Nejmcpc 2300904

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Case Records of the Massachusetts General Hospital
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Case 21-2023: A 61-Year-Old Man

with Eyelid Swelling
Natalie Wolkow, M.D., Ph.D., Laura V. Romo, M.D., Camille V. Edwards, M.D.,
and Anna M. Stagner, M.D.
Pr e sen tat ion of C a se

From the Departments of Ophthalmol‑ Dr. Jonathan E. Lu (Ophthalmology, Massachusetts Eye and Ear): A 61-year-old man
ogy (N.W., A.M.S.) and Radiology (L.V.R.), was evaluated in an ophthalmology clinic affiliated with this hospital because of
Massachusetts Eye and Ear, the Depart‑
ments of Ophthalmology (N.W., A.M.S.), eyelid swelling.
Radiology (L.V.R.), and Pathology (A.M.S.), Eight years before the current presentation, the patient noticed mild puffiness
Harvard Medical School, the Depart‑ of the eyelids that was worst in the morning and typically resolved by midday. Five
ments of Radiology (L.V.R.) and Pathology
(A.M.S.), Massachusetts General Hospi‑ years before the current presentation, the eyelid swelling began to progressively
tal, the Department of Medicine, Boston worsen and to last throughout the day. The patient had a history of glaucoma;
Medical Center (C.V.E.), and the Depart‑ when the eyelid swelling began to interfere with his vision, he asked for a consul-
ment of Medicine, Boston University
School of Medicine (C.V.E.) — all in Boston. tation with the ophthalmologist who had treated his glaucoma. A diagnosis of
dermatochalasis with fat prolapse was suspected, and the patient was referred to
N Engl J Med 2023;389:166-75.
DOI: 10.1056/NEJMcpc2300904 the ophthalmic plastic and reconstructive surgery clinic affiliated with this hospi-
Copyright © 2023 Massachusetts Medical Society. tal for consideration of blepharoplasty.
In the clinic, the patient reported that eyelid puffiness was interfering with his
CME
at NEJM.org
ability to read and drive. He did not have dry eye. He had a sensation of pressure
behind the eyes and intermittent double vision. There was generalized joint stiff-
ness in the mornings that resolved after 1 hour. There was left lateral hip pain that
radiated to the left buttock and thigh, with associated paresthesia in the left foot.
Human immunodeficiency virus (HIV) infection had been diagnosed 31 years
before the current presentation and was well controlled with antiretroviral therapy,
although lipodystrophy had occurred with treatment. Other medical history in-
cluded carpal tunnel syndrome, cataracts, depression, dyslipidemia, hypertension,
allergic rhinitis, obstructive sleep apnea, and asthma, in addition to primary open-
angle glaucoma. Surgical history included carpal tunnel release surgery (per-
formed 2 months before the current presentation), intraocular lens replacement in
both eyes, and lipectomy for the reduction of dorsocervical lipohypertrophy due to
lipodystrophy. Medications included antiretroviral therapy (elvitegravir, cobicistat,
emtricitabine, and tenofovir alafenamide), bupropion, fluoxetine, triamterene,
amlodipine, atorvastatin, inhaled albuterol, and topical testosterone. The admin-
istration of iodinated contrast material had caused hives. The patient lived part
166 n engl j med 389;2 nejm.org July 13, 2023
The New England Journal of Medicine

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Case Records of the Massachuset ts Gener al Hospital
A B
C D
E F
Figure 1. Clinical Photographs at Presentation.

