52-year-old Filipino male presents for the evaluation of vision loss in the right eye
10 days prior to presentation he started to develop graying in his vision lasting 30 minutes at a time. This progressively worsened in severity and duration, lasting for hours
5 days prior to presentation, his vision completely went dark in the right eye
He was treated for orbital cellulitis at an outside hospital without improvement
Past medical history: Acute lymphocytic leukemia diagnosed in 2013, Philadelphia chromosome positive
Status post allogenic bone marrow transplant and full body radiation in 2014
Two prior relapses, including CNS relapse, currently achieved second remission
Current treatment: Intrathecal cytarabine and PO dasatinib
OD: Mild erythema and edema of upper and lower eyelids without significant proptosis, mild resistance to retropulsion, trace injection with no chemosis
OS: Unremarkable
Dilated Fundus Exam
OD: Significant optic disc edema with congestion, 360 degree flame and dot blot hemorrhages throughout, resembling blood and thunder appearance. Relative whitening of the retina. Areas of elevated retina consistent with serous retinal detachment
OS: 360 degree optic disc elevation with blurred disc margins, no obscuration of disc vessels. Lumpy bumpy appearance of optic nerve, superotemporal flame hemorrhage. Hemorrhage along superior arcade with white center. Scattered hemorrhages in all 4 quadrants in the periphery.
Figure 1: In leukemic infiltration of the optic disc, the features of the disc are obscured by a whitish fluffy infiltrate that is often associated with true disc swelling and peripapillary hemorrhage (Fig. 8.16B). The visual acuity in such patients is minimally affected unless the infiltration or associated edema and hemorrhage extend into the macula. Figure 2: Infiltration of the proximal optic nerve just posterior to the lamina cribrosa usually produces markedly decreased visual acuity associated with true optic disc swelling. Such patients have a variety of visual field defects, and a relative afferent pupillary defect is invariably present unless the infiltration is bilateral and symmetric. In addition, there are often peripapillary and peripheral retinal hemorrhages.
Differential Diagnosis
Inflammatory:
Sarcoidosis
IgG4 disease
Idiopathic orbital inflammation
Thyroid ophthalmopathy
Infectious:
Tuberculosis
Syphilis
Invasive fungal sinus infection
Neoplastic:
Primary Tumors:
Invasive head and neck tumors
Neurofibroma, meningioma
Secondary Tumors:
Metastasis
New leukemia
Lymphoma
Additional Investigations
B-scan: confirmed serous retinal detachments OD
OCT RNFL:
OD: Poor signal strength, segmentation error
OS: Moderate signal strength, average RNFL thickness 158, diffuse edema
HVF:
OD: Unable
OS: Moderate reliability, infero-central scotoma with scattered superior depression
MRI brain and orbits with and without contrast:
T1 post-contrast with fat suppression axial cuts through the orbits demonstrates ring of enhancing soft tissue circumferentially surrounding both optic nerves, extending along the entire length of both optic nerves into the orbital apices
There is also a 4 mm nodular enhancing focus at the right optic disc and 1 mm enhancing focus at the left optic disc
Lumbar punctures:
Initial: 2 WBC, 241 RBC, normal protein and glucose, CSF cytology negative for malignant cells
Repeat 4 days later: Cytology positive for malignant cells
Figure 3: On T2 weighted sequence– can more obviously see 1 focus at the left optic disc – also enhances post-contrast.
Diagnosis
Leukemic infiltration of bilateral optic nerves, OD greater than OS
Infiltrative orbitopathy OD
Secondary:
CRVO OD
Ophthalmic artery occlusion OD
Serous retinal detachment OD
Pathophysiology
Acute lymphoblastic leukemia (ALL) is a malignant transformation of cells destined to be a lymphocyte, which occurs at the level of the bone marrow, and affects the lymphoid stem cell lineage, predominantly affecting immature cells
The eye is an immunoprivileged site, often with poor penetration of chemotherapeutic agents, and therefore cannot be a site of clinical recurrence in the setting of systemic remission
Most ophthalmic changes seen in leukemia and lymphoma are secondary, resulting from the sequala of immature/dysplastic cells or as an effect of chemotherapy, including anemia, thrombocytopenia, hyperviscosity
These changes are typically seen in the retina, including intraretinal hemorrhages, white centered hemorrhages, dilated tortuous veins, cotton-wool spots, vitreous hemorrhage, central retinal vein occlusion
Typically do not need dedicated treatment
Primary ophthalmic changes, resulting from direct infiltration of leukemic cells
These include orbital infiltration (proptosis), optic nerve infiltration, choroidal infiltration (serous retinal detachments)
