As a consequence of RPE clump. The left eye shows distortion and irreg- increased resistance to venous outflow by the vortex ularity of the inner retina, subretinal fluid, and atten- veins as a result of the thick a progressive uation or shadowing of the RPE layer. congestion of the usually occurs in the third to The most important piece of information is the axial fifth decade of life. Initially there may be retinal folds length. Microphthalmos can occur in different forms. in the macula with decreased vision eventually leading Simple microphthalmia is an eye that is normal except to a chronic effusion resulting in a nonrhegmatog- for a short total axial length. Complex microphthal- enous . mos is associated with either anterior or posterior Although the fluorescein angiogram is usually nor- malformations. A rare form of microphthalmos is pos- mal in nanophthalmos there can be a leopard-spot terior microphthalmos, which is associated with pap- appearance of the RPE as a result of uveal effusions. illomacular folds, absence of the capillary free zone, In posterior microphthalmos an absence of the capil- and hyperopia. This form of microphthalmos dispro- lary free zone may occur. The findings demonstrated portionately affects the posterior segment with a nor- in this patient have certain findings seen in atypical mal external appearance of the eye.1 Nanophthalmos and chronic idiopathic central serous chorioretinopa- refers to a bilateral condition in which the eye is less thy (ICSC). Typically these bilateral findings include than 19 mm in length with extremely thick sclera, a multiple leaks and a mottled appearance of the RPE. normal or slightly thicker crystalline lens, and severe The fluorescein angiogram of this patient showing hyperopia. Nanophthalmos may be associated with punctate leakage and pooling and the OCT showing uveal effusions and congested choroid that may begin serous detachments are consistent with these findings. 932 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2005 ● VOLUME 25 ● NUMBER 7

Fig. 3. Optical coherence tomograms show irregular retinal surface, macular thickening, and serous detachments, left Ͼ right.

A single case of ICSC with multiple leaks of the effectively ruled out. Kenny-Caffey syndrome is char- choroid resulting in chorioretinal pigment changes has acterized by 1) nanophthalmos associated with been described with Hallerman-Streiff syndrome. This crowded optic nerves or pseudopapilledema, and tor- syndrome includes nanophthalmos and dwarfism.2 tuous blood vessels, 2) medullary stenosis of the long The OCT in the patient presented demonstrates sig- bones, 3) proportional dwarfism, and 4) intermittent to nificant irregularity of the inner retina and folds that long-standing hypocalcemia due to mild to complete are consistent with nanophthalmos and there may be a hyperparathyroidism. Typically the patients have nor- thin ERM seen in the OCT of right eye. It is presumed mal intelligence.4,5 that the retinal folds result from a redundancy of the Therefore the patient described may have Kenny- retinal layer caused by retarded growth of the scleral and Caffey syndrome associated with nanophthalmos, tor- RPE layers. However, we do not see the severe infolding tuous retinal vessels, proportional dwarfism, and, that is more typically seen in posterior microphthalmos.1 since he is a graduate student, normal intelligence. Nanophthalmos generally is not associated with This syndrome occurs either sporadically or by auto- systemic syndromes although there are three that need somal recessive inheritance. This is consistent with to be considered in this patient: Hallermann-Streiff- this patient’s short stature and normal appearing par- Francois syndrome, oculodentodigital syndrome, and ents. The fluorescein angiogram demonstrates punc- Kenny-Caffey syndrome.3,4 Hallerman-Streiff-Fran- tate leakage, however this is not typically seen with cois is associated with birdlike facies, proportional nanophthalmos and leakage is not thought to be the dwarfism, cutaneous atrophy, and dental abnormali- cause of the uveal effusions that occur later in life in ties. Oculodentodigital syndrome is also associated these small eyes, rather it is a result of increased with dental abnormalities, as well as syndactyly, but resistance to venous outflow. ICSC has been reported not dwarfism. The patient described denied any dental in the Hallerman-Streiff syndrome but not in Kenny- or skin abnormalities so these two syndromes are Caffey syndrome. The two syndromes share similar DIAGNOSTIC AND THERAPEUTIC CHALLENGES ● McDONALD 933 features of nanophthalmos and proportional dwarfism Mucopolysaccharidoses are a group of lysosomal so it is reasonable to suggest that this patient may have enzyme storage disorders in which the body lacks the mild choroidal congestion as a result of the nanoph- ability to degrade glycosaminoglycans. There are dif- thalmos as well as chronic bilateral ICSC. Kenny- ferent subtypes depending on the actual enzymatic Caffey syndrome can be diagnosed by a radiologic deficiency. The sclera in patients with this disorder is evaluation of the long