Photographs of the eyes were obtained in several gaze positions. In primary gaze, the patient has edema and mild
erythema of the upper eyelids, along with festoons of the lower eyelids (Panel A). The upper‑eyelid edema is more
pronounced when viewed from below (Panel B). There is mild limitation of extraocular motility in all gaze positions,
including up gaze (Panel C), right gaze (Panel D), left gaze (Panel E), and down gaze (Panel F).
time in Florida and part time in New England. range, 12 to 18). Slit-lamp examination revealed
He was a lifelong nonsmoker, drank alcohol oc- 1+ chemosis and trace injection in the conjunc-
casionally, and did not use illicit substances. tivae; there was no evidence of superficial punc-
On examination, the corrected visual acuity tate keratopathy or cells in the anterior cham-
was 20/25 in the right eye and 20/30 in the left bers. Funduscopic examination revealed an
eye. The pupils were symmetric and reactive to increased cup-to-disk ratio in the optic nerves, a
light. Confrontation testing revealed deficits in finding consistent with the patient’s known his-
the outer superior temporal visual fields and the tory of glaucoma. The tongue was enlarged, and
superior nasal visual fields, which abated with there was dorsocervical lipohypertrophy on the
manual elevation of the eyelids. Supraduction posterior aspect of the neck.
and abduction were limited in both eyes. Soft The blood levels of thyrotropin, free thyrox-
edema of the upper and lower eyelids was pres- ine, triiodothyronine, thyroid peroxidase anti-
ent, along with mild erythema of the upper eye- bodies, and thyroid-stimulating immunoglobu-
lids (Fig. 1). The upper-eyelid skin was over- lins were normal. Imaging studies were obtained.
hanging the lashes medially, a finding indicative Dr. Laura V. Romo: Computed tomography (CT)
of dermatochalasis. There was upper-eyelid ptosis. of the face and orbits (Fig. 2A and 2B), per-
The globes were moderately resistant to retro- formed without the administration of intrave-
pulsion, and there was mild proptosis. The leva- nous contrast material, revealed bilateral en-
tor palpebrae superioris muscles had impaired largement of the extraocular muscles and fat
function, with an eyelid elevation of 8 mm in the stranding in the orbits and elsewhere in the
right eye and 11 mm in the left eye (reference face. Magnetic resonance imaging (MRI) of the
n engl j med 389;2 nejm.org July 13, 2023 167

A B
* *
* *
C D
* *
*
E F
face and orbits (Fig. 2C through 2F), performed ing and mild, symmetric, diffuse extraocular-
before and after the administration of intrave- muscle enlargement. A short-tau inversion recovery
nous contrast material, revealed orbital fat strand- sequence showed an increased signal that spared

Figure 2 (facing page). Imaging Studies of the Face nonreactive. An interferon-γ release assay for
and Orbits. Mycobacterium tuberculosis complex infection was
CT of the face and orbits was performed. A coronal im‑ negative.
age (Panel A) shows abnormal, curvilinear stranding in A diagnostic procedure was performed.
otherwise normal, low-attenuation orbital fat (red arrow).
Mild, diffuse enlargement of the extraocular muscles,
including the superior and medial rectus muscles in Differ en t i a l Di agnosis
both eyes, is also present (asterisks). An axial image
(Panel B) shows abnormal, curvilinear stranding in other‑ Dr. Natalie Wolkow: I participated in the care of
wise normal, low-attenuation orbital fat (red arrow); this patient, and I am aware of the final diagno-
preseptal soft-tissue thickening along the anterior mar‑ sis. I evaluated this patient for upper-eyelid
gin of both globes (blue arrow); and fat stranding along
blepharoplasty for the treatment of dermatocha-
both temples (yellow arrow). MRI of the face and orbits
