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Show Topiramate-Induced Palinopsia: A Case Series and Review of the Literature Samuel H. Yun, MD, Patrick J. Lavin, MD, Martha P. Schatz, MD, Robert L. Lesser, MD Background: To report palinopsia as a possible side effect of topiramate. Methods: Case series and review of the literature. Results: Nine patients in our series, and 4 previously reported patients, who developed palinopsia while on top-iramate, are reviewed. All patients were women, and comorbidities included migraine, idiopathic intracranial hypertension, and bulimia nervosa. Palinopsia resolved in 8 patients after stopping or decreasing the dose of top-iramate. The lowest dose of topiramate causing palinopsia was 25 mg twice a day. More than half of our patients reported exacerbation of visual disturbance in early morning or late evening. Conclusions: Topiramate-induced palinopsia may be under-diagnosed because physicians do not inquire about such visual symptoms. Journal of Neuro-Ophthalmology 2015;35:148-151 doi: 10.1097/WNO.0000000000000216 © 2015 by North American Neuro-Ophthalmology Society Palinopsia is the persistence or recurrence of visual images after the initial stimulus has been removed and is believed to be caused by failure to suppress after images (1,2). It may be due to dysfunction of the coordinate systems of the parietal lobes (3). Typical symptoms of palinopsia include echoing, ghosting, multiple images, smearing, streaming, trailing, or vibrating of the initial image. Palinopsia may occur in otherwise normal patients (4) or those with migraine (5), epilepsy (6), mitochondrial disease (7), diseases affecting parieto-occipital pathways (8), multiple sclerosis (9), non-Hodgkin's lymphoma (10), stroke (11), glioma (12) metabolic disorders (carbon monoxide poisoning [13] and nonketatic hyperglycemia [14]), drugs including marijuana (15), mescaline (16), lysergic acid diethylamide (LSD) (17), methylenedioxymethamphetamine (MDMA) (18), interleukin (19), trazodone (20), zonisamide (4), nefa-zodone (21), clomiphene (22), and topiramate (23-25). Topiramate is an antiepileptic drug with multiple mechanisms of action including: 1) blocking the repetitive action of sodium channels and L-type calcium channels, 2) potentiating gamma-aminobutyric acid inhibition, 3) mod-ulating glutamate receptors, and 4) inhibiting carbonic anhydrase (26,27). It is frequently used to treat epilepsy, migraine prophylaxis (28), and, occasionally, for idiopathic intracranial hypertension (29). Common side effects of topiramate therapy include paresthesia, fatigue, anxiety, cognitive impairment, and dizziness (27). Ocular side effects include increasing myopia and angle closure glaucoma (30). We report 9 cases of topiramate-induced palinopsia (Table 1) and present 3 illustrative cases. CASE REPORTS Case 1 A 42-year-old woman with history of migraine since adolescence, on topiramate for about a year, complained of "tracer vision." She reported that after moving her arm, she continued to see images of the arm moving for a few seconds. The images were noticeable particularly with movement of her arms but not with movement of her legs or other objects. Her symptoms were worse in the morning and improved later in the day. The symptoms improved, but did not resolve completely, after stopping topiramate. She had no history of seizures, significant head injury, or illicit drug use. She had taken trazodone for many years but Department of Ophthalmology and Visual Sciences (SHY, RLL), Yale School of Medicine, New Haven, Connecticut; Departments of Neurology, and Ophthalmology and Visual Sciences (PL), Vanderbilt University School of Medicine, Nashville, Tennessee; and Depart-ment of Ophthalmology (MS), University of Texas Health Science Center, San Antonio, Texas. Supported by an unrestricted grant from Research to Prevent Blindness, Inc (Vanderbilt and Yale) and in part by the Connecticut Lions Eye Research Foundation (Yale). The authors report no conflicts of interest. Address correspondence to Samuel H. Yun, MD, Department of Ophthalmology and Visual Sciences, Yale University School of Medicine, 40 Temple Street suite 3B, New Haven, CT 06511; E-mail: huisokyun@gmail.com 148 Yun et al: J Neuro-Ophthalmol 2015; 35: 148-151 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Reported cases of topiramate-induced palinopsia Report Age Gender Indication Topiramate Dose* Resolution Exacerbation Palinopsia Description† Other Possible Causes Evans (24) Case 1 57 F Migraine with aura 200 mg QHS 25 mg QAM Resolved 23 d Morning "Multiple hands" or "multiple people" Migraine/ trazodone Case 2 43 F Migraine 75 mg QD Resolved 4 d Night/dark "Shadow images of objects" Migraine Fontenelle (23) 35 F Bulemia/alcohol abuse 100 mg QD NR NR "Frozen pictures" - Sierra-Hidalgo and de Pablo- Fernandez (25) 23 F Migraine with aura 50 mg QHS Resolved 6 d Morning "Frame by frame" Migraine Yun Case 1 42 F Migraine with aura NR Improved after cessation Morning "Tracer vision" Migraine/ trazodone Case 2 36 F Idiopathic intracranial hypertension 50 mg BID NA‡ NR "Tracing of images" - Case 3 40 F Migraine without aura 200 mg QD Improved at 100 mg QD NR "Objects leave a trail as in cartoon" Migraine Case 4 33 F Idiopathic intracranial hypertension 100 mg