Title | Diagnosis of Acute Promyelocytic Leukemia After Presentation to Neuro-Ophthalmology |
Creator | Andrew B. Paxton, BMSc; Jonathan A. Micieli, MD, CM |
Affiliation | Faculty of Medicine (ABP), University of Toronto, Toronto, Canada; Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada; Kensington Vision and Research Centre (JAM), Toronto, Canada; and Division of Neurology (JAM), Depart- ment of Medicine, University of Toronto, Toronto, Canada |
Abstract | Acute promyelocytic leukemia (APML) is a medical emergency that can initially present with neuro- ophthalmologic signs. Early recognition is crucial, and immediate treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) can be life-saving. The goal of this study was to describe patients who first presented to neuro- ophthalmology and were subsequently diagnosed with APML. |
Subject | APML; Arsenic Trioxide; ATRA |
OCR Text | Show Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Diagnosis of Acute Promyelocytic Leukemia After Presentation to Neuro-Ophthalmology Andrew B. Paxton, BMSc, Jonathan A. Micieli, MD, CM Background: Acute promyelocytic leukemia (APML) is a medical emergency that can initially present with neuroophthalmologic signs. Early recognition is crucial, and immediate treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) can be life-saving. The goal of this study was to describe patients who first presented to neuroophthalmology and were subsequently diagnosed with APML. Methods: We retrospectively reviewed consecutive patients seen at a tertiary neuro-ophthalmology centre. Patients with an unknown diagnosis of APML at presentation who subsequently went on to receive this diagnosis were included. Clinical characteristics, neuro-ophthalmologic findings, and outcome were retrieved. Results: A total of 3 patients (2 women and 1 men) with a mean age of 30.7 (range 24–33) years were included in the study. Neuro-ophthalmologic diagnoses at presentation were severe hemorrhagic papilledema related to dural venous sinus thrombosis, hemorrhagic bilateral optic disc edema, and left homonymous hemianopia related to an occipital lobe hemorrhage. At diagnosis, the average hemoglobin was 83.7g/L (range 78–104), and the platelet count was 39.3 · 109/L (range 15–77). All patients were treated with ATRA and ATO. One patient developed papilledema and sixth nerve palsies related to this treatment, which resolved with acetazolamide. Clinical follow-up ranged from 6 to 12 months, and all patients were in clinical remission about systemic APML. Conclusion: Neuro-ophthalmologic symptoms may be the first manifestations of APML, and a complete blood count is an essential test in patients presenting with optic disc edema, especially if hemorrhagic. Journal of Neuro-Ophthalmology 2022;42:e181–e186 doi: 10.1097/WNO.0000000000001259 © 2021 by North American Neuro-Ophthalmology Society A cute promyelocytic leukemia (APML) is a specific subtype of acute myeloid leukemia (AML). It is genetically characterized by a balanced and reciprocal translocation between the promyelocytic leukemia gene on chromosome 15 and the retinoic acid receptor-alpha (RAR-alpha) gene on chromosome 17 (1). APML is a medical emergency that can rapidly become fatal if left untreated, often from hemorrhaging complications as a result of disseminated intravascular coagulation. Early identification of affected patients along with rapid treatment is crucial for preventing death in what has become a readily curable leukemia in adults (2). When APML is suspected, treatment with differentiating agents such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) should be initiated even before histologic and genetic testing confirms the diagnosis (3,4). Patients with APML can present with a multitude of symptoms related to bleeding, including epistaxis, bruising, gastrointestinal bleeding, and pulmonary hemorrhage. In addition, patients can often present with generalized symptoms of weakness, fatigue, and headaches (5). Furthermore, patients with APML may develop optic neuropathy, cranial nerve palsies, papilledema, hemianopia, and optic disc edema (ODE) during their clinical course (6). Patients may also present to neuro-ophthalmologists with their first symptoms of APML, but this is very rare (7). We present a case series of young patients who were seen in neuroophthalmology consultation for vision