was also performed. A coronal T1-weighted image lasis (excess upper-eyelid skin); however, the
(Panel C) shows abnormal stranding (gray) in normal clinical examination findings were atypical,
orbital fat (white), which has high signal intensity (red prompting further investigation. He had derma-
arrow). A coronal short-tau inversion recovery image tochalasis, but the skin was puffy, edematous,
(Panel D) shows abnormal stranding (white), which
and mildly erythematous. He also had lower-
has high signal intensity that spares the myotendinous
junctions, in normal orbital fat (gray), where the signal eyelid edema (festoons) and mild conjunctival
is suppressed (red arrow). Diffuse enlargement of the chemosis and injection, findings suggestive of
extraocular muscles, including the superior and medial inflammation. These features, in combination
rectus muscles, is also present and has high signal inten‑ with upper-eyelid ptosis, mild limitation of ex-
sity (asterisks). An axial T1-weighted, contrast-enhanced,
traocular motility in several gaze positions, im-
fat-saturated image (Panel E) shows abnormal strand‑
ing and enhancement in the retrobulbar and episcleral pairment of levator-muscle function, and moder-
fat (red arrows), diffuse thickening and enhancement of ate resistance to retropulsion when pressing over
the preseptal soft tissue (blue arrow), and enhancement the eyes, were suggestive of a chronic orbital
along the optic-nerve sheaths (yellow arrows), a finding inflammatory process.
consistent with perineuritis. An axial T2-weighted image
(Panel F) shows diffuse preseptal soft-tissue thickening
with low signal intensity along the anterior margin of
Thyroid Eye Disease
both globes (red arrow). The most common cause of orbital inflamma-
tion is thyroid eye disease. The patient’s eyelid
edema and erythema, orbital resistance to retro-
the myotendinous junctions. Diffuse thickening pulsion, limited extraocular motility, impaired
and stranding of the skin on the preseptal eye- levator-muscle function, and conjunctival che-
lids and face, episcleritis along the posterior mosis and injection were consistent with thyroid
margin of both globes, and perineuritis around eye disease. There was no eyelid retraction, lag,
the optic nerves were also noted. or flare, which are typical findings of thyroid
Dr. Lu: The blood levels of glucose and electro- eye disease. Instead, there was eyelid ptosis.
lytes and the results of kidney-function tests were Patients with thyroid eye disease occasionally
normal, as were the blood levels of angiotensin- present with ptosis, but it is uncommon.1 The
converting enzyme (ACE), lysozyme, rheumatoid patient had no history of systemic thyroid dis-
factor, and C-reactive protein. The erythrocyte ease, but more than 20% of patients present
sedimentation rate was 22 mm per hour (refer- with thyroid eye disease before systemic disease
ence range, 0 to 20). The blood IgG level was is diagnosed.2
1980 mg per deciliter (reference range, 767 to It is notable that the patient’s clinical course
1590), the IgG1 level 283 mg per deciliter (refer- was atypical for thyroid eye disease. Most pa-
ence range, 341 to 894), and the IgG2 level 1750 tients with thyroid eye disease have progression
mg per deciliter (reference range, 171 to 632); of inflammation for 1 to 2 years followed by
the blood IgG3 and IgG4 levels were normal. improvement, whereas this patient had slow
Indirect immunofluorescence testing for anti- progression for many years. In addition, the re-
neutrophil cytoplasmic antibodies (ANCAs) was sults of tests for thyroid function and thyroid
negative, including an enzyme-linked immuno- antibodies were normal in this case. On review
sorbent assay for antibodies to proteinase 3 and of the patient’s imaging studies, the bilateral
myeloperoxidase. A rapid plasma reagin test was extraocular-muscle enlargement with fusiform

