Leukemia is a malignant tumor caused by clonal proliferation of white blood cells or higher hematopoietic stem cells, leading to systemic lesions due to cell infiltration. Intraocular infiltration includes direct infiltration by leukemia cells and indirect conditions caused by blood changes such as anemia, hypoxia, thrombotic thrombocytopenia, increased blood viscosity, and immunosuppression.
Leukemia is clinically classified into non-lymphocytic and lymphocytic types, each further divided into acute and chronic forms. Ocular findings are more common in acute cases. Leukemic retinopathy occurs in about 70% of all leukemia patients, affecting both acute and chronic leukemia, but is especially frequent during relapse of acute leukemia. Fundus findings serve as diagnostic indicators reflecting leukemia activity; if organ relapse is suspected, bone marrow relapse is predicted within weeks to months, necessitating re-evaluation by hematology 3).
Intraocular infiltration is classified into the following five categories.
| Category | Typical Findings | Characteristics |
|---|---|---|
| Leukemic retinopathy | Roth spots, hemorrhages, venous dilation | Most common, about 70% of all patients |
| Anterior segment infiltration | Pseudohypopyon, corkscrew vessels | Uveitis masquerade syndrome |
| Optic nerve infiltration | Papilledema, decreased vision | Common in pediatric ALL, requires urgent management |
| Orbital infiltration | Proptosis, motility disturbance | Associated with eye pain |
| GVHD-related | Dry eye, corneal disorder | Long-term post-transplant management required |
Intraocular infiltration associated with adult T-cell leukemia/lymphoma (ATL) is classified as an HTLV-1-related ocular complication and is also mentioned in the uveitis clinical practice guidelines7).
Yes. There have been multiple reports of cases where fundus findings (retinal hemorrhage, Roth spots) appeared as the initial sign of leukemia3). For unexplained bilateral retinal hemorrhage or pseudohypopyon, referral to hematology is necessary. Collaboration between ophthalmology and hematology prevents delays in diagnosis.
Many patients are asymptomatic in the early stages. Symptoms appear in the following situations.
Primary lesions (direct infiltration)
Changes due to direct infiltration of leukemic cells into the retina and vitreous.
Includes retinal infiltrates, vitreous cell infiltration, and optic nerve infiltration. Can occur even with relatively mild blood abnormalities.
In the anterior segment, pseudohypopyon, corkscrew vessels, limbal infiltration, and secondary glaucoma may be observed.
Secondary lesions (blood changes)
Changes due to blood abnormalities such as anemia, thrombocytopenia, and hyperviscosity.
Severe anemia with Hb ≤4.6 g/dL, thrombocytopenia with Plt ≤8,000/μL3)4), and extreme leukocytosis with WBC ≥200,000/μL are major risk factors1).
Roth spots, multiple hemorrhages, venous dilation, and cotton-wool spots occur.
Infiltration of leukemic cells around retinal blood vessels leads to vascular occlusion, resulting in the following findings.
| Finding | Characteristic |
|---|---|
| Venous dilation and tortuosity (sausage-like changes) | Most common. Accompanied by caliber variation |
| Roth spots | Retinal hemorrhage with a white center. Characteristic finding |
| Retinal hemorrhage (multilayered) | Flame-shaped to dome-shaped |
| Cotton-wool spots | Capillary occlusion. Suggests poor prognosis |
| Vascular sheathing | Infiltration of vessel walls |
| Elevated lesions | Due to leukemic cell infiltration |
| Neovascularization | Appears with significant ischemia |
In extreme leukocytosis with WBC ≥200,000/μL, retinal peripheral ischemia and neovascularization may be observed 1). Cases presenting with a CRVO-like appearance have also been reported 2).
Optic nerve infiltration occurs in up to 18% of acute leukemia and up to 16% of chronic leukemia 6). A review of 92 cases found that acute lymphoblastic leukemia (ALL) was the most common, followed by CLL, AML, and CML 6). Direct cellular infiltration of the optic nerve is particularly common in pediatric acute leukemia (ALL).
