A 51-year-old woman with binocular diplopia and unilateral ptosis
Digital Journal of Ophthalmology 2019
Volume 25, Number 3
August 18, 2019
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Landon J. Rohowetz, BS | University of Missouri – Kansas City School of Medicine, Kansas City, Missouri
Anjulie K. Quick, MD | Department of Ophthalmology, University of Kansas School of Medicine, Prairie Village, Kansas

A 51-year-old woman with a history of acute myeloid leukemia (AML) in remission and no past ocular history presented emergently at the University of Kansas Hospital with binocular diplopia and right-sided ptosis of 3 days’ duration. The patient also complained of fatigue. She originally attributed her symptoms to allergies, stating that she had also recently experienced mild right-sided eye discharge and sinus pressure. Past medical history was significant for mild hypertension and AML with myelodysplasia-related features that was treated about 6 months prior with haploidentical peripheral stem-cell transplantation. The patient was a former smoker (40 pack-years) and had a family history of glaucoma (sister). She had recently finished a regimen of fluconazole for prophylaxis after stem-cell transplantation and was also taking acyclovir, letermovir, dapsone, and tacrolimus.

Best-corrected near visual acuity with +2.50 reading glasses was 20/30 in the right eye and 20/30 in the left eye. In room light, the right pupil measured 6 mm and was 1+ reactive; the left pupil, 4 mm and 3+ reactive. Confrontation visual field testing was unremarkable. There was no relative afferent pupillary defect. Motility in the right eye was −4 to adduction and supraduction and −3 to infraduction (Figure 1). Left eye motility was full. The right eye was exo- and hypotropic, and there was complete ptosis, with no observable corneal light reflex. (Given the inpatient setting and the acuteness of the patient’s condition, prism correction was not measured at this time but was deferred until outpatient follow-up.) The left eye was without ptosis. No exophthalmos nor enophthalmos was apparent. The rest of the examination, including fundus and the remainder of the cranial nerve examination, was unremarkable.

Figure 1.

Ocular motility testing demonstrating impaired adduction, supraduction, and infraduction of the right eye. Left eye motility was full.

Ancillary Testing
A complete blood count revealed anemia, with a hemoglobin concentration of 11 g/dL, but platelet and white blood cell counts were within normal limits. Electrolytes and coagulation studies were also within normal limits. With findings consistent with oculomotor nerve palsy, the patient was managed with the intent to urgently rule out aneurysm. Immediate computed tomography angiogram (CTA) of the head and neck was ordered, followed by magnetic resonance imaging (MRI), with and without contrast, of the head and orbits. CTA was unremarkable. T2-weighted MRI revealed mild right-sided proptosis and slightly increased cerebrospinal fluid (CSF) signal surrounding the right optic nerve but no abnormal enhancement and no mass or retrobulbar inflammation (Figure 2).

Lumbar puncture for CSF analysis revealed a normal opening pressure (15 cm H2O) and elevated concentrations of glucose (103 mg/dL) and protein (58 mg/dL). White blood cell count was within normal limits and differential analysis revealed 25% monocytes and 47% blasts. Gram stain, culture, fungal studies, and viral studies were negative. Flow cytometry revealed 41% myeloid blasts, consistent with relapse of AML. The following day, bone marrow biopsy was performed, revealing no bone marrow involvement.

Figure 2
T2-weighted magnetic resonance imaging demonstrating mild right-sided proptosis and slightly increased cerebrospinal fluid signal surrounding the right optic nerve but no abnormal enhancement and no mass or retrobulbar inflammation.

Intrathecal chemotherapy was started on day 3, and the patient was discharged 4 days later with plans for weekly intrathecal chemotherapy (Figure 3). The patient’s ophthalmic signs and symptoms, including diplopia, ptosis, and misalignment resolved 1 month after initiation of intrathecal chemotherapy. This coincided with the dissipation of myeloid blasts from the CSF. She has experienced no ophthalmic symptoms in the ensuing 8 months.

There was a brief reappearance of CSF myeloid blasts about 5 months after initiation of intrathecal chemotherapy that again resolved within 1 month. At 9 months, the patient’s bone marrow biopsy and CSF analysis revealed no phenotypic evidence of AML, and the patient was deemed in complete remission.

Figure 3
Timeline and hospital course. Imaging was obtained emergently to rule out aneurysm, followed by definitive diagnosis with lumbar puncture and treatment. AML, acute myeloid leukemia; CTA, computed tomography angiogram; MRA, magnetic resonance angiogram; MRI, magnetic resonance imaging.

