Acute Sixth Nerve Palsy and Retinal Hemorrhages as the Presenting Features of Acute Lymphoblastic Leukemia

A 36-year-old apparently healthy man presented with acute onset of diplopia. Examination demonstrated left sixth nerve palsy with 3 retinal hemorrhages noted in one eye. Gadolinium-enhanced high-resolution skull base MRI revealed left sixth nerve enhancement involving the cisternal segment. Complete blood count, cerebrospinal fluid analysis, bone marrow biopsy, and flow cytometry confirmed acute T-cell lymphoblastic leukemia with central nervous system involvement. This case demonstrates the value of high-resolution MRI in the evaluation of cranial nerve palsy in young adults and also emphasizes the importance of systemic work up in these cases, particularly when retinal findings are present.

Photo Essay Section Editors: Melissa W. Ko, MD Dean M. Cestari, MD Peter Quiros, MD Acute Sixth Nerve Palsy and Retinal Hemorrhages as the Presenting Features of Acute Lymphoblastic Leukemia Malek A. Alrobaian, MD, Maria Adelita Vizcaino, MD, Amanda D. Henderson, MD Downloaded from http://journals.lww.com/jneuro-ophthalmology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 05/04/2022 FIG. 1. T1-weighted, postgadolinium, axial image from high-resolution skull base MRI demonstrates enhancement of the cisternal segment of the left sixth nerve. Abstract: A 36-year-old apparently healthy man presented with acute onset of diplopia. Examination demonstrated left sixth nerve palsy with 3 retinal hemorrhages noted in one eye. Gadolinium-enhanced high-resolution skull base MRI revealed left sixth nerve enhancement involving the cisternal segment. Complete blood count, cerebrospinal fluid analysis, bone marrow biopsy, and flow cytometry confirmed acute T-cell lymphoblastic leukemia with central nervous system involvement. This case demonstrates the value of high-resolution MRI in the evaluation of cranial nerve palsy in young adults and also emphasizes the importance of Division of Neuro-Ophthalmology (MA, ADH), Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Ophthalmology (MA), King Abdulaziz Medical City, Riyadh, Saudi Arabia; and Department of Pathology (MAV), Johns Hopkins University School of Medicine, Baltimore, Maryland. 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] Alrobaian et al: J Neuro-Ophthalmol 2021; 41: e131-e133 systemic work up in these cases, particularly when retinal findings are present. Journal of Neuro-Ophthalmology 2021;41:e131–133 doi: 10.1097/WNO.0000000000000920 © 2020 by North American Neuro-Ophthalmology Society A 36-year-old apparently healthy man presented to clinic with a 5-day history of horizontal, binocular diplopia. Review of systems was significant only for a cough starting 3 weeks before presentation. Examination demonstrated a complete abduction deficit of the left eye with an esotropia in primary gaze that increased in left gaze. Anterior segments were normal in both eyes. Dilated fundus examination showed 3 white-centered retinal hemorrhages in the left eye. Neuro-ophthalmic examination was otherwise unremarkable. Because the patient was clinically stable, further evaluation was pursued on an outpatient basis. Highresolution skull base MRI, which was performed using e131 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Photo Essay a 3T magnet and 0.8-mm postcontrast cuts through the brainstem to allow for optimal cranial nerve visualization, showed left sixth nerve enhancement involving the cisternal segment and was otherwise unremarkable (Fig. 1). Cerebrospinal fluid analysis demonstrated elevated white blood cells (WBC) with 77% blasts (Fig. 2). Complete blood count was significant for a WBC count of 66.25 K/mm3 with 63% blasts, hemoglobin 7.5 g/dL, and platelets 39 K/mm3. When evidence of the blast crisis was identified, the patient was admitted to oncology the same day for further evaluation and treatment. The level of lactate dehydrogenase was elevated at 3,370 U/L. Electrolytes, blood urea nitrogen, creatinine, thyroid stimulating hormone, C-reactive protein, erythrocyte sedimentation rate, and uric acid were all normal. The bone marrow biopsy revealed extensive infiltration by sheets of small, round blue tumor cells with numerous mitoses and scattered apoptotic bodies (Fig. 3). Flow cytometry confirmed the diagnosis of acute T-cell lymphoblastic leukemia (ALL). Other imaging studies identified no additional extramedullary disease. The patient was treated with systemic and intrathecal chemotherapy per protocol E1910 followed by protocol PAALL0434 Arm D, and central nervous system (CNS) radiation (1). Three months later, his diplopia resolved, although he had mild residual left abduction weakness. Retinal hemorrhages also resolved. Repeated serial