QID Resolved after cessation NR "Tracer/shutter vision" - Case 5 40 F Migraine 100 mg QHS NA‡ Early morning or late night "Echo line" Migraine Case 6 58 F Migraine 50 mg TID Resolved at 50 mg BID Early morning "Multiple snapshots" Migraine Case 7 34 F Migraine 100 mg QD Resolved at 50 mg QD NR NR Migraine Case 8 34 F Migraine 200 mg QHS Resolved at 100 mg BID Evenings "Trailing or smearing" Migraine Case 9 49 F Migraine 25 mg BID Resolved spontaneously NR NR Migraine/ trazodone *Lowest dose of topiramate in which palinopsia was observed. †Description of palinopsia in patient's own words. ‡Patient preferred to stay on the medication. BID, twice daily; d, days; NA, not applicable; QAM, every day before noon; QD, every day; QHS, every night at bedtime; NR, not reported; TID, three times a day. Yun et al: J Neuro-Ophthalmol 2015; 35: 148-151 149 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. did not develop palinopsia until on topiramate. Magnetic resonance imaging (MRI) of the brain was normal. Case 3 A 40-year-old woman presented with a diagnosis of migraine without aura and history of a pretectal glioma. She had tried multiple medications to control headache including tricyclic antidepressants, beta-blockers, ergotamine, antiepileptics, calcium-channel blockers, nonsteroidal anti-inflammatory medications, triptans, serotonin receptor inhibitors, muscle relaxants, narcotics, steroids, benzodiazepines, and neuro-leptics. She developed palinopsia when she was prescribed topiramate, 200 mg daily. She reported that objects left a trail as in cartoons and persistence of an image when she looked away from it. In addition to palinopsia, she complained of poor concentration and memory and word-finding difficulty. At her 5 years follow-up appointment, she reported signif-icant improvement of symptoms, although she was still taking topiramate 100 mg daily. Case 6 A 58-year-old woman with history of left frontal meningi-oma and migraine presented with palinopsia. After her topiramate dose was increased from 50 mg twice a day to 3 times a day, she reported seeing "multiple snap shots" of hands as from the movie "Look Who's Talking." This occurred every other day, most notably early in the morning after awakening from sleep. Once the dose of topiramate was decreased to 50 mg twice a day, her palinopsia resolved. Brain MRI showed a left frontal meningioma that was unchanged from previous scans. DISCUSSION Our 9 patients and the 4 patients previously reported developed palinopsia while on topiramate. All patients were women, 76.9% had migraine, 15.4% had idiopathic intra-cranial hypertension, and 7.7% had bulimia nervosa (Table 1). The preponderance of women in our series is likely due to the fact that the associated disorders are more common in women. The lowest dose of topiramate that caused palinopsia was 25 mg twice a day. Symptoms resolved in 8 patients after stopping or reducing the medication. More than half of our patients had palinopsia in early morning or late evening. We do not have an explanation for this finding. Topiramate, like other systemic drugs that induce palinop-sia, may inhibit neural activity. Palinopsia may occur in patients with a predisposition to decreased speed of visual processing with additional decreased neural activity from a central nervous system suppressant such as topiramate. Alternatively, Dubois and Vanrullen (31) proposed failure of motion streak suppres-sion as a possible mechanism of palinopsia. Topiramate affects sodium and calcium ion channels, impairs glutamate transmission and carbonic anhydrase function, and also potentiates gamma-aminobutyric acid inhibition (26,27). The pathophysiology of palinopsia has been proposed to be an increase in serotonergic activity secondary to 5-HT2 receptors. Several drugs associated with palinopsia affect 5-HT2 receptor including LSD, MDMA, nefazodone, trazodone, risperidone, zonisamide, and mirta-zapine (18,23,25,32). Weight loss seen in patients on top-iramate also may be secondary to 5-HT2c receptor activation (16,33). Topiramate also inhibits CYPD6 gene (34), which may precipitate the serotonin syndrome (35). Some of our patients presented with potential confound-ing risk factors for developing palinopsia. Case 1 was on trazodone chronically. Although the patient developed palinopsia only after starting on topiramate, trazodone may have potentiated the effect of topiramate. Case 9 also had taken trazodone before starting topiramate, but with symp-toms again developing only after starting topiramate. Seven patients also had migraine as a potential confounding factor. In 8 of 9 patients, symptoms either improved after decreasing the dose or resolved after lowering the dose or stopping topiramate. Two patients (Cases 2 and 5) preferred to stay on topiramate to control their headache despite persistent palinopsia. In one patient, palinopsia did not resolve after stopping the medication, perhaps because of use of trazodone. The time between starting topiramate and onset of palinopsia could not accurately be documented. In most cases, the time course was either omitted or described as "briefly" or "soon after." In Case 4, the time of onset was documented as 3 months after starting the medication. 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