Systemic Amyloidosis and Extraocular Muscle Deposition

A 47-year-old woman developed severe bilateral visual loss 4 years after a Roux-en-Y gastric bypass and 24 years after vertical banded gastroplasty. Her serum copper level was 35 μg/dL (normal, 80-155 μg/dL). She was prescribed elemental copper tablets. Because her methylmalonic acid was slightly elevated, she received vitamin B12 injections as well. Five weeks later, she reported that her vision had improved and, at 10 months, her vision had recovered from 20/400 bilaterally to 20/25 in each eye. This case highlights the importance of checking copper levels in addition to the 'more routine' vitamin levels, such as B1, B6, B12, E, and serum folate in patients with suspected nutritional optic neuropathy after bariatric surgery, particularly if it involved a bypass procedure.

Clinical Observation Systemic Amyloidosis and Extraocular Muscle Deposition Veeral S. Shah, MD, PhD, Kara M. Cavuoto, MD, Hilda Capo, MD, Sara F. Grace, MD, Sander R. Dubovy, MD, Norman J. Schatz, MD Abstract: Isolated amyloid deposition in an extraocular muscle is a rare event but can be a presenting feature of systemic amyloidosis. A 67-year-old woman with an acquired exotropia and hypertropia was found to have unilateral diffuse extraocular muscle enlargement on magnetic resonance imaging. Owing to the progressive nature of her strabismus and the negative laboratory testing for thyroid disease, she underwent an extraocular muscle biopsy that revealed amyloid deposition. Further workup demonstrated a monoclonal gammopathy consistent with systemic amyloidosis. This case demonstrates the need to consider amyloidosis in the differential diagnosis of patients presenting with an atypical acquired strabismus. We review other reports of isolated amyloid deposition in extraocular muscles and its association with systemic amyloidosis, emphasizing the importance of the ophthalmologist in the early recognition of this disease to prevent irreversible, life-threatening end organ damage. Journal of Neuro-Ophthalmology 2016;36:167-173 doi: 10.1097/WNO.0000000000000358 © 2016 by North American Neuro-Ophthalmology Society secondary), and 3) specific molecular type of amyloid protein (3). The systemic form of amyloid involves more than one organ system, whereas the localized form is isolated to a single organ tissue. Amyloidosis can occur secondary to infection, inflammation, or malignancy, but in the absence of an underlying process, it is considered primary amyloidosis (4). Regardless of the type of classification, orbital amyloidosis is rare. Orbital amyloidosis was once believed to be a predominantly localized disease without systemic significance, (5,6) but more recent case reports have questioned this notion (7). Orbital amyloid deposition has been previously described in the periorbital fat, extraocular muscles and lacrimal gland (8,9). Laboratory and clinical evidence suggests that systemic amyloidosis has a predilection for deposition in muscles (4,10). We describe a case of orbital amyloidosis isolated to the extraocular muscles and review the literature for isolated amyloid deposition of the extraocular muscles to explore its association with systemic amyloidosis. CASE REPORT A myloidosis is a complex disease characterized by the extracellular deposition of protein fibrils arranged in a b-pleated sheet formation known as amyloid (1). Insoluble and highly resistant to proteolysis, amyloid that aggregates in tissue has a characteristic Congo red stain uptake and exhibits "apple" green birefringence under polarized light (2). Amyloidosis can be classified in 3 ways: 1) degree of tissue involvement (localized or systemic), 2) etiology (primary or Department of Ophthalmology (VS), Texas Children's Hospital, Baylor College of Medicine, Houston, Texas; Department of Ophthalmology (KMC, HC, SFG, SRD, NJS), Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. The authors report no conflicts of interest. Address correspondence to Veeral S. Shah MD, PhD, Assistant Professor of Pediatric Neuro-Ophthalmology, Department of Ophthalmology, Texas Children's Hospital, Baylor College of Medicine, 6701 Fannin Street, Suite 610.25, Houston, TX 77030; E-mail: vsshah@ texaschildrens.org Shah et al: J Neuro-Ophthalmol 2016; 36: 167-173 A 67-year-old woman with hypertension, breast cancer treated with bilateral mastectomies and chemotherapy, and bilateral carotid endarterectomies for atherosclerotic occlusive disease was evaluated in an emergency department with a 10-day history of diplopia. Visual acuity was 20/25 in both eyes. Her eye movements revealed an exotropia and small left hypertropia with decreased motility on