Case of the Month
Edited by Robert N. Johnson, MD
Case #105, March, 2018
Presented by Judy Chen, MD
A 66-year-old Caucasian woman presents with bilateral retinal hemorrhages found on routine examination.
Figures 1A and B: Fundus photographs of the right and left eyes. Note the retinal angiopathy, including multiple dot and blot hemorrhages and telangiectasis with beading, attenuation, and segmental sheathing of retinal veins in each eye.
Figures 1C and D: Fluorescein angiograms of the right and left eye. Note the multiple areas of retinal vascular angiopathy with areas of nonperfusion, vascular sheathing, telangiectasis and beading and microaneurysms. Areas of retinal hemorrhage are present as well.
A 66-year-old Caucasian woman was referred for evaluation of bilateral, non-resolving retinal hemorrhages found on routine eye examination. Prior to presentation, she had undergone an extensive workup for systemic hypertension, diabetes mellitus, and embolic disease, including magnetic resonance imaging (MRI) of the head and neck followed by carotid ultrasonography, all of which were unrevealing. Her past medical history was notable for hypothyroidism, asthma, degenerative arthritis, and breast cancer, for which she received chemotherapy 20 years prior and which was in remission. Family and social history were noncontributory. Review of systems was notable for transient, recent memory and speech difficulties, but otherwise revealed no neurologic, cardiac, and integumentary signs or symptoms.
On examination, best-corrected visual acuity was 20/30 on the right and 20/40 on the left. Intraocular pressures were normal. Anterior segment examination was unremarkable, with no evidence of abnormal conjunctival vessels, amyloid deposition on the iris or lens, or scalloping or neovascularization of the iris. Posterior segment examination revealed evidence of retinal angiopathy, including multiple dot/blot hemorrhages, telangiectasis with beading, attenuation, and segmental sheathing of retinal veins in each eye extending to the periphery (Figure 1 A & B). Fluorescein angiography revealed large areas of non-perfusion with multiple microaneurysms, capillary telangiectasis and segmental staining of the affected retinal veins (Figure 1B & C). No vitreous opacities or retinal neovascularization was noted. Horizontal spectral domain-optical coherence tomography (SD-OCT) through the fovea of each eye showed mild epiretinal membrane with surface retinal folds, worse on the left, and temporal atrophy in the areas of non-perfusion (Figure 1E & F)
Figures 1E and F: SD-OCT of the right and left eyes. Retinal thinning is present temporally in both eyes. A mild epiretinal membrane is present in both eyes (very mild in the left eye), and some retinal folds are noted in the left eye.
What is your Diagnosis?
Inflammatory (Behcet’s disease, sarcoidosis, lupus, Wegener’s granulomatosis, polyarteritis nodosa, Churg-Strauss, rheumatoid arthritis, HLA-B27 uveitis, pars planitis), infectious (tuberculosis, syphilis, lyme disease, Bartonella, HSV/VZV), neurologic (multiple sclerosis, Susac syndrome), neoplastic (lymphoma, leukemia, paraneoplastic), hypercoagulable (protein C/S deficiency, homocystinuria, lupus anticoagulant, DIC, sickle cell, multiple myeloma), Eales’ disease, IRVAN
Additional Case History
Rheumatologic and systemic workup including testing for inflammatory (ANA, ACE, ESR, CRP, CCP, RF, lysozyme, HLA-B27), infectious (RPR, FTA-ABS, Lyme titers, B. henselae and B. Quintana titers, Hep B surface Ag), and hypercoagulable (protein C/S, AT3, homocysteine, PT/PTT, lupus anticoagulant, fibrinogen degradation products, cardiolipin AB, hemoglobin electrophoresis, SPEP) causes for the angiopathy were unrevealing. The patient was reluctant to begin immunosuppressive therapy due to her previous history of breast cancer, and so opted for periodic monitoring.
Over subsequent years the patient developed recurrent vitreous hemorrhages with neovascularization of the optic nerve and iris, which prompted treatment with intravitreal bevacizumab followed by panretinal photocoagulation (PRP) (Figure 2A & 2B). She also underwent uncomplicated cataract extraction with intraocular lens placement in each eye.
Five years after initial presentation, the patient had a syncopal episode that led to an echocardiogram revealing concentric right and left ventricular hypertrophy, biatrial enlargement, thickening of the interventricular septum, and poor nulling of the myocardium, suspicious for amyloidosis. She also complained of tremors, postural dizziness, numbness and tingling of her extremities, voice “shaking”, dysphagia, and alternating periods of diarrhea and constipation. Both myocardial and terminal ileal biopsies were performed, revealing positive Congo red staining (Figure 3) and apple green birefringence (Figure 4) diagnostic for amyloidosis. Sequencing of the TTR gene confirmed the presence of the common amyloidogenic V30M mutation.
