Diagnosing Light Chain Amyloidosis on Temporal Artery Biopsies for Suspected Giant Cell Arteritis

Although still rarely diagnosed, amyloid light chain (AL) amyloidosis is the most common form of systemic amyloidosis. It is characterized by misfolded monoclonal immunoglobulin light chain fragments that accumulate extracellularly as amyloid fibrils, with consequent organ dysfunction. We report 2 such cases where initial symptoms and signs were identical to and mistaken for those of giant cell arteritis, associated with polymyalgia rheumatica. Neither patient responded to high-dose corticosteroids; instead, their temporal artery biopsies revealed amyloid deposits and other investigations confirmed a diagnosis of systemic AL amyloidosis. Review of the literature reveals similar cases of diagnostic confusion spanning 75 years. We have summarized the findings and learning points from cases reported in the past 30 years and highlight the need for increased awareness and investigation of this underrecognized syndrome.

Original Contribution Diagnosing Light Chain Amyloidosis on Temporal Artery Biopsies for Suspected Giant Cell Arteritis Rosanna A. M. Ghinai, BSc, MBChB, MRCP, DTMH, MSc, Shameem Mahmood, BSc, MB BCh BAO, MA, MRCP, FRCPath, Pinias Mukonoweshuro, MBChB, FRCPath, Sally Webber, MRCP, FRCOphth, Ashutosh D. Wechalekar, FRCP, FRCPath, DM, Sally E. Moore, BMedSci, BMBS, MRCP, FRCPath Abstract: Although still rarely diagnosed, amyloid light chain (AL) amyloidosis is the most common form of systemic amyloidosis. It is characterized by misfolded monoclonal immunoglobulin light chain fragments that accumulate extracellularly as amyloid fibrils, with consequent organ dysfunction. We report 2 such cases where initial symptoms and signs were identical to and mistaken for those of giant cell arteritis, associated with polymyalgia rheumatica. Neither patient responded to high-dose corticosteroids; instead, their temporal artery biopsies revealed amyloid deposits and other investigations confirmed a diagnosis of systemic AL amyloidosis. Review of the literature reveals similar cases of diagnostic confusion spanning 75 years. We have summarized the findings and learning points from cases reported in the past 30 years and highlight the need for increased awareness and investigation of this underrecognized syndrome. Journal of Neuro-Ophthalmology 2017;37:34-39 doi: 10.1097/WNO.0000000000000447 © 2016 by North American Neuro-Ophthalmology Society A myloid light chain (AL) amyloidosis typically presents with renal, cardiac, hepatic, and peripheral or autonomic nervous system impairment. However, recent guidelines acknowledge marked clinical heterogeneity. AL amyloidosis with symptoms mimicking giant cell arteritis (GCA) or myalgia and fatigue simulating polymyalgia rheumatica (PMR) is not a new phenomenon but it is unusual. We present 2 cases Haematology (RG), Severn Deanery, Bristol, United Kingdom; National Amyloidosis Centre (SM, AW), University College London, London, United Kingdom; Departments of Histopathology (PM), Ophthalmology (SW), and Haematology (SM), Royal United Hospital Bath, Bath, United Kingdom. The authors report no conflicts of interest. Address correspondence to Rosanna Ghinai, BSc, MBChB, MRCP, DTMH, MSc, Royal United Hospital Bath, Combe Park, Bath BA1 3NG, United Kingdom; E-mail: [e-mail] 34 of AL amyloidosis masquerading as GCA and review the literature since 1986 (1). We draw attention to the similarities and distinguishing features of AL amyloidosis vs GCA. CASE REPORTS Patient 1 A 67-year-old man with Waldenstrom macroglobulinemia experienced myalgias, weight loss, fatigue, jaw claudication, and sudden visual loss in the left eye. Visual acuity in the left eye was 20/80, with a left relative afferent pupil defect (RAPD) and left optic disc pallor with blurring of the nasal margin. His C-reactive protein (CRP) was 39 mg/L (normal: ,5 mg/L) and platelets were 520,000/mL (normal: 150,000-400,000/mL). Temporal artery biopsy was not performed, but the patient received prednisolone (1 mg/kg) for a presumed diagnosis of arteritic anterior ischemic optic neuropathy. With this treatment, there was minimal improvement in his vision and his other symptoms persisted. Because of severe myalgias, the patient underwent magnetic resonance imaging (MRI) of the quadriceps muscles. The findings were suggestive of myositis, and a muscle biopsy stained positive with Congo red (Fig. 1A) and showed apple green birefringence under polarized light (Fig. 1B), diagnostic of the presence of amyloid. The patient was referred to the National Amyloidosis Center (NAC), where immunostaining of the muscle biopsy was positive for antibodies to kappa light chains (Fig. 1C) and negative for antibodies to lambda light chains (Fig. 1D). Transthyretin deposition