CSF and bone marrow analyses revealed no evidence of lymphoblasts. Having attained remission, he was transitioned to maintenance chemotherapy. Unfortunately, bone marrow biopsy 15 months after his initial diagnosis was consistent with relapse of ALL, and plan was made to proceed with allogeneic stem cell transplant. INTERPRETATION Sixth nerve palsy is rare in young adults and necessitates a more aggressive diagnostic approach than is required for isolated sixth nerve palsies in older adults. Peters et al (2) reported that the most common cause for sixth nerve palsy in patients aged 20–50 years was CNS mass lesion in 33% of cases, followed by multiple sclerosis in 24% of cases. Other FIG. 2. Cerebrospinal fluid analysis shows blast cells (arrows). H&E, 40·. e132 FIG. 3. Bone marrow biopsy shows infiltration by sheets of small, round blue tumor cells with numerous mitotic figures (arrows). H&E, 40·. causes identified in their study included idiopathic, viral infection, pseudotumor cerebri, meningitis, microvascular, and progressive spinocerebellar degeneration. There were no cases of hematologic malignancy in their cohort; however, the high prevalence of CNS disease in these young patients underscores the need for urgent diagnostic evaluation. Use of high-resolution, gadolinium-enhanced MRI in our case allowed for expeditious identification of the sixth nerve abnormality, which led to further evaluation including CSF analysis, and the diagnosis of ALL with florid CNS involvement. This case highlights the use of modern neuroimaging protocols in the diagnosis of life-threatening disease. Sixth nerve palsy is an exceedingly rare presenting feature of acute leukemia, especially in adults. Few case reports of CNP as a presenting sign of acute leukemia in children and young adults have been published, including cases of third, sixth, and multiple CNP (3–8). MRI was abnormal in 2 of these cases, with findings including replacement of the skull bone marrow with enhancing material with extension to the cerebellopontine angle and the cavernous sinus, and enlargement and enhancement of the cranial nerves (3,6). Of the 3 cases with available neuroimaging results and normal MRI, one case of bilateral sixth nerve palsy was felt to represent a false localizing sign in the setting of increased intracranial pressure from a superior vena cava syndrome (5). The remaining 2 MRIs were reportedly normal, although the publications suggest that these were routine brain protocol MRIs, as available at the time of publication of these cases, rather than high-resolution skull base imaging (4,7). MRI was not performed in one case (8). There were no retinal hemorrhages described in any of these cases. In this particular case, the finding of white-centered retinal hemorrhages, in addition to the sixth nerve palsy in an otherwise healthy young adult, was key in prompting further systemic evaluation. A previous report showed that Alrobaian et al: J Neuro-Ophthalmol 2021; 41: e131-e133 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Photo Essay 8 percent of patients with ALL had white-centered retinal hemorrhages when examined within a few days of diagnosis, and adults were more likely than children to have this particular retinal finding (9). Although white-centered hemorrhages are not specific for hematologic malignancy, their presence heightened suspicion for an underlying systemic disease in this case. In summary, underlying etiologies of sixth nerve palsy in young adults are diverse and can include neoplastic disease requiring urgent treatment. In patients under age 50 and in those patients without underlying vascular risk factors, thorough and expedited evaluation of acute CNP, including high-resolution skull base MRI with contrast, is required to evaluate for life-threatening disease. The presence of additional ophthalmic findings, such as the white-centered retinal hemorrhages seen in this patient, also may help guide further systemic evaluation. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. Alrobaian and A. D. Henderson; b. Acquisition of data: M. Alrobaian, M. A. Vizcaino, and A. D. Henderson; c. Analysis and interpretation of data: M. Alrobaian and A. D. Henderson. Category 2: a. Drafting the manuscript: M. Alrobaian and A. D. Henderson; b. Revising it for intellectual content: M. A. Vizcaino and A. D. Henderson. Category 3: a. Final approval of the completed manuscript: M. Alrobaian, M. A. Vizcaino, and A. D. Henderson. Alrobaian et al: J Neuro-Ophthalmol 2021; 41: e131-e133 REFERENCES 1. Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: children’s Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015;26:1176–1183. 2. Peters GB, Bakri SJ, Krohel GB. 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