The patient has maintained good visual acuity with best-corrected visual acuities of 20/20 on the right and 20/25 on the left, and no further episodes of vitreous hemorrhage.
Figures 2A and B: Wide-field fundus photos of the right and left eye after treatment with intravitreal bevacizumab and panretinal photocoagulation for recurrent vitreous hemorrhages and neovascularization of the optic nerve and iris.
Figure 3: Histopathologic sections through myocardium (A) and terminal ileum (B) show staining of amyloid with Congo red.
Figure 4: Characteristic Congo red staining (A) and darkfield apple green birefringence with polarized light (B) of amyloid deposits in the terminal ileum
First described by Andrade in 1952,1 familial amyloidotic polyneuropathy (FAP) is a group of rare, autosomal dominantly inherited conditions that result from the systemic accumulation of amyloid fibrils within the peripheral nervous system and other organs, including the eyes.2 Transthyretin (TTR) V30M-related familial amyloidosis is the most common form of hereditary amyloidosis, accounting for almost 50% of mutations worldwide.3 Most often found in patients of Portuguese and Swedish descent, the disease is due to an unstable mutation within the TTR protein caused by a single amino acid substitution of methionine for valine at position 30. Although the mutant TTR is mainly produced by the liver, the protein is also synthesized in the retina and choroid.
Ocular manifestations of FAP TTR V30M are well-documented and are thought to be secondary to amyloid deposition within different structures of the eye. In a cross-sectional study of 513 patients with genetically confirmed V30M mutations, Beirão and colleagues3 reported nine distinct FAP-related ocular manifestations. Listed from most to least common, these included abnormal tear breakup time (79.5%), abnormal Schirmer test (67.0%), amyloid deposition on the iris (38.4%), amyloid deposition on the lens (32.9%), scalloped iris (27.9%), glaucoma (20.3%), vitreous amyloidosis (17.4%), abnormal conjunctival vessels (14.3%), and retinal angiopathy (4.4%). Of note, the vast majority of patients with retinal angiopathy had other ocular manifestations of amyloidosis. Concurrent vitreous amyloidosis was particularly common, occurring in 22 of 32 (68.8%) eyes with angiopathy. Neovascularization and vitreous hemorrhage associated with TTR V30M amyloidosis is rare, but have been reported in other forms of FAP.4
Treatment of FAP TTR amyloidosis involves both systemic and local control of disease processes. Liver transplantation is the first-line systemic treatment and can effectively reduce systemic TTR levels,5 both halting progression and improving survival. However, ocular disease can develop or even progress following liver transplantation,6 since ocular tissues continue to produce mutant TTR protein, and recent studies have shown no significant reduction in the prevalence of dry eye or abnormal conjunctival vessels, both thought to be due to deposition of systemic circulating TTR, in post-transplant patients.3 The small molecule TTR stabilizers tafamidis meglumine and diflunisal have shown promising results for the treatment of systemic complications of amyloidosis, but neither has been studied specifically for ocular disease.7
Local control of ocular manifestations of amyloidosis includes use of intravitreal anti-vascular endothelial growth factor (anti-VEGF), PRP, and pars plana vitrectomy. Panretinal photocoagulation is thought to achieve local control of disease by destroying the retinal pigment epithelium, which produces the mutant TTR proteins, as well as local proteoglycans that support the formation of amyloid in the vitreous and retinal surface.8 Sandhu et al9 described a case of FAP TTR E89K that presented with neovascularization of the disc and vitreous hemorrhage, treated with panretinal photocoagulation with excellent results. The use of anti-VEGF was reported in a case of neovascular glaucoma post-vitrectomy for vitreous opacities in FAP with resolution of neovascularization and normalization of intraocular pressure.10 Pars plana vitrectomy is also an important form of localized treatment, particularly when the retinal angiopathy is associated with dense vitreous opacities or non-clearing vitreous hemorrhage. Reduced vitreous collagen matrix in vitrectomized eyes is thought to prevent further amyloid aggregation and deposition.
This Case of the Month was adapted from the article “Transthyretin V30M familial amyloidosis presenting as isolated retinal angiopathy” by Judy Chen, Ananda Kalevar, Emmett Cunningham, et al, published in Retinal Cases and Brief Reports on October 9, 2017.
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