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Michele McHale, O.D. Optometry Resident Boston Healthcare System‐West Roxbury Division Telephone: 617.323.7700 x35440 Title:
Hyperviscosity syndrome secondary to Multiple Myeloma leads to devastating vision loss after
sequential central retinal vein and central retinal artery occlusion.
Abstract:
Central retinal vein occlusion followed by a central retinal artery occlusion in the setting of
multiple myeloma. The causative agent is hyperviscosity syndrome leading to in-situ venous and
in-situ arterial thrombus.
Case History:
A 74 year old Hispanic male presented for his annual diabetic eye examination with the chief
complaint of blurry vision for the past several months more so in his right eye than the left eye.
His last eye examination was one year ago at which the patients ocular history was remarkable
for only a few mild crossing changes O.U.
His medical history was significant for multiple myeloma, non-insulin dependent diabetes
mellitus, essential hypertension, hyperlipidemia, benign prostatic hyperplasia and 4 levels of
lumbar disc herniation. His medications included: finasteride, glipizide, lisinopril, simvastatin,
terazosin, and aspirin.
Pertinent Findings:
The patient’s best-corrected visual acuity was 20/20 in both eyes. Confrontation fields were full
O.D. and O.S. Pupils were equal, round and reactive to light with no afferent pupillary defect.
Extraocular muscles were smooth and accurate O.U. Slit lamp examination revealed temporal
pingueculas O.U., and 2+ nuclear sclerotic cataracts in both eyes.
Intraocular pressures were 17 mmHg in both eyes using Goldmann applanation tonometry.
Dilated fundus examination showed a cup-to-disc ratio of 0.45/0.45 O.D. and 0.4/0.4 O.S. with
distinct margins in both eyes. The right eye was noted to have multiple flame shaped
hemorrhages on the rim tissue of the optic nerve, scattered dot, blot and flame shaped
hemorrhages scattered throughout the four quadrants of the posterior pole with blot hemorrhages
extending into the periphery. In addition, there were 2 cotton wool spots and retinal venules
were noted to have marked tortuosity and segmentation of the vascular column. The left eye was
only remarkable for one cotton wool spot. There were no hemorrhages or vascular tortuosity
noted in the left eye. The patient was diagnosed with a non-ischemic central retinal vein
occlusion (CRVO) O.D.
On serial follow-ups over the next 8 weeks the patient's best-corrected visual acuity decreased
from 20/20 to 20/200 O.D. and remained stable at 20/20 O.S. The dilated fundus examination
noted continued venous dilation and pan hemorrhages O.D. with the addition of macular edema
O.D. Fundus evaluation of the left eye remained stable. OCT of the right eye revealed
subretinal fluid under the papillomacular bundle extending to the fovea. The patient received a
2 mg intravitreal injection of Kenalog (triamcinalone) O.D. to solicit resolution of the macular
thickening.
1 Michele McHale, O.D. Optometry Resident Boston Healthcare System‐West Roxbury Division Telephone: 617.323.7700 x35440 Six weeks post intravitreal Kenalog O.D. the patient presents with best-corrected visual acuity as
count fingers at three feet O.D. and 20/20 O.S. Dilated fundus evaluation revealed flame shaped,
dot and blot hemorrhages in all four quadrants, twelve cotton wool spots concentrated in the
superior and inferior temporal arcades and a ring of retinal whitening surrounding the macula
with a cherry red spot O.D. The fellow eye showed two cotton wool spots with a few blot
intraretinal hemorrhages OS. OCT exhibited massive cystic foveal edema O.D. Fluorescein
fundus angiography (FFA) showed delayed transit time, enlargement of hypofluorescent foveal
avascular zone, classic petaloid macular edema, a large area of retinal non-perfusion greatest
temporal to the macula with no late stage leakage. The patient was diagnosed with a now
sequential central retinal artery occlusion (CRAO) O.D. Upon initial presentation the patient did
not display an afferent papillary defect (APD) as expected with a CRAO, but upon follow up for
the 2 weeks after onset a 1+ APD was noted O.D.
Differential diagnosis:
Upon initial evaluation the patient's differential diagnoses were diabetic retinopathy, branch
retinal vein occlusion and central retinal vein occlusion. The patients other co-morbidities
included hypertension, anemia, and chemotherapy treatment all of which may be contributing to
the patients initial presentation and retinopathy.
