Download Retinal Artery Occlusion Associated with Waldenstrom`s

Bilateral Central Retinal Vein Occlusion Leads to the Diagnosis of
Waldenstrom’s Macroglobulinemia
Resident: Samantha L. C. Nogales, OD
Attending: Amy Grimes, OD, FAAO
ABSTRACT:
Concurrent bilateral CRVO with no known associated underlying systemic condition at
presentation will be discussed. The diagnosis of Waldenstrom’s macrogobulinemia was
later revealed.
I. CASE HISTORY
 Patient Demographics and Chief Complaints: 74-year-old Caucasian
male, new to the clinic, presented with a complaint of gradually declining
distance and near vision OU over the past six months. Current glasses are
1.5 years old and he felts that they needed updating.
 Ocular History: Non-contributory
 Medical History: Gout, Anemia, Impaired fasting glucose, DJD/chronic
back pain, GERD, Hypertension, Asthma, Obesity
 Medications: Acetaminophen 500mg/Hydrocone 5mg 1 tab po TID;
Albuterol HFA 90mcg/dose 6.7gm inhaler po Q4H/PRN; Colchicines
0.6mg po BID; Lisinopril 40mg 1 tab po daily; Omeprazole 20mg 1 cap
po daily
 Allergies: beta-lactams antimicrobials
 Other: Reported dizziness and gait instability with overall fatigue for the
past several months
II. PERTINENT FINDINGS:
Clinical findings:
 BCVA:
OD +1.00 +1.50 x 174
20/50
OS +1.00 +1.50 x 004
20/40-1
 Pupils: (3/3) RRL (2+/2+), No APD
 Confrontations: Full to Finger Counting OD, OS
 Slit Lamp Examination: unremarkable other than mild cataract OU
 Applanation Tonometry: (Fluress/mmHg) 23/23 @ 9:35am
 Gonioscopy: OU cilliary body band 360/ no peripheral anterior
synechae, no neovascularization of the angle/ slightly
bowed approach/ 1+ pigment
 Pachemetry: OD 633/ OS 619

Dilated Fundus Exam
Vit
OD PVD
OS PVD, mild peripheral asteroid hyalosis
C/D OD 0.4 round, full pink rim, distinct margins, no edema
OS 0.4 round, full pink rim, distinct margins, no edema
Mac OD diffuse central thickening w/ scattered dot hemorrhages, mild
surrounding pigment mottling
OS diffuse central thickening w/ petalloid, surrounding pigment
mottling, few dot hemorrhages
PP
OU diffuse dot/blot hemorrhages w/ a few flame
hemorrhages in all four quadrants extending to the
periphery
Ves OU A/V 1:4, marked venous beading w/ dilated & tortuous
veins, arterial attenuation, no cotton wool spots
Peri OU no tears/holes/breaks; scattered dot/blot hemorrhages 360 in
mid periphery extending to periphery

OCT Cirrus Macular Cube:
OD
CT: 590; diffuse retinal thickening (> inferior) and low intraretinal
reflectivity consistent w/ intraretinal fluid accumulation and edema
OS
CT: 524; diffuse diffuse retinal thickening (> inferior) and low
intraretinal reflectivity consistent w/ intraretinal fluid accumulation
and edema
Physical Findings:
 Blood pressure: 136/74
 HbA1c: 6.2
 Pulse: 91
 Temperature: 98 F [36.7 C]
 Respiration: 16
Laboratory Tests:
 PROTN
 EGFR
 Potassium
 Creatinine
 Urea Nitrogen
 Calcium (serum)
 Magnesium

TOTAL PROTIEN



WBC
RBC
Hemoglobin
11.6 High
40 Low
5.8 High
1.7 High
60 High
11.1 High
3.1 High
Range 6.0 – 8.0
Range >= 60
Range 3.5 – 5.5
Range 0.7 – 1.4
Range 5 – 20
Range 8.4 – 10.2
Range 1.5 – 2.6
Units g/dL
11.4 HIGH
Range 6.0 – 8.0
Units g/Dl
3.3 Low
1.99 Low
7.4 Low
Range 4.5 – 11.0
Range 4.7 – 6.1
Range 14 – 16
Units mEq/L
Units mg/dL
Units mg/dL
Units mg/dL
Units mg/Dl
Units #x1000/Ul
Units million/uL
Units g/dL