features was typical of thyroid eye disease. How- mal gland enlargement and tends to cause
ever, the uniform pattern of extraocular-muscle enlargement of trigeminal nerve branches, par-
enlargement and the presence of episcleritis, ticularly the infraorbital nerve, but extraocular-
perineuritis, orbital fat stranding, and skin muscle enlargement can also occur.9 Although a
thickening were atypical and prompted consid- normal IgG4 level alone would not rule out
eration of alternative causes of orbital inflam- IgG4-related disease, the combination of the nor-
mation. mal IgG4 level and the absence of lacrimal gland
and infraorbital nerve enlargement lowers the
Cancer likelihood of IgG4-related disease in this case.
Metastatic cancer, lymphomatous or leukemic Orbital granulomatosis with polyangiitis usu-
infiltration, or paraneoplastic disease can cause ally causes lacrimal gland enlargement or orbital
extraocular-muscle enlargement, at times with masses, but isolated extraocular-muscle enlarge-
an inflammatory clinical appearance.3-6 Patients ment can occur occasionally.10 In this patient,
with these diseases may present with unilateral the negative ANCA testing, the absence of lacri-
or bilateral limitation of extraocular motility, mal gland enlargement and orbital masses, and
conjunctival chemosis and injection, resistance to the absence of symptoms and imaging findings
retropulsion, or eyelid edema. Metastatic lesions of sinus disease make extraocular-muscle en-
that affect the extraocular muscles typically largement due to granulomatosis with polyangi-
manifest as nodular or focal enlargement; in itis unlikely.
rare cases, lymphoma or leukemia manifests as
bilateral, diffuse extraocular-muscle involvement. Medication-Induced Orbital Myositis
He had no history of cancer, but extraocular- Medications such as bisphosphonates11,12 and im-
muscle enlargement can be the presenting sign mune checkpoint inhibitors13 can cause orbital
of cancer. myositis, although it is typically acute and pain-
However, this patient’s clinical course was ful. None of this patient’s medications have
atypical for cancer or paraneoplastic disease. known associations with orbital inflammation.
Metastatic cancer or lymphomatous or leukemic The initiation of antiretroviral therapy in pa-
infiltration of the extraocular muscles would tients with HIV infection has been associated
progress over a period of weeks to months, and with immune reconstitution inflammatory syn-
when diffuse bilateral disease is present, there drome (IRIS). Cases of orbital myositis due to
can be rapid symptom progression and vision delayed-onset IRIS that developed 1 and 3 years
loss.4 By contrast, this patient had an 8-year his-after the initiation of antiretroviral therapy have
tory of progressive symptoms without the devel- been described,14,15 but patients with this condi-
opment of systemic signs of cancer. tion usually present with acute eye pain, ery-
thema, and edema. IRIS is unlikely in this pa-
Chronic Inflammatory Orbital Myositis tient, given the absence of acute symptoms and
Several systemic inf lammatory diseases can the long-standing use of antiretroviral therapy.
manifest with orbital inflammation, including
extraocular-muscle enlargement due to chronic HIV-Related Lipodystrophy
orbital myositis. Sarcoidosis can cause bilateral Lipodystrophy can manifest as lipoatrophy, lipo-
extraocular-muscle enlargement, but in such hypertrophy, or both.16 The mechanisms of lipo-
cases, it would usually also cause lacrimal gland dystrophy are not fully understood, but inflam-
enlargement or orbital masses.7,8 The extraocular- matory responses to HIV infection and effects
muscle enlargement can progress slowly, at of antiretroviral therapy in adipose tissue are
times with no pain. In this patient, the normal thought to lead to these changes.16 Certain anti-
ACE and lysozyme levels and the absence of lac- retroviral therapies are associated with lipohy-
rimal gland enlargement and orbital masses pertrophy and others with lipoatrophy. This pa-
make sarcoidosis an unlikely diagnosis. tient had a history of marked dorsocervical
IgG4-related disease is another inflammatory lipohypertrophy, for which he had undergone
process that can have orbital involvement with lipectomy. At the time of the current presenta-
slow progression and minimal pain. Orbital tion, abnormal reticulation and thickening in
IgG4-related disease most often results in lacri- the subcutaneous tissue of the face and neck and

