Acneiform Rash Caused by an Unlikely Drug: Topiramate

Novel Insights from Clinical Practice Skin Appendage Disord 2018;4:25–28 DOI: 10.1159/000477742 Received: March 27, 2017 Accepted: May 22, 2017 Published online: July 6, 2017 Acneiform Rash Caused by an Unlikely Drug: Topiramate Yesenia Bello-Hernández a Jessica Espinoza-Hernández b Gabriela Moreno-Coutiño a a Sección de Micología y b Sección de Dermatopatología, Hospital General “Dr. Manuel Gea González,” Mexico City, Mexico Established Facts • It is necessary to report all adverse effects of a drug to assess its safety and to know how to act in case of an adverse reaction. Novel Insights • Aromatic antiepileptic drugs may cross-react in 40–58% of the cases, so patients with a documented rash to these medications should be prescribed the less likely drug to produce it. This particular case report is useful because there are no reports of skin rashes induced by topiramate used for migraine prophylaxis. Keywords Topiramate · Migraine · Adverse event · Rash Abstract Topiramate is an antiepileptic drug that can also be used for migraine prophylaxis, weight control, and even for methamphetamine dependence; the dosage margin is wide, and the list of side effects is shorter than with other anticonvulsants. We present the case of a 35-year-old man with a disseminated rash of the trunk and extremities after treatment with 25 mg of topiramate daily as a prophylactic migraine treatment. This case report is useful, as this patient was not polymedicated and had a score of 7 on the Naranjo Adverse Drug © 2017 S. Karger AG, Basel E-Mail [email protected] www.karger.com/sad Reaction Probability Scale. The patient was diagnosed as atypical DRESS syndrome and resolved satisfactorily with symptomatic treatment and topiramate withdrawal; slowly, the lesions regressed. He required no further drugs for the dermatologic condition. © 2017 S. Karger AG, Basel Introduction Topiramate is an antiepileptic drug classified in the atypical enzyme-inducing group as this induction is dose dependent. It has also been used for migraine prophylaxis, weight control [1], and even for methamphetamine dependence [2]. Gabriela Moreno-Coutiño, MD Sección de Micología, Hospital General “Dr. Manuel Gea González” Calzada de Tlalpan 4800, Sección XVI Tlalpan, Mexico City 14080 (Mexico) E-Mail gmorenocoutino @ gmail.com Color version available online Color version available online Fig. 1. Maculopapular rash. Fig. 2. Close-up of maculopapular rash. Topiramate is a sulfamate-substituted monosaccharide, and although its mechanism of action in migraine treatment is not fully understood, it does block sodium and calcium channels, increases GABA concentrations, and enhances inhibitory effects, while stabilizing cortical excitability and inhibiting glutamate receptors and carbonic anhydrase [3, 4]. Even though the most common antiepileptic drugs to cause rash are aