Transthyretin amyloidosis and herpes zoster infection: a mimic of temporal arteritis

Abstract

We describe the case of a patient who presented with symptoms of persistent headaches, left-sided facial pain and blurry vision of the left eye. The patient had recovered from a herpes zoster infection of the V1 division of the trigeminal nerve 1 month prior. Serum inflammatory markers were elevated, raising concern for temporal arteritis. Empiric high-dose prednisone was initiated. Bilateral temporal artery biopsies were performed but did not show evidence of vasculitis or multinucleated giant cells. Instead, extracellular material deposits were present within the vessel walls. Congo red staining was diagnostic for amyloidosis. Liquid chromatography and mass spectrometry identified the amyloid fibrils to be transthyretin-type (ATTR) consistent with age-related amyloidosis. Temporal artery involvement of amyloidosis is rare but when present is most often due to light chain amyloidosis. Based on our review of the literature, only a few cases of temporal artery ATTR amyloidosis have been reported.

Background

Transthyretin amyloidosis (ATTR) is a form of systemic amyloidosis characterised by an abnormal extracellular deposition of misfolded transthyretin fibrils in tissues. Transthyretin is a serum protein which functions as a carrier for thyroxine and retinol-binding protein. ATTR tends to deposit in cardiac or peripheral nervous tissue. Cardiac involvement may manifest as restrictive cardiomyopathy, arrythmias or valvular disease. Peripheral nerve involvement presents with peripheral neuropathy.^{1 2} Deposition in the carpal tunnel leading to carpal tunnel syndrome (CTS) is also common, and bilateral CTS is classically associated with amyloidosis.³ ATTR amyloidosis can have a familial predisposition, caused by a genetic mutation to transthyretin, or may be sporadic. The sporadic form, also known as wild-type ATTR, is most frequently seen in elderly males.¹

Giant cell arteritis (GCA), also known as temporal arteritis, is a large-vessel vasculitis which primarily affects the major branches of the aorta.⁴ The disease has a predilection for the extracranial branches of the aorta, without involvement of the intracranial branches. It is most prevalent in Caucasian females and predominantly affects patients aged ≥50 years.⁵ The most common signs and symptoms of GCA include fever, fatigue, headaches, temporal pain and claudication of the jaw and tongue. Anterior ischaemic optic neuropathy is a severe complication of GCA and leads to irreversible blindness. Other complications include stenosis of arterial branches of the aorta, aneurysms, aortic dissection, stroke and vertebrobasilar insufficiency. GCA carries a strong association with polymyalgia rheumatica (PMR).⁶ Recent evidence suggests herpes zoster infection may be a risk factor for the development of GCA.⁷ The vasculitis of GCA appears to arise from CD4-positive T cells which gain access to the medium and large vessels through the vasa vasorum. Through interactions with resident dendritic cells, an inflammatory process is activated which eventually leads to a destruction of the arterial wall, subsequent fragmentation and intimal hyperplasia result.⁸ It is this neointimal formation that leads to stenosis of the vessels and downstream tissue ischaemia. Treatment of GCA always involves glucocorticoids.⁹

Although uncommon, cases of amyloid deposition in the temporal arteries have been reported in the literature.^10–14 These cases present similarly to GCA, and it is the suspicion for GCA which prompts temporal artery biopsy. Thus, diagnosis of temporal artery amyloidosis is often serendipitous on histologic examination of artery tissue. When found, light chain amyloid (AL) is the most frequently identified type and is associated with plasma cell dyscrasias.¹⁰ We present a case of wild-type ATTR with temporal artery involvement.

Case presentation

An 88-year-old man presented to our rheumatology clinic with left-sided facial pain, headaches and episodes of blurry vision of the left eye for 1 month. His medical history was notable for chronic obstructive pulmonary disease, non-small cell lung cancer which was in remission after chemoradiation and left lower lobe wedge resection, sick sinus syndrome with a single-chambered pacemaker, coronary artery disease and type II diabetes mellitus.

One month prior, the patient had been diagnosed with left V1 herpes zoster without zoster ophthalmicus after presenting to his primary care physician with new skin lesions on the left side of his face. He received a course of valacyclovir which improved the appearance of the lesions. Three days after the lesions appeared, he developed severe burning pain along the left side of his face. The pain waxed and waned with bouts lasting approximately 30 s. Pain also radiated posteriorly to the occiput and neck. The pain was exacerbated by palpation or wearing a hat. Review of systems was notable for an unintentional 10-pound weight loss over the previous 4 weeks. He denied fever, aura symptoms, tinnitus, jaw claudication, myalgia, arthralgia or new rashes.

Physical examination demonstrated a thin, emaciated, wheelchair-bound man. He was unable to ambulate without assistance. Muscle wasting was noted in both proximal and distal musculature with atrophy of the thenar and hypothenar eminences. The anterior shoulders were not enlarged. Macroglossia was not present. Skin examination revealed several small, erythematous, crusted lesions over the left scalp. Petechiae, purpura or other rashes were not present. The left scalp was tender to palpation. Auscultation of the lungs revealed diminished breath sounds with faint, scattered wheezes bilaterally. Neurologic examination revealed no focal deficits with intact motor strength and sensation throughout.

Investigations

Complete blood count showed moderate anaemia with haemoglobin of 95 g/L, with white blood cell and platelet counts within the normal range. Serum chemistries including sodium, potassium, urea nitrogen, creatinine and calcium were within the normal range. Albumin and total protein levels were slightly low at 3.7 g/dL and 6.1 g/dL, respectively. Erythrocyte sedimentation rate was markedly elevated at 91 (0–15 mm/hour) even with adjustment for age. C reactive protein was also elevated at 56.8 (<8.0 mg/L). Creatine kinase and aldolase levels were normal.

Serum and urine protein electrophoresis studies did not detect any paraproteins. Serum-free light chain analysis showed kappa light chains of 18.8 (normal range: 3.3–19.4 mg/L), lambda light chains of 14.5 (normal range: 5.7–26.3 mg/L) and a normal kappa/lambda ratio of 1:30. Autoantibodies to ferritin peptide were not checked as this was not a standard part of our clinical practice. Colour Doppler ultrasound was not performed as an ultrasound is not readily accessible at our clinic.

Bilateral temporal artery biopsies were performed. The left-sided biopsy was obtained from a painful site. Standard H&E staining showed moderate concentric intimal hyperplasia with luminal narrowing and eosinophilic hyaline material in the media. There was no evidence of vascular or perivascular inflammation, and multinucleated giant cells were absent. To further characterise the eosinophilic material, Congo red staining was performed which revealed patchy areas of congophilic extracellular material within the tunica intima and media. These areas demonstrated apple-green birefringence under polarised light consistent with amyloidosis (figure 1). To identify the form of amyloid, the specimen was sent to Mayo Clinic for liquid chromatography and mass spectrometry (LC-MS), using a QExactive-Plus mass spectrometer (Thermo-Fisher, Waltham, MA, USA) connected to a Dionex (Thermo-Fisher) nanoflow liquid chromatography system. This investigation revealed the amyloid fibrils to be ATTR. LC-MS did not detect any mutations of the ATTR. Based on these findings, age-related ATTR amyloidosis was diagnosed.

Figure 1.

Temporal artery amyloidosis, ATTR (transthyretin)-type. (A) Temporal artery segment (H&E, 200x) shows artery luminal narrowing associated with patchy eosinophilic hyaline material in media and no inflammatory cells. (B) Congo red (200x) stains the medial deposits red. (C) Congo red-stained slide under polarised light microscopy displays the characteristic apple-green birefringence diagnostic of amyloid (200x). Liquid chromatography tandem mass spectrometry performed (at Mayo Clinic, Rochester, MN, USA) on peptides extracted from Congo red-positive microdissected areas of the paraffin-embedded tissue demonstrated the amyloid deposition to be ATTR (transthyretin)-type.

A transthoracic echocardiogram was performed which showed increased left ventricular wall thickness with normal cavity size and an estimated left ventricular ejection fraction of 55%–60%. Mild biatrial enlargement was observed. Valvular assessment revealed mild aortic stenosis with a peak aortic velocity of 2.4 m/s and a calculated peak gradient of 23 mm Hg.

Differential diagnosis

The primary differential diagnosis in this case was temporal arteritis in the setting of postherpetic neuralgia. Although postherpetic neuralgia was likely a contributing factor to the patient’s pain, it did not fully explain the clinical picture of persistent headaches, blurry vision and unintentional weight loss in an elderly patient. GCA was strongly suspected due to age, symptoms and the clinical course. Association with herpes zoster further increased suspicion for GCA. It was this clinical picture that prompted temporal artery biopsy. However, the biopsy showed no evidence of vasculitis or multinucleated giant cells and revealed amyloid deposits instead.

Treatment

The constellation of signs and symptoms was concerning for GCA, so a course of prednisone 60 mg daily was started empirically and continued for 3 weeks until the biopsy resulted. Once the diagnosis of amyloidosis was confirmed, the patient was tapered off prednisone over the course of several weeks. Low-dose gabapentin was started for postherpetic neuralgia. Treatment of amyloidosis is still being considered at this time.

Outcome and follow-up

At 3-month follow-up, the patient’s facial pain had resolved. His vision has not worsened. He continues to be followed by cardiology, haematology/oncology and rheumatology examinations.