Require further localized treatment
Infiltration of the optic nerve can occur with 2 distinct clinical appearance, with the dividing anatomic structure being of the lamina cribrosa
Infiltration at the optic disc head anterior to the lamina cribrosa: The features of the disc are obscured by a whitish fluffy infiltrate, or cheesy appearance, often associated with true disc swelling and peri-papillary hemorrhage. The visual acuity in such patients is typically minimally affected unless the infiltration or associated edema and hemorrhage extend into the macula
Infiltration of the immediate retro-laminar portion of the proximal optic nerve: The appearance is that of true optic disc swelling, usually with marketed the decreased visual acuity, a variety of visual field defects, and a relative afferent pupillary defect, unless the infiltration is bilateral and symmetric. There may also be peri-papillary and peripheral retinal hemorrhages
The classic definition of CNS involvement in lymphoma and leukemia includes the presence of leukemic blasts in CSF, or greater than 5 mononuclear cells/millimeter cubed of CSF
95% specificity
50% sensitivity
Often numerous high-volume lumbar puncture are required to demonstrate CNS involvement and optic nerve infiltration, often delaying or confounding the diagnosis
Other definitions of CNS involvement also include imaging documenting lesions consistent with leukemia, including cranial nerve enhancement, or brain and spinal lesions related to leukemia or lymphoma
Typical MRI findings in patients with leukemia and positive CSF cytology
Pachymeningeal enhancement (29%)
Leptomeningeal enhancement (19%)
Cranial nerve enhancement (29%)
Mass-like enhancement (10%)
However, around 25% of patients with positive CNS cytology do not MRI findings
A last resort to diagnose optic nerve infiltration can include optic nerve sheath biopsy, however, most surgeons/clinicians will advocate for at least 3 large volume lumbar punctures to be sent for cytology prior to pursuing biopsy of tissue
Treatment
Optic nerve infiltration is a neuro oncologic emergency, requiring:
Emergent orbital and whole brain radiation
Pulse dose steroids
Systemic and intrathecal chemotherapy
Timely diagnosis and treatment is essential, as delaying treatment can lead to irreversible blindness
Prognosis and Future Directions
Overall, CNS involvement is a poor prognostic factor in leukemia and lymphoma
Timely diagnosis and treatment is essential, as delaying treatment can lead to irreversible blindness and overall mortality
Given the poor sensitivity of CSF cytology, there have been investigations of other methods to detect malignant cells in CSF
Flow cytometry
lactate dehydrogenase isozyme 5
β2-microglobulin
immunoglobulin heavy chain rearrangement
Positive CSF cytology and tissue biopsy remain the current gold standards for diagnosis of CNS involvement
References
Miller NR, Subramanian PS, Patel VR. Walsh & Hoyt’s Clinical Neuro-ophthalmology, The Essentials, Third Edition. Wolters Kluwer. 2016:61-69.
Reddy, S. C., Jackson, N., & Menon, B. S. (2003). Ocular Involvement in Leukemia – A Study of 288 Cases. Ophthalmologica, 441–445.
Myers, K. A., Nikolic, A., Romanchuk, K., Weis, E., Brundler, M., Lafay-cousin, L., & Costello, F. (2017). Neuro-Oncology Practice lymphoma : diagnostic approach to a neuro-oncologic emergency. Neuro-Oncology Practice, 4(1), 60–66.
Thomas, X., Le, Q., Thomas, X., & Le, Q. (2013). Central nervous system involvement in adult acute lymphoblastic leukemia Central nervous system involvement in adult acute lymphoblastic leukemia. Hematology, 8454.
Ellis, W., & Little, H. L. (1973). Leukemic Infiltration of the Optic Nerve Head. American Journal of Ophthalmology, 75(5), 867–871.
Guenette JP, Tirumani SH, Keraliya AR, Shinagare AB, Ramaiya NH, Jagannathan JP (2016) MRI findings in patients with leukemia and positive CSF cytology: a single-institution 5-year experience. AJR Am J Roentgenol 207:1278–1282.
Cheung, M., Fang, B., & Lee, R. (2019). Optic neuropathy as the first sign of central nervous system relapse in acute myeloid leukaemia: MRI findings and its diagnostic challenge. BMJ Case Reports, 1–4.
Khan K, Malik AI, Almarzouqi SJ, Morgan ML, Yalamanchili S, Chevez- Barrios P, Lee AG (2016) Optic neuropathy due to chronic lymphocytic leukemia proven with optic nerve sheath biopsy. J Neuroophthalmol 36(1):61–66.
Ahluwalia MS, Wallace PK, Peereboom DM. Flow cytometry as a diagnostic tool in lymphomatous or leukemic meningitis: ready for prime time? Cancer. 2012;118(7):1747-175322025088.
Scott BJ, Douglas VC, Tihan T, Rubenstein JL, Josephson SA. A Systematic Approach to the Diagnosis of Suspected Central Nervous System Lymphoma. JAMA Neurol. 2013;70(3):311–319. doi:10.1001/jamaneurol.2013.606.
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