When the patient presented with a sequential central retinal artery occlusion following his central
retinal vein occlusion, it was speculated to be thrombotic in nature. The literature notes that a
majority of patients with a CRAO is more than likely secondary to an embololic event. These
emboli typically consist of cholesterol (74%), calcified material (10.5%), or platelet-fibrin
(15.5%). Upon presentation, the patient did not show any other clinical signs or symptoms of
stroke, hence the medical team did not believe the patient was at risk for an embolic event and no
further investigations were warranted. Also, it was reassuring that the recent carotid noninvasive study (Duplex ultrasound) was bilaterally unremarkable with no significant stenosis of
either the right or left internal carotid arteries. In addition, the patient's recent echocardiogram
reported sinus bradycardia with first degree A-V block, but was otherwise unremarkable.
Diagnosis and Discussion:
The patient was diagnosed with a non-ischemic central retinal vein occlusion with sequential
central retinal artery occlusion secondary to hyperviscosity syndrome in the setting of multiple
myeloma IgA kappa. It is suspected that the causative agent of this ophthalmic presentation was
in-situ venous and in-situ arterial thrombus.
One year prior to his initial eye examination, the patient was diagnosed with Multiple Myeloma
IgA Kappa subsequent to a hospital admission complaining of 1-2 week of progressive fatigue
associated with an unintentional eleven pound weight loss and recent onset cough. His workup
revealed a previously undocumented anemia associated with diminished creatinine clearance,
elevated serum total protein and a large monoclonal IgA kappa serum protein electrophoresis
(SPEP) The patients IgA fraction was 5820 mg/dL (Normal 82-453 mg/dL) and kappa fraction
was 8070 mg/dL (Normal 629-1350 mg/dL). The patient’s initial treatment was chemotheraphy
with Bortezomib (Valcade) and dexamethasone. At the end of his fifth round of treatment he
2 Michele McHale, O.D. Optometry Resident Boston Healthcare System‐West Roxbury Division Telephone: 617.323.7700 x35440 exhibited poor gastrointestinal tolerance and dehydration that delayed the sixth round of
treatment [which was scheduled to begin two months prior to his eye examination.]
Multiple myeloma is the most common form of bone malignancy. The frequency is increased in
older patients with the median age of diagnosis in the 7th decade (1). Multiple myeloma is a
disease in which there is an uncontrolled proliferation of cells involved in antibody synthesis
known as plasma cell dyscrasias. These dyscrasias demonstrate excessive production of
monoclonal gammopathy with a concurrent decrease in normal immunoglobulins.(2).
Immunoglobulins are composed of four polypeptide chains: two "light" chains (lambda or
kappa), and two "heavy" chains (alpha, delta, gamma, epsilon or mu). The type of heavy chain
determines the immunoglobulin isotype (IgA, IgD, IgG, IgE, IgM, respectively). IgA
paraproteinemias are responsible for approximately 29% of cases of multiple myeloma, sixty-six
percent of which are shown to be kappa (3).
The associated increase in blood proteins seen in MM leads to increased global blood viscosity,
which is an important determinant of blood flow (4). The delay in initiating the patient's sixth
round of chemotherapy resulted in a relapse in his multiple myeloma and therefore increased his
total serum concentration of IgA kappa. At the time of his central retinal vein occlusion
laboratory testing shows that his IgA fraction was 4120 mg/dL and his kappa fraction was 5090
mg/dL. The increased serum IgA kappa lead to the patient developing hyperviscosity syndrome.
Hyperviscosity syndrome refers to the clinical sequelae of increased blood viscosity usually
resulting from increased circulating serum immunoglobulins(5). This syndrome rarely occurs in
Multiple myeloma, having an incidence of only 2-4%. Of these patients who usually have IgA
paraprotein peaks show that it typically needs to be greater than 5000 mg/dl (6). Of this small
percentage, IgA paraproteins have shown to be more commonly associated with hyperviscosity
because the tendancy of the IgA molecules to form polymers (5).
The symptoms of hyperviscosity syndrome are spontaneous mucous membrane bleeding,
retinopathy, pulmonary symptoms, and neurologic symptoms including dizziness, headache, and
stroke (7). Ophthalmic examination may reveal decreased visual acuity, dilated retinal veins,
"sausage-linked" or "boxcar segmentation" of the retinal veins, or retinal hemorrhages (8).
