Seven eyes of 4 patients (87.5%) had acceptable quality images for each image type. The mean age at presentation was approximately 45 years (51 ± 14.28 years). The gender distribution was 1:1 (male to female). Family history was positive in 2 patients (50%).The median follow-up was 85.3 months (range, 2 to 150 months). Recurrence and secondary glaucoma developed in 2 eyes of 1 patient (25%). No patients subsequently were observed to develop systemic amyloidosis or dysfunction during the follow-up time. A summary of the clinical, gene mutation, ultrasonographic features, and treatment outcomes of these 4 cases is presented in Table 1.
Table 1
Ocular amyloidosis in Asian patients: A study of 8 eyes of 4 patients
Patient
|
Age/Gender, Years
|
Family History
|
Ocular involvement
/Laterality
|
Gene Mutation
|
Symptoms of Systemic Amyloidosis
|
Primary Treatment
|
Pre- BCVA
|
Final BCVA
|
Follow-up Duration, Months
|
Complications
|
1
|
F/48
|
(-)
|
Vitreous (OU)
|
Declined
|
None
|
23G Vitrectomy
|
HM, 20/60
|
20/80/, 20/80
|
57ms
|
None
|
2
|
M/42
|
(-)
|
Retina, Vitreous (OU)
|
Declined
|
None
|
23G Vitrectomy
(OD)
|
HM, 20/25
|
20/100, 20/25
|
132ms
|
None
|
3
|
M/42
|
(+)
|
Vitreous (OU)
|
Val30 Met
|
None
|
20G Vitrectomy
|
20/40, 20/60
|
20/100, 20/200
|
150ms
|
Glaucoma
|
4
|
F/72
|
(+)
|
Vitreous (OU)
|
Arg54Gly
|
None
|
25G Vitrectomy
|
20/200, HM
|
20/80, 20/66
|
2ms
|
KCS
|
F: Female; M: Male; HM: hand motion; BCVA: best corrected visual acuity; KCS: keratoconjunctivitis sicca. |
Case Reports
Patient 1
A 48-year-old Asian woman sought treatment at our clinic in November 2017 with significant bilateral visual deterioration. The patient had no history of systemic disease or family history of amyloidosis.
At presentation, her BCVA was hand motion (HM) in the right eye and 20/60 in the left eye, and the IOP was within normal limits. Anterior segment examination revealed bilateral pseudopodia lentis and waxy wool-like opacities suspended throughout the vitreous cavity (Fig. 1. A, B). No abnormalities were seen in the conjunctiva, cornea, pupil, iris, or trabecular meshwork. The media opacities varied from grade 2 to 3 in both eyes (Endophthalmitis Vitrectomy Study grading)14. White tufts resembling seaweed projected from the normal-appearing retinal surface to the vitreous in both eyes, but the posterior fundus was visible through the vitreous haze in the right eye. Dilated funduscopy revealed vitreous opacities and tortuous vessels, but no active lesions or hemorrhages in the retinal periphery. Despite the vitreous opacities, there was no evidence of vascular leakage on FFA (Fig. 1. C). However, dot and rod-shaped diffuse high fluorescence were observed in the vitreous distributed along the vitreous fibers throughout the entire ICGA period (Fig. 1. D). SD-OCT in the right eye revealed subtle thickening of the internal limiting membrane (ILM) of the foveal area. However, in the left eye, retinal surface deposits with a needle-shaped pattern extending from the ILM to the vitreous were present (Fig. 1. E). CDU imaging of both eyes demonstrated massive echoes in the central portion of the vitreous cavity and sheet-like echoes involving the posterior cortical portion of the vitreous body (Fig. 1. F).
We performed bilateral pars plana vitrectomy and vitreous biopsy, which revealed eosinophilic amorphous material consistent with amyloid (Congo red staining and apple green birefringence) (Fig. 1. G), and no evidence of lymphoma or malignancy. Unfortunately, the patient declined genetic testing because she could not afford the expense. The systemic examinations did not reveal symptoms of amyloidosis. Three months later, the BCVA was 20/80 bilaterally and the postoperative SD-OCT revealed residual focal adhesion to the macular fovea but without any progression of the previous findings (Fig. 1. H).
At the 5-year follow-up, the final BCVA was 20/80, and there were no signs of recurrence and no systemic disease had developed.
Patient 2
A 42-year-old Asian man was referred to our clinic in September 2009 with significant right visual deterioration. The patient first noted visual floaters in his right eye at age 40, at which time the BCVA was 20/20 in both eyes.