Hematocrit
MCV
MCH
Platelets
Neutrophil




Alpah-1 Globulin
Beta Globulin
Gamma Globulin
M – Protein


21.0 Low
105.6 High
37.5 High
72 Low
70.3 High
Range 40 – 52
Range 80 – 99
Range 27 – 31
Range 150 – 400
Range 36 – 68
Units %
Units fL
Units pg
Units #x1000/uL
Units %
Range 0.3 – 0.5
Range 0.6 – 1.1
Range 0.7 – 1.6
Units g/dL
Units g/dL
Units g/dL
Units g/dL
SERUM VISCOSITY >4.6 High
Range 1.1- 2.0
Units mPa.s
IgM
Range 40 - 250
Units mg/dL
0.2 Low
0.5 Low
7.6 High
7.0 High
2218 High
Other Tests:
 Bone Marrow Biopsy: Lymphoplasmacytic lymphoma/ Waldenstrom’s
Macroglobulinemia
 IVFA was scheduled but the patient declined to have the test preformed
III. DIFFERENTIAL DIAGNOSIS
Leading ocular diagnosis:
 Bilateral Non-ischemic CRVO: Referral to PCP for systemic workup to
r/o hypervicosity syndrome
Other ocular diagnosis:
 Concurrent venous stasis retinopathy OU
 Borderline Ocular HTN with thick CCT
 Mild Cataract OU
Leading medical diagnosis:
 Waldenstrom’s Macroglobulinemia
Other differential medical diagnosis:
 IgM monoclonal gammopathy
 Lymphoplasmacytic lymphoma
 Small lymphocytic lymphoma
IV. DIAGNOSIS AND DISCUSSION
Diagnosis: Bilateral central retinal vein occlusion w/ chronic macular edema OU
secondary to Waldenstrom’s Macroglobulinemia
Waldenstrom’s Macroglobulinemia (WM) is hemotologic cancer
characterized by a combination of bone marrow infiltration by
lymphoplasmacytic lymphoma and IgM monoclonal gammopathy. Incidence of
WM is approximately three per million people per year1,2 and accounts for
approximately 2% of hematolitic cancers.3 WM is more common in Caucasians
with African-Americans and patients of Mexican decent accounting for about five
percent of all cases.4,5 Age of onset usually varies between 63 and 68 years with
55% or greater being males.4,6 The etiology of WM is unknown but some studies
have shown a familial predisposition present in approximately 20 percent of
cases.7-12 The most common complication related to WM is hyperviscosity
syndrome and is seen in approximately 30 percent of patients.13 Hyperviscosity
syndrome usually always occurs with in patients who have under lying lymphoma
and is caused high levels of circulating IgM.3 Symptoms of hyperviscosity include
fatigue, dizziness, vertigo, ataxia, blurred vision, diplopia, tinnitus, sudden
deafness, and easy bleeding of mucus membranes. In approximately 34 percent of
cases hyperviscosity causes funduscopic abnormalities including dilated, tortuous
retinal veins with a “sausage link” appearance, retinal hemorrhages, exudates,
papilledema,14 central retinal vein occlusion,15-17 and serous macular
detachments.18,19 Other complications from WM include cryoglobulinemia, cold
agglutinin anemia, neuropathy, glomerular disease, amyloidosis, and tumor
infiltration in to bone marrow, lymph nodes and the spleen.20,21
V. TREATMENT AND MANAGEMENT
This patient was admitted to VA hospital for symptoms of hyperviscosity
and was treated with 2 cylces of plasmapheresis, as well as a transfusion of 8 units
of pRBC’s for symptoms of anemia. At the time of admission, the patient was
also treated for acute renal failure likely secondary to paraproteinemia, with
Kayexalate and was also given IV fluids. The patient was then discharged to the
palliative care unit and was started on cycle 1 of chemotherapy with Rituximab
375 mg/m2 on day 1 plus Cladribine 0.12 mg/kg for five days. Fluconazole
200mg po daily, Acyclovir 400mg po BID, and Dapsone 100mg po daily were
given for infection prophylaxis.
Chemotherapy was well tolerated but on the fifth day of treatment the
patient developed some mild lightheadedness, hot flashes, and nausea. A degree
of myelosuppression was noted after treatment but not more than would expected
with the underlying disease and chemotherapy treatment (cladribine is nucleoside
analog and can result in prolonged myelosuppression). IgM was markedly
