Neuro-Ophthalmic Manifestations of Acute Leukemia

Ophthalmic involvement in acute leukemia is common, with 36% of patients having ophthalmic involvement at the time of diagnosis. However, neuro-ophthalmic involvement is relatively rare. We present a characterization of neuro-ophthalmic findings in patients with acute leukemia and discuss the implications of these findings on patient management and prognosis

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Neuro-Ophthalmic Manifestations of Acute Leukemia Malek A. Alrobaian, MD, Amanda D. Henderson, MD Background: Ophthalmic involvement in acute leukemia is common, with 36% of patients having ophthalmic involvement at the time of diagnosis. However, neuro-ophthalmic involvement is relatively rare. We present a characterization of neuro-ophthalmic findings in patients with acute leukemia and discuss the implications of these findings on patient management and prognosis. Methods: We performed a retrospective review of cases of acute leukemia with central nervous system (CNS) involvement and neuro-ophthalmic manifestations that were evaluated at the Wilmer Eye Institute between January 2013 and September 2019. Data collected included demographic information, leukemia details, results of diagnostic testing, and features of associated neuro-ophthalmic manifestations. Results: Twelve patients with mean age 42 years (range 9– 65, median 39) were included. Seven (58%) patients were men and 5 (42%) women. Eight (67%) were diagnosed with acute myeloid leukemia and 4 (33%) with acute lymphoid leukemia. Neuro-ophthalmic findings included 4 patients with isolated sixth nerve palsies, 2 with multiple cranial nerve palsies, 2 with orbital lesions with proptosis, 4 with optic disc swelling, and 1 with isolated fourth nerve palsy. Five (42%) neuro-ophthalmic presentations were associated with known CNS disease, 3 (25%) were associated with active disease but heralded the discovery of CNS involvement, 3 (25%) were the presenting features of relapse, and 1 (8%) led to the original leukemia diagnosis. Neuroimaging showed 4 with leptomeningeal enhancement, 4 with cranial nerve enhancement/thickening, 3 with optic nerve/sheath enhancement, 1 with lytic lesion of bone, 1 with soft tissue mass, and 1 with cytotoxic brain edema. One case had normal neuroimaging. Overall, patients had a poor prognosis, with 7 patients dying from leukemia or its complications and only 1 achieving a sustained remission. In 58% of the cases in our series, the discovery of neuro-ophthalmic leukemic involvement directly led to a change in leukemia treatment. Division of Neuro-Ophthalmology (MAA, ADH), Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland; and Division of Ophthalmology (MAA), King Abdulaziz Medical City, Riyadh, Saudi Arabia. The authors report no conflicts of interest. Address correspondence to Amanda D. Henderson, MD, Division of Neuro-Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Wilmer 233, Baltimore, MD 21287; E-mail: [e-mail] e584 Conclusions: Neuro-ophthalmic manifestations of leukemia may occur as presenting features of diagnosis, relapse, or CNS involvement, and portend a poor prognosis. Detection of neuro-ophthalmic involvement often triggers a prompt change in management. Therefore, familiarity with potential neuro-ophthalmic presentations of acute leukemia may avoid delayed diagnosis, and resultant inadequate treatment, of primary disease, relapse, or CNS involvement. Journal of Neuro-Ophthalmology 2021;41:e584–e590 doi: 10.1097/WNO.0000000000001071 © 2020 by North American Neuro-Ophthalmology Society A cute leukemia results when mutations occur in an early hematopoietic precursor cell, which can be either lymphoid or myeloid in origin, thus allowing for unchecked proliferation. The resulting large population of immature blast cells then replaces the bone marrow and inhibits its normal hematopoietic functions. The blast cells travel into the blood stream from where they can accumulate in distant body sites, including lymph nodes and healthy tissues (1). Central nervous system (CNS) involvement has been reported to occur clinically in 13% of patients with acute leukemia overall and is more common in acute lymphoid leukemia (ALL) than acute myeloid leukemia (AML) (2). Ophthalmic involvement has been reported in 36% of patients at the time of diagnosis of acute leukemia (3). Retinal vascular changes, including intraretinal hemorrhages, cotton wool spots, white-centered retinal hemorrhages, and central retinal vein occlusion, are most frequently seen. Other manifestations include direct infiltration of the orbit, optic nerves, iris, choroid, ciliary body, or retina, as well as papilledema and cranial nerve palsies (3,4). Ocular or orbital lesions may portend a poor prognosis (5), although this finding has not been consistent (6). Despite the frequency of ocular involvement, only a small minority of patients with eye involvement have neuro-ophthalmic findings (3,5). Whereas leukemic retinopathy typically is self-limited, neuro-ophthalmic manifestations may require immediate treatment to prevent vision loss or may herald CNS leukemic involvement, thus Alrobaian and Henderson: J Neuro-Ophthalmol 2021; 41: e584-e590 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution changing the immediate leukemia treatment plan. To the best of our knowledge, there has not been a study that specifically has focused on the neuro-ophthalmic complications of acute leukemia. We present a characterization of neuro-ophthalmic findings in patients with acute leukemia, with particular focus on how the presence of these findings may change patient management and prognosis. METHODS This study was approved by the Institutional Review Board of the Johns Hopkins University School of Medicine and adhered to the tenets of the Declaration of Helsinki and Health Insurance Portability and Accountability Act. We performed a retrospective chart review of patients evaluated by any ophthalmologist at the Wilmer Eye Institute/Johns Hopkins Hospital from January 2013 to September 2019, with an International Classification of Disease diagnosis code for acute leukemia plus a Current Procedural Terminology code for intrathecal chemotherapy. Patients were included if they had acute leukemia with CNS involvement and a neuro-ophthalmic manifestation, including optic neuropathy, diplopia, orbital process, or visual field defect. Demographics, medical history, and clinical details were recorded and summary statistics calculated using Microsoft Excel (Redmond, WA). RESULTS We identified 156 patients meeting the search criteria. Fifteen were excluded because of no acute leukemia diagnosis, 46 because of no CNS involvement, and 83 because of no neuro-ophthalmic involvement. Twelve patients were included (Fig. 1). The mean age was 42 years (range 9–65 years, median 39). Seven (58%) patients were men and 5 (42%) women. Eight (67%) were diagnosed with AML and 4 (33%) with ALL. Neuro-ophthalmic findings included 4 patients with isolated sixth nerve palsies, 2 with multiple cranial nerve palsies, 2 with orbital lesions with proptosis, 4 with optic disc swelling, and 1 with isolated fourth nerve palsy. Five (42%) neuro-ophthalmic presentations were associated with known CNS disease, 3 (25%) were associated with active disease but heralded the discovery of CNS involvement, 3 (25%) were presenting features of relapse, and 1 (8%) led to the original leukemia diagnosis. In 7 cases (58%), the neuro-ophthalmic finding directly led to escalation of leukemia treatment. Neuroimaging showed 4 with leptomeningeal enhancement, 4 with cranial nerve enhancement/thickening, 3 with optic nerve/sheath enhancement, 1 with bony lytic lesion, 1 with soft tissue mass, and 1 with cytotoxic brain edema. One case had normal neuroimaging. Overall, patients had a poor prognosis, with 7 patients dying from leukemia or its complications and only 1 achieving sustained remission. Individual cases are described further in the text, and findings are summarized in Table 1. Alrobaian and Henderson: J Neuro-Ophthalmol 2021; 41: e584-e590 FIG. 1. Flowchart demonstrating categorization of patient charts identified by searching the electronic medical record database for patients with an International Classification of Disease diagnosis code for acute leukemia plus a Current Procedural Terminology code for intrathecal chemotherapy plus a history of ophthalmologic examination at the Wilmer Eye Institute. A total of 156 patients met initial search criteria. After exclusion of patients without acute leukemia, without central nervous system involvement, and without neuro-ophthalmic manifestations, a total of 12 patients were included in the study. Case 1 A 31-year-old woman with a history of breast carcinoma, complicated by treatment-related myelodysplastic syndrome that evolved to AML with biopsy-confirmed spinal involvement, presented with left eye pain, periocular swelling, and proptosis. Orbital computed tomography showed left orbital roof lytic lesion (Fig. 2). She was treated with continued chemotherapy, including intrathecal administration, and dexamethasone. Proptosis and periorbital edema resolved, and follow-up eye examination was unremarkable aside from a single white-centered retinal hemorrhage in the left eye. She died 1 month later because of complications of AML. Case 2 A 9-year-old girl, with a history of ALL and with 3 previous CNS relapses, presented with left ptosis. Ophthalmic examination was otherwise unremarkable. Brain MRI showed only post-treatment gliotic changes. However, 1 month later, MRI showed new leptomeningeal enhancement. The cerebrospinal fluid (CSF) analysis confirmed CNS leukemia relapse. She received intrathecal chemotherapy and palliative spinal radiation. Ptosis resolved, and she attained leukemia remission. Three years after the ptosis episode, she developed meningitis and died secondary to sepsis. Her leukemia