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Amyloid fibril protein is a protein that is deposited as insoluble fibrils, mainly in extracellular spaces of organs and tissues as a resrult of a sequence of changes in protein folding.
By definition, amyloid must exhibit both affinity for Congo red and green birefringence when samples that are stained with Congo red are viewed under polarized light.
It can accumulate in all body tissues, including the brain, skin, respiratory tract, genitourinary tract, gastrointestinal tract, heart, spleen, soft tissues, and ocular and orbital tissues.
Depositions most commonly occur in the tarsal conjunctiva, eyelids, and lacrimal gland. The lack of lymphatic drainage in other orbital structures, and the involvement of clonal B-lymphocytes in the pathophysiology of this disease have been quoted as putative explanations for this observation.
In addition to describing in detail the presentation and management of a case of primary localized eyelid and orbital amyloidosis, an English-language search was conducted using PubMed and OvidSP MEDLINE with the terms “orbital amyloidosis,” “conjunctival amyloidosis,” “eyelid amyloidosis,” and “ocular adnexal amyloidosis.” The reference sections of all resulting articles were screened for further articles. Only cases in which the amyloidosis was confined to the orbital and ocular adnexa were included in this review. Because Taban et al. covered this topic (excluding conjunctival amyloidosis) until early 2004, this review includes reports published since then.
A 38-year-old male presented to the emergency eye clinic with 4 weeks of gradual-onset, painless left upper eyelid ptosis. Medical history was non-contributory, and ophthalmic history was unremarkable. In particular, there was no history of trachoma, surgery, or trauma to the eyelid. On examination, left upper eyelid swelling and left globe ptosis were noted in addition to blepharoptosis (Fig. 1A). Vision was 20/20 OU. Pupils, intraocular pressure, extraocular motility, and alignment were within normal limits. Marginal reflex distance 1 (MRD1) was 5 mm OD and 2 mm OS. Pupillary fissures were 10 mm OD and 7 mm OS. Levator function was normal and symmetrical bilaterally. There was no proptosis. Eversion of the left upper eyelid showed a thickened reddish-brown plaque overlying the tarsal plate (Fig. 1B). Eversion of the other 3 eyelids, as well as anterior and posterior segment examination, revealed no abnormalities.
Fig. 1A, Patient at presentation, showing lid thickening, ptosis, and slight globe ptosis. B, Patient at presentation, showing mass on palpebral surface of left upper lid.
Pathological examination of a 2.5-mm punch biopsy of the lesion suggested amyloid light chain amyloid deposits within the conjunctival substantia propria. There was extensive eosinophilic amorphous material occupying the substantia propria associated with focal chronic inflammation in the form of lymphocytes and plasma cells scattered throughout the lesion as well as occasional multinucleated giant cells. The overlying epithelium was absent. Congo red staining showed apple green dichroism and birefringence. Immunohistochemistry for the amyloid precursor protein was negative, but kappa and lambda light chains were strongly positive. Transthyretin and fibrin stains were negative (Fig. 2).
Fig. 2A, High-power photomicrograph of conjunctival excision showing amorphous eosinophilic material in the substantia propria with associated chronic inflammatory infiltrate. B, Material shows birefringence and dichroism with Congo red staining characteristic of amyloid.
Computed tomography of the head and orbits showed no intracranial masses, but there was subtle thickening of the superolateral preseptal soft tissues of the left orbit with probable extension into thickened pre- and postseptal components of the left lacrimal gland (Fig. 3).
Fig. 3Coronal section of noncontrast computed tomography scan of orbits showing subtle thickening of the superolateral preseptal soft tissues of the left orbit with probable extension into thickened pre- and postseptal components of the left lacrimal gland.
Systemic evaluation revealed no evidence of amyloidosis elsewhere. The eyelid lesion was resected surgically by approaching it from the side of the tarsal conjunctiva. Over the course of the next 10 months, the ptosis and lid swelling resolved. A small amount of globe ptosis remains (Fig. 4).