decreased from 7 g/dL to 3.6 g/dL and serum viscosity was stable at 1.4 which
was also decreased from >4.6. After a few more days the patient was discharged
and scheduled to return in 3 weeks for Cycle 2 of chemotherapy. Four cycles of
chemotherapy are anticipated with a seven-day inpatient stay for each cycle. An
optometry follow up with dilated fundus exam and repeat Cirrus macular cube is
to be scheduled during Cycle 3 of chemotherapy. The patient was advised to
continue prophylactic infection control with the above named medications for a
six-month minimum and a SPEP, serum viscosity, and beta-2 microglobulin were
ordered to be taken prior to the next cycle of chemotherapy.
Treatment for Waldenstrom’s Macroglobulinemia is meant to improve
quality and duration of life while minimizing side effects. Among the treatments
that are available there is not a specific treatment that is considered a first-line
therapeutic agent for WM so choices must be made on individual basis.22 The
main treatments for WM include alkylating agents (chlorambucil,
cyclophosphamide, melphalan), nucleoside analogs (cladribine, fludarabine), and
monoclonal antibody (rituximab [anti-CD20]). 23 Studies have shown a response
rate for Cladribine to range from 44% to 90%. 24,25 In patients with IgM
autoantibody-related neuropathies, high dose Rituximab has been shown to
improve nerve conduction velocities and decrease anti-MAG antibody titers.26,27
Fifty four percent of patients who start rituximab have shown increases in IgM
titers that may persist for up to four months. However, this does not indicate
treatment failure but does necessitate the use of plasmapheresis to reduce
hyperviscosity.28,29 Plasmapheresis has been shown to be effective in the removal
of circulating IgM and is indicated patients with hyperviscosity symptoms. 23,30
WM patients with retinal vein occlusions may also experience an improvement in
vision after plasmapheresis16 and it may be effective in resolving neurosensory
retinal detachments. 18 Combination therapy of nucleoside analogs (cladribine)
and monoclonal antibodies (rituximab) have been shown to increase response
rates and is considered a reasonable choice for primary treatment of WM. 31,32
Nucleoside analogs combined with alkylating agents have also been shown to be
an effective treatment. 31,32
VI. CONCLUSION
Hyperviscosity should be considered in patients presenting with bilateral CRVO.
Referral for additional testing including, serum electrophoresis and CBC, should
always be indicated in these cases.
REFERENCES
1. Herrington LJ, Weiss NS. Incidence of Waldenstrom’s macroglobulinemia.
Blood. 1993; 82: 3148-3150.
2. Groves FD, Travis LB, Devesa SS, Ries LA, Fraumeni JF Jr. Waldenstrom’s
macroglobulinemia: incidence patterns in the United States, 1988-1994. Cancer.
1998; 82: 1078-1081.
3. Dimopoulos MA, Alexanian R. Clinical Review Article: Waldenstrom’s
macroglobulinemia. Blood. Vol 83, No 6(March 15), 1994: pp 1452-1459
4. Benjamin M, Reddy S, Brawley OW. Myeloma and race: a review of the
literature. Cancer Metastasis Rev. 2003;22:87-93.
5. Fonseca R, Hayman S. Waldenstrom macroglobulinemia. Br J Haematol 2007;
138: 700.
6. Dimopoulos MA, Panayiotidis P, Moulopoulos LA, Sfikakis P, Dalakas M.
Waldenstrom’s macroglobulinemia: clinical features, complications, and
management. J Clin Oncol. 2000;18:214-226.
7. Renier G, Ifrah N, Chevailler A, et al. Four brothers with Waldenstrom’s
macroglobulinemia. Cancer 1989; 64: 1554.
8. McMaster ML, Csako G, Giambarresi TR, et al. Long-term evaluation of three
multiple-case Waldenstrom macroglobulinemia families. Clin Cancer Res 2007;
13:5063.
9. McMaster ML, Goldin LR, Bai Y, et al. Genomewide linkage screen for
Waldenstrom macroglobulinemia susceptibility loci in high-risk families. Am J
Hum Genet 2006; 79: 695.
10. Treon SP, Hunter ZR, Aggarwal A, et al. Characterization of familial