in the orbital fat were observed on CT and MRI. sult of amyloid deposition in the optic-nerve
I considered whether these changes were consis- sheath (dura), sclera, and episclera.23
tent with HIV-related lipohypertrophy. The face Only 2 to 16% of patients with ocular adnexal
is not typically a site of lipohypertrophy. Orbital amyloidosis have extraocular-muscle involve-
lipoatrophy has been reported,17,18 but orbital lipo- ment.20,21 Among such patients, those with bilat-
hypertrophy has not. eral, diffuse extraocular-muscle enlargement are
Overall, none of the diagnoses that I initially more likely to have systemic amyloidosis than
considered fit well with this patient’s presenta- those with unilateral extraocular-muscle enlarge-
tion. His systemic symptoms were revisited, and ment.22 This patient had bilateral orbital disease,
he was referred to the rheumatology clinic af- no discrete orbital or eyelid masses, and no vis-
filiated with this hospital for evaluation of joint ible amyloid deposits on eyelid eversion, features
stiffness, hip pain, and foot paresthesia. Before that made unilateral localized amyloidosis un-
his evaluation in the rheumatology clinic, he likely (although it is more common than sys-
was evaluated for new dyspnea on exertion and temic disease) and thus were suggestive of sys-
received a diagnosis of cardiomyopathy. Given temic amyloidosis. His slow disease progression,
the presence of new cardiomyopathy, paresthesia, history of carpal tunnel syndrome, and new car-
and carpal tunnel syndrome, amyloidosis was diomyopathy were also consistent with systemic
added to the differential diagnosis. amyloidosis.
Systemic amyloidosis was the leading diagno-
Amyloidosis sis for this patient. To establish the diagnosis of
Amyloidosis can involve any tissue of the ocular systemic amyloidosis, amyloid must be detected
adnexa, but such involvement is very uncommon. in tissue, so biopsy of affected ophthalmic tissue
Patients usually present to ophthalmologists was indicated. Because biopsy of extraocular
with localized disease, most often with unilat- muscle requires general anesthesia and carries a
eral eyelid ptosis or an eyelid mass.19 Less than risk of permanent diplopia, biopsy of eyelid skin
10% of patients with ocular adnexal amyloidosis and orbital fat was performed with the patient
have systemic amyloidosis, with involvement of under local anesthesia.
other organs.20,21
Although amyloidosis can in rare cases cause Dr . Nata l ie Wol kow ’s Di agnosis
extraocular-muscle enlargement, ocular adnexal
amyloidosis is not typically considered to be an Systemic amyloidosis.
inflammatory process. This patient’s ocular find-
ings were suggestive of inflammation, so I had Pathol o gic a l Discussion
not initially considered the diagnosis. Some pa-
tients with amyloidosis affecting the extraocular Dr. Anna M. Stagner: Hematoxylin and eosin stain-
muscles can present with eyelid edema,22 and ing of the biopsy specimen from the left upper
when there is extensive amyloid deposition in eyelid (Fig. 3A) showed a paucity of inflamma-
the ocular adnexa, the eyelids can take on an tion. Vessel walls within the dermis, subcutis, and
inflammatory appearance, with festoons and superficial skeletal muscle (orbicularis oculi)
red discoloration of the skin, findings that were were markedly thickened and were expanded by
seen in this case.20 faintly eosinophilic material. At higher magnifi-
The bilateral extraocular-muscle enlargement, cation (Fig. 3B), the material was acellular and
the subcutaneous and orbital fat stranding, and had a pale-pink, amorphous, homogenized ap-
the inflammatory appearance of the eyelids in pearance. On Congo red staining (Fig. 3C), the
this patient could be explained by amyloid depo- faintly eosinophilic material was highlighted in
sition in the extraocular muscles, orbital fat, and bright magenta and was associated with apple-
skin, respectively. In addition, the glaucoma green birefringence when viewed under cross-
could possibly be the result of amyloid deposi- polarized light. Liquid chromatography with
tion in the arterial circle of Zinn–Haller, which tandem mass spectrometry showed a peptide
supplies the optic-nerve head. The conjunctival pattern consistent with lambda immunoglobulin
chemosis and injection, as well as the episcleritis light-chain amyloid.
and perineuritis seen on MRI, could be the re- After the diagnosis of amyloidosis was estab-