supraduction, infraduction, and adduction of the right eye. Ductions of the left eye were normal (Fig. 1). The ophthalmic examination was otherwise unremarkable. She was presumed to have a pupil-sparing partial, right third cranial nerve palsy given her medical history of microvascular disease and clinical presentation of uncontrolled hypertension. On follow-up examination, her exotropia progressed (Fig. 2). In addition, she had restricted forced ductions, but there was no evidence of eyelid retraction or lag, or aberrant regeneration. Orbital magnetic resonance imaging (MRI) revealed 167 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 1. The patient has an exotropia and small left hypertropia, with restricted motility in supraduction, infraduction, and adduction of the right eye. diffuse thickening of the right medial, inferior, and lateral rectus muscles with sparing of the tendons, consistent with thyroid eye disease (Fig. 3A, B). In addition, there was patchy hyperintensity of extraocular muscles in the right orbit (Fig. 3C). Thyroid function tests, thyroid peroxidase, thyroid stimulating immunoglobulin, serum anti-acetylcholine receptor antibody assays, and edrophonium chloride testing were all negative. Evaluation by the endocrinology service revealed multiple thyroid nodules; however, repeat thyroid testing and myasthenia testing were normal. Given the progressive and restrictive nature of the strabismus, a right medial rectus biopsy was performed. Histopathological examination showed amorphous, eosinophilic extracellular material that stained pink with Congo red. Under polarized microscopy, sectioned tissue revealed the apple-green birefringence characteristic amyloid (Fig. 4). The patient was evaluated for systemic amyloidosis. Serum protein electrophoresis showed an elevated M-spike with a free kappa of 3.370 g/dL and free lambda of 2.820 g/ dL. Urine protein electrophoresis showed elevated protein. Serum mass spectrometry was consistent with lambda amyloid light chain (AL) amyloidosis. Pathologic examination of a left arm papule biopsy showed lichen amyloid. Chest radiography demonstrated cardiomegaly with vascular congestion, and serum brain natriuretic peptide was found to be elevated at 2134 pg/mL (normal: 0.5-30 pg/mL). An echocardiogram showed diastolic dysfunction with right ventricular thickening suggestive of cardiac amyloid FIG. 2. Initial and follow-up ocular motility demonstrates progressive worsening of exotropia and hypertropia at 3, 6, and 12 months. ET, esotropia; LHT, left hypertropia; RH, right hyperphoria; RHT, right hypertropia; XT, exotropia. 168 Shah et al: J Neuro-Ophthalmol 2016; 36: 167-173 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation involvement. Collectively, these findings were consistent with systemic AL amyloidosis. The guarded prognosis of systemic amyloidosis was discussed with the patient, and elective systemic treatment with dexamethasone and bortezomib was initiated. During 2 years of follow-up, the patient developed complete ophthalmoplegia of her right eye, whereas her left extraocular motility remains preserved. She is followed by hematology-oncology and has systemically responded to treatment with dexamethasone and bortezomib. DISCUSSION FIG. 3. Coronal T1 (A) and axial T2 (B) magnetic resonance imaging shows thickening of the right medial, inferior, and lateral rectus muscles. Postcontrast axial T1 scan with fat suppression (C) demonstrates heterogenous and decreased enhancement of the right medial rectus compared with more homogenous enhancement of the left medial rectus muscle. Amyloidosis represents a heterogeneous disease of protein misfolding and deposition that manifests in varied growth patterns, penetrance, and locations (1). Although infrequent, it can affect conjunctiva, and periocular and orbital adnexa. The presentation of our patient with amyloidosis of the extraocular muscles initially masqueraded as cranial nerve palsy and then as thyroid eye disease. Several observations can provide lessons for early detection, diagnosis, and management of amyloidosis in extraocular muscles. First, our patient presented with a motility pattern suggestive of a microvascular third nerve palsy. However, strabismus secondary to microvascular cranial nerve palsies resolves in 3-6 months, whereas our patient's eye movements progressively worsened. In addition, forced ductions were consistent with a restrictive, not paralytic, strabismus. Second, neuroimaging showed diffuse extraocular muscle enlargement with sparing of the tendons, initially consistent with thyroid eye disease. However, our patient was atypical as most thyroid patients present with esotropia and our