The patient underwent ophthalmologic and systemic examinations at our ophthalmic department. BCVA was HM in the right eye and 20/25 in the left eye. The anterior ocular segment was unremarkable, and the IOP was normal in both eyes. Dilated fundus examination showed a white, dome-shaped lesion located at the inferotemporal retina, with fine vitreous hemorrhage in the fundus of the right eye (Fig. 2. A). CDU of the right eye demonstrated dome-shaped massive echoes in the central portion of the vitreous cavity and medium reflectivity involving the posterior cortical portion of the vitreous body (Fig. 2. B). The mass was measured at 6.2 mm in the largest basal diameter and 4.5 mm in thickness. FFA/ICGA showed hypofluorescence without signs of leakage during the whole stage (Fig. 2. C). Magnetic resonance imaging (MRI) demonstrated a semi-spherical T1-and T2-weighted medium signal, which was not contrast-enhancing (Fig. 2. D). Pars plana vitrectomy and biopsy of the retinal lesion of the right eye were performed. The vitreous fluid obtained at surgery contained amyloid deposits. The retinal specimens and vitreous were subjected to histopathological examination and confirmed retinal amyloid (Fig. 2. E, F). Postoperatively, the BCVA in the right eye improved to 20/66.
Evaluation for systemic amyloidosis, including neurological evaluation, echocardiogram, and bone marrow biopsy, revealed no evidence of amyloidosis. Initially, the BCVA was 20/66 in his right eye postoperatively but later decreased to 20/100 due to the formation of a posterior subcapsular cataract. Mild strands of amyloid were evident in his left eye, but the BCVA remained at 20/25. Family members, including his parents, maternal uncle, brother, and 2 children, did not have clinical symptoms to suggest systemic or ocular amyloidosis. He declined genetic testing.
At 12 years of follow-up, the final BCVA in the right eye was 20/100, and there were no signs of recurrence or the development of systemic disease.
Patient 3
A 42-year-old Asian man proband (patient II-2) presented to our clinic in May 2008 with a 2-year history of floaters in both eyes. The patient’s father, 2 sisters, and 2 paternal uncles all had ocular impairments from complications of amyloidosis. His paternal grandmother was blind 10 years prior to her death. The family history is plotted in Fig. 3. A.
The BCVA was 20/40 and 20/60 in the right and left eyes, respectively. The anterior segment was normal with normal IOP. White tufts resembling seaweed projected from the normal-appearing retinal surface to the vitreous in both eyes. Dilated fundoscopy showed thin, wispy vitreous haze, which were more prominent in the left eye, as well as snowflake opacities in the posterior fundus of the right eye, and bilateral posterior vitreous detachments (PVD), but no active lesions or hemorrhages in the peripheral fundus (Fig. 3. B, C). SS-OCT demonstrated subtle thickening of the ILM, and a thin layer of retinal surface deposits with hyperreflectivity. A few needle-shaped patterns extending from the ILM to the vitreous were present (Fig. 3. D) and involved the optic disc of both eyes (Fig. 3. E). SS-OCTA (retina code 6*6 mm) revealed tortuous small vessels and pseudo destruction of the foveal avascular zone (FAZ) on the superficial retinal vascular layer (SRL). There was no evidence of nonperfusion of the macular area (Fig. 3. F). The systemic examination revealed no sign of amyloid or no other metastases origins were suspected. Standard three-port 23-gauge pars plana vitrectomy and biopsy bilaterally were performed, followed by histopathologic examination. The findings of the vitreous specimens revealed apple green birefringence in polarized light in Congo red, typical of amyloid. Genetic testing for the TTR gene revealed a heterozygous Val30 Met mutation, confirming the diagnosis of familial amyloidosis. Postoperatively, the BCVA in the right eye improved to 20/20.
However, 7 years after presentation, the BCVA dropped to 20/66 in the left eye, and new branching vitreous opacities appeared. The vitreous of the right eye was unchanged. The patient underwent further vitrectomy of the left eye, and the BCVA was 20/40 postoperatively. During the next 5 months, the visual acuity further deteriorated to counting fingers at 0.5 m in the left eye, and 20/100 in the right eye, and the IOPs were increased (42 mmHg in the right and 37 mmHg in the left eye). The optic discs were cupped, and the C/D ratio was 0.6 in the right eye and 0.7 in the left eye. Threshold visual fields revealed early glaucomatous changes. Initially, the IOPs were controlled with topical medication. Trabeculectomy was performed 6 months later, and samples of the trabecular meshwork were sent for histopathologic analysis. However, the specimens were insufficient for analysis. Bilateral cataract extraction was performed 1 year later.
At the last follow-up, the central vitreous was clear bilaterally with dense amyloid deposition in the peripheral vitreous. The BCVA was 20/100 and 20/ 200 in the right eye and left eye, respectively, but the patient declined further systemic examination and treatment.