was excluded, and kappa lightchain-type amyloid was confirmed by liquid chromatography mass spectrometry and proteomic analysis. Further investigations showed: no visceral amyloid deposits by 123I Ghinai et al: J Neuro-Ophthalmol 2017; 37: 34-39 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Patient 1. Muscle biopsy stains positively with Congo red (A) and demonstrates apple-green birefringence under polarized light (B). There is positive immunostaining for antibodies to kappa light chains (C) but negative for antibodies to lamda light chains (D). serum amyloid P component (SAP) scintigraphy; no cardiac involvement by echocardiography; and no evidence of amyloid on bone marrow or renal biopsies. Eight months after left visual loss, the patient experienced sudden loss of vision in his right eye. Visual acuity was 20/200, right eye, and light perception, left eye, with a left RAPD. The right optic disc was pale and swollen, and the left disc was atrophic. His CRP was 93 mg/L and platelet count was 180,000/mL. A right temporal artery biopsy was performed, showing eosinophilic infiltrates and focal inflammation within the media (Fig. 2A), confirmed as amyloid with Congo red staining (Fig. 2B). There was no evidence of GCA. The patient developed diarrhea, breathlessness, hypotension, and edema. He commenced rituximab, bortezomib, and dexamethasone but died during his first treatment cycle. Patient 2 A 69-year-old man with a 35-year history of immunoglobulin D kappa monoclonal gammopathy of undetermined significance with a stable paraprotein of 5 g/L and ankylosing spondylitis was referred to the rheumatology service for symptoms of myalgias, fatigue, global weakness, jaw claudication, and scalp tenderness. Recently, he had been investigated for paraesthesias and diagnosed with carpal tunnel syndrome and axonal neuropathy. His CRP was 33 mg/L and platelet count was 486,000/mL. Duplex ultrasonography of the temporal arteries revealed arterial wall edema (hyperechoic "halo") consistent with arteritis, normal velocities, and no stenosis (2). He was diagnosed with GCA and PMR and treated with high-dose steroids without symptomatic relief. Therefore, he underwent temporal artery biopsy which FIG. 2. Patient 1. Temporal artery biopsy. A. There are amyloid deposits (dark pink color) in the media of the vessel wall (hematoxylin and eosin, ·5). B. More extensive deposition of amyloid is seen with Congo red stain (·5). Ghinai et al: J Neuro-Ophthalmol 2017; 37: 34-39 35 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Patient 2. Temporal artery biopsy. A. There are amyloid deposits in the vessel wall detected with Congo red stain. B. This is confirmed as amyloid with appearances of apple-green birefringence under polarized light. C. The Congo red-stained amyloid fluoresces under tetramethylrhodamine isothiocyanate (TRITC) filter. The biopsy specimen stains positively for antibodies to kappa light chains (D) but not for antibodies to lamda light chains (E). stained positively with Congo red (Fig. 3A), showing applegreen birefringence in polarized light (Fig. 3B) and orange fluorescence under tetramethylrhodamine isothiocyanate (TRITC) filter (Fig. 3C). Immunostaining was positive for antibodies to kappa light chains (Fig. 3D) and negative for antibodies to lambda light chains (Fig. 3E). No transthyretin was detected. Giant cells were present as a foreign body reaction to amyloid deposits but not centered on the internal elastic lamina as in GCA. Cardiac involvement was detected on MRI. The patient had lytic bone lesions, renal impairment, hypercalcemia, and anemia. His bone marrow confirmed myeloma, with up to 90% plasma cells and evidence of amyloid with Congo red staining. At the NAC, a fat biopsy was positive for amyloid, and 123I SAP scintigraphy did not reveal visceral amyloid deposits. DISCUSSION Reviewing the literature of AL amyloidosis mimicking GCA yielded 15 reports in the past 30 years (3-16). These 36 are combined with our 2 patients and summarized in Table 1. These cases illustrate aspects of diagnostic confusion between GCA/PMR and AL amyloidosis, including clinical findings, investigation results, and response to steroid treatment. A patient with AL amyloidosis involving the temporal artery is likely to fulfill the classification criteria for GCA on a clinical basis in the absence of histology (2). AL amyloidosis may mimic GCA with jaw claudication (9% of cases (1)) and neuro-ophthalmologic involvement including anterior ischemic optic neuropathy (Table 2). In addition, nonspecific symptoms such as myalgias and fatigue may overlap with those of PMR (17). Patients with a known plasma cell dyscrasia or hematological malignancy and features of PMR should be investigated for AL amyloidosis. This includes histological diagnosis