Differential Diagnosis
Isolated, pupil-sparing oculomotor nerve palsy is most often due to a microvascular cause, whereas isolated pupil-involving oculomotor nerve palsy is most commonly due to compression from an aneurysm or tumor.(1) Because of the potential for imminent subarachnoid hemorrhage caused by an intracerebral aneurysm, emergent imaging (magnetic resonance angiogram or CTA) is warranted in cases of oculomotor nerve palsy with partial or complete pupil involvement. While our patient’s pupil was dilated, the pupillary light reflex was diminished but not absent. CTA was performed emergently to rule out intracranial aneurysm, followed by MRI, with and without contrast. In a study of 24 patients manifesting similar presentations of relative pupil-sparing oculomotor nerve palsy,(2) Jacobson reported that 10 (42%) had microvascular involvement, 10 (42%) had mass lesions (aneurysm or tumor) compressing the nerve, and 1 (4%) had carcinomatous infiltration (from primary breast cancer). These findings illustrate the importance of the provider’s certainty in non-pupil involvement when deciding to forego imaging studies, a course of action that should only be considered in patients over 50 years of age with atherosclerotic risk factors that increase the probability of microvascular involvement.(3)

When aneurysm was ruled out via imaging in this patient with a history of malignancy and immunosuppression, the differential diagnosis was narrowed to metastatic or infectious processes. As illustrated in our case, these etiologies can be differentiated by lumbar puncture and CSF analysis.

Diagnosis and Discussion
Central nervous system (CNS) involvement in AML is rare; therefore, AML patients without signs of CNS involvement do not routinely undergo diagnostic evaluation or prophylactic treatment for CNS involvement. The prevalence of CNS involvement in AML, however, is significantly higher at relapse (2.9%) than at initial presentation (0.6%).(4) CNS involvement is also more common in patients with myelomonocytic or monocytic leukemia.(5) The process by which leukemia spreads to the CNS may involve hematogenous spread or direct extension from cranial bone marrow to the dura and/or leptomeninges, termed leptomeningeal lymphomatosis.(6) Tumor cells that reach the CNS before treatment may be protected from stem cell therapy and chemotherapy by the blood-brain-barrier.(7) CNS recurrence is known to occur in hematologic malignancies after successful chemotherapy because of the presence of the blood-brain barrier, which may protect leukemic cells from the cytotoxic effects of treatment.(8)

Involvement of the bone marrow is usually seen in cases of AML CNS relapse, which occurs more often in those who have not undergone allogenic hematopoietic stem cell transplantation.(9) However, even in cases without bone marrow involvement and with prior stem cell transplantation, suspicion for leptomeningeal metastasis must be high in patients with focal neurologic deficits and a history of leukemia or lymphoma. MR imaging should be obtained but may be normal in 29%-88% of patients with leptomeningeal metastasis.(10-12) Thus, CSF sampling should be performed, because it is more sensitive, with a false negative rate as low as 11% (and lower with repeat sampling).(10,13) Current guidelines recommend CSF studies in conjunction with MRI in the initial workup of a patient with suspected leptomeningeal metastasis.(14-16) Once diagnosed, treatment consists of intrathecal chemotherapy with repeat clinical and CSF evaluation after induction therapy.(15)

To our knowledge, this is the first case of AML presenting as an isolated pupil-involving oculomotor nerve palsy due to leptomeningeal metastasis. Similar cases have been reported, but in those cases either the pupil was spared or other cranial nerves were involved in addition to the oculomotor nerve.(17-20) Furthermore, this is the only oculomotor nerve–involving case of AML relapse in which CNS involvement was not apparent on imaging. While similar manifestations of AML relapse have been described, all cases involving the oculomotor nerve presented with imaging findings correlating with clinically observed neurologic deficits.(17-19) Although our patient’s MRI revealed mild proptosis, signs of oculomotor nerve dysfunction as evident on examination were absent on imaging.

A similar case of abducens nerve–involving AML relapse not apparent on imaging was recently described by Fozza et al.(21) That case parallels the present one insofar as it was in a patient in their first AML remission presenting with CNS relapse manifesting as a cranial nerve palsy in the absence of imaging findings that was ultimately diagnosed with CSF evaluation. Our patient had undergone hematopoietic stem cell transplantation, though, whereas the patient reported by Fozza et al had not, making our case somewhat more atypical, because CNS relapse is less common after stem cell transplantation.(9) Moreover, their patient presented with bilateral abducens nerve deficits and systemic symptoms characteristic of intracranial hypertension, including nausea, vomiting, and dizziness. The abducens nerve is particularly susceptible to elevated intracranial pressure, and as such it is possible that generalized intracranial hypertension was the cause of the patient’s deficits rather than localized leptomeningeal invasion, as suspected in our patient, who only presented with an isolated, unilateral oculomotor nerve palsy and fatigue. Both patients illustrate the range of potential presentations and the importance of CSF evaluation in the assessment of a patient with suspected AML CNS relapse.

Literature Search
PubMed was searched on December 9, 2019, without date or language restriction, using the following terms, singly and in combination: acute myeloid leukemia AND leptomeningeal metastasis, oculomotor nerve, oculomotor nerve palsy, relapse, or third nerve palsy; oculomotor nerve OR oculomotor nerve palsy AND cancer, etiology, leukemia, leptomeningeal metastasis, and leptomeningeal lymphomatosis.

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