patient demonstrated exotropia. Vargus et al (11) reported 4 patients with thyroid eye disease who presented with exotropia and were found to have concurrent ocular myasthenia gravis. The presence of multiple enlarged rectus muscles and exotropia would suggest a dual diagnosis of FIG. 4. Extraocular muscle biopsy. A, There are deposits of amorphous eosinophilic extracellular material (asterisks) with scattered lymphocytes (hematoxylin and eosin, ·20). B, Areas of the specimen stains pink with Congo red (·20). C, When viewed with polarized light, there is apple-green birefringence (Congo red, ·20). Shah et al: J Neuro-Ophthalmol 2016; 36: 167-173 169 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Case Age/Gender Medical History Presenting Symptom Ocular Examination Findings Shah et al: J Neuro-Ophthalmol 2016; 36: 167-173 Lacey et al (15) 44/F Graves' orbitopathy Diplopia Proptosis, eyelid edema Banerjee et al (24) 45/F None Eye strain Esophoria Erie et al (25) 28/F None Diplopia, exophthalmos Goebel et al (26) 75/M None Holmstrom et al (27) 60/F Muscle weakness, urinary retention, heart block - Right exotropia, restriction of right adduction and abduction - Jeon et al (28) 37/F Katz et al (29) 48/F Lett et al (30) Macoul et al (31) 58/F 64/M Okamoto et al (32) 47/M Macroglossia, sleep apnea, cardiomyopathy, carpal tunnel syndrome None Heart failure, adrenocortical insufficiency, hypothyroidism None Pasternak et al (33) Paula et al (34) 44/F 47/F Hyperthyroidism None Raflo et al (35) 60/M Muscle weakness, heart failure Teoh et al (36) 69/F None Exophthalmos Eyelid swelling, diplopia, skin papules Decreased vision, eyelid swelling Decreased vision Extraocular Muscle Involvement Location Systemic Involvement Case Lacey et al (15) Banerjee et al (24) Erie et al (25) Goebel et al (26) Holmstrom et al (27) Jeon et al (28) Katz et al (29) Diplopia CT scan, muscle biopsy CT, muscle biopsy, ultrasound CT, Muscle biopsy Postmortem biopsy CT, muscle biopsy Diplopia Right exotropia, restriction of right adduction Unilateral proptosis, unilateral restriction of adduction and abduction Esotropia, restrictive ophthalmoparesis Diplopia, ptosis Ptosis, diplopia Complete ophthalmoplegia, exotropia Bilateral ophthalmoplegia CT, muscle biopsy Muscle biopsy Diplopia, exophthalmos Left eye restrictive ophthalmoplegia, left exotropia Bilateral proptosis Left eye proptosis, left eyelid edema CT, MRI, muscle biopsy CT, muscle biopsy CT, muscle biopsy Complete ophthalmoplegia Muscle biopsy Hypoglobus, Supraduction deficit CT, muscle biopsy Exophthalmos Bilateral diffuse Right lateral rectus Right medial and lateral rectus Bilateral diffuse Right medial rectus Unilateral diffuse Bilateral diffuse Diagnostic Testing - - - Liver, kidney, spleen, heart, leptomeninges - - Positive biopsies: tongue, skin, vagina Amyloidosis Systemic vs Localized Localized Localized Localized Systemic Localized Localized Systemic CT, muscle biopsy MRI, systemic biopsies Management - - Strabismus surgery Deceased Strabismus surgery - Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation 170 TABLE 1. Reported cases of amyloidosis of extraocular muscles Right superior rectus Teoh et al (36) F, female; M, male; AL, amyloid light chain; CT, computed tomography; MRI, magnetic resonance imaging. Bilateral diffuse Raflo et al (35) Eyelid papules, elevated serum IgG, elevated free kappa chains in urine - Systemic (multiple myeloma) Localized Prisms, observation - - - Bone marrow transplant Melphalan and prednisone - Systemic Systemic Localized Systemic Systemic Positive biopsy: rectum Positive biopsies: submaxillary gland, skin - AL monoclonal population Positive biopsy: skin Bilateral diffuse Bilateral diffuse Left diffuse Bilateral diffuse Left superior oblique Lett et al (30) Macoul et al (31) Okamoto et al (32) Pasternak et al (33) Paula et al (34) Case (Continued ) Extraocular Muscle Involvement Location Systemic Involvement Amyloidosis Systemic vs Localized Management Clinical Observation Shah et al: J Neuro-Ophthalmol 2016; 36: 167-173 active thyroid eye disease and ocular myasthenia gravis (12). However, our patient was found to be euthyroid and had a negative workup for thyroid eye disease (thyroid function tests, thyroid antibody panels) and for myasthenia gravis (antibody panel, endoplasmic chloride test). The presence of thyroid nodules was a nonspecific misleading clinical feature. Additional etiologies to consider in the differential diagnosis of extraocular muscle enlargement include metastatic disease, inflammatory disorders, acromegaly, arteriovenous shunts, vitamin A and E deficiency (13), and lithium toxicity. Metastatic cancer was considered in our