from an affected organ, measurement of serum-free light chains, and immunofixation of blood and urine (18). In AL amyloidosis, amyloid is thought to occlude the arterioles feeding the masseter, causing jaw claudication in Ghinai et al: J Neuro-Ophthalmol 2017; 37: 34-39 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Ghinai et al: J Neuro-Ophthalmol 2017; 37: 34-39 Clinical Presentation ESR/ Age/ Reference Gender Jaw TAC H/a Vis. F/W A/S CTS Wt. CRP O Taillan et al 86/M (3) Lafforgue 68/M et al (4) Rao et al (5) Salvarani et al (6) Salvarani et al (6) Rodon et al (7) Ing et al (8) Estrada et al (9) Churchill et al (10) Barrett et al (11) Audemard et al (12) Azari et al (13) Neri et al (14) Chana and Quick (15) Emmungil et al (16) Current report Current report 70/M O 66/M O 73/M O O O O O O O O O O 77/M 68/F O O O O O 76/M O O 64/M O 80/M O Myeloma O 128/- None IgM l O 86/22 MGUS IgD l O O - 61/- Myeloma Myeloma - l LC O O 70/- Myeloma k LC O O O 61/- IgG; l LC O O O -/,5 Plasma cell dyscrasia Myeloma 66/M O - Myeloma - O O O O O O O O O O O O k LC O O 78/,5 MGUS IgG k O 108/ 65 Myeloma - 87/F O O 67/M O O 67/M O 69/M O O O O O O O O O O High O O TA Bx Findings Initial Treatment Symptomatic Response IgA l; l LC Amyloid, CR+, Prednisolone, Rapid, complete Wright's AL melphalan 100/- Lymphoplasmacytic IgA, G l; IgM AL amyloid, CR+, Prednisolone, None dyscrasia k; l LC IHC l+, thioflavin+ chlorambucil, colchicine 66/- None l LC Amyloid, CR+ IV methylprednisolone Partial (vision and on restaining headache) 40/- None k LC Amyloid, CR+ Prednisolone Partial (not jaw) O O O O O PP/LC O 136/- O 78/M 64/F O Additional Diagnoses -/39 -/33 Normal, CR negative Amyloid, CR+, Wright's AL Amyloid, CR+ GCs, inflamed lam, IHC l+ Amyloid, CR+ IHC k+ CR+ restain after renal Bx Inflamed lam, IHC k+, SAP+ 3 layers CR+ amyloid, GCs Amyloid, k IHC+, SAP+ Inflamed lam, GCs, CR+ IgG l; l LC Not done, CR+ salivary gland Waldenstrom IgM k; k LC Amyloid, CR+, macroglobulinemia muscle IHC k+ Myeloma IgD k Amyloid, CR+, IHC k+, GCs Myeloma None Prednisolone - Prednisolone, melphalan Prednisolone Prednisolone, methotrexate Dexamethasone, melphalan - IV methylprednisolone Partial (over 6 months) Progressed - Partial (jaw, headache) Partial (jaw with 60 mg) Progressed Partial (jaw, headache) - None IV methylprednisolone Partial (jaw, not vision) Prednisolone, methotrexate Prednisolone, IV methyl pred. Prednisolone Partial (vision) Progressed None +, positive; A/S, aching (myalgia or arthralgia) or stiffness; Bx, biopsy; CR, Congo red; CRP, C-reactive protein (mg/L); CTS, carpal tunnel syndrome; ESR, erythrocyte sedimentation rate (mm/h); F, female; F/W, fatigue or weakness; GCs, giant cells; H/a, headache; Ig, immunoglobulin; IHC, immunohistochemistry; IV, intravenous; Jaw, jaw claudication; lam, internal elastic lamina; LC, light chains; M, male; methyl pred., methylprednisolone; MGUS, monoclonal gamnopathy of undetermined significance; PP, paraprotein; SAP, serum amyloid P component; TA, temporal artery; TAC, temporal artery changes; Vis., visual disturbance; Wt., weight loss. Original Contribution 37 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. AL amyloidosis mimicking giant cell arteritis: cases reported from 1986 to 2016 Original Contribution TABLE 2. Visual involvement reported in patients with AL amyloidosis mimicking GCA Reference Rao and Allen (5) Estrada et al (9) Churchill et al (10) Churchill et al (10); Barrett et al (11) Azari et al (13) Neri et al (14) Chana and Quick (15) Emmungil et al (16) Current report Visual Involvement Blurred vision in the right eye after presentation. Marked improvement with IV methylprednisolone persisted despite steroid taper and progressive disease. Intermittent blurred vision in the right eye associated with jaw claudication (previous melphalan and pred.). Claudication improved with pred. 60 mg but vision not mentioned and disease progressed. Two episodes of diplopia associated with jaw claudication on low-dose steroids for PMR. Claudication improved with pred. 60 mg but vision not specifically mentioned. Treatment with melphalan planned. Transient spontaneously resolving episodes (5-10 minutes) of visual loss in the left eye on original presentation, described as a gray curtain falling. No improvement with low-dose steroids. Ophthalmologic examination reported as normal. Long delay in diagnosis, progressive disease; autograft planned. Superior scotoma in the left eye on presentation; with optic nerve oedema, a small peripapillary hemorrhage and a supratemporal cotton wool spot on fundoscopy. Complete superior altitudinal defect on visual field testing. Sudden bilateral painless visual loss (complete in the right eye, inferior in the left with an altitudinal scotoma); known AL amyloidosis previously treated with