loss, and a diagnosis of APML was subsequently made. METHODS Faculty of Medicine (ABP), University of Toronto, Toronto, Canada; Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada; Kensington Vision and Research Centre (JAM), Toronto, Canada; and Division of Neurology (JAM), Department of Medicine, University of Toronto, Toronto, Canada. The authors report no conflicts of interest. Address correspondence to Jonathan A. Micieli, MD, CM, Kensington Vision and Research Centre, 340 College Street, Suite 501, Toronto, ON M5T 3A9, Canada; E-mail: jmicieli@kensingtonhealth.org Paxton and Micieli: J Neuro-Ophthalmol 2022; 42: e181-e186 This study was approved by the Research Ethics Board at the University of Toronto. Patients with APML referred to a tertiary neuro-ophthalmology practice between July 1, 2018, and December 1, 2020, were screened for involvement in the study. For inclusion in the study, patients must have presented with a neuro-ophthalmologic syndrome that led to the diagnosis of APML. This included an optic neuropathy, optic nerve changes, papilledema and raised e181 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution intracranial pressure, ocular motility deficits, and visual field defects. Patients with a known diagnosis of APML were excluded, and those who presented with a relapse related to APML were also excluded. Demographics, clinical characteristics, neuroimaging findings, systemic workup, treatment, and follow-up were retrieved. RESULTS A total of 3 patients were included with a visual complaint related to an unknown diagnosis of APML. The mean age was 30.7 (range 24–33) years, and presenting visual complaints were unilateral blurred vision in 2 patients and bilateral blurred vision in 1 patient. Neuro-ophthalmologic diagnoses at presentation were severe hemorrhagic papilledema related to dural venous sinus thrombosis, hemorrhagic bilateral ODE, and left homonymous hemianopia related to an occipital lobe hemorrhage. At diagnosis, the average hemoglobin was 83.7g/L (range 78–104), and the platelet count was 39.3 · 109/L (range 15–77). MRI findings included filling defects in the bilateral transverse/sigmoid sinuses, multiple subacute infarcts, and a large right occipital lobe hemorrhage. All patients were treated with ATRA and ATO. One patient developed papilledema and sixth nerve palsies related to this treatment, which resolved with acetazolamide. Clinical follow-up ranged from 6 to 12 months, and all patients were in clinical remission with respect to their systemic APML. Case 1 A 33-year-old woman was seen in neuro-ophthalmology consultation for papilledema. She had a medical history of obesity, chronic migraines, and asthma. She sought medical attention because of a 1-week history of blurred vision in the right eye. The visual acuity at presentation was 20/20 in the right and left eyes, and there was no relative afferent pupillary defect (RAPD). Dilated fundus examination demonstrated bilateral hemorrhagic ODE, right greater than left (Fig. 1A). The bilateral ODE and preserved central acuity was most consistent with papilledema, and she underwent MRI and magnetic resonance venography of the head that revealed filling defects in the bilateral transverse and sigmoid sinuses (Fig. 1B). Automated 24-2 SITAFast visual field testing showed enlarged blind spots and nasal steps in both eyes with an early superior arcuate defect in the right eye (Fig. 1C) Complete blood count was notable for a hemoglobin of 104g/L, white blood cell (WBC) count of 1.7g/L, and platelets of 77 · 109/L. Lumbar puncture demonstrated an opening pressure of 42 cm of water with normal cerebrospinal fluid (CSF) contents. She was started on tinzaparin 20,000 units subcutaneously daily and acetazolamide 500 mg twice per day. Bone marrow biopsy showed few myeloblasts and predominantly abnormal promyelocytes with multiple auer rods and prominent granulation (Fig. 1D). She was diagnosed with APML, and induction treatment with ATRA and ATO was initiated. She tolerated this well, FIG. 1. A 33-year-old woman presented with blurred vision in her right eye for 1 week. Dilated fundus examination revealed bilateral optic disc edema in both eyes (A) and magnetic resonance venography demonstrated filling defects in the bilateral sigmoid and transverse sinuses (B; arrows). Automated 24-2 SITA-Fast visual fields showed enlarged blind