Reversal of Anisocoria in Horner Syndrome Following Commencement of Oral Reboxetine, a Selective Norepinephrine Reuptake Inhibitor

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Reversal of Anisocoria in Horner Syndrome Following Commencement of Oral Reboxetine, a Selective Norepinephrine Reuptake Inhibitor Blake D. Colman, MBBS, Anthony J. Fok, MBBS, FRACP, Randy H. Kardon, MD, PhD H orner syndrome results from an interruption to the sympathetic nerve supply to the eye and is characterized by the classical triad of ipsilateral miosis, partial ptosis, and anhidrosis. The etiology varies across age groups and is classified by location in relation to the superior cervical ganglion, although the cause remains unknown in up to 40% of individuals. Pharmacological confirmation of the diagnosis can be made using topical cocaine or apraclonidine, noting a change in pupillary size within the sympathetically denervated pupil. We report a case of anisocoria reversal in idiopathic Horner syndrome, with ipsilateral pupillary dilatation due to the combined action of adrenergic receptor sensitivity and the commencement of reboxetine, an oral selective noradrenaline reuptake inhibitor. A 24-year-old woman with a diagnosis of right idiopathic Horner syndrome made 8 years prior presented with an enlarged right pupil. Her medical history consisted of depression requiring electroconvulsive therapy 12-months prior, while her medications included reboxetine, mirtazapine, and quetiapine. Idiopathic Horner syndrome was initially diagnosed by an ophthalmologist in 2014 after presenting with new right miosis and partial ptosis, pharmacologically confirmed at the time with 0.5% apraclonidine. A photograph taken 1 year earlier demonstrated evidence of partial ptosis and miosis, not evident on photographs prior. MRI of her brain, neck, and upper chest did not identify a cause. Over 10 months, she had noticed an enlarged right pupil, corresponding with the commencement of reboxetine. There was no change in vision, headache, or pain, and there had been no concurrent anticholinergic use or any exposure to belladonna alkaloid plants. Her visual acuity was 6/6 with normal color vision and confrontational visual fields in each eye. Pupils measured 3 mm in the right eye and 2.5 mm in the left eye in light and 7 mm in the right eye and 5 mm in the left eye in dark. Palpebral fissure distance measured 10 mm in the right eye and 11 mm in the left. There was no relative afferent pupillary defect, and funduscopy was normal. She had normal fixation, saccades, pursuits, and full range of extraocular movements. The remainder of her cranial nerve, and upper and lower limb examination were normal. Apraclonidine was again used to confirm the presence of a Horner syndrome, demonstrated by dilatation of her right pupil by 0.5 mm and an increase in palpebral fissure (Fig. 1). We hypothesized that reboxetine had caused right pupillary dilatation by action of a systemic adrenergic agent in the context of adrenergic supersensitivity. We asked the patient to take photographs of her pupils before and after reboxetine use (Fig. 2). Both the right pupil and the palpebral fissure were widest 1 hour after oral reboxetine. Reboxetine, the first serotonin noradrenaline reuptake inhibitor used in the treatment of depression, primarily acts by binding to the noradrenaline transporter, inhibiting Department of Neuroscience (BDC), Central Clinical School, Faculty of Medicine, Nursing and Health Science, Monash University, Melbourne, Victoria, Australia; Department of Neurology (BDC), Alfred Hospital, Melbourne, Victoria, Australia; Department of Neurology (BDC, AF), Royal Melbourne Hospital, Melbourne, Victoria, Australia; Department of Neuro-Ophthalmology (BDC, AF), Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia; and Department of Ophthalmology and Visual Sciences (RHK), NeuroOphthalmology Division, University of Iowa, Iowa City, Iowa. The authors report no conflicts of interest. Address correspondence to Blake D. Colman, MBBS, Department of Neuroscience, Central Clinical School, Faculty of Medicine, Nursing and Health Science, Monash University, Melbourne, Victoria, Australia 3004; E-mail: [e-mail] Colman et al: J Neuro-Ophthalmol 2024; 44: e261-e262 FIG. 1. Pupillary change observed after administration of 0.5% apraclonidine. A. Baseline pupil size before apraclonidine administration in room light. B. Right dilatation of 0.5 mm after apraclonidine administration in room light. e261 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Prominent right pupil dilatation after administration of oral reboxetine 8 mg. A. Baseline pupil size of .12 hours after the last dose. B. One hour after reboxetine administration. C. Two hours after reboxetine administration demonstrating pupillary enlargement by 2 mm and an increase in vertical palpebral fissure distance by 2.7 mm. noradrenaline reuptake (1). Although exhibiting markedly superior selectivity for the noradrenaline transporter, reboxetine has been demonstrated to show weak affinity for a range of other binding sites, including a1 and a2-adrenergic receptors (2). Repeated administration of reboxetine has been shown in animal models to evoke increased affinity of a1adrenergic receptors toward its natural agonist (3). Although mydriasis has been documented to occur in humans with reboxetine administration in a dose-dependent manner, this was hypothesized to arise secondary to the sympathomimetic effect from noradrenaline reuptake blockade in the iris, present in a normally innervated sympathetic system (4). Horner syndrome is strongly associated with denervation supersensitivity whereby oculosympathetic paresis leads to upregulation of ɑ1-adrenergic receptors in iris dilator muscle fibers (5). Such denervation is used in pharmacological testing with 0.5% apraclonidine, an ɑ-adrenergic agonist that predominantly activates ɑ2 receptors but demonstrates weak ɑ1-adrenergic activity. Oculosympathetic denervation and upregulation of ɑ1-receptors on postsynaptic dilator muscle fibers allows for the weaker ɑ1 action of apraclonidine to act, dilating the pupil and reversing anisocoria (6). In our patient, we suspect the denervated (right) pupil from Horner syndrome demonstrated more pronounced e262 dilatation than the normal innervated pupil from reboxetine through a combination of 2 mechanisms: reboxetine induced increased affinity of upregulated ɑ1-receptors toward its natural agonist and by noradrenaline reuptake inhibition. Such inhibition increases circulating noradrenaline reaching the iris, which then causes a more pronounced dilatation of the sympathetically denervated pupil through adrenergic supersensitivity. Increase in circulating noradrenaline can also occur during exercise and 1 case in the literature has reported a similar reversal of anisocoria during exercise in a patient with Horner syndrome (7). In summary, the temporal association of reboxetine commencement and new ipsilateral mydriasis with photographic evidence of pupil dilatation greatest at 1 hour post intake demonstrates a clear pharmacological explanation for the anisocoria reversal seen in our patient. With the combination of upregulated postsynaptic ɑ1-receptors from denervation supersensitivity, increased affinity of ɑ1receptors toward noradrenaline through circulating reboxetine exposure, and an increase in circulating noradrenaline through reuptake blockade, reboxetine produces a dilatation effect greater in the sympathetically denervated pupil, reversing the anisocoria associated with idiopathic Horner syndrome. REFERENCES 1. 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