chemotherapy. Visual acuity corrected to perception of light in right eye and 20/20 in left with lens. Marked RAPD of right eye. Normal anterior segments at biomicroscopy; bilateral ONH oedema on fundoscopy and MRI showed bilateral ONH thickening. No response to Methylprednisolone for AION; commenced Aspirin and steroids weaned. Almost complete resolution of oedema at one month; pale atrophic ONHs at one year with reduced thickness of retinal nerve fibre layers consistent with original presentation. Sudden loss of vision in the left eye. Pale, blurred optic disc at fundoscopy with retinal haemorrhages consistent with AION. Known myeloma, palliated with Pred. No improvement in vision following high dose steroids. Initial presentation to ophthalmology with bilateral loss of vision; diagnosed as AION and improved with high dose steroids although disease progressed. Delayed diagnosis of AL amyloidosis as temporal artery biopsy not done. Sudden visual loss left in the left eye and later in the right (no lens correction) with RAPD and optic atrophy. Minimal and later no response to high-dose steroids for AION (temporal artery biopsy not done until second episode) and disease progressed; for more details, please see first case report above (Patient 1). AION, anterior ischemic optic neuropathy; IV, intravenous; ONH, optic nerve head; pred., prednisolone. a similar manner to lower limb claudication in predominantly vascular amyloidosis (M. Gertz, MD, personal communication, April 2016). Estrada et al (9) reported a case of "co-existent GCA and AL amyloidosis," but giant cells and macrophages were specifically engulfing amyloid deposits. It may be misleading to label this as a case of GCA, but instead to refer to it as a secondary arteritis. Because amyloid also may cause arterial narrowing leading to ischemia, Neri et al (14) speculated that ischemic optic neuropathy in AL amyloidosis could be due to reduced adaptability to fluctuations in blood pressure (nocturnal hypotension). Other areas of diagnostic confusion include laboratory findings, imaging, and response to steroids. Raised inflammatory markers (ESR, CRP), thrombocytosis, and a normocytic anemia may all be seen in GCA, PMR, and AL amyloidosis (12). Dhodapkar et al (19) reported that 60% of their cohort of 93 patients with symptomatic amyloidosis had at least some initial symptomatic response to high-dose steroids. This is another potential factor in delayed diagnosis of 38 AL amyloidosis. Without acknowledging the possibility of an alternative diagnosis, current guidelines for GCA state that patients with negative biopsies should be managed as GCA if there are typical clinical and laboratory features, ultrasound findings, and steroid response (20). Several patients in this case series displayed all of these, leading to delayed recognition and treatment of AL amyloidosis. In 2 cases, amyloid was only identified on restaining original temporal artery biopsies with Congo red many months later, showing that deposits are easily missed on hematoxylin and eosin staining alone. It is essential that an experienced pathologist is aware of alternate diagnoses when examining temporal artery biopsy specimens as "false negative and false positive diagnoses on the basis of histology are not infrequent" (18). Our report illustrates the potential perils of overlooking histology, especially in our first patient. Delays in diagnosis and management of AL amyloidosis are a major factor in morbidity and mortality, and heightened suspicion of this diagnosis by clinicians is required. Ghinai et al: J Neuro-Ophthalmol 2017; 37: 34-39 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution In summary, in suspected GCA (even with neuroophthalmic involvement), prompt temporal artery biopsy and Congo red staining is crucial. If GCA is not evident, investigation for an underlying plasma cell dyscrasia must follow, with serum-free light chains and immunofixation of blood and urine. If there are features of PMR in the context of a known plasma cell dyscrasia, muscle biopsy should be performed. Finally, atypical response to steroids also should trigger assessment for AL amyloidosis. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. Moore and R. Ghinai; b. Acquisition of data: S. Moore, R. Ghinai, and S. Mahmood; c. Analysis and interpretation of data: R. Ghinai, S. Webber, S. Moore, A. Wechalekar, S. Mahmood, and P. Mukonoweshuro. Category 2: a. Drafting the manuscript: R. Ghinai. b. Revising it for intellectual content: S. Mahmood, S. Moore, S. Webber, P. Mukonoweshuro, and A. Wechalekar. Category 3: a. Final approval of the completed manuscript: R. Ghinai, S. Moore, S. Mahmood, S. Webber, P. Mukonoweshuro, and A. Wechalekar. 7. 8. 9. 10. 11. 12. 13. 14. 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