Discussion

Amyloidosis affecting the temporal arteries has been described previously in the literature. In many cases, GCA was suspected and amyloid deposits were discovered incidentally on histologic examination of a biopsy. Histology generally does not show vasculitis or multinucleated giant cells.¹⁰

Salvarani et al¹¹ described a review of case records at the Mayo Clinic of all patients with biopsy-proven amyloidosis and clinical manifestations of temporal arteritis and/or polymyalgia rheumatica from 1969 to 1992. They reported 13 cases which met the 1990 American College of Rheumatology classification criteria for GCA or PMR. Of these, one case showed evidence of ATTR deposition in the temporal artery. ATTR was also identified in two other cases, one at the carpal tunnel on autopsy and another from an endomyocardial biopsy. Four patients had AL amyloidosis. Other cases demonstrated amyloid deposits localised to other organs including the orbit, breast, seminal vesicle and myocardium, respectively.

The cases with AL amyloidosis were investigated further. In one case, a patient presented with myalgias and stiffness of the shoulder girdle and neck muscles. The patient was treated with 15 mg of prednisone with resolution of symptoms. Over the next 3 months, the patient developed weight loss and purpura. AL amyloid was identified from multiple biopsies and the patient was treated with nine cycles of melphalan and prednisone. Interestingly, prednisone was unable to be weaned <15 mg/day due to recurrence of myalgias and stiffness. These symptoms suggest concurrent PMR.¹¹ In another case from the same study, a patient presented with bilateral carpal tunnel syndrome, intermittent claudication of the upper extremities and weight loss. Audible bruits over left and right brachial arteries were documented and an aortogram showed arteritis of the aortic arch vessels. Interestingly, temporal artery biopsies showed concomitant granulomatous vasculitis and intimal amyloid deposits. Amyloid was also identified from a rectal biopsy and ligamentous tissue from both carpal tunnels. Bone marrow biopsy showed 25% plasmacytosis. The patient was ultimately diagnosed as having multiple myeloma with AL amyloidosis and concurrent GCA with aortic arch syndrome.¹¹ Another case from the same study described a patient presented with new-onset headache, scalp tenderness and weight loss. Bilateral temporal artery biopsies revealed AL amyloid deposits but no evidence of vasculitis.¹¹ All four patients with AL amyloidosis in the case study ultimately died from refractory heart failure. In the case of our patient, no PMR-like syndrome was present. However, with a history of sick sinus syndrome, myocardial deposition of ATTR is certainly possible.

Successful treatment of temporal artery involvement of AL amyloidosis was also described by Audemard et al.¹² The patient presented with bilateral jaw claudication and headache which improved after treatment with melphalan and dexamethasone. In the case of concurrent GCA and AL amyloidosis described by Salvarani et al, the patient was treated with prednisone 40 mg/day and melphalan. After a month of prednisone, the patient reportedly had significant improvement in upper extremity claudication.¹¹ To date, no cases or trials have investigated treatment for ATTR amyloidosis of the temporal artery.

Another aspect of this case to consider is the presence of herpes zoster and subsequent postherpetic neuralgia which ultimately prompted evaluation. GCA was considered in the differential diagnosis, in part, because of the patient’s age. Perhaps, the amyloid found on biopsy was incidental and not the aetiology of pain, particularly since it was found bilaterally, and pain was unilateral. However, not all symptoms, particularly the weight loss and blurry vision, can be explained by zoster alone. Concomitant GCA and ATTR, like the case described by Salvarani et al, is possible but unlikely given the lack of vasculitis on both biopsies and the fact that symptoms did not return after prednisone was stopped. Autoantibodies to ferritin peptide may be seen in patients with GCA and PMR, particularly when untreated.¹⁵ However, they are seen less frequently in patients already being treated with glucocorticoids, and temporal artery biopsy remains the gold standard for diagnosis of GCA.

Although the number of reported cases in the literature suggests temporal artery involvement of amyloidosis is rare, it raises the question of whether Congo red staining should be performed more routinely on temporal artery biopsies. Since Salvarani et al, there have not been studies investigating the differences between GCA and temporal artery amyloidosis in terms of clinical presentation and laboratory findings. GCA is notorious for having skin lesions, making the disease sometimes difficult to definitively diagnose. Perhaps some of these negative biopsies in fact had amyloid deposits that were not found. If so, temporal artery amyloidosis may be more common than previously thought. Further investigation is needed to better characterise this disease entity.

Learning points.

• Findings of persistent headaches and unintentional weight loss in a patient >50 years of age should raise suspicion for temporal arteritis and prompt consideration for a temporal artery biopsy.

• Amyloidosis may involve the temporal arteries and can mimic giant cell arteritis clinically.

• Temporal artery involvement of amyloidosis is most often due to light chain amyloid, but transthyretin amyloidosis may be seen.

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