remained in remission. e585 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Neuro-ophthalmic manifestations of leukemia Case Age Sex Acute Leukemia Type Laterality 1 31 F AML Left 2 9 F ALL 3 34 F 4 29 5 6 Examination Findings Findings on Neuroimaging Left Proptosis and periorbital edema Left ptosis ALL Bilateral Optic disc edema M ALL Bilateral Sixth nerve palsy 65 59 M M AML AML Left Right Sixth nerve palsy Proptosis 7* 36 M ALL Left Sixth nerve palsy 8 21 M ALL Bilateral 9 10 61 41 M F AML ALL Right Bilateral Bilateral third, fifth, sixth, and seventh cranial nerve palsies, right optic disc swelling, as well as left optic disc pallor Fourth nerve palsy Esotropia 11 56 F AML Bilateral Bilateral disc edema, peripapillary flame hemorrhages, and intraretinal hemorrhages 12 62 M AML Bilateral Bilateral disc edema; multiple right cranial nerve palsies Orbital roof lytic lesion on computed tomography head Treatment-related gliosis on brain MRI and leptomeningeal enhancement on spine MRI Leptomeningeal enhancement and cytotoxic edema of the cerebellum Thickening and enhancement of bilateral third and fifth nerves, and enhancement of left sixth nerve Normal Soft tissue mass in inferior orbit Enhancement of the left sixth nerve Enhancement of left optic nerve sheath, enhancement and enlargement of right optic nerve, bilateral third nerves, and left inferior rectus Unavailable Bilateral third nerve enhancement Enhancement of leptomeninges, pachymeninges, bilateral optic nerve sheaths; lesion of splenium of the corpus callosum Enhancement of bilateral optic nerve sheaths and leptomeninges *This case previously was reported in another publication (7). ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; F, female; M, male. Case 3 Case 4 A 34-year-old woman, with a history of ALL, status post bone marrow transplant (BMT) 1 year before, presented with blurred vision, headaches, and pulsatile tinnitus. Two months before presentation, she had undergone MRI for headaches that showed leptomeningeal enhancement and cytotoxic edema of the cerebellum. The CSF analysis confirmed CNS relapse, and she was under treatment with intrathecal chemotherapy. Both optic discs were swollen with hemorrhages. She maintained a normal acuity. Automated visual fields demonstrated enlarged blind spots and nasal changes in both eyes. Examination was essentially stable 2 weeks later, and she was lost to ophthalmic followup. Since that time, she achieved leukemia remission. A 29-year-old man, with a history of ALL and with recently diagnosed CNS relapse treated with intrathecal chemotherapy, presented with transient blurred and double vision. Ophthalmic examination was remarkable for esotropia increasing in left gaze. MRI showed thickening and enhancement of bilateral third and fifth and left sixth cranial nerves in the subarachnoid space, compatible with leukemic infiltration (Fig. 3). His symptoms resolved with the addition of dexamethasone. With further treatment, he achieved leukemia remission. Unfortunately, 2 years later, he re-presented with blurred vision and headaches. MRI again demonstrated thickening and enhancement of multiple cranial nerves, and the CSF analysis confirmed CNS e586 Alrobaian and Henderson: J Neuro-Ophthalmol 2021; 41: e584-e590 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (Fig. 4). Orbitotomy with biopsy showed myeloid sarcoma, indicating leukemia relapse. The CSF and peripheral blood demonstrated blasts. He was started on chemotherapy. Postbiopsy ophthalmic examination showed normal afferent function, global limitation of right eye motility, ptosis, and right disc edema with diffuse choroidal folds. Two months later, he showed some improvement in motility. Ptosis and disc edema resolved. He since has been treated for multiple systemic leukemia relapses. Case 7 FIG. 2. Bone window from coronal computed tomography of the orbits demonstrates osteolytic lesion of the left orbital roof. recurrence. He was started on dexamethasone, and his blurred vision improved. His neuro-ophthalmic examination 2 days later was unremarkable. He was treated with dexamethasone and chemotherapy including intrathecal administration with some radiologic improvement. Case 5 A 65-year-old man, with a history of relapsed AML with CNS and skin involvement, undergoing treatment with intrathecal and systemic chemotherapy, presented with diplopia. Ophthalmic examination demonstrated a left eye abduction deficit and scattered retinal hemorrhages. Brain MRI was unremarkable. With treatment, there was some initial improvement in his diplopia; however, he represented 4 months later with worsening diplopia. Because of markedly declining clinical condition, he was placed on comfort care and died 6 days later. Case 6 A 60-year-old man, with a history of AML diagnosed 3 years before and in remission, presented with right proptosis. MRI showed a 3.5-cm soft tissue mass in the floor of the right orbit, inseparable from inferior rectus A 