A B
*
*
*
C D
E F
*
*
lished, a bone marrow biopsy (Fig. 3D) revealed Pathol o gic a l Di agnosis
evidence of a plasma-cell neoplasm, with an in-
creased number of mature plasma cells (ac- Deposition of light-chain amyloid in the ocular
counting for 15 to 20% of the marrow cellu- adnexa due to a systemic plasma-cell neoplasm.
larity) in a background of normal maturing
trilineage hematopoiesis. The plasma cells were Discussion of Surgic a l
highlighted on immunostaining for CD138 M a nagemen t
(Fig. 3E) and showed lambda light-chain restric-
tion on immunostaining for kappa and lambda Dr. Wolkow: The patient was referred to an amy-
immunoglobulin light chains (Fig. 3F). loidosis center for the management of systemic

Figure 3 (facing page). Specimens from Eyelid Biopsy A

and Bone Marrow Biopsy.
Hematoxylin and eosin staining of the biopsy specimen
from the left upper eyelid (Panel A) shows a relatively
unremarkable epidermis and no substantial dermal in‑
flammatory infiltrate. However, vessel walls within the
dermis are markedly thickened and are expanded by
acellular eosinophilic material (circles). The same mate‑
rial is seen in the vasculature of the adipose tissue in
the preseptal eyelid (inset, arrows). A photomicrograph
with higher magnification (Panel B) shows that the eo‑ B
sinophilic material has a pale‑pink, amorphous appear‑
ance with a cracking artifact. The material is distributed
in a strikingly perivascular pattern (arrows) and extends
into the orbicularis oculi muscle (asterisks). Focal, small,
admixed lymphoid aggregates are present (circle). Congo
red staining (Panel C) highlights the vessel walls in bright
magenta (top), and cross‑polarization reveals apple‑
green birefringence of the congophilic material (bottom).
These findings are consistent with a diagnosis of amy‑ Figure 4. Clinical Photographs before and after Blepharo-
loidosis. Hematoxylin and eosin staining of the biopsy plasty.
specimen from the bone marrow (Panel D) shows an A photograph of the eyes obtained at the preoperative
increased number of mature plasma cells, both singly visit (Panel A) shows upper‑eyelid puffiness, edema,
(arrows) and in small clusters (circles), in a background and dermatochalasis, with skin overhanging the upper‑
of maturing myeloid and erythroid elements and mega‑ eyelid margin. A photograph of the eyes obtained at the
karyocytes. The plasma cells have eccentric nuclei, 3‑month postoperative visit (Panel B) shows clinical
clumped nuclear chromatin (known as “clockface nu‑ improvement.
clei”), perinuclear clearings, and purplish‑blue cyto‑
plasm. Overall, plasma cells account for 15 to 20% of
the marrow cellularity (normal range, 2 to 3%). Immu‑
The patient has persistent diplopia, which is
nostaining for CD138 (Panel E) highlights the plasma
cells (in brown); the area of highest density within the his most prominent source of functional impair-
bone marrow specimen is shown, with asterisks indi‑ ment. He has been referred to a strabismus
cating the bone spicules. Immunostaining for kappa and specialist, but the diplopia remains very chal-
lambda immunoglobulin light chains (Panel F; top and lenging to treat.
bottom, respectively) shows expression of lambda light
chains in the plasma cells (circle, in brown) without sub‑
stantial staining for kappa light chains (normal range for Discussion of A m y l oid osis
kappa:lambda ratio, 2:1 to 3:1), a finding that confirms M a nagemen t
the presence of a clonal plasma‑cell population.
Dr. Camille V. Edwards: This patient had an underly-
ing clonal plasma-cell disorder, as evidenced by
immunoglobulin light-chain (AL) amyloidosis. a monoclonal spike of 1.29 g per deciliter on
However, he requested to have more upper-eyelid serum protein electrophoresis. Serum and urine
tissue removed because he had noticed an in- immunofixation testing confirmed the presence
crease in his visual field after the eyelid biopsy. of an IgG lambda monoclonal protein, and the
Bilateral upper-eyelid blepharoplasty with re- serum free lambda light-chain level was 134.7 mg
moval of skin and fat was performed. Repair of per liter (reference range, 5.0 to 26.3). In addi-
eyelid ptosis was deferred in the context of amy- tion, there was bone marrow plasmacytosis,
loidosis with impaired levator-muscle function. with a high burden of plasma cells in bone mar-
Owing to amyloid deposition, the vessel walls row (>10%).
were more friable, which resulted in increased Because deposition of amyloid fibrils can oc-
intraoperative bleeding. After the surgical proce- cur in various organs and systems, AL amyloido-
dure, the patient noticed improvement in his vi- sis can involve the heart, kidneys, liver, periph-
sion (Fig. 4). Histopathological examination of eral nervous system (including the autonomic