spots, nasal steps in both eyes, and superior arcuate defects in the right eye (C). Bone marrow biopsy showed promyelocytes with multiple auer rods (D; black arrows) and promyelocytes with prominent granulation (E). e182 Paxton and Micieli: J Neuro-Ophthalmol 2022; 42: e181-e186 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution and repeat bone marrow biopsy 1 month later showed morphological remission. She then underwent 2 rounds of consolidation treatment with ATRA and ATO and tolerated this well. Neuro-ophthalmology follow-up 12 months after initial presentation revealed a visual acuity of 20/20 in both eyes, and normal automated visual fields and resolution of ODE. Case 2 A 34-year-old man was seen in neuro-ophthalmology consultation for bilateral ODE. He had a medical history of obesity and photorefractive keratectomy for myopia. His presenting complaint was blurred vision in his right eye for 2 weeks. He saw an ophthalmologist who detected bilateral ODE with a few peripapillary hemorrhages and requested a neuro-ophthalmology consultation. At that time, his visual acuity was 20/20 in both eyes, there was no RAPD and automated 24-2 SITA-Fast visual fields were normal. Dilated fundus examination revealed mild bilateral ODE, peripapillary wrinkles in the right eye, and severe nerve fiber layer hemorrhages emanating from the optic nerves that were significantly worse compared with his initial ophthalmology assessment (Fig. 2). The peripheral retina revealed a white-centered hemorrhage in the retina in both eyes (Roth spots). The severe optic disc hemorrhaging and Roth spots prompted an urgent complete blood count that revealed a hemoglobin of 69 g/L, WBC count of 7.5g/L, and platelets of 15 ·109/L. MRI of the brain showed multiple subacute infarcts in the brain and a lesion in the right parietal bone, likely due to leukemic infiltration. Bone marrow biopsy revealed abnormal promyelocytes, irregular and clefted nuclei, auer rods, and prominent granulation in a subset. He was diagnosed with APML and initiated on induction therapy with ATRA and ATO. He achieved morphological remission 1 month later on repeat bone marrow biopsy. He was started on intravenous heparin given the multiple brain infarcts seen on MRI and transitioned to enoxaparin 120mg subcutaneously twice a day. His disease course was complicated by varicella zoster viremia, PCP pneumonia, delirium and anxiety, and methicillin-sensitive Staphylococcus aureus line-infection necessitating intravenous antibiotics. He continued induction treatment with ATRA and ATO. At the 6-month neuro-ophthalmology follow-up appointment, his vision was 20/20, and automated visual fields were normal. The optic disc hemorrhaging and edema had resolved. Case 3 A 24-year-old woman previously healthy woman presented with blurred vision on the left side of her visual field, extreme fatigue, and lethargy. Initial neuro-ophthalmologic examination revealed a visual acuity of 20/20 in both eyes, no RAPD, and a few retinal nerve fiber layer hemorrhages in the retina on dilated fundus examination in both eyes. Automated visual field testing revealed a left homonymous hemianopia (Fig.3A). Complete blood count showed a hemoglobin count of 78g/L, WBC count of 204.8g/L, and platelets of 26 · 109/L, and MRI showed multiple widely distributed brain parenchymal hemorrhages of varying size and age with the largest in the right occipital lobe (Fig. 3C/D). She was transferred to internal medicine and then the intensive care unit and treated urgently with intravenous fluids and started on infusional cytarabine to lower her WBC count. Bone marrow biopsy was consistent with APML on morphological criteria, and she was started on induction chemotherapy with ATRA and ATO. Onemonth after induction chemotherapy, she developed new headache and horizontal binocular diplopia. She was found to have a visual acuity of 20/20, mild bilateral ODE with optic disc hemorrhages, and a mild bilateral abduction deficits. This was related to papilledema and raised intracranial pressure, which resolved with acetazolamide 500mg twice a day and completion of the ATRA induction cycle. The patient continued on maintenance chemotherapy with ATRA and ATO and achieved morphological remission and undetectable PML-RARA transcripts. She pretreated with acetazolamide 500 mg twice a day when she took ATRA. She was seen in