36-year-old apparently healthy man presented with diplopia. Examination demonstrated a complete abduction deficit of the left eye and 3 white-centered retinal hemorrhages. MRI showed left sixth nerve enhancement involving the cisternal segment. The CSF analysis showed elevated white blood cells with 77% blasts. Further serologies and bone marrow biopsy-confirmed ALL. He was treated with systemic and intrathecal chemotherapy as well as CNS radiation. Three months later, diplopia and retinal hemorrhages had resolved. He attained remission and was placed on maintenance chemotherapy. Unfortunately, he relapsed 15 months after his initial diagnosis, and a plan was made to proceed with BMT. This case was previously published (7). Case 8 A 21-year-old man, with a history of ALL in remission, presented with left facial palsy and, shortly thereafter, left eye blurred vision as well as right facial palsy. MRI showed bilateral facial nerve enhancement and left optic nerve sheath enhancement. Bone marrow biopsy confirmed ALL relapse. He underwent chemotherapy, radiation to the involved nerves, and, ultimately, BMT. He re-presented 8 months after onset of the facial palsy with diplopia. Efferent examination showed bilateral third and seventh and left sixth nerve palsies. He had reduced corneal sensation in both eyes. There were no abnormal cells identified in peripheral blood, CSF, or bone marrow. MRI showed no acute findings. He was treated with intravenous immunoglobulin and prednisone with no improvement. Two FIG. 3. Postcontrast T1 axial MRI demonstrates thickening and enhancement of the (A) bilateral oculomotor nerves, (B) bilateral trigeminal nerves, and (C) left abducens nerve. Alrobaian and Henderson: J Neuro-Ophthalmol 2021; 41: e584-e590 e587 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 4. Postcontrast T1 (A) axial and (B) coronal MRI show right inferior orbital mass with associated mass effect. months later, he had acute loss of vision in the right eye. Vision was no light perception (NLP) in the right eye and 20/200 in the left eye. Examination showed right optic disc swelling with hemorrhage, left disc pallor, bilateral nonreactive pupils, and complete bilateral ophthalmoplegia. MRI showed enhancement and enlargement of intraorbital right optic nerve, bilateral oculomotor nerves, and left inferior rectus, consistent with leukemic infiltration (Fig. 5). The patient requested comfort care and died 3 days later. Case 9 A 61-year-old man, with a history of AML with CNS and skin involvement, undergoing chemotherapy including intrathecal treatment, presented with diplopia. Examination was consistent with right fourth nerve palsy. Over the next several months, his palsy resolved. He achieved remission and underwent BMT. Unfortunately, his AML relapsed, and he died secondary to AML complications, 2.5 years after initial diagnosis. Case 10 A 41-year-old woman, with a history of relapsed ALL, presented with diplopia. Examination was unremarkable aside from a comitant esotropia. MRI demonstrated bilateral oculomotor nerve enhancement, and the CSF analysis confirmed blasts. She was treated with intrathecal chemotherapy with complete resolution of the diplopia. Unfortunately, her CNS involvement progressed, and she died a few months later. Case 11 A 56-year-old woman with newly diagnosed AML presented with new floaters in both eyes. Ophthalmic examination was significant for bilateral optic disc swelling FIG. 5. Postcontrast T1 MRI shows right optic nerve enlargement and enhancement on (A) axial and (B) coronal images. Coronal cut also demonstrates enlargement and enhancement of the left inferior rectus. e588 Alrobaian and Henderson: J Neuro-Ophthalmol 2021; 41: e584-e590 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution with prominent peripapillary flame hemorrhages and intraretinal hemorrhages. Automated visual fields showed double arcuate defects in the right eye and an inferior altitudinal defect in the left eye. Urgent MRI demonstrated diffuse leptomeningeal, pachymeningeal, and bilateral optic nerve sheath enhancement as well as a lesion within the splenium of the corpus callosum, all concerning for leukemic infiltration (Fig. 6). She was treated with intrathecal chemotherapy, with improvement in meningeal thickening and enhancement. She maintained her acuity, and visual fields improved. Case 12 A 62-year-old man with a history of CML, with recent AML conversion with CNS involvement, complained of right eye vision loss. Acuity was NLP in the right eye and J7 in the left eye with a right relative afferent pupillary defect and grade 2 swelling in both optic nerves. MRI demonstrated bilateral optic nerve sheath enhancement and leptomeningeal enhancement, suggestive of leukemic infiltration. He was treated with intrathecal chemotherapy, and vision improved to J1+ in the left eye but remained NLP in the right eye. Over the next several days, he developed multiple cranial nerve palsies on the