Intracranial Hypertension Induced by Megestrol Acetate Withdrawal

Intracranial hypertension has been associated with endocrine dysregulation in conditions such as obesity, pregnancy, oral contraceptive use, excess of Vitamin A, Addison disease, and corticosteroid use/withdrawal (1-6). Megestrol acetate (MA), commercially known as Megace, is a synthetic progesterone used as an appetite stimulant for cachexia secondary to cancer or AIDS and more recently used to treat failure to thrive (FTT) in the pediatric population (7-10). MA administration has been linked to adrenal insufficiency with variable clinical presentations (10-13). The use of MA in our patient links MA usage with intracranial hypertension.

Clinical Correspondence Intracranial Hypertension Induced by Megestrol Acetate Withdrawal Laraib Z. Safeer, BS, Madhuri Chilakapati, MD, Veeral S. Shah, MD, PhD I ntracranial hypertension has been associated with endocrine dysregulation in conditions such as obesity, pregnancy, oral contraceptive use, excess of Vitamin A, Addison disease, and corticosteroid use/withdrawal (1-6). Megestrol acetate (MA), commercially known as Megace, is a synthetic progesterone used as an appetite stimulant for cachexia secondary to cancer or AIDS and more recently used to treat failure to thrive (FTT) in the pediatric population (7-10). MA administration has been linked to adrenal insufficiency with variable clinical presentations (10-13). The use of MA in our patient links MA usage with intracranial hypertension. A 6-year-old boy developed diplopia, headaches, and optic disc edema. A neuro-ophthalmic evaluation was requested due to concerns of elevated intracranial pressure. His medical history was significant for sleep apnea with apneic episodes and a subtotal adenoidectomy. At the time, his parents denied that their son was taking any medications. His general physical examination was normal. Visual acuity was 20/25 in right eye and 20/25 in the left eye with a normal pupillary reactions, full color vision, and intact visual fields on confrontational testing of both eyes. He had an esotropia of 16 prism diopters with an abduction deficit in the right eye. On funduscopy there was mild bilateral optic disc edema (Fig. 1). The patient's body mass index was 13.4 kg/m2. MRI/magnetic resonance venography studies were unremarkable. A lumbar puncture showed an opening pressure .45 cm of H2O. After the procedure, he developed CSF hypotension requiring a blood patch and was prescribed acetazolamide, 250 mg twice daily. Over the next 2 weeks, diplopia, lethargy, and headaches persisted despite increased doses of acetazolamide. At 2-week follow-up, his mother recalled that the Department of Ophthalmology (LZS, MC, VSS), Baylor College of Medicine, Texas Children's Hospital, Houston, Texas. Supported in part by the clinical programs at Texas Children's Hospital-Baylor College of Medicine, Houston, Texas. The authors report no conflicts of interest. Address correspondence to Veeral S. Shah, MD, PhD, Department of Ophthalmology, Baylor College of Medicine, Texas Children's Hospital, 6701 Fannin, Suite 610.25, Houston, TX 77030; E-mail: [e-mail] Safeer et al: J Neuro-Ophthalmol 2019; 39: 107-110 patient had been taking MA as an appetite stimulant for almost 2 years. It was discontinued 3 weeks before his initial presentation. A repeat lumbar puncture showed an opening pressure of 46 cm of H2O. Concern for hypocortisolism led to an endocrine consult. Further testing revealed a cortisol level ,0.2 mg/dL (normal = 2-21 mg/ dL) and ACTH hormone ,5 pg/mL (normal = 9-57 pg/ mL). An ACTH stimulation test yielded results of ,0.2, 1.4, and 1.9 mg/L at 0, 30, 60 minutes, respectively. Testing for renin and 21-hydroxylase antibodies yielded normal results. Collectively, these findings were consistent with central adrenal insufficiency. He was discharged on acetazolamide 500 mg twice a day and daily hydrocortisone replacement. At his 4-month examination, his sixth-nerve palsy and papilledema had resolved (Fig. 2). He was tapered off acetazolamide and hydrocortisone over the following year. At the 1-year follow-up, his baseline ACTH was 27 pg/mL and an ACTH stimulation test showed normal results. Our patient received MA for 2 years as an appetite stimulant for his FTT before discontinuing the medication 3 weeks before presentation. The refractory nature of his intracranial hypertension to acetazolamide suggested an underlying systemic abnormality. Low serum cortisol, ACTH, and an abnormal ACTH stimulation test confirmed the diagnosis of central adrenal insufficiency. Laboratory evaluation of 21-hydroxylase antibody testing and normal renin level ruled out Addison disease and mineralocorticoid deficiency. The differential diagnosis for central adrenal insufficiency includes exogenous glucocorticoids, genetic mutations (TPIT/ POMC genes), pituitary tumor, and postpartum pituitary gland necrosis (Sheehan syndrome) (9). Prepubescent, young males with no weight association may present with endocrine abnormalities including hypocortisolism (14). In our patient, the presumed mechanism for intracranial hypertension was chronic use of exogenous glucocorticoids with an abrupt discontinuation resulting in steroid withdrawal syndrome (4). Previous studies have demonstrated that MA is not only a significant activator of the progesterone receptor, but also has a very strong binding affinity to glucocorticoid receptors (15-17). It is this inherent glucocorticoid-like effect that causes direct suppression of 107 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Initial examination demonstrates mild bilateral optic disc edema (A) and thickening of the retinal nerve fiber layer on optical coherence tomography (B). OD right eye; OS left eye. 108 Safeer et al: J Neuro-Ophthalmol 2019; 39: 107-110 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. A follow-up examination at 4 months shows resolution of optic disc edema (A) and normal retinal nerve fiber layer thickness (B). OD right eye; OS left eye. Safeer et al: J Neuro-Ophthalmol 2019; 39: 107-110 109 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence the hypothalamus-pituitary axis resulting in low serum ACTH and cortisol levels. MA is an effective appetite stimulant and can help restore nutritional value to critically ill patients. This association has not previously been reported because of the lack of detection or masking of symptoms due to the severity of the primary disease in a palliative population. Children, in particular, are sensitive to MA-associated adrenal suppression. In a pediatric oncology study, in which MA was administered to 19 children with malignant disease, all patients showed signs of moderate to severe adrenal suppression, with one child going into adrenal crisis (10). Adrenal suppression can occur while receiving or withdrawing MA therapy. These findings strongly support using more conservative methods for treating FTT. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: V. S. Shah; b. Acquisition of data: V. S. Shah and M. Chilakapati; c. 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