History
Patients with leukemia often have ophthalmologic manifestations. Some of these result from direct infiltration of leukemic cells. In other cases, ophthalmic findings are secondary to indirect causes such as the hematologic abnormalities caused by the leukemia, involvement of the central nervous system, opportunistic infections, and drug-related adverse events. In most patients, a diagnosis of leukemia has been made before presenting to an ophthalmologist. However, in some patients, ocular symptoms and examination lead to a diagnosis of leukemia.
In a 2020 review of ophthalmic involvement in CLL, 25% of cases were diagnosed with CLL after presentation to the ophthalmologist. [20] In other cases, ocular manifestations may occur during systemic relapse or even during a complete remission. [21]
Recently the ophthalmic manifestations as the initial presentation of CML were reviewed. [22] The most frrequent ocular manifestation was leukemic retinopathy. Other manifestations include hypopyon, anterior uveitis, optic nerve infiltration, iris infiltration and exudative retinal detachment.
Most patients do not develop symptoms as a result of intraocular involvement.
Physical
Posterior segment manifestations
The posterior segment manifestations are protean in nature and may be secondary to direct invasion of the leukemic cells.
They result from systemic hematological abnormalities, such as anemia, thrombocytopenia, and hyperviscosity or opportunistic infections secondary to the immune dysfunction.
Direct infiltration
Retinal grayish white nodules that may be surrounded by hemorrhage manifest direct infiltration.
Perivascular sheathing may be another manifestation of a leukemic infiltrate.
Roth spots, white-centered retinal hemorrhages, may represent a cluster of leukemic cells. On the other hand, septic emboli or platelet-fibrin material gives a similar funduscopic finding.
Rarely, pale gray swelling of the optic nerve head may indicate optic nerve infiltration. [23]
Leukemic retinopathy
Retinal lesions are the most common ocular manifestation of leukemia. They are found most often in adults and in patients with myeloid leukemia.
Retinal hemorrhages are the most common finding in most series and are thought to be secondary to anemia and thrombocytopenia. These hemorrhages may be dot-shaped, flame-shaped, intraretinal, subretinal, or subhyaloid.
An impending retinal vein obstruction and intraretinal hemorrhage are shown in the images below.
An impending bilateral central retinal vein obstruction was discovered during a routine examination of a 76-year-old man. Further workup revealed a WBC count of 709,000, a hemoglobin count of 12 mg/dL, and a platelet count of 104,000. The man was eventually diagnosed with CML. This image is a red-free photograph of the right fundus. Notice the intraretinal hemorrhages.
Same patient as in the image above. This image is a red-free photograph of the left eye showing intraretinal hemorrhages.
Cotton-wool spots are known to represent nerve fiber layer infarcts. However, they are not correlated with hematologic parameters of anemia or blood viscosity.
Retinal vein tortuosity and dilation are thought to be secondary to hyperviscosity.
Peripheral retinal microaneurysms and retinal neovascularization may be seen, particularly in patients with CML. They are thought to occur as a result of peripheral nonperfusion and ischemia from hyperviscosity.
Sea fans reminiscent of sickle cell retinopathy may be seen.
Neovascularization of the disc has been reported in a case where no apparent ischemia was present. It was recognized that angiogenic factors secreted from the tumor may play a role in the pathogenesis of retinal and optic nerve head neovascularization. In patients with CLL, optic neuropathy was always associated with CLL infiltration. [20]
The vitreous seldom is involved.
The choroid is the most commonly affected ocular structure in pathological studies. However, choroidal involvement is difficult to detect clinically owing to the subtle choroidal changes. The introduction of SD-OCT into routine clinical practice has made the detection of choroidal involvement much easier. This is important, as choroidal involvement may be the only site of relapse. [24]
Occasionally, serous retinal detachments and retinal pigment epithelium (RPE) changes have been reported. In rare cases, they can be the first sign of relapsing leukemia. [25] Serous retinal detachment may be the presenting sign of ALL. [26]
Papilledema occurs as a result of increased intracranial pressure which may be secondary to cerebral venous sinus thrombosisdue to hyperviscosity, direct leukemic infiltration, superinfection from immunosuppresion, a secondary malignancy or following treatment with corticosteroids and/or Vitamin A. [27]
Opportunistic infections include cytomegalovirus retinitis, toxoplasma chorioretinitis, endogenous fungal endophthalmitis, and herpetic retinitis.
Anterior segment manifestations
Anterior segment involvement in leukemia is rare but significant because it often is an extramedullary site of relapse. Anterior segment manifestations occur more commonly in ALL than in all the other types of leukemia.
A change in iris color, iris nodules, hyphema, hypopyon, glaucoma, a sterile corneal ring ulcer, and a pannus all have been described in patients with leukemia. [28] A case report has described a man with AML relapse characterized by iris infiltration and pseudohypopyon. [29]
Corneal involvement is rare. Scleral, episcleral, and conjunctival involvement usually is silent and is limited to perivascular infiltration that can be demonstrated on pathological sections.