the eyelid skin and fat excised during blepharo- nervous system), gastrointestinal tract, and soft
plasty revealed the same features that were ob- tissue.24 In this patient, the first step in the
served in the eyelid-biopsy specimen. management of his newly diagnosed AL amyloi-

dosis was a detailed evaluation in order to assess nance therapy for up to 2 years; if he did not
the extent of organ involvement and select an have an adequate hematologic response to in-
appropriate treatment regimen.25 His macroglos- duction therapy, he was to receive high-dose
sia and eye symptoms with biopsy-confirmed melphalan in combination with autologous
amyloidosis of the eyelids were indicative of soft- stem-cell transplantation.29
tissue involvement of AL amyloidosis. Fortunately, the patient had a very good par-
An assessment for cardiac involvement includ- tial hematologic response to induction chemo-
ed biomarker testing and imaging.26 The B-type therapy and is now receiving daratumumab
natriuretic peptide (BNP) level was mildly elevat- maintenance therapy. Nonetheless, he has per-
ed (56.0 pg per milliliter; reference range, 0.0 to sistent eye symptoms due to resistant amyloid
53.2). The N-terminal pro-BNP level was normal fibrils that are not amenable to current plasma-
(167 pg per milliliter; reference range, 0 to 899), cell–directed treatments.
as was the troponin I level (0.010 ng per milli
liter; reference value, <0.033). Echocardiography Pat ien t Per spec t i v e
revealed a mildly increased interventricular sep-
tal thickness (12 mm; reference value, ≤11) with The Patient: Over a period of 16 months, I re-
focal thickening of the mid-to-upper septum ceived diagnoses of glaucoma, cataracts, carpel
(14 mm) and reduced global longitudinal strain tunnel syndrome, and heart failure. I also had a
(–15.5%). Subsequent cardiac MRI confirmed the host of unexplained symptoms, such as an en-
presence of increased wall thickness but did not larged tongue, tingling and numbness in my
show late gadolinium enhancement or a radio- feet, jaw pain when eating, and pain in the el-
logically significant increase in extracellular vol- bows, hip, and pelvis. Initially, I was very dis-
ume; the absence of these features is not consis- couraged by my eyelid swelling and its effects on
tent with the presence of cardiac amyloidosis. my vision. Fortunately, my doctor did not give up
The patient was also assessed for renal in- on me and instead continued to pursue the cause
volvement. The estimated glomerular filtration of my eyelid swelling.
rate, measured according to the method of the After the biopsy of my eyelid showed amy-
Chronic Kidney Disease Epidemiology Collabo- loid, we could look back on those new diagno-
ration, was normal (>60 ml per minute per 1.73 m2 ses and unexplained symptoms and see the
of body-surface area). However, a 24-hour urine common thread of amyloidosis as the root
collection showed a protein level of 630 mg (ref- cause. I began treatment in the amyloidosis
erence range, 0 to 150). Thus, the patient was center, and I think I am in better health than I
considered to have early renal involvement.27 was 2 years ago. As for my vision, it continues
Because the soft-tissue involvement was af- to worsen very slowly. The “good days” are less
fecting the patient’s vision, a treatment plan was frequent than they were 6 months ago. When I
formulated with the goal of eradicating the un- move my eyes, it’s like I’m watching an old reel-
derlying plasma-cell clone in order to prevent to-reel movie slowed down to the point where
further amyloid deposition that could worsen you can see one frame move to the next. That’s
his vision. The patient had a high burden of what it’s like — no smooth movement, just one
plasma cells in bone marrow, so induction chemo- picture after another. When I’m in the airport
therapy was indicated. He was offered standard or some other busy location, it’s dizzying and
induction therapy with six cycles of daratumu overwhelming.
mab, cyclophosphamide, bortezomib, and dexa- One of the key things for doctors to know
methasone.28 In addition, on the basis of his from my story is how important the exemplary
excellent performance status and organ func- communication among departments, facilities,
tion, he was considered to be a candidate for and physicians across specialties was for me as
consolidation therapy with high-dose melphalan a patient. Collaboration is so important with a
and autologous stem-cell transplantation. If the complex disease like amyloidosis, with its ability
patient had an adequate (very good partial or to mimic other diseases and attack multiple
complete) hematologic response to induction body systems and its potential to cause irrevers-
therapy, he was to receive daratumumab mainte- ible harm over a short period of time.

