Ophthalmology – Leukemia / Blood Dyscrasias

Basics

Description

Ocular involvement in leukemia and other blood dyscrasias can occur through several different mechanisms:

• Direct infiltration by malignant leukemic cells
• Secondary hematologic abnormalities, especially anemia and thrombocytopenia
• Hyperviscosity and vascular occlusion
• Opportunistic infection caused by immunosuppression
• Complications of chemotherapy, radiotherapy, or other treatment

Intraocular leukemia refers to direct accumulation of leukemic cells within ocular tissues.

Potential sites include:

• Choroid — most common site of direct infiltration
• Retina
• Optic nerve
• Iris
• Ciliary body
• Vitreous
• Anterior chamber

However, leukemic retinopathy caused by hematologic abnormalities is considerably more common than true leukemic infiltration.

Epidemiology

Ocular abnormalities are relatively common in patients with leukemia, particularly in acute leukemia.

Important points:

• Ocular findings are more common in acute than chronic leukemia.
• Many patients with ocular findings are asymptomatic.
• Adults appear to develop ocular manifestations more frequently than children.
• Retinal hemorrhages are among the most frequent findings.
• Only a minority of ocular lesions represent direct malignant infiltration.

Because ocular disease may be clinically silent, ophthalmic examination can reveal abnormalities even in patients without visual complaints.

Age Considerations

Children

Acute lymphoblastic leukemia (ALL) is the predominant childhood leukemia.

Ocular involvement can result from:

• Leukemic infiltration
• Anemia
• Thrombocytopenia
• Hyperleukocytosis
• Opportunistic infection
• Treatment-related complications

Adults

Acute myeloid leukemia (AML) is the predominant acute leukemia in adults.

Chronic leukemias occur more commonly in older adults and may initially follow a relatively indolent course.

Risk Factors for Leukemia

Important associations and risk factors include:

• Previous chemotherapy
• Previous radiation exposure
• Myelodysplastic syndromes
• Certain genetic disorders, including Down syndrome
• Benzene exposure
• Cigarette smoking
• Family history of leukemia

Pathophysiology of Ocular Disease

There are four major mechanisms.

1. Direct Leukemic Infiltration

Malignant leukocytes directly infiltrate ocular structures.

The choroid is the most commonly infiltrated ocular tissue histopathologically because of its rich vascular supply.

Other sites include:

• Retina
• Optic nerve
• Iris
• Ciliary body
• Vitreous
• Anterior chamber

2. Leukemic Retinopathy

Leukemic retinopathy usually does not represent direct invasion of the retina by malignant cells.

Instead, it commonly results from:

• Anemia
• Thrombocytopenia
• Abnormal coagulation
• Hyperviscosity
• Vascular endothelial injury

This produces retinal hemorrhage and ischemic changes.

3. Hyperviscosity Syndrome

Hyperviscosity results from abnormally increased blood viscosity.

It can occur with:

• Marked leukocytosis in leukemia
• Polycythemia vera
• Waldenström macroglobulinemia
• Multiple myeloma and other monoclonal gammopathies

The resulting sluggish retinal circulation produces a venous stasis retinopathy.

4. Opportunistic Infection

Both leukemia itself and its treatment can produce profound immunosuppression.

Important ocular infections include:

• CMV retinitis
• Herpetic retinal necrosis
• Ocular toxoplasmosis
• Candida and other fungal infections

Distinguishing infection from direct leukemic infiltration can sometimes be difficult but is crucial because treatment is very different.

Diagnosis

History

Patients may be:

• Completely asymptomatic
• Known to have leukemia
• Presenting with ocular manifestations before systemic leukemia has been recognized

Ocular symptoms can include:

• Blurred or decreased vision
• Floaters
• Visual field abnormalities
• Photopsias

Systemic clues include:

• Fever
• Persistent fatigue
• Weight loss
• Recurrent infections
• Easy bruising or bleeding
• Pallor
• Dyspnea
• Lymphadenopathy

These manifestations reflect the major hematologic consequences of leukemia:

• Anemia → pallor, fatigue, dyspnea
• Thrombocytopenia → bleeding
• Abnormal leukocytes → infection and immune dysfunction

Ocular Manifestations

Leukemic Retinopathy

This is considerably more common than direct retinal leukemic infiltration.

Retinal Hemorrhages

Retinal hemorrhage is the most common ocular finding.

