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Clinicopathologic Reports, Case Reports, and Small Case Series
July 2003

Pseudotumor Cerebri Induced by All-trans Retinoic Acid Treatment of Acute Promyelocytic Leukemia

Arch Ophthalmol. 2003;121(7):1064-1065. doi:10.1001/archopht.121.7.1064

In acute promyelocytic leukemia (APML), a chromosomal translocation(t(15; 17)) gene rearrangement fuses the retinoic acid receptor (RAR) gene from chromosome 17 and the promyelocytic leukemia (PML) gene from chromosome 15, forming the basis for production of a chimeric (fusion) protein that causes a block in cell differentiation. Molecular diagnosis and follow-up after treatment is now possible with detection of PML/RAR fusion messenger RNA.1

Normally, the RAR gene encodes a member of the nuclear hormone receptor family of transcription factors. After binding retinoic acid, the retinoic acid receptor can promote expression of a variety of genes. However, in APML, the PML/RAR fusion protein tends to suppress gene transcription and blocks differentiation of the promyelocytes. Treatment with the RAR ligand, all-trans retinoic acid (ATRA), relieves the block and promotes differentiation and is associated with an 80% complete remission rate. This report describes the occurrence of pseudotumor cerebri induced by ATRA treatment of APML.

Report of a Case

A 30-year-old man with APML being treated with ATRA had had headaches and diplopia within 2 weeks of the initiation of ATRA treatment. Examination disclosed a visual acuity of 20/15 OU, a left abducens palsy, and a blood pressure of 120/92 mmHg. The fundus picture is shown in Figure 1. The right fundus was similar in appearance. Spontaneous venous pulsations were absent.

Stereoscopic pair showing disc edema, hemorrhage, and circumferential retinal folds temporal to the disc (Paton lines) in the left eye.

Stereoscopic pair showing disc edema, hemorrhage, and circumferential retinal folds temporal to the disc (Paton lines) in the left eye.

A brain magnetic resonance imaging scan showed no abnormalities. Lumbar puncture showed an increased opening pressure (225 cm H2O), but the cerebrospinal fluid showed no cells, no hypoglycorrhachia, and no elevation in the protein concentration.

Treatment with ATRA was discontinued, and the APML was treated with a combination of arsenic trioxide, daunorubicin hydrochloride, and cytosine arabinoside. Over the next 6 weeks, subsequent to and corresponding with the discontinuation of ATRA therapy, the headache, papilledema, and abducens palsy resolved. Treatment with arsenic trioxide, daunorubicin, and cytosine arabinoside was continued for 3 months, and the patient has remained in remission.


The differential diagnosis in this case included meningeal invasion of APML cells that then caused increased intracranial pressure and bacterial meningitis in an immunocompromised (APML) patient. Pseudotumor cerebri (secondary to ATRA treatment) was diagnosed. Abducens palsy and papilledema reversed following discontinuance of treatment with ATRA (the combination of arsenic trioxide, daunorubicin, and cytosine arabinoside were successful in the induction of remission).

In this patient, papilledema was secondary to pseudotumor cerebri induced by treatment with ATRA. Retinoic acid is an oxidized form of retinol (vitamin A). The pathogenesis of pseudotumor cerebri in patients with APML being treated with ATRA is thought to be similar to the mechanism in vitamin A overdose: overdosage of vitamin A is postulated to impair cerebrospinal fluid absorption at the level of the arachnoid villi or granulations.25 Normalization of intracranial pressure resolved other accompaniments of increased intracranial pressure, such as abducens palsy and headache. This case emphasizes the importance of recognition by ophthalmologists of this potential side effect of ATRA in the treatment of APML.

The author has no relevant financial interest in this article.

This study was presented at the Atlantic Coast Retina Conference, January 18, 2002, Philadelphia, Pa.

Corresponding author and reprints: Michael Colucciello, MD, South Jersey Eye Physicians, 509 S Lenola Rd, Suite 11, Moorestown, NJ 08057 (e-mail: retina7@pol.netmichael@macula.us).

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