Patient 4
A 65-year-old Asian woman proband (patient II-2) sought consultation for significant bilateral visual deterioration and dry eyes. The patient’s myopic refraction was within − 5.00 D. Her eyes were quiet with 20/100 visual acuity. White, pearl string-like opacities adhered to the vitreous fibrils, and smaller vitreous haze adhered to the posterior lens capsule (Fig. 4. A-C). At 72 years of age, she experienced vision deterioration and progressive vitreous haze in both eyes. Her BCVA was 20/200 in the right eye and HM in the left eye. More pearl string-like and isolated vitreous haze were seen in both eyes (Fig. 4. D, E). The fundus details were no longer visible. The patient’s father, brother, paternal aunt, and 2 uncles were all blind with vitreous haze before they died from systemic complications of unspecified amyloidosis. The family history is plotted in Fig. 4. F.
The patient underwent bilateral standard three-port pars plana vitrectomy and vitreous biopsy. Fresh vitreous was stained with alkaline Congo red stain and the findings were positive. However, the vitreous samples were insufficient for immunohistochemical analysis.
DNA was extracted from the peripheral blood by standard protocols, and TTR gene sequencing identified a previously reported base pair exchange in exon c.160A, resulting in a heterozygous mutation Arg54Gly (late-onset), confirming the diagnosis of familial amyloidosis. The patient’s 2 daughters had the same gene mutation.
Postoperatively, the BCVA in both eyes improved to 20/80. SS-OCT showed a thick, lamellar deposited material with hyperreflectivity before the surface of the ILM, which was one of the factors affecting the improvement in visual acuity. The thickness of the choroid was significantly thinner, and the measured submacular choroidal thickness was only 40.26 um (Fig. 4. G).
At the last follow-up, the central vitreous was clear bilaterally with dense amyloid deposition in the peripheral vitreous. Occasionally, the shifting from residual peripheral vitreous to central vitreous was seen. The BCVA was 20/80 and 20/66 in the right eye and left eye, respectively. To date, there have been no clinical symptoms to suggest systemic amyloidosis.
SD/SS-OCT/OCTA Features
In our case series, choroidal thickness was measured by SD-EDI-OCT (in um at a wavelength of 840 nm since 2008, Spectralis; Heidelberg Engineering, Inc.), as well as optical coherence tomographic angiography (SD/SS-OCTA, at a wavelength of 1050 nm since 2019, VG200D, SVision Imaging, Ltd., China). It was impossible to perform SD/SS-OCT/OCTA in all eyes due to the significant media haze. Seven eyes of 4 patients (87.5%) had acceptable quality OCT/A images. However, despite the vitreous opacities, there was no evidence of cystoid macular edema on OCT/OCTA in any of the eyes.
We identified vertical hyperreflective lesions that appeared to be punctate with moderate or high reflectivity and affected all layers of the neuroretina (from the RPE to the ILM) in 7 eyes of 4 patients (7 of 8 eyes [87.5%]) (Fig. 1E, H; Fig. 3D, E; and Fig. 4G). In 6 of 8 eyes (75%), the SD/SS-OCT B-scan revealed subtle thickening of the ILM with retinal surface deposits with a subtle needle-shaped pattern extending from the ILM to the vitreous, involving the optic disc (Fig. 3. D, E).
Notably, SD/SS-OCT revealed a thin layer of retinal deposited materials with hyperreflectivity on the surface of the ILM with morphologic changes of the macular fovea (Fig. 1. H; Fig. 4. G) postoperatively. Others revealed residual focal adhesion to the macular fovea (Fig. 1. H).
SS-OCTA (retina code 6*6 mm) revealed tortuous macular small vessels and pseudo destruction of the FAZ on the superficial retinal vascular layer (SRL), and a pseudo disrupted area corresponding to the area of vitreous haze projected on the retina (Fig. 3. F). There was no evidence of nonperfusion of the macular area (retina code 6*6 mm) or posterior retinal area (retina code 12*12 mm).
In addition, an abnormally thinned choroidal layer (measuring only 40.26 um), as well as the scleral layer, was also observed in the SS-OCT imaging of patient 4.
Operative Characteristics
During the vitrectomy, we noted several peculiar features in the consistency and attachment of the vitreous in all eyes. The posterior vitreous hyaloid had firm adhesions not only beyond the major arcades and along a few retinal blood vessels, but also in the posterior fundus involving the macular area. Perivascular white deposits of amyloid were also observed (Fig. 5. A). Vitreous consistency was modified due to the deposited abnormal protein, and it was difficult to induce PVD from the optic disc. During the surgery, the vitreous was cut like rigid, waxy paper (Fig. 5. A, B), and in our experience, a 20-G vitrectomy was relatively easy to cut. However, it was challenging to cut the rigid vitreous in the 23- to 25-G vitrectomy.
Cytospin smears prepared from the vitreous aspirate showed amorphous acellular material that stained positively with Congo red and revealed apple green birefringence on polarized microscopy, consistent with amyloidosis.
After surgery, the periphery residual vitreous tended to shift to the central vitreous space, mimicking a recurrence. The OCT showed significant, thickened materials with hyperreflectivity on the surface of the ILM, indicating that the amyloid deposits in the vitreous firmly adhered to the retina.