Hemorrhages are often:

• Bilateral
• Multifocal

They may occur at different retinal levels:

• Preretinal
• Intraretinal
• Subretinal

Severe hemorrhage can break through into the vitreous.

Roth Spots

Large retinal hemorrhages may contain white centers, producing the classic appearance of Roth spots.

The white centers can represent:

• Fibrin-platelet aggregates
• Ischemic material
• In some cases, leukemic cellular infiltration

Roth spots are not specific for leukemia and occur in several systemic diseases.

Cotton-Wool Spots

Cotton-wool spots may occur because of retinal microvascular ischemia.

They represent focal disruption of axoplasmic flow within the retinal nerve fiber layer.

Direct Retinal Leukemic Infiltration

A characteristic infiltrative lesion can appear as a:

• Fuzzy
• Flat
• White retinal lesion

It may be associated with:

• Retinal hemorrhage
• Overlying vitreous cells

Lesions can be:

• Unifocal or multifocal
• Unilateral or bilateral

Choroidal Infiltration

The choroid is the most common site of direct ocular leukemic infiltration.

Choroidal involvement may be:

• Localized
• Diffuse

It can produce:

• Choroidal thickening
• Retinal pigment epithelial abnormalities
• Serous retinal detachment
• Visual loss

Optic Nerve Infiltration

Leukemia may infiltrate the optic nerve.

Possible findings include:

• Optic disc swelling
• Disc infiltration
• Reduced visual acuity
• Color vision impairment
• Relative afferent pupillary defect when asymmetric
• Visual field defects

Optic nerve infiltration is particularly important because it may represent central nervous system leukemic involvement and requires urgent systemic evaluation.

Anterior Segment Infiltration

Direct leukemic involvement can affect the:

• Iris
• Ciliary body
• Anterior chamber

Possible manifestations include:

• Iris thickening or nodules
• Anterior chamber cells
• Secondary glaucoma
• Hyphema
• Pseudohypopyon

Pseudohypopyon

A leukemic pseudohypopyon represents accumulation of malignant cells in the anterior chamber rather than ordinary inflammatory leukocytes.

It should raise suspicion for direct leukemic infiltration, particularly in a patient with known leukemia.

Vitreous Involvement

Direct infiltration may produce:

• Vitreous cells
• Vitreous haze

However, vitreous inflammation in an immunocompromised patient also raises concern for opportunistic infection.

Hyperviscosity Retinopathy

Typical findings include:

• Dilated and tortuous retinal veins
• Multiple retinal hemorrhages
• Microaneurysms
• Retinal edema
• Intraretinal or subretinal fluid
• Peripheral retinal nonperfusion
• Neovascularization in severe disease

The appearance can resemble a mild central retinal vein occlusion, particularly when bilateral.

Bilateral venous stasis-type retinopathy should prompt consideration of a systemic hyperviscosity disorder.

Chronic Myeloid Leukemia

Patients with chronic myeloid leukemia can develop:

• Peripheral retinal capillary nonperfusion
• Microaneurysms
• Retinal hemorrhage
• Retinal neovascularization

Severe hyperleukocytosis can markedly disturb retinal microcirculation.

Opportunistic Ocular Infections

CMV Retinitis

CMV is an important infectious retinitis in severely immunocompromised patients.

Other Important Infections

Consider:

• Toxoplasmosis
• Candida
• Cryptococcus
• Nocardia
• Herpes-family viral retinitis

Infection can closely mimic malignant infiltration.

Diagnostic Tests

Hematologic Evaluation

When leukemia is suspected, evaluation should be performed together with hematology/oncology.

Investigations can include:

• Complete blood count with differential
• Peripheral blood smear
• Bone marrow aspiration and/or biopsy
• Appropriate systemic staging

Depending on the clinical circumstances, additional testing may include:

• Lumbar puncture with CSF analysis
• Coagulation studies
• Serum protein electrophoresis
• Other tests for hyperviscosity disorders

Ocular Imaging

Depending on the findings, useful studies can include:

• Fundus photography
• Optical coherence tomography (OCT)
• Fluorescein angiography
• B-scan ultrasonography

Fluorescein angiography can help demonstrate:

• Capillary nonperfusion
• Microaneurysms
• Neovascularization
• Vascular leakage

Neuroimaging

If optic nerve infiltration is suspected, obtain appropriate neuroimaging, generally:

• MRI of the orbits
• MRI of the brain

Evaluation for CNS leukemia may also be necessary.