Orbital manifestations
Leukemic cells may infiltrate the orbit during the course of acute or chronic leukemia. Unusual orbital involvement with leukemia has been reported to include infiltration of the lacrimal gland and drainage system, rectus muscles, and dermis.
Orbital involvement in children is more common in acute leukemias, whereas orbital involvement in adults is more common in chronic leukemias.
The leukemic infiltrate may range from insignificant, where it is virtually asymptomatic, to a space-occupying lesion with its concomitant symptoms.
The patient may have proptosis, ecchymosis, chemosis, diplopia, visual disturbance, or motility disturbances.
AML may present as gaze palsy. [30]
In children, the orbital involvement is characterized by an acute and rapid process that may be confused with orbital cellulitis. In general, these infiltrates are bilateral and do not destroy bone.
Granulocytic sarcoma of the orbit, also known as chloroma, is an extramedullary form of myelogenous leukemia.
Unilateral, painless proptosis develops over weeks to months prior to a diagnosis of leukemia. Eyelid redness or violaceous discoloration may be present, which turns into ecchymosis that may be confused with rhabdomyosarcoma or metastatic neuroblastoma. If AML or CML is already present, then a rapid and fulminant bilateral proptosis is characteristic.
Rarely patients may present with bilateral extraocular involvement with compressive optic neuropathy. [31]
An example of orbital presentation and outcome of leukemia are shown in the images below.
Same patient as in the image above. A CBC revealed anemia (Hb 8.6 mg/dL), thrombocytopenia (64,000), and leukocytosis (12,900). The peripheral smear revealed the presence of blasts 28%, lymphocytes 44%, segmented 14%, monocytes 6%, bands 2%, metamyelocytes 1%, and myelocytes 1%. The boy was diagnosed with AML type M4-M5 chloroma of the left orbit.
Systemic chemotherapy was instituted, and the proptosis resolved. Unfortunately, 4.5 months later, the boy passed away secondary to multiorgan failure.
Causes
The etiology of the leukemias appears to be multifactorial. Genetic, viral, and environmental factors, such as ionizing radiation, drugs, and chemicals, have been implicated in the pathogenesis of leukemia.
It is believed that the final common pathway is damage to the DNA. This damage may rearrange the genetic material, thereby allowing previously silent oncogenes to be expressed.
Patients with an abnormal number of chromosomes (eg, trisomy 21) and chromosomal translocations are at an increased risk of developing ALL.
Risk factors implicated in the development of AML include the following:
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Myelotoxic agents (eg, ionizing radiation, benzene, alkylating agents)
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Chromosomal abnormalities (eg, Down syndrome, chromosomal instability syndromes)
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Predisposing hematological disorders (eg, aplastic anemia, chronic myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria)
Chromosomal abnormalities, especially trisomy 12, are common in patients with CLL. Familial case clusters have been reported in CLL. HTLV-1 infection has also been implicated in CLL.
Damage to the bone marrow by agents, such as benzene and ionizing radiation, may cause CML.
Of patients with CML, 90% have an acquired chromosomal abnormality, the Philadelphia chromosome, which is a translocation of half of the long arm of chromosome 22 to another chromosome, usually chromosome 9.
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A 4-year-old boy presented with sudden proptosis of his left eye.
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Same patient as in the image above. A CBC revealed anemia (Hb 8.6 mg/dL), thrombocytopenia (64,000), and leukocytosis (12,900). The peripheral smear revealed the presence of blasts 28%, lymphocytes 44%, segmented 14%, monocytes 6%, bands 2%, metamyelocytes 1%, and myelocytes 1%. The boy was diagnosed with AML type M4-M5 chloroma of the left orbit.
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CT scan reveals infiltration in the left orbit. Notice that the bone is uninvolved. A lumbar puncture revealed that the cerebral spinal fluid was clean of leukemic cells.
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Systemic chemotherapy was instituted, and the proptosis resolved. Unfortunately, 4.5 months later, the boy passed away secondary to multiorgan failure.
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An impending bilateral central retinal vein obstruction was discovered during a routine examination of a 76-year-old man. Further workup revealed a WBC count of 709,000, a hemoglobin count of 12 mg/dL, and a platelet count of 104,000. The man was eventually diagnosed with CML. This image is a red-free photograph of the right fundus. Notice the intraretinal hemorrhages.
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Same patient as in the image above. This image is a red-free photograph of the left eye showing intraretinal hemorrhages.
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A 14-year-old boy with a past medical history of ALL complained of a sudden loss of vision OD. Visual acuities were counting fingers OD and 20/20 OS. Notice the macular hemorrhage responsible for the loss of vision. Courtesy of Dr Rafael Jiménez.
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Same patient as in the previous image. The hematological workup revealed a hemoglobin count of 5.6, a WBC count of 1800, and a platelet count of 3000. Courtesy of Dr Rafael Jiménez.