Symptoms usually are not seen at viscosities of less than 4 units, and the hyperviscosity
syndrome typically requires a viscosity greater than 5 units (9). Normal relative serum viscosity
ranges from 1.4-1.8 units (10). Upon laboratory testing it was shown that our patient had an
increased serum viscosity of 3.4 units. The patient displayed no other remarkable symptoms
besides the vision loss in his right eye. The literature noted that severity of the hyperviscosity
syndrome is not directly related to the serum viscosity; each patient responds differently to
hyperviscosity (11).
The patient's increase in serum viscosity incited venous stasis. The stasis evoked resistance that
damaged the endothelial cells lining the blood vessel walls culminating leaking and thrombus
formation. The overall turbulent flow interfered first with small vessels showing intraretinal
hemorrhages, followed by larger vessels in the retina. Once the larger vessels became involved
thrombi formed leading to the central retinal vein occlusion (12). Ultimately the severity of
retinopathy is dependent on the sight of occlusive event. The more posterior the occlusion
occurs manifests a milder form of retinopathy, similar to this patient's initial presentation. This
3 Michele McHale, O.D. Optometry Resident Boston Healthcare System‐West Roxbury Division Telephone: 617.323.7700 x35440 can be attributed to the availability of more collateral channels draining the inner retina (13).
Conversely, the more anterior occlusions present with greater amounts of hemorrhages and
increased ischemia (14).
During the time that the patient was being closely monitored for sequelae related to the CRVO,
chemotherapy was not re-initiated which fostered further elevation in the patients IgA Kappa to
6330 mg/dL and 6800mg/dL, respectively. This further augmentation of continued stasis
throughout the retinal vasculature caused more insidious damage. Concurrently the underlying
vein occlusion caused an increase in intravenous pressure across the capillary bed impairing
retinal arterial filling (15). This environment synergized arterial thrombosis formation leading
to the central retinal artery occlusion. It is speculated that in this case the central retinal artery
was only transiently occluded secondary to the causative nature in which it manifested. Hayreh
states that a transient non-arteritic central retinal artery occlusion (NA-CRAO) will produced the
classic fundus findings of attenuated arterioles, ring of retinal whitening and cherry red spot with
normal FFA findings (16). The increased perfusion is the reason the patient did not initial
present with an afferent pupillary defects. He also goes on to say that in patients with transient
NA-CRAO the visual outcomes can be completely different from any of the other types of
CRAO (17). The patient's outcome is solely dependent upon the duration of the transient NACRAO, which may vary from several minutes to many hours (18).
Treatment:
The patient was admitted for three sessions of urgent plasmaphoresis before transitioning to
alternative chemotherapy, Revlimid (lenalidomide). The change in therapeutic agents was incited
to reduce the stress on the renal system. The initiation of plasmaphoresis also helped reduce the
associated risk of central retinal vein occlusion and/or central retinal artery occlusion in the
fellow eye. Upon discharge from the hospital, the patient's serum plasma levels postplasmaphoresis was 1.7 mg/dl. The patient was instructed to continue with aspirin and Lovenox
(enoxaparin) as continued prophylaxis against further thrombotic events.
In a 23 case retrospective study by Brown et al, it was reported that 81 % of patients with
combined CRVO-CRAO developed rubeosis iridis (19). Retinal ischemia is thought to play a
major role in the pathogenesis of the disease process, which is probably more severe that that
seen with either entity independently. The mean time required to develop rubeosis iridis was
11.8 weeks with the median being 6 weeks. (11). Neovascular glaucoma can result in further
visual decline as well as significant morbidity in the form of eye pain. The authors suggest
aggressive laser therapy to be considered soon after the obstructive event.
The visual prognosis for the patient's right eye is poor secondary to extensively enlarge foveal
avascular zone present on FFA. The patient was issued new polycarbonate lenses due to his new
monocular status. The patient will continue to be monitored closely for neovascularization at 2-3
week intervals (20).
4 Michele McHale, O.D. Optometry Resident Boston Healthcare System‐West Roxbury Division Telephone: 617.323.7700 x35440 Conclusion:
Although hyperviscosity syndrome in multiple myeloma is rare it is important to understand the
disease process to prevent its visually devastating effects. This uncommon clinical entity which
typically has poor visual outcomes may be prevented with proper awareness. I suggest that all
multiple myeloma patients receive dilated fundus evaluation at six month intervals, I advocate
for antithrombotic prophylaxis and monitoring of each patients serum viscosity levels.
5 Michele McHale, O.D. Optometry Resident Boston Healthcare System‐West Roxbury Division Telephone: 617.323.7700 x35440 References:
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