The optic nerve is a “sanctuary site” protected by the blood-brain barrier (BBB) and blood-retinal barrier (BRB), so optic nerve lesions may persist or progress even when systemic chemotherapy is effective. Even patients who have received prophylactic intrathecal chemotherapy still have a risk of relapse and LON.
Three mechanisms are involved in papilledema: (1) congestive optic disc due to increased intracranial pressure, (2) circulatory disturbance due to direct infiltration of leukemia cells, and (3) ischemic changes due to increased blood viscosity. Infiltration on the optic disc side of the lamina cribrosa may result in normal to mildly decreased visual acuity, while infiltration on the central side of the lamina cribrosa presents with severe visual acuity loss 7).
Orbital infiltration and retrobulbar hemorrhage cause eyelid edema, ptosis, proptosis, ocular movement disorders, and eye pain. Rarely, the lacrimal gland is also infiltrated.
When hemorrhage or edema extends to the macula, central vision decreases rapidly. If peripheral lesions are predominant, subjective symptoms may be scarce. When optic disc edema is present, the central visual field may become dark (central scotoma). If pseudohypopyon or proptosis occurs, eye pain and photophobia may appear.
The development of intraocular infiltration in leukemia involves multiple hematological abnormalities. The frequency and pattern of ocular complications vary depending on the type of leukemia.
| Leukemia subtype | Optic nerve infiltration frequency | Characteristics of ocular complications |
|---|---|---|
| Acute lymphoblastic leukemia (ALL) | Most common6) | Common in children, characteristic optic nerve infiltration, CNS recurrence is a concern |
| Chronic lymphocytic leukemia (CLL) | Second most common6) | Slowly progressive. Intraocular infiltration is rare |
| Acute myeloid leukemia (AML) | 3rd most common6) | May cause orbital granulocytic sarcoma |
| Chronic myeloid leukemia (CML) | 4th most common6) | Cases of leukostasis retinopathy reported2) |
Major risk factors:
Ocular findings can serve as indicators for initiating systemic treatment and prognosis. The diagnostic role of ophthalmology is important; if organ recurrence is suspected, bone marrow recurrence is predicted within weeks to months, requiring re-evaluation by hematology.
If optic nerve infiltration (LON) is suspected, thorough and urgent ophthalmologic and oncologic evaluation is necessary.
If bilateral multiple retinal hemorrhages or Roth spots are observed, referral to a hematologist is necessary. Checking the CBC (complete blood count) and peripheral blood smear is the first step 3). If pseudohypopyon is present, anterior segment infiltration due to leukemia should be suspected, and systemic evaluation is required. Collaboration between ophthalmology and hematology prevents delays in diagnosis.
Treatment is selected based on the type and severity of leukemia and the extent of ocular symptoms. Systemic chemotherapy is the mainstay, and fundus findings often improve in response to systemic treatment. Since systemic chemotherapy may not adequately reach the ocular tissues, radiation therapy may be combined.
Systemic Chemotherapy
CML: Tyrosine kinase inhibitors (TKIs) are first-line. Dasatinib has been reported to improve retinopathy 2).
AML: Daunorubicin + cytarabine (DA therapy) is standard.
ALL: Remission induction therapy. Intrathecal chemotherapy is administered to prevent CNS relapse.
CEL: Imatinib is considered effective 3).
Adjunctive cytoreduction: Rapid WBC reduction with hydroxyurea 1)3).
Local Ocular Treatment
Radiation therapy (retinopathy and anterior segment): For iris infiltration, leukemic retinopathy, and secondary glaucoma, 2.5 Gy for 5 days is considered to induce remission.
Radiation therapy (optic nerve infiltration): When visual acuity decreases, 7–20 Gy is used. Orbital radiation of 2000 cGy (over 1–2 weeks) combined with intrathecal chemotherapy is the mainstay of treatment for optic nerve infiltration.
