Vitamin A as a Cause of Pseudotumor Cerebri Syndrome: Not to Be Forgotten

Trainees’ Corner Section Editors: Vivek R. Patel, MD Prem Subramanian, MD, PhD Vitamin A as a Cause of Pseudotumor Cerebri Syndrome: Not to Be Forgotten Jonathan S. Fuerst, MD, Robert C. Wann, MD, Lanning B. Kline, MD R eports of vitamin A causing the symptoms of pseudotumor cerebri syndrome (PTCS) date back to 1596 when Dutch artic explorers ate large amounts of polar bear liver (1). However, it was not until the 1960s that hypervitaminosis A was widely reported as a cause of PTCS (2). Given this causal relationship, large doses of vitamin A are avoided in clinical care whenever possible. Yet, the use of all-trans retinoic acid (ATRA), a vitamin A derivative, is an essential part of the treatment regimen for patients with acute promyelocytic leukemia (PML) (3). Although the association of ATRA causing PTCS is well described in the oncology and neurology literature, there are relatively few reports in the ophthalmology literature, especially in recent years (4–6). We describe 2 patients with PML treated with ATRA, to highlight the clinical profile and management options of this particular cause of PTCS. CASE 1 A 25-year-old woman was admitted to the hospital having recently been diagnosed with PML. Induction chemotherapy consisted of gemtuzumab and ozogamicin, followed by hydroxyurea, ATRA, and arsenic trioxide. She developed disseminated intravascular coagulopathy precipitated by PML and reported headaches accompanied by nausea and vomiting. She had no visual complaints. Ophthalmology was consulted to perform a dilated fundus examination assessing for retinal hemorrhages in the setting of disseminated intravascular coagulation. At the time of ophthalmic examination, the patient was on the fifth day of ATRA, taking oral doses of 40 mg each morning and 50 mg each evening. Visual acuity was 20/20 bilaterally with normal color vision and pupillary reactions. Eye movements were intact and anterior segment examination was normal in both eyes. Automated perimetry demonstrated an enlarged blind spot in the right eye and a nasal field defect in the left eye (Fig. 1), whereas ophthalmoscopy revealed bilateral Frisen Grade 3 optic disc edema with retinal hemorrhages (Fig. 2). Brain MRI and magnetic resonance venography (MRV) were unremarkable while her lumbar puncture showed an Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, Alabama. Address correspondence to Lanning B. Kline, MD, Department of Ophthalmology, Sute 601, 700 South 18th Street, Birmingham, AL 35233; E-mail: [e-mail] Fuerst et al: J Neuro-Ophthalmol 2021; 41: e403-e406 opening pressure of 45 cm H2O with normal cerebrospinal fluid (CSF) composition and cytological analysis. Based on previous reports of successful ATRA-induced PTCS treatment, we recommended starting acetazolamide 500 mg twice daily and temporarily reducing ATRA dosing (7). The patient was started on acetazolamide at recommended dosing, and ATRA was stopped for 3 days then restarted at half dose. After 1 week on acetazolamide and half-dose ATRA, the patient had persistent papilledema and moderate headache. Acetazolamide was increased to 500 mg 3 times daily, and ATRA was continued at half dosing. Two weeks later, there was marked improvement in her papilledema from Frisen Grade 3 to Grade 1. Half-dose ATRA treatment was continued for another 4 weeks until beginning the first round of consolidation therapy. This consisted of 8-week cycles of full-dose ATRA (90 mg in 2 divided doses) for 2 weeks and then no administration of ATRA for 2 weeks. Acetazolamide 500 mg twice daily was given continuously throughout her first treatment cycle. On completion of the patient’s first treatment cycle, her acuity remained 20/20 bilaterally with full visual fields and normal fundusscopy. She had no headache or visual symptoms, and the decision was made to discontinue the acetazolamide therapy at that time. She remained without papilledema and symptom-free during her second consolidation treatment, but during her third treatment cycle, she did report headaches and pulsatile tinnitus to her oncologist. Those symptoms resolved with completion of her third treatment cycle. She is to begin her fourth and final treatment cycle soon. There has been no recurrence of her papilledema. CASE 2 A 22-year-old man, who had been previously diagnosed with PML 6 weeks earlier, was evaluated for a 1-week history of blurred vision and diplopia. He had been undergoing induction therapy with arsenic trioxide and ATRA 40 mg in the morning and 50 mg in the evening for the past 6 weeks. On examination, visual acuity was 20/20 bilaterally with normal pupillary responses and color vision. There were bilateral sixth nerve palsies with 25% abduction deficit in both eyes and otherwise full extraocular movements. Visual fields showed blind spot enlargement in the right eye (Fig. 3), and fundus examination was notable for Frisen Grade 2 optic disc edema (Fig. 4). e403 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner FIG. 1. Case 1. Automated visual fields (Humphrey 24-2) demonstrate enlargement of the right blind spot and nasal field loss in the left eye. Brain MRI and computed tomographic venography were normal. The oncology team, to whom the patient was admitted, decided to defer a lumbar puncture, believing that the risk of the procedure outweighed the diagnostic benefit. Involvement of the central nervous system from PML was believed to be unlikely, and the patient’s