Fig. 4Ten months after surgical excision of palpebral amyloid deposits, upper eyelid ptosis and lid thickening have resolved, but slight globe ptosis remains.
Our extensive review of the literature for all cases of primary localized orbital and ocular adnexal amyloidosis since 2004 yielded 71 cases (Table 1): 64% were female, sex was unspecified in 2 cases, and 22% showed bilateral disease. The age range was 15 to 86 years, with most cases clustered in the fifth to seventh decade of life. See Table 2 for location of involvement and Table 3 for presenting symptoms and signs.
Table 1Review of all cases of primary localized orbital and ocular adnexal amyloidosis reported in the literature since 2004
At least 6 out of 71 cases (8.5%) had amyloid deposits in the orbit with extension to either the lids or the conjunctiva. While the vast majority of cases were treated surgically with either excision or at least debulking, 5.5% were treated with external beam radiation, 4% of cases were observed, another 4% received levator resection, 2.6% received liquid nitrogen, 1.3% needed canaliculotomy, and 1.3% received electrocauterization and CO2 laser vaporization of conjunctival vegetations. Recurrence was reported in 19.4%, but many of these cases had not received complete excision at initial presentation, and some studies reported excising the same lesion more than once.
Discussion
In a review of the literature, Taban et al. uncovered 31 cases of primary localized orbital amyloidosis reported until 2004.
The most predominant symptoms were ptosis, proptosis, and globe displacement, and 81% of cases were unilateral and most were also in the upper part of the orbit. Visual impairment was only recorded in 5 patients.
Our patient exhibits some typical features such as ptosis, globe displacement, extension into upper orbit, and unilaterality. As with most other cases in the literature, he did not require levator resection and was treated with surgical excision of the palpebral portion of the amyloid. However, his sex and younger age make him somewhat atypical. Nonetheless, given the high recurrence rate of amyloidosis especially in patients with orbital extension,
he will require regular follow-up well into the foreseeable future.
Most studies defined ptosis based on a reduction in the distance from the upper eyelid margin to the corneal light reflex (MRD1). While ptosis was present in 62.5% of cases, only 1.3% of cases showed levator muscle infiltration by amyloid, and only 4% required levator resection. This illustrates the multifactorial nature of the ptosis caused by orbital and ocular adnexal amyloidosis. The downward mechanical effect of the amyloid deposits on the eyelid was implicated in many cases, including ours, and eyelid edema–caused amyloid deposits were the cause of ptosis in a few others.
Orbital and ocular adnexal amyloidosis has been reported in association with multiple myeloma,
Therefore, patients presenting with amyloid accumulations in 1 organ system should be worked up for systemic involvement. The following tests are commonly used: physical examination, complete blood count, serum electrolytes, urine analysis, serum/urine protein electrophoresis and immunofixation, liver function tests, prothrombin time, activated partial prothrombin time, 24-hour urine protein, Bence Jones protein, electrocardiogram, abdominal ultrasound, and bone scan.
This case and the subsequent review of the literature serve to reinforce several important points. First, amyloidosis of the orbit or ocular adnexa can have varying presentations, the most common of which is ptosis and visible mass. Second, since conjunctival or palpebral amyloidosis can coexist with orbital amyloidosis in at least 8.5% of cases, orbital imaging is warranted in all cases of ocular adnexal amyloidosis. Third, although surgical excision or debulking is the most common treatment option, observation and other modalities have been reported. Fourth, although most cases of orbital and ocular adnexal amyloid are localized, systemic associations with many organ systems have been reported and can be ruled out through extensive blood work and selected imaging modalities. Lastly, because of a substantial rate of recurrences, patients require long-term follow-up.
Disclosure
The authors have no proprietary or commercial interest in any materials discussed in this article.
Acknowledgements
This material has not been presented elsewhere, and we received no funding from any source to complete this work.
References
Sipe J.D.
Benson M.D.
Buxbaum J.N.
Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis.
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