neuro-ophthalmology followup 12 months after presentation, and she had a visual acuity of 20/20 in both eyes and improvement in the left homonymous hemianopia (Fig. 3B). There was no ODE, and ocular motility and alignment were normal. CONCLUSIONS FIG. 2. Fundus photographs at neuro-ophthalmology presentation revealing severe hemorrhaging optic disc edema with Roth spots (white arrows). Paxton and Micieli: J Neuro-Ophthalmol 2022; 42: e181-e186 Acute promyelocytic leukemia is a bleeding diathesis characterized by thrombocytopenia, fibrinolysis, and disseminated intravascular coagulation (DIC) (5). Our small case series found hemorrhagic papilledema, ODE, and homonymous visual field defects as rare presenting signs of APML. Although bleeding risk is often a focus in patients with APML, ocular involvement in leukemia has been cited to be between 35% and 64%, with vision changes being most commonly seen in adult AML (8). Retinal vascular changes have been reported to be the most common ocular lesion in leukemia, and one study found only 2% of e183 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Automated 24-2 SITA-Fast visual field testing at presentation revealing a left homonymous hemianopia (A). MRI FLAIR postcontrast (C) and T1 postcontrast (D), revealing a right occipital lobe hemorrhage. patients with any type of leukemia had neuroophthalmologic findings, and of these, all had already received their diagnosis before being evaluated (9). Furthermore, direct infiltration of the optic nerve itself is considered to be relatively rare and has been documented during disease recurrence, not initial diagnosis (10,11). Based on the literature, neuro-ophthalmologic manifestations leading to a diagnosis of AML, specifically APML, are incredibly rare. In addition to our cases, a review of the literature revealed 8 cases where a diagnosis of APML was made after ophthalmologic or neuro-ophthalmologic manifestations (8,12–18). The cases are summarized in Table 1. The mean age was 36 (range 11–59) years, with 5 patients presenting with unilateral blurry vision, 2 patients with bilateral decreased vision, and 1 patient with unspecified blurred vision. Neuro-ophthalmologic signs were only observed in 2 of these patients, which were papilledema and an RAPD. Concurrent with the literature, retinal hemorrhage was the most common finding during ophthalmologic evaluation in these cases, seen in 5 patients (62.5%). It is worth noting that patients undergoing ATRA therapy may also develop papilledema, usually as a manifestation of psuedotumour cerebri. The mechanism is believed to be related to an excess of Vitamin A, which enhances CSF production while also impairing absorption at the arachnoid villi. This is an uncommon side effect of ATRA therapy documented in many case reports and literature reviews (19,20). e184 Thrombotic events (TEs) are also a problem encountered in patients with APML. The mechanism behind thrombosis in APML is complex and still being investigated. DIC likely plays a role because it can lead to microvascular occlusion by fibrin thrombi in the acute setting (21). Furthermore, leukemic promyelocytes themselves express tissue factor which helps initiate the extrinsic pathway of the coagulation cascade (22). Treatment with ATRA may also increase the risk of thrombosis as it increases expression of adhesive molecules on promyelocytes and endothelium, while also increasing the risk of differentiation syndrome which has been associated with a higher incidence of thrombosis and coagulopathy (23,24). Prevalence of TE has been reported to occur in up to 20.9% of patients, which has been on the rise since the pre-ATRA era where only approximately 2% of patients were affected (23). A comprehensive review by Rashidi et al demonstrated that the most common types of APML-related thromboses are DVT/PE, cardiac, and cerebrovascular accident. Furthermore, arterial thrombosis was found to be more common than venous thrombosis (54.9% vs 45.1%). More specifically, cerebral venous sinus thrombosis was relatively uncommon, occurring in 7/94 (7.4%) of patients (25). This highlights the variety of ocular manifestations that can lead to a diagnosis of APML. The role of the ophthalmologist in diagnosing or managing acute leukemia usually falls secondary to that of Paxton and Micieli: J Neuro-Ophthalmol 2022; 42: e181-e186 