right. Despite continued intrathecal chemotherapy, he re-presented 3 months later with acute vision loss in the left eye. His acuity was NLP in both eyes, with pale right disc and swollen left disc. He was treated with immediate steroids and whole brain radiation, initiated the same day as presentation. Unfortunately, he had no visual recovery and died 1 month later. FIG. 6. Postcontrast T1 axial MRI demonstrates diffuse leptomeningeal, pachymeningeal, and bilateral optic nerve sheath enhancement, concerning for leukemic infiltration. Alrobaian and Henderson: J Neuro-Ophthalmol 2021; 41: e584-e590 CONCLUSIONS Neuro-ophthalmic manifestations of acute leukemia in our series included optic neuropathy associated with optic nerve swelling, cranial nerve palsies, and orbital lesions with proptosis. Although findings sometimes occurred in the setting of known CNS leukemia, they more often heralded a change in clinical condition, including relapse, new CNS involvement, or even initial leukemic blast crisis. Cases of neuro-ophthalmic involvement indicating leukemia relapse in patients believed to be in clinical remission have been previously reported (8–12), as have rare cases of visual changes secondary to bilateral leukemic infiltration of the optic nerves as the presenting symptom of ALL (13,14). However, most of these have been single case reports, with only 1 series of 3 cases. Our larger series indicates that neuro-ophthalmic involvement most often is a harbinger of a significant change in the status of the leukemia that marks the need for escalation of therapy. Our series also suggests that neuro-ophthalmic involvement portends a poor prognosis in patients with acute leukemia. Therefore, particularly in patients with any previous history of leukemia, ophthalmologists and neuro-ophthalmologists should have a low threshold for pursuing further workup for CNS involvement or relapse of the disease, which would prompt a change in patient management. Preferred treatment of CNS leukemic involvement is with the administration of intrathecal chemotherapy (15). Although intrathecal chemotherapy is appropriate in the setting of many neuro-ophthalmic complications of acute leukemia, such as those caused by leptomeningeal disease or by leukemic infiltration of the ocular motor nerves, leukemic infiltration of the optic nerve represents a vision threatening neuro-ophthalmic emergency and may require a different treatment approach to prevent permanent vision loss. As exemplified by case 12 in our series, in which the patient lost vision in 1 eye followed by the fellow eye 3 months later, intrathecal chemotherapy may not be sufficient to eradicate the leukemic cells in the perineural space of the optic nerve (16). This may be attributable to individual anatomic variation in the septations of the perineural subarachnoid space and the resultant CSF dynamic alterations (17) as well as pathologic expansion of an infiltrated optic nerve further reducing flow of CSF in the perineural subarachnoid space, thus decreasing the effectiveness of intrathecal chemotherapy on the optic nerve. Therefore, emergent radiation is typically the recommended treatment for leukemic infiltration of the nerve (18–20). Although it is difficult to determine whether earlier radiation therapy could have prevented vision loss in the second eye in this patient, the anatomy of the optic nerve and surrounding structures, as well as the alterations of this structure in the setting of leukemic infiltration, provides support for the use of radiation to eliminate leukemic cells that may not be reached by intrathecal chemotherapy alone. e589 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Prolonged survival after leukemia diagnosis has been correlated with higher rates of CNS leukemic involvement (2); therefore, it is likely that the CNS complications will be encountered more and more frequently as systemic treatment regimens continue to improve. As the long-term survival of acute leukemia patients increases, the ophthalmologist and neuro-ophthalmologist may play important roles in recognizing patients with relapsed or progressive disease who require escalated treatment either with emergent radiation in the setting of leukemic infiltration of the optic nerve or with expedited oncology involvement and intrathecal chemotherapy for other CNS disease. Limitations of this study include its retrospective nature. Because not all patients with leukemia undergo neuroophthalmologic examination, asymptomatic lesions may not be represented in this series. In addition, as our study was conducted at a tertiary referral center, our patient population may be biased toward more severe disease; therefore, we cannot comment on the overall prevalence of neuro-ophthalmic findings among patients with leukemia. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. A. Alrobaian and A. D. Henderson; b. Acquisition of data: M. A. 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