bones and because of the po- abnormally thickened from deposition of mucopo- tentially severe systemic complications an evaluation lysaccharides, resulting in impaired uveoscleral flow for hypocalcemia is recommended. and decreased venous outflow. Nanophthalmos and choroidal effusions have been reported in patients Drs. James C. Lai and Jeffrey L. Shakin (Great with MPS IIA and IIB (Hunter’s) and MPS VIA and Neck, NY): VIB (Maroteaux-Lamy) syndrome.7 Although this pa- Dr. Young describes a 23-year-old man of short tient is short, he does not exhibit the other typical stature who presents with a 4-month history of pro- traits of Hunter’s syndrome: coarse facies, skeletal gressively worsening vision bilaterally. Fundus pho- dysplasias, hydrocephalus, or progressive deafness. tographs reveal crowded discs with slightly increased This patient is also unlikely to have Maroteaux-Lamy vascular tortuosity. Faint chorioretinal folds with syndrome, which is characterized by skeletal, cardiac, overlying epiretinal membranes and RPE pigmentary and hepatic abnormalities, as well as corneal clouding changes are present in both macula. Fluorescein an- and optic nerve atrophy. giography demonstrates pinpoint areas of hyperfluo- VKH syndrome, posterior , and sarcoidosis rescence with mild late leakage at the level of the RPE can all present with choroidal thickening with second- and the OCT confirms the presence of subretinal fluid ary serous retinal detachments. The presence of vitre- left Ͼ right. B-scan ultrasonography reveals a short ous cells is not commented on by Dr. Young, although axial length and diffuse choroidal thickening. the anterior segment is noted to be normal. The ab- The differential diagnosis of this case centers sence of accompanying neurologic symptoms, cutane- around conditions that lead to choroidal thickening ous findings, and anterior segment inflammation with the development of chorioretinal folds, serous would argue against VKH, particularly in a white retinal detachments, and secondary chronic macular patient. The bilateral nature of disease, and the ab- changes such as macular pucker and RPE hyperplasia. sence of ocular pain, fluorescein disk leakage, and The fact that this nanophthalmic individual is other- classic ЉTЉ sign on ultrasonography make posterior wise healthy, but of short stature as compared to his scleritis less likely. Finally, this patient lacks the in- normal sized parents, also alters the differential. Pos- traocular inflammation, nodules, or subretinal sible conditions include nanophthalmic uveal effusion granulomas that would raise the suspicion for sarcoid. syndrome, mucopolysaccharidoses (MPS), Vogt-Koy- Central serous can sometimes present anagi-Harada (VKH) syndrome, posterior scleritis, sar- with a fluorescein pattern that is similar to this case. In coidosis, and less likely, central serous retinopathy fact, when Gass first described the uveal effusion (CSR), idiopathic choroidal neovascularization, and ve- syndrome, he reported a patient who was initially mis- nous stasis retinopathy. The short axial length of the diagnosed as having CSR.8 However, findings in this patient’s eyes would argue against idiopathic uveal ef- case that argue against CSR are the presence of nanoph- fusion syndrome, which occurs in normal-sized eyes. thalmos and choroidal thickening. The absence of sub- Nanophthalmos, or pure microphthalmos, is a rare retinal hemorrhages and the presence of bilateral disease disorder in which the eyes are small (anteroposterior with choroidal thickening also make idiopathic choroidal length generally between 15 and 20 mm), but other- neovascularization unlikely in this patient. wise grossly normal in function. Nanophthalmos may Finally, one must consider conditions that can lead be inherited in a sporadic, autosomal dominant, or to increased vascular tortuosity, although they are autosomal recessive manner and is usually not asso- certainly much lower on the differential. There is no ciated with systemic abnormalities. These patients are evidence of dilated conjunctival veins, , or often hyperopic and predisposed to angle closure glau- pulsating exophthalmos to suggest a carotid cavernous coma because of the propensity of the crystalline lens fistula. Coarctation of the aorta is also unlikely be- to be slightly enlarged. Although this patient’s refrac- cause it is usually picked up at a younger age, and the tive status was not discussed, the crowded appearance tortuosity of the retinal arterioles is more dramatic. of his discs would be consistent with that of a hyper- Hematologic conditions such as increased blood vis- ope. Nanophthalmic eyes also have abnormally thick- cosity could result in increased venous tortuosity. ened sclera, predisposing them to spontaneous choroi- However, the nanophthalmos with choroidal thicken- dal effusions and secondary serous detachments.6 ing suggests that the increased vascular tortuosity is a 934 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2005 ● VOLUME 25 ● NUMBER 7 result of a mechanical inhibition to venous outflow, of other possible diagnoses should be considered, but rather