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Case reports in the literature of ophthalmologic and neuro-ophthalmologic symptoms leading to APML diagnosis Signs on Ophthalmologic Examination Age/Sex Presenting Visual Symptoms 11/M12 Bilateral vision loss (NLP) Bilateral papilledema Retinal hemorrhages 40/F13 Blurred vision 59/M14 Visual disturbance OD 44/F15 Unilateral loss of VA 14/M16 Unilateral vision loss OD Bilateral retinal hemorrhage OD: retinal hemorrhage Cotton wool spot OS: intraretinal hemorrhage Retinal hemorrhage Retinal detachment OD: macula-off RD Vitreous hemorrhage RAPD 30M8 Blurry vision OU 42/F17 Decreased vision OS 43/F18 Vision loss OS Bilateral intraretinal and peripheral hemorrhages; BRVO OS: retinal hemorrhage OD: retinal edema Retinal hemorrhage Preretinal hemorrhages OS: serous RD *33/F Blurry vision OD Bilateral papilledema *34/M Blurry vision OD Bilateral ODE Bilateral Roth spots *24/F Blurry vision OS Left homonymous hemianopia Treatment Initial VA Final Outcomes Final VA Heparin IV Chemotherapy Steroids Mannitol N/A N/A N/A Death N/A N/A N/A Appropriate supportive and specific therapy (unspecified) OD 20/60 OS 20/17 OD 20/20 Retinal hemorrhages partially resolved Idarubicin ATRA ATRA MTX Idarubicin ATO ATRA Cytarabine N/A N/A APML remission OD LP OS 20/30 OD LP APML remission OD 20/25 OS 20/50 N/A Treatment with arranged follow-up ATRA Fibrinogen concentrate OD 20/160 OS CF 1m N/A Death ATRA OD 20/13 OS 20/25 OD 20/20 OS 20/20 OD 20/13 OS 20/20 OD 20/20 OS 20/20 APML remission RD resolved APML remission ODE resolved OD 20/20 OS 20/20 N/A OD 20/20 OS 20/20 OD 20/20 OS 20/20 APML remission ODE and hemorrhaging resolved APML remission Homonymous hemianopia improvement ATRA and ATO Tinzaparin Acetazolamide ATRA and ATO Heparin IV to enoxaparin SC ATRA and ATO Acetazolamide *Denotes our patients. APML, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; ATO, arsenic trioxide; IV, intravenous; LP, light perception; MTX, methotrexate; NLP, no light perception; ODE, optic disc edema; OD, right eye; OS, left eye; RAPD, relative afferent pupillary defect; RD, retinal detachment; RNFL, retinal nerve fiber layer; SC, subcutaneous; VA, visual acuity. an hematologist. However, bleeding as a manifestation of APML can first present itself in the eye. Hemorrhage is also one of the main causes of early death in APML, which is defined as death within 30 days of diagnosis and starting treatment (1). Thus, bleeding represents a significant obstacle in achieving a cure for APML. It is worth noting that ocular manifestations of leukemia tend to occur at an advanced state of disease (12), and ocular involvement has also been linked to a poorer prognosis in acute leukemia compared with cases without. However, prompt recognition and administration of ARTA have been linked to decreasing the early death rate, specifically from bleeding, in patients with APML (26). Initially, older chemotherapybased regimens with anthracyclines such as daunorubicin had a 61% survival rate at 9 years postdiagnosis (27). Currently, quick recognition and treatment with modern therapies such as ATO/ATRA, or ATRA/idarubicin have turned APML into the most curable form of leukemia in Paxton and Micieli: J Neuro-Ophthalmol 2022; 42: e181-e186 adults. Prognosis is excellent with 90% of patients achieving complete remission, and 80% being permanently cured (2). This underscores the critical role of the ophthalmologist when it comes to recognizing possible signs, no matter how rare, of hematologic disease in the eye. This case series illustrates that ophthalmologic and neuro-ophthalmologic symptoms may be the first manifestations of APML in patients. 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Date | 2022-03 |
Language | eng |
Format | application/pdf |
Type | Text |
Publication Type | Journal Article |
Source | Journal of Neuro-Ophthalmology, March 2022, Volume 42, Issue 1 |
Collection | Neuro-Ophthalmology Virtual Education Library: Journal of Neuro-Ophthalmology Archives: https://novel.utah.edu/jno/ |
Publisher | Lippincott, Williams & Wilkins |
Holding Institution | Spencer S. Eccles Health Sciences Library, University of Utah |
Rights Management | © North American Neuro-Ophthalmology Society |
ARK | ark:/87278/s6xreeae |
Setname | ehsl_novel_jno |
ID | 2197458 |
Reference URL | https://collections.lib.utah.edu/ark:/87278/s6xreeae |