Diagnostic Vitrectomy or Biopsy

When the diagnosis remains uncertain, particularly when distinguishing malignant infiltration from opportunistic infection, diagnostic procedures may include:

• Aqueous sampling
• Vitreous sampling
• Diagnostic pars plana vitrectomy
• Biopsy in selected lesions

Samples can undergo:

• Cytology
• Flow cytometry
• Microbiologic testing
• Molecular testing as appropriate

Differential Diagnosis

Important differentials include:

Infectious

• CMV retinitis
• Candida
• Toxoplasmosis
• Nocardia
• Cryptococcus
• Syphilis
• Other opportunistic infections

Noninfectious

• Primary vitreoretinal lymphoma
• Sarcoidosis
• Intermediate uveitis
• Other causes of retinal hemorrhage
• Central retinal vein occlusion
• Other hyperviscosity syndromes

Treatment

Systemic Leukemia Treatment

The primary treatment is directed at the underlying hematologic malignancy.

Management should be performed by a hematologist/oncologist and may include:

• Systemic chemotherapy
• Targeted therapy
• Immunotherapy
• Hematopoietic stem-cell transplantation

The exact treatment depends on the type and molecular characteristics of the leukemia.

Most secondary ocular manifestations improve when the underlying leukemia and hematologic abnormalities are controlled.

Treatment of Direct Ocular Infiltration

Direct leukemic infiltrates frequently respond to systemic treatment.

If ocular infiltration persists despite adequate systemic therapy, additional treatment may be considered, including:

• Local ocular radiotherapy in selected cases
• Other local or CNS-directed therapy according to the site of involvement and leukemia subtype

Treatment of Leukemic Retinopathy

Treatment is primarily correction of the underlying systemic abnormalities.

This may involve:

• Treatment of leukemia
• Correction of severe anemia
• Management of thrombocytopenia
• Blood product support when clinically indicated

Hemorrhagic retinopathy can improve substantially once the hematologic abnormalities resolve.

Hyperviscosity Syndrome

The underlying hematologic disorder must be treated urgently when hyperviscosity is clinically significant.

Depending on the cause, emergency therapy can include:

• Leukapheresis for selected cases of severe symptomatic hyperleukocytosis
• Plasma exchange for certain paraproteinemias such as Waldenström macroglobulinemia

Definitive systemic therapy is still required.

Retinal Neovascularization

When significant peripheral nonperfusion produces retinal neovascularization, panretinal photocoagulation may be indicated in selected cases.

Opportunistic Infection

Ocular infection requires organism-specific antimicrobial treatment.

This is particularly important because increasing immunosuppression for presumed leukemic infiltration could worsen an unrecognized infection.

Follow-Up

Patients with leukemia require coordinated management between:

• Hematology/oncology
• Ophthalmology

Ophthalmic monitoring should assess:

• Visual acuity
• Anterior segment
• IOP
• Vitreous
• Retina and macula
• Optic nerve

More frequent follow-up is warranted with:

• Direct leukemic infiltration
• Significant retinal hemorrhage
• Hyperviscosity retinopathy
• Optic nerve involvement
• Opportunistic infection

Prognosis

Visual prognosis depends on the mechanism of ocular involvement.

Hemorrhagic leukemic retinopathy may improve substantially when anemia and thrombocytopenia are corrected and the leukemia is controlled.

Direct leukemic infiltration generally indicates more significant systemic disease and has historically been associated with a poorer prognosis.

Ocular findings can therefore provide important information about both visual and systemic disease severity.

Key Clinical Pearls

• Retinal hemorrhage is the most common ocular manifestation of leukemia.
• Most leukemic retinopathy is caused by anemia and thrombocytopenia rather than direct malignant infiltration.
• The choroid is the most common site of direct leukemic ocular infiltration histopathologically.
• White-centered retinal hemorrhages (Roth spots) are suggestive but not specific for leukemia.
• Bilateral venous stasis retinopathy should raise suspicion for hyperviscosity.
• Optic nerve infiltration is an ophthalmic and oncologic concern because it may indicate CNS involvement.
• In an immunocompromised leukemia patient with a new retinal or vitreous lesion, always distinguish leukemic infiltration from opportunistic infection.