than an underlying hematologic abnormality. most can be eliminated with additional testing. An Additional workup at this time would start with a MRI scan of the with contrast to rule out orbital careful family history, concentrating on any history of masses or thyroid disease is indicated, but unlikely to inherited diseases. The diagnosis of mucopolysaccha- uncover undiagnosed pathology. Thyroid function ridoses can be made by the detection of the enzymatic tests should be done to look for even deficiency or by elevated levels of urinary glycosami- if the MRI is negative for extraocular muscle enlarge- noglycans. Because patients with mucopolysacchari- ment. The MRI will also help to rule out posterior doses can often have fatal cardiac abnormalities, a scleritis or orbital inflammation, which does not ap- complete cardiac workup would be important. It would pear to be present by clinical examination, and to also be reasonable to consider a very limited and make certain the reduced axial lengths are not second- coagulopathy workup by obtaining a chest x-ray, com- ary to orbital masses. It is still possible the patient had plete blood count, and basic metabolic panel. Testing for previous posterior scleritis in the past since chorioreti- ANA, ANCA, rheumatoid factor, homocysteine, protein nal folds may persist after resolution of the inflamma- C and S activity, antiphospholipid antibodies, and tion. Disk edema from pseudotumor cerebri may be anticardiolipin antibodies would only be warranted if associated with chorioretinal folds,12 but the disk there was a positive review of systems or family shows no definite edema and the fluorescein has no history to suggest any thrombophilia. late disk leakage. A lumbar puncture could be consid- The management goals in this patient would be ered to exclude pseudotumor cerebri since disk edema directed primarily at addressing the serous retinal de- may not always be present. The patient’s short stature tachments. Systemic steroids have been used with raises the question of other systemic diseases such as mixed success in uveal effusion syndromes. However, Alagille’s syndrome13 but he lacks posterior embryo- patients often require posterior sclerectomies with or toxon or abnormal facies. The patient does not have without vortex vein decompression to control the ef- cutaneous manifestations of scleromyxedema.14 Cho- fusions and retinal detachments. Once the serous ret- roidal neovascularization and hypotony can be elimi- inal detachments have resolved, removal of any symp- nated based on the examination. If the MRI scan, tomatic macular pucker could be considered. lumbar puncture, and thyroid function tests are nor- mal, then hyperopia is the likely cause of his chori- Dr. John T. Thompson (Baltimore, MD): oretinal folds. Another important question relates to Dr. Young’s patient presents an interesting differ- whether anything can be done to improve the visual ential of ocular and systemic disorders that could acuity in the left eye with the more prominent epireti- cause chorioretinal folds. The patient does appear to nal membrane. have chorioretinal folds rather than retinal folds, al- The OCT shows substantial serous detachment, though the presence of bilateral epiretinal membranes which could be secondary to a combination of hyper- should raise consideration of retinal folds alone. The opia associated choroidal folds and distortion of the presence of an epiretinal membrane is uncommon in inner retina from the epiretinal membrane. The serous eyes with chorioretinal folds and could be secondary detachment in the left eye and visual acuity might be to chronic serous detachments. The ultrasound shows improved by intravitreal triamcinolone. This potential one typical feature of chorioretinal folds where the treatment should be discussed, but the serous detach- posterior curvature of the globe is flattened.9 The OCT ment may recur when the triamcinolone is absorbed shows typical features of chorioretinal folds in the several months later. The left epiretinal membrane outer retina with a serous detachment in addition to an appears to be causing substantial macular distortion epiretinal membrane causing wrinkling of the inner both on the red free photographs and OCT. I would retina. The fluorescein angiogram does not show the suggest combining vitrectomy with epiretinal mem- typical alternating hyper- and hyperfluorescent bands brane removal and intravitreal triamcinolone injection from chorioretinal folds, but these may not be prom- since the visual acuity has deteriorated from 20/25 2 inent in all eyes. years ago to 20/100 now. I would not recommend any The most likely etiology of the chorioretinal folds is treatment to the much milder epiretinal membrane in the patient’s hyperopia. Hyperopia is often associated the right eye. with bilateral chorioretinal folds10 and eyes with very short axial lengths (18.5 mm bilaterally) have a greater likelihood of choroidal folds. Males with hy- Editor’s Note: peropia seem more prone than females to develop Dr. Young presents a short 23-year-old man with chorioretinal folds for unknown reasons.11 A number