This case was presented at Ophthalmology Grand Rounds at

Fina l Di agnosis Massachusetts Eye and Ear.
Disclosure forms provided by the authors are available with
Systemic immunoglobulin light-chain (AL) amy- the full text of this article at NEJM.org.
We thank Dr. Mary Beth Cunnane for review of the neuroim-
loidosis. aging portion of the article.
References
1. Vasanthapuram VH, Naik MN. Bleph- ent orbital manifestations of granuloma- amyloid: adnexal and systemic involve-
aroptosis in thyroid eye disease: etio- tosis with polyangiitis. Graefes Arch Clin ment. Orbit 2020;39:13-7.
pathogenesis, clinical features and cor- Exp Ophthalmol 2018;256:1751-6. 21. Leibovitch I, Selva D, Goldberg RA,
relation with thyroid eye disease. Int 11. Lefeuvre L, Caruso A, Biver E, Fayolle et al. Periocular and orbital amyloidosis:
Ophthalmol 2022;42:13-8. D. Orbital myositis induced by alendro- clinical characteristics, management, and
2. Bartley GB, Fatourechi V, Kadrmas nate: a case report. Eur J Neurol 2023;30: outcome. Ophthalmology 2006;113:1657-
EF, et al. Chronology of Graves’ ophthal- 1828-30. 64.
mopathy in an incidence cohort. Am J 12. Lefebvre DR, Mandeville JT, Yoneka- 22. Shah VS, Cavuoto KM, Capo H, Grace
Ophthalmol 1996;121:426-34. wa Y, Arroyo JG, Torun N, Freitag SK. A SF, Dubovy SR, Schatz NJ. Systemic amy-
3. Leung V, Wei M, Roberts TV. Metasta- case series and review of bisphosphonate- loidosis and extraocular muscle deposi-
sis to the extraocular muscles: a case re- associated orbital inflammation. Ocul tion. J Neuroophthalmol 2016;36:167-73.
port, literature review and pooled data Immunol Inflamm 2016;24:134-9. 23. Campos EC, Melato M, Manconi R,
analysis. Clin Exp Ophthalmol 2018;46: 13. Jebaraj AP, Etheridge TJ, Winegar BA, Antonutto G. Pathology of ocular tissues
687-94. Marx DP. Ipilimumab-related orbitopathy: in amyloidosis. Ophthalmologica 1980;
4. McCoskey M, Reshef ER, Wolkow N, a case report. Orbit 2022 May 17 (Epub 181:31-40.
Yoon MK. Bilateral enlargement of all ex- ahead of print). 24. Merlini G, Dispenzieri A, Sanchora
traocular muscles: a presenting ophthal- 14. Wang Y, Zhao N, Yang J, Wen Y. Case wala V, et al. Systemic immunoglobulin
mic sign of hematologic malignancy. Or- report: orbital myositis and myasthenia light chain amyloidosis. Nat Rev Dis
bit 2022 June 22 (Epub ahead of print). gravis as symptoms of immune reconsti- Primers 2018;4:38.
5. Watkins LM, Carter KD, Nerad JA. tution inflammatory syndrome in a patient 25. Palladini G, Milani P, Merlini G. Man-
Ocular adnexal lymphoma of the extra- with human immunodeficiency virus in- agement of AL amyloidosis in 2020. Blood
ocular muscles: case series from the Uni- fection. Front Immunol 2020;11:595068. 2020;136:2620-7.
versity of Iowa and review of the litera- 15. Manta A, Ugradar S, Murta F, Ezra D, 26. Lilleness B, Ruberg FL, Mussinelli R,
ture. Ophthalmic Plast Reconstr Surg Cormack I. Immune reconstitution in- Doros G, Sanchorawala V. Development
2011;27:471-6. flammatory syndrome in a case of non- and validation of a survival staging sys-
6. Mehta P, Chickadasarahally S, Hedley specific orbital inflammation. Ophthal- tem incorporating BNP in patients with
N, Ahluwalia H. Extraocular muscle en- mic Plast Reconstr Surg 2018; 34(2): light chain amyloidosis. Blood 2019;133:
largement as a paraneoplastic effect of e54-e56. 215-23.
breast carcinoma in a male patient. Oph- 16. Koethe JR, Lagathu C, Lake JE, et al. 27. Gertz MA, Comenzo R, Falk RH, et al.
thalmic Plast Reconstr Surg 2011;27(6): HIV and antiretroviral therapy-related fat Definition of organ involvement and
e146-e147. alterations. Nat Rev Dis Primers 2020;6: treatment response in immunoglobulin
7. McNab AA. Orbital myositis: a com- 48. light chain amyloidosis (AL): a consensus
prehensive review and reclassification. 17. De Niro JE, Silkiss RZ. Severe enoph- opinion from the 10th International Sym-
Ophthalmic Plast Reconstr Surg 2020;36: thalmos and lagophthalmos secondary to posium on Amyloid and Amyloidosis,
109-17. HIV-associated lipoatrophy. BMJ Case Rep Tours, France, 18-22 April 2004. Am J He-
8. Vahdani K, Rose GE. Sarcoid orbital 2011;2011:bcr0620114376. matol 2005;79:319-28.
myopathy: clinical presentation and out- 18. Merchante N, García-García JA, Verg- 28. Kastritis E, Palladini G, Minnema
comes. Ophthalmic Plast Reconstr Surg ara S, Mira JA, Macías J, Pineda JA. Bilat- MC, et al. Daratumumab-based treatment
2020;36:61-6. eral enophthalmos as a manifestation of for immunoglobulin light-chain amyloi-
9. Lai KKH, Chu WCW, Li EYM, et al. HIV infection-related lipoatrophy. HIV dosis. N Engl J Med 2021;385:46-58.
Radiological determinants of complicat- Med 2004;5:448-9. 29. Sanchorawala V, Boccadoro M, Gertz
ed immunoglobulin G4-related ophthal- 19. Hu WF, Yoon MK, Wolkow N. Slowly M, et al. Guidelines for high dose chemo-
mic disease: a territory-wide cohort study. progressive unilateral blepharoptosis in a therapy and stem cell transplantation for
Asia Pac J Ophthalmol (Phila) 2022; 11: 37-year-old woman. JAMA Ophthalmol systemic AL amyloidosis: EHA-ISA work-
417-24. 2020;138:704-5. ing group guidelines. Amyloid 2022;29:
10. Ismailova DS, Abramova JV, Novikov 20. Kang S, Dehabadi MH, Rose GE, Ver- 1-7.
PI, Grusha YO. Clinical features of differ- ity DH, Amin S, Das-Bhaumik R. Ocular Copyright © 2023 Massachusetts Medical Society.


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The n e w e ng l a n d j o u r na l of m e dic i n e

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Case 21-2023: A 61-Year-Old Man

Pr e sen tat ion of C a se

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Figure 1. Clinical Photographs at Presentation.

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Figure 3 (facing page). Specimens from Eyelid Biopsy A

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This case was presented at Ophthalmology Grand Rounds at

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