patient, but was less likely given the smooth contour of the extraocular muscles in contrast to the nodular appearance typically seen in metastatic cases (14). Inflammatory conditions, such as orbital myositis, IgG4-related disease, systemic lupus erythematosus, and sarcoidosis were considered as they can cause rectus muscle enlargement. However, our patient did not present with the pain or inflammatory orbital signs typical for these disorders (15). In particular, the extraocular muscle enlargement of IgG4-related diseases is due to ocular myositis that can be unilateral or bilateral with acute or insidious onset. In the vast majority of these cases, orbital myositis is associated with dacryoadenitis and an orbital mass that is readily distinguishable on neuroimaging (16-18). There are 15 types of systemic amyloidosis with primary AL amyloidosis subtype accounting for most cases. AL amyloidosis is due to the pathogenic deposition of a monoclonal light chain amyloid protein produced by plasma cells located in the bone marrow. AL amyloidosis involves multiple systems including the heart, kidney, peripheral nerves, liver, and the skin (1,19,20). The life expectancy of patients with AL amyloidosis is typically less than 1 year, as systemic amyloid deposition leads to functional end organ damage and to multiple myeloma in 20% of the cases (7). Orbital amyloidosis is an infiltrative process that can extend to all orbital tissues, including orbital fat, extraocular muscles, lacrimal gland, optic nerve sheath, and orbital blood vessels (5,6,8,9,21-23). We reviewed the literature and found 14 cases of amyloid deposition isolated to the extraocular muscles (Table 1). The average age of presentation was 52 years (range: 28-69) with the most common symptoms being diplopia followed by ptosis, eyelid edema, proptosis, and decreased vision. Most patients (11/14) were imaged with computed tomography (CT) or MRI and all had muscle biopsies to confirm the diagnosis. Seven patients had bilateral diffuse amyloid deposition of the extraocular muscles, whereas in the 7 unilateral cases, 4 had involvement of a single rectus muscle and 3 involved more than 1 muscle. Six of the 7 patients with bilateral diffuse amyloid deposition were found to have systemic amyloidosis; such was the case in only 1 patient with isolated muscle involvement. Several studies have reported imaging findings characteristic of localized amyloid deposition in extraocular 171 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation muscles. On occasion, CT can demonstrate enlarged extraocular muscles with punctuate calcifications representing amyloid deposits (37). Okamoto et al (32) described heterogeneous hypointensity in extraocular muscles on T2 MRI and homogenous enhancement on fat-suppressed and contrast-enhanced T1 images. In our patient, we found that the T2 images reviewed punctate, irregular, discrete hypointensities in the affected extraocular muscles. In contrast in patients with thyroid eye disease, there is typically bilateral, symmetric, fusiform muscle involvement with smooth margins that spares the tendon (37). MRI T1 images demonstrate enlarged extraocular muscles that are isointense to normal muscles, but slightly hyperintense in T2 images (34,38). The tissue diversity of amyloid deposition has been an area of intense research. Advances in understanding the pathogenesis of the disease at the molecular level suggest that several factors favor the formation of amyloid fibrils (39). These include high local protein concentration, low pH, proteolytic activity, interactions with cell surface molecules and tissue proteins (i.e., collagen) (19,40,41). Interestingly, extraocular muscles share several of these qualities including high protein concentration and metabolic activity and collagen-based tendinous insertions with surrounding endomysium. Campos et al (10) performed autopsies on 29 individuals with systemic amyloidosis and found amyloid deposits in the extraocular muscles in 28 cases. Moreover, 17 of 29 patients had known systemic AL amyloidosis or multiple myeloma, and all but 1 had extraocular amyloid deposition. There are number of limitations of our study, which include a selection bias of cases of amyloid deposition (isolated to extraocular muscles vs gross orbital amyloidosis), an absence of a case control group, a small sample size, and information/recall bias in previous case reports. However, the strength of our analysis is that it summarizes the features of a rare disease with ophthalmic findings and potentially life-threatening consequences. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: V. 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