TITLE: A Tale of White Spots
ABSTRACT: This case documents a progressive retinal micro-angiopathy caused by systemic
methotrexate toxicity induced pancytopenia. Prompt work up and communication with the prescribing
physician is imperative to save lives.
I.
Case History
a. 52 y/o White female
b. No complaints – routine exam
c. Last eye exam: 1 year prior – glasses
d. Systemic history/meds: 12.5 mg/week oral methotrexate for rheumatoid arthritis x
11 years; 1 mg/d folic acid supplementation
e. Denies smoking, drinking or drug use
II.
Pertinent Findings
a. Clinical
1. Best corrected VA 20/20 O.D., O.S.
2. Pupils, EOM’s, Confrontation VF’s - WNL OD, OS
3. Slit lamp OU – normal findings
4. Goldmann IOP: 14mm Hg OD, 15 mmHg OS
5. Blood pressure: 110/60 mmHg
6. DFE:
1. Single cotton wool spot O.S.
2. Healthy optic nerves
7. Denies weakness, fatigue, sudden weight loss, paresis or paresthesias.
Denies risk for sexually transmitted diseases
b. Contacted rheumatologist and patient referred for laboratory work-up
c. Initial laboratory work-up ordered
1. CBC with differential, ESR, CRP, RF, FBS, HgBA1c, HIV antibody, lipid
panel, lupus panel.
d. Ocular Follow-up 2 weeks later
1. No visual complaints
2. Patient did NOT get blood work yet (missed appointment)
3. BCVA 20/20 O.D., O.S.
4. Entrance/anterior seg findings all normal
5. DFE:
1. Multiple cotton wool spots both eyes
2. Healthy optic nerves O.U.
6. Blood work obtained same day and results (to be presented after DDX)
1. White blood cell, red blood cell, hemoglobin, hematocrit and
platelet counts at critically low levels
2. Neutrophils, lymphocytes and monocytes – low
3. ESR – critically high level
4. CRP - high
5. HIV antibody negative
6. Glucose, HgBA1c, lipid panel, lupus panel – normal/negative
7. Lab contacted myself and rheumatologist same day to admit patient to
hospital due to critical results of blood cells. Patient was admitted the
same day and had hematologist consult.
e. Further lab tests (ordered by rheumatologist)
1. Liver panel – normal
III.
Differential Diagnosis
a.
b.
c.
d.
IV.
Blood dyscrasia retinopathy
Diabetic retinopathy
HIV retinopathy
Lupus/autoimmune retinopathy
Diagnosis and Discussion:
a. Diagnosis:
1. Progressive, retinal micro-angiopathy secondary to pancytopenia from
systemic methotrexate toxicity
b. Rheumatoid Arthritis (RA)
1. Chronic, progressive autoimmune inflammatory disorder
2. Primarily results in joint destruction but may also affect other organs.
3. Current approach to RA therapy = early, more aggressive treatment with
disease-modifying anti-rheumatic drugs such as methotrexate
c. Methotrexate
1. Folic acid antagonist used in treatment of variety of inflammatory
disorders and cancers
2. Low dose (5-30mg/week) – reduces joint damage by decreasing disease
activity and enhances effects of other therapies – has become treatment of
choice for many RA patients.
3. Side effects:
1. Mild: gastro-intestinal irritation, alopecia, skin rash, stomatitis oral
ulcers
2. Severe/life threatening: pancytopenia, myelosuppression,
hepatotoxicity and pulmonary complications
4. Because of potential life-threatening complications associated with
methotrexate therapy, patients are monitored with blood work every 1-3
months by their prescribing physician. (this patient had actually missed
her most recent follow-up with her rheumatologist, but had never had
abnormal blood work in past 11 years of therapy prior to this episode).
d. Pancytopenia
1. Potentially fatal complication
2. Reduction of all 3 cellular components found in blood: white blood cells,
red blood cells, platelets
3. ~1-1.5% patients on low dose methotrexate
4. Sudden without warning signs
5. Most within 10 days of starting therapy – late reactions have been reported
6. Mechanism unknown
7. Associations: bone marrow suppression especially in kidney insufficiency,
hypoalbuminemia, low folate levels, concomitant infections, use of more
than 5 medications and lack of folate supplementation (this patient had
none of these)
e. Ocular effects in methotrexate therapy
1. RARE
2. Usually in patients receiving high dose, intravenous therapy (30250mg/kg)
3. Periorbital edema, ocular pain, blurred vision, photophobia, conjunctivitis,
blepharitis and decreased reflex tear secretion
4. Isolated reports: optic neuropathy and internuclear ophthalmoplegia,
macular edema, epiphora, lacrimal duct stenosis and optic nerve
demyelination; but, concomitant other anti-cancer medications were also
used.
f. Cotton wool spots
1. Acute, focal, inner-retinal ischemia caused by occlusion of pre-arteriolar
capillary network in retina
2. Transient, non-specific finding
3. Common in diabetes, hypertension and vein occlusions
4. When these causes are excluded, serious systemic disease can be found in
95% of cases.
5. Additional causes include blood dyscrasia, autoimmune etiologies, and
other immunosuppressant medications (interferon alpha and beta)
6. In this case, cotton wool spots could be due to immunologic or
hematologic disorders.
1. Immunologic less likely: rarely, systemic vasculitis in RA could
result in vaso-occlusive disease; most cases described are with
anterior ischemic optic neuropathy.
2. Hematologic most likely: may be linked to decreased hemoglobin
and hematocrit levels < 50% of normal
7. Although RA can’t be ruled out as the cause of cotton wool spots, the
progressive nature of the ischemic lesions, as well as their resolution with
decreased methotrexate therapy, makes it unlikely.
8. Cotton wool spots in this case most likely a consequence of blood
dyscrasia (pancytopenia), which was induced by methotrexate.
V.
Treatment/Management
a. Tapering of methotrexate by hematologist and rheumatologist to 5mg/wk over 3
months resulted in normalized blood work and resolution of cotton wool spots.
VI.
Conclusion
a. Methotrexate induced pancytopenia can be fatal
b. Patients taking methotrexate and presenting with ischemic retinal findings warrant
investigation for pancytopenia
c. Thorough history, prompt work-up and communication with the prescribing
physician may be life saving.
VII.
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