Waldenstrom’s macroglobulinemia. Ann Oncol 2006; 17:488.
11. Altieri A, Bermejo JL, Hemminki K. Familial aggregation of lymphoplasmacytic
lymphoma with non-Hodgkin lymphoma and other neoplasms. Leukemia 2005;
19: 2342.
12. Kristinsson SY, Bjorkolm M, Goldin LR, et al. Risk of lymphoproliferative
disorders among first-degree relatives of lymphoplasmacytic
lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in
Sweden. Blood 2008; 112: 3052.
13. Garcia-Sanz R, Montoto S, Torrequebrada A, et al. Waldenstrom
macroglobulinemia: presenting features and outcome in a series with 217 cases.
Br J Haematol 2001; 115: 575.
14. Fahey JL, Barth WF, Solomon A: Serum hyperviscosity syndrome. JAMA 192:
120, 1965.
15. Chanana B, Gupta N, Azad RV. Case report: Bilateral simultaneous central retinal
vein occlusion in Waldenstrom’s macroglobulinemia. Optometry 2009; 80: 350353.
16. Alexander P, Flanagan D, Rege K, Foss A and Hingorani M. Bilateral
simultaneous central retinal vein occlusion secondary to hyperviscosity in
Waldenstrom’s macroglobulinemia. Eye. 2008; 22: 1089-1092.
17. Fadilah SAW, Muhaya M, Azlin I. Irreversible Visual Loss and Optic Nerve
Dysfunction Associated with Central Retinal Vein Occlusion in Waldenstrom
macroglobulinemia. Med J Malaysia. Vol 62; No 4:October 2007.
18. Pilon AF, Rhee PS, Messner LV. Bilateral, Persistent Serous Macular
Detachments with Waldenstrom’s macroglobulinemia. Optometry and Vision
Science. Vol 82, No 7; July 2005.
19. Quhill F, Khan I, Rashid A. Bilateral serous macular detachments in
Waldenstrom’s macroglobulinemia. Postgrad Med J 2009; Vol 85: No 1005.
20. Kraus MD. Lymphoplasmacytic Lymphoma/Waldenstrom macroglobulinemia.
Am J Clin Pathol 2001; 116:799-801.
21. Mansoor A, Medeiros LJ, Weber DM, Alexanian R, et al. Cytogenic findings in
lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia. Am J Pathol
2001; 116: 543-549.
22. Treon SP, Gertz MA, Dimopoulos M, et al. Update on treatment
recommendations from Third International Workshop on Waldenstrom’s
macroglobulinemia. Blood. 2006; 107: 3442-3446.
23. Vijay A, Gertz MA. Review in translational hematology: Waldenstrom
macroglobulinemia. Blood. June 2007; Vol 109, No 12.
24. Delannoy A, Van Den Neste E, Michaux JL, Bosly A, Ferrant A. Cladribine for
Waldenstrom’s macroglobulinemia. Br J Haematol. 1999; 104: 933-934.
25. Fridrik MA, Jager G, Baldinger C, Krieger O, Chott A, Bettelheim P. First-line
treatment of Waldenstrom’s disease with cladribine. Arbeitsgemeinschaft
Medikamentose Tumortherapie. Ann Hematol. 1997; 74:7-10.
26. Gertz MA, Anagnostopoulos A, Anderson K, et al. Treatment recommendations
in Waldenstrom;s macroglobulinemia: consensus panel recommendations from
the Second International Workshop on Waldenstrom’s Macroglobulinemia. Semin
Oncol. 2003; 30: 121-126.
27. Renaud S, Fuhr P, Gregor M, et al. High-dose rituximab and anti-MAGassociated polyneuropathy. Neurology. 2006;66:742-744.
28. Ghobrial IM, Fonseca R, Greipp PR, et al. Initial immunoglobulin M ‘flare’ after
rituximab therapy in patients diagnosed with Waldenstrom macroglobulinemia: an
Eastern Cooperative Oncology Group Study. Cancer. 2004; 101: 2593-2598.
29. Treon Sp, Branagan AR, Hunter Z, Santos D, Tournhilac O, Anderson KC.
Paradoxical increases ins erum IgM and viscosity levels following rituximab in
Waldenstrom’s macroglobulinemia. Ann Oncol, 2004; 15: 1481-1483.
30. Patel TC, Moore SB, Pineda AA, Witzig TE. Role of Plasmapheresis in
Thrombocytopenic Purpura Associated with Waldenstrom’s macroglobulinemia.
Mayo Clin Proc 1996; 71: 597-600
31. Tedesh A, Alamos SM, Ricci F, Greco A, Morra E. Fludarabine-based
combination therapies for Waldenstrom’s macroglobulinemia. Clin Lymphoma
Myeloma: 2009 Mar; 9(1):67-70.
32. Dimopoulos MA, Gertz MA, Kastritis E, et al. Update on treatment
recommendations from the Fourth International Workshop on Waldenstrom’s
macroglobulinemia. J Clin Oncol. 2009 Jan 1; 27(1): 120-6.