decreased vision, nanophthalmos, choroidal folds, and DIAGNOSTIC AND THERAPEUTIC CHALLENGES ● McDONALD 935 serous macular detachments. The differential diagno- Follow-up: sis is provided by our consultants. Dr. Young considered the Hallermann-Streiff syn- drome but, given the absence of dental abnormalities I. Syndromes associated with nanophthalmos and characteristic Љbeak-likeЉ facies, rejected this diag- A. Uveal effusion syndrome nosis. An MRI with contrast was performed. No thick- B. Hallermann-Streiff-Francois syndrome ened sclera was noted and therefore no sclerectomy/ C. Oculodentodigital syndrome sclerotomy was performed. The vision at the last D. Kenny-Caffey syndrome examination was 20/40 in the right eye, 20/50 in the left. II. Mucopolysaccharidoses A. IIA, IIB (Hunter’s) References B. VIA, VIB (Maroteaux-Lamy) III. Idiopathic central serous chorioretinopathy 1. Boynton JR, Purnell EW. Bilateral microphthalmos without microcornea associated with unusual papillomacular retinal IV. Vogt-Koyanagi-Harada folds and high hyperopia. Am J Ophthalmol 1975;79:820– V. Posterior scleritis 826. VI. Alagille’s syndrome 2. Blair NP, Brockhurst RJ, Lee W. Central serous choroidopa- VII. Scleromyxedema thy in the Hallermann-Streiff syndrome. Ann Ophthalmol 1981;13:987–990. The intriguing part of this diagnostic puzzle re- 3. Serrano JC, Hodgkins PR, Taylor DS, Gole GA, Kriss A. The nanophthalmic macula. Br J Ophthalmol 1998;82:276–279. volves around the patient’s short stature and nanoph- 4. Boynton JR, Pheasant TR, Johnson BL, Levin DB, Streeten thalmos. As Dr. Gross points out, dwarfism and nan- BW. Ocular findings in Kenny’s syndrome. Arch Ophthalmol ophthalmos are components of Hallermann-Streiff 1979;97:896–900. syndrome, a condition in which multiple choroidal 5. Larsen JL, Kivlin J, Odell WD. Unusual cause of short leaks have been described. The leaks and serous de- stature. Am J Med 1985;78:1025–1032. 6. Brockhurst RJ. Nanophthalmos with uveal effusion: a new tachment are probably the result of choroidal effusion clinical entity. Trans Am Ophthalmol Soc 1974;72:371–403. associated with nanophthalmos. However, this syn- 7. Vine AK. Uveal effusion in Hunter’s syndrome: evidence drome includes skin and dental abnormalities, which that abnormal sclera is responsible for the uveal effusion were denied by the patient. Kenny-Caffey syndrome is syndrome. Retina 1986;6:57–60. also associated with dwarfism and nanophthalmos, 8. Gass JD, Jallow S. Idiopathic serous detachment of the cho- roid, , and retina (uveal effusion syndrome). and radiologic evaluation of the long bones (looking 1982;89:1018–1032. for medullary stenosis of the long bone) and metabolic 9. Atta HR, Byrne SF. The findings of standardized echography evaluation (assessing possibility of hypocalcemia due for choroidal folds. Arch Ophthalmol 1986;106:1234–1241. to hyperparathyroidism) should be conducted to con- 10. Leahey AB, Brucker AJ, Wyszynski RE, Shama P. Chori- firm this diagnosis. oretinal folds: a comparison of unilateral and bilateral cases. Arch Ophthalmol 111:357–359. Drs. Lai and Shakin mention the possibility of mu- 11. Dailey RA, Mills RP, Stimac GK, et al. The natural history copolysaccharidoses, liposomal enzyme storage disor- and CT appearance of acquired hyperopia with choroidal ders that may cause abnormal thickening of the sclera. folds. Ophthalmology 1986;93:1336–1342. Patients with these disorders have been reported to 12. Griebel SR, Kosmorsky GS. Choroidal folds associated with have nanophthalmos and choroidal effusions. How- increased intracranial pressure. Am J Ophthalmol 2000;129: 513–516. ever, this patient does not exhibit the other abnormal- 13. Wells KK, Pulido JS, Judisch GF, et al. Ophthalmic features ities associated with these enzymatic deficiency dis- of Alagille syndrome (arteriohepatic dysplasia). J Pediatr eases. These consultants recommend a careful family Ophthalmol 1993;30:130–135. history and an evaluation for these storage disorders. 14. Davis ML, Barley GB, Gibson LE, Maguire LJ. Ophthalmic Dr. Thompson concentrates on the chorioretinal findings in scleromyxedema. Ophthalmology 1994;101:252– 255. folds in his analysis of this patient, pointing to the patient’s hyperopia. He suggests an MRI to rule out orbital masses or thyroid disease, and thyroid function ® tests to look for hyperthyroidism. He also suggests RETINA , The Journal of Retinal and Vitreous Dis- consideration for lumbar puncture to exclude pseudo- eases, encourages readers to submit Diagnostic and Ther- apeutic Challenges to H. Richard McDonald, MD, One tumor cerebri. Daniel Burnham Court, Suite 210C, San Francisco, CA Therapeutically, our consultants mention the possi- 94109. Cases for the Diagnostic and Therapeutic Chal- bility of posterior sclerectomies to reduce the uveal lenges section should include a detailed history of the pa- effusion as well as vitrectomy, epiretinal membrane tient, the diagnosis, the workup, the management, and fi- removal, and intravitreal triamcinolone injection (on nally, the question or questions that the submitter wishes to the left eye). have answered by the consultants.