Leukemic Optic Neuropathy
Leukemic optic neuropathy (LON) is a condition characterized by optic nerve dysfunction resulting from direct infiltration of neoplastic leukocytes. The extent of infiltration may involve the entire nerve or can be limited to the optic sheath. As the optic nerve is a direct extension of the central nervous system (CNS), this finding in patients with leukemia is an indicator of CNS involvement. LON is a neuro-oncologic emergency and warrants immediate intervention to avoid permanent vision loss. The optic nerve can be the site of CNS relapse in leukemia even if there is presumed systemic and medullary remission. Clinicians should be aware of the importance of a thorough, urgent ophthalmologic and oncologic assessment in patients with vision loss in order to diagnose LON.
Leukemia is an umbrella term encompassing several hematologic malignancies of white blood cells. Each variant of leukemia has the potential to directly infiltrate almost any ocular tissue. LON-related optic nerve infiltration can occur in up to 18% and 16% of acute and chronic leukemias respectively.
The incidence of CNS leukemia and secondary LON is likely rising as a result of improved patient survival rates from more effective chemotherapy and targeted cancer therapy regimens for the disease. Although most leukemia patients have other systemic or neurologic manifestations, some can present with isolated optic nerve involvement (LON) as the sign of CNS relapse.
The optic nerve has been referred to as a potential “sanctuary” for leukemic cells despite treatment with chemotherapy, negative imaging and negative CSF . The blood brain barrier and blood retinal barrier may not allow for adequate penetration of therapeutic drugs into the optic nerve and can lead to ineffective eradication of leukemic cells.  Patients with a history of leukemia and who have received intrathecal, prophylactic chemotherapy may still be at risk for a relapse and LON.
Optic nerve involvement has been observed in several subtypes of leukemia and appears to occur more commonly in acute variants. In a review of 92 cases of optic neuropathy in patients with leukemia/lymphoma, up to 35 were deemed to be from LON. Of these cases, the most common association was acute lymphoblastic leukemia (ALL), followed chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myelogenous leukemia (CML). Of the lymphomas, the most commonly associated one was Non-Hodgkin’s B-cell lymphoma (NHL) .
CNS infiltration may occur as a part the initial presentation or as a sign of leukemia recurrence. The spread to the optic nerve is presumed to be from the leptomeninges via pial septae and perivascular spaces. This pattern allows for extension into the superficial layers of the brain and cranial nerves from the perineurium and endoneurium. Leukemic cells also tend to accumulate about blood vessels within the optic nerve and have the potential to disrupt its blood flow. Infiltration into the pial septae can cause axoplasmic flow stasis, which may delay axonal conduction and eventually result in nerve demyelination.
A detailed medical history is necessary to establish the diagnosis of LON. Involvement of the optic nerve is rarely the sole presenting sign and often occurs in conjunction with neurologic or systemic symptoms. Important history findings and presenting signs include:
- History of leukemia
- Eye movement deficits, eye pain
- Visual disturbances (e.g. vision loss, blurred vision)
- Hematologic manifestations (e.g. petechiae, gum bleeding, ecchymosis)
- Systemic symptoms (e.g. fever, weight loss, malaise)
full neuro-ophthalmological examination is important including ( but not limited to ) best corrected visual acuity, pupillary examination for a relative afferent pupillary defect (RAPD), dilated fundus exam, anterior segment examination, IOP, extraocular muscle motility. Further testing with automated visual field evaluation and Optical coherence tomography (OCT) – OCT may show thickening (infiltration) or thinning and loss of the retinal nerve fiber layer. Optic nerve head swelling or atrophy may also be seen. 
- Optic disc edema or pallor, presence of optic nerve infiltrates in the form of peripapillary cotton wool spots.
- Roth spots and multilevel hemorrhages including pre-retinal, sub-retinal, and intra-retinal hemorrhages are characteristic of leukemic retinopathy. This phenomenon is secondary to underlying anemia/thrombocytopenia and may not be due to leukemic infiltration per se.
- Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast – An MRI study should be considered in patients suspected of having LON. Optic nerve enhancement or thickening may be seen; however, imaging may be normal in some cases. In addition, neuroimaging can identify lesions amenable to biopsy if necessary. Negative MRI can not exclude the disease.
- Optic nerve biopsy – Biopsy could be considered in patients with LON with severe vision loss and inconclusive preliminary testing (e.g., lumbar puncture, cerebrospinal fluid (CSF) cytology, neuroimaging). Despite the significant procedure morbidity, a missed or delayed diagnosis of LON may have significant consequences. In cases where the intra-orbital portion of the optic nerve is involved, an orbital (e.g., transconjunctival) rather than intracranial (neurosurgical) approach may be considered.
- Lumbar puncture with cytology and flow cytometry – A lumbar puncture may be performed to evaluate for CNS leukemia. The diagnosis of CNS leukemia requires the presence of leukemic blast cells (e.g., > 5 cells per mL) in the CSF. A positive specimen is helpful in confirming metastatic spread to the CSF, however, the results may be normal. Flow cytometric (FCM) immunophenotyping is another test that may be helpful in the detection of CNS leukemia. One study found FCM was able to detect lymphoblasts with a sensitivity and specificity of up to 100%.  In patients with non-Hodgkin and Burkitt lymphomas, a single positive FCM sample has been associated with a higher risk of CNS leukemia.
- Complete blood count – If leukemia is suspected, a complete blood count (CBC) is a valuable initial test. Leukocytosis, often greater than 100,000 cells per μL, is seen in chronic leukemias. CBC findings consistent with acute leukemia include anemia, thrombocytopenia, leukopenia, or pancytopenia.
- Peripheral blood smear – A peripheral blood smear may be obtained to examine for the presence of blast cells and Auer rods in patients with signs and symptoms suspicious for acute leukemia.
- Bone marrow biopsy – A bone marrow aspirate or biopsy may reveal infiltration by blast cells and is used as a confirmatory test for the diagnosis of acute leukemias.
- Flow cytometry and immunophenotyping – Flow cytometry aids in leukemia diagnosis by identifying certain cell markers and reveals the lineage of leukemic blast cells.
Optic neuropathy in the setting of leukemia can be due to autoimmune, infectious, inflammatory, infiltrative, and medication induced etiologies. An MRI of the brain and orbit and a CSF study to look for leukemic cells can help guide urgent management for LON. Management of LON is multidisciplinary. Patients with LON may require intrathecal chemotherapy and orbital radiation, and prompt oncology consultation is recommended for all cases. Adjunctive corticosteroids may be used, but they may alter CSF diagnostic, pathologic, and neuroimaging findings. Therefore, the diagnosis should be established prior to treatment in suspected cases of LON. 
Leukemic cells are radiosensitive. Although there is some risk related to radiation therapy near the optic nerve, a course of 2000 cGy over a 1-2-week period is a typical regimen and may result in significant improvement of vision. Intrathecal chemotherapy alone may result in limited treatment efficacy. This therapy can improve other CNS manifestations of leukemia but may not improvement symptoms of optic neuropathy from leukemic infiltration. One theory suggests that the massive invasion of leukemic cells may act as a barrier between optic nerve lesions and the rest of the central nervous system. Nonetheless, intrathecal chemotherapy in combination with orbital radiation is a keystone therapy in the treatment of leukemic optic neuropathy.
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