Photocoagulation: Performed for significant retinal ischemia.
Pars plana vitrectomy (PPV): Performed in stages for massive non-absorbing hemorrhage4).
Dexamethasone implant: Useful for cystoid macular edema (CME)4).
Leukapheresis: For acute visual impairment due to WBC ≥200,000/μL, leukocytes are selectively removed via extracorporeal circulation. ASFA (American Society for Apheresis) grade 2B recommendation1). Rapid visual recovery can be expected, but it is not a curative treatment and is positioned as a bridge to chemotherapy.
| Leukemia type | First-line drug | Time to visual improvement |
|---|---|---|
| CML | TKIs such as Dasatinib | Weeks to months |
| AML | DA therapy (daunorubicin + cytarabine) | Improves after remission |
| ALL | Remission induction therapy + intrathecal chemotherapy | Watch for CNS relapse |
| CEL | Imatinib | Effective in some cases |
This treatment involves extracorporeal circulation of blood to selectively remove white blood cells. It is used as a bridge until chemotherapy takes effect for emergency vision impairment caused by hyperleukocytosis (WBC >200,000/μL)1). ASFA recommends it as grade 2B.
Even when the systemic and bone marrow are in remission, the optic nerve can be a site of CNS relapse. Because the optic nerve is a “sanctuary site” where drug penetration is hindered by the BBB and BRB, infiltration can occur even if chemotherapy, imaging, and CSF tests are all negative6).
The pathogenesis of leukemic intraocular infiltration is broadly divided into primary and secondary types1).
Leukemia cells directly infiltrate the retinal vessels, parenchyma, and vitreous, causing local tissue damage. Infiltration of leukemia cells around retinal vessels leads to vascular occlusion, resulting in dilation, tortuosity, and ischemia of retinal veins.
The pathways of optic nerve involvement are as follows:
Anemia, thrombocytopenia, and hyperviscosity act in combination.
Leukostasis: When WBC count is ≥200,000/μL, leukocytes physically occlude retinal capillaries, leading to retinal ischemia and hemorrhage 2). The deep capillary plexus (DCP) has lower perfusion pressure than the superficial capillary plexus (SCP) and is more susceptible to leukostasis. After treatment, vascular density in the DCP is slow to recover 2), affecting long-term visual prognosis.
Outer retinal damage (EZ loss) is thought to reflect photoreceptor damage due to chronic ischemia 4).
Immunosuppression predisposes to opportunistic infections (e.g., CMV retinitis, herpetic keratitis). Various ocular complications arise from intensive chemotherapy, radiotherapy, and hematopoietic stem cell transplantation. The blood-brain barrier and blood-retinal barrier impede penetration of therapeutic agents into the optic nerve and intraocular space, which is a fundamental cause of incomplete eradication of leukemic cells.
In recent years, the number of long-term survivors after hematopoietic stem cell transplantation has increased, and management of post-transplant ocular complications has become increasingly important.
Among ocular complications associated with graft-versus-host disease (GVHD), dry eye is the most common, and in refractory cases, it can lead to corneal melting and perforation, requiring strict dry eye management.
Ophthalmologic follow-up after transplantation requires regular combination of dry eye evaluation (Schirmer test, tear break-up time measurement), slit-lamp examination, and fundus examination.
Jamshidi et al. (2025) reported that in cases of leukemic retinopathy, OCTA can detect decreased vessel density in the deep capillary plexus before clinically apparent retinopathy appears 4). OCTA has potential as a tool for early detection of asymptomatic retinal lesions in leukemia patients.
Jamshidi et al. (2025) reported a case of severe leukemic retinopathy treated with staged vitrectomy 4). The effectiveness of a dexamethasone implant (Ozurdex) for residual cystoid macular edema (CME) after surgery was also demonstrated, leading to visual improvement 4). The combination of ocular intervention and systemic treatment may contribute to improved prognosis.