papilledema was most likely due to the use of ATRA. Therefore, the patient’s oncology team discontinued ATRA and started acetazolamide 250 mg twice daily. Two weeks later, acuity remained 20/20 in each eye, eye movements were full, and there was improvement in the bilateral papilledema from Frisen Grade 2 to Grade 1. Six weeks later, the patient’s ATRA was restarted at the previous dose for a 2week cycle, followed by 2 weeks of no treatment. Acetazolamide 250 mg twice daily was continued for 4 more weeks and then discontinued. Acetazolamide and ATRA regimens were managed by the patient’s oncology team, who proposed that 2-week cycles of ATRA during consolidation cycles mitigated the risk of PTCS and in mild cases of PTCS, acetazolamide can be discontinued. Currently, the patient continues on 2-week cycles of ATRA therapy without acetazolamide and has had no further headaches or visual complaints. Promyelocytic leukemia is an aggressive myeloid malignancy characterized by a translocation gene between chromosomes 15 and 17 and termed the PML-RARa fusion gene (8). The protein produced by this chimeric gene prevents activation of target genes required for normal myeloid differentiation. This leads to accumulation of promyelocytes in the blood and bone marrow. ATRA induces terminal differentiation of promyelocytic cells by cleaving the PML-RARa oncoprotein (9). When combined with arsenic trioxide or chemotherapeutic agents (“differentiation therapy”), complete recovery from PML is achieved in more than 90% of patients (10–12). FIG. 2. Case 1. There is bilateral Frisen Grade 3 optic disc edema with retinal hemorrhages. e404 Fuerst et al: J Neuro-Ophthalmol 2021; 41: e403-e406 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner FIG. 3. Case 2. Automated visual fields (Humphrey 24-2) demonstrate enlargement of the blind spot in the right eye. The successful use of ATRA in the treatment of PML was first described in the 1980s (13). This was followed by reports demonstrating an association between ATRA and PTCS (14). Initially, this was believed to only occur in pediatric patients (15), but subsequently, it became clear that this can occur in the adult population as well (6). There are few publications in the ophthalmology literature documenting ATRA as a cause of PTCS. In 2003, Colucciello (4) described a 30-year-old man who experienced headaches and diplopia beginning 14 days after initiation of ATRA for PML. Vision was 20/20 in each eye, left sixth nerve palsy was present, and there was bilateral optic disc edema. Brain MRI was unremarkable. Lumbar puncture showed an opening pressure of 22.5 cm H2O with normal composition of cerebrospinal fluid (CSF). ATRA was discontinued for 6 weeks and the patient’s headaches, diplopia, and papilledema resolved. Guirgis and Lueder (5) reported 2 patients (ages 16 and 17 years) who developed PTCS after treatment with ATRA for PML. In both cases, the clinical evaluation was consistent with PTCS, and both had resolution of their papilledema with the use of acetazolamide while remaining on ATRA. Finally, Yeh et al (6) reported a 27-year-old woman receiving ATRA for PML who complained of blurred vision and headache. Once again, the clinical course was that of PTCS. ATRA was stopped and within 4 weeks the patient’s papilledema had resolved. The association of ATRA causing PTCS has been well established in the neurology and oncology literature (16– 21). Reported patients’ age ranged from 8 to 35 years, with no sex predilection. The clinical course is quite stereotypical, with patients complaining of headache, blurred vision, and, at times, diplopia. Symptoms may appear within a day of starting ATRA. Visual acuity typically is normal, visual fields are full with the exception of enlarged blind spots, and there is bilateral papilledema. Diplopia is due to sixth nerve FIG. 4. Case 2. There is bilateral Frisen Grade 2 optic disc edema. Fuerst et al: J Neuro-Ophthalmol 2021; 41: e403-e406 e405 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner palsy as a nonlocalizing sign of raised intracranial pressure. Neuroimaging studies are unremarkable, whereas lumbar puncture shows an elevated opening pressure with normal CSF constituents. These patients have a favorable prognosis for vision, and none have been reported to have residual deficits of visual function. There are a variety of treatment options for PTCS caused by ATRA. In most patients, ATRA is discontinued for a short period and/or dosing is reduced. In others, various medications for PTCS have been used, including acetazolamide, topiramate, and corticosteroids (7,12,16,20). However, in some instances, acetazolamide alone along with temporarily reducing ATRA dosing was successful at resolving headaches and papilledema. In evaluating patients undergoing treatment for PML who develop headache, diplopia, and papilledema, other potential causes must be considered. These include leukemic infiltration of the central nervous system (CNS), intracranial hemorrhage, and cerebral venous sinus thrombosis. The diagnostic studies of greatest importance are brain MRI and MRV. If both are normal, a lumbar puncture is required to measure the opening pressure and perform cytological analysis of the CSF. The mechanism by which ATRA causes raised intracranial pressure remains to be established. ATRA is enzymatically derived from vitamin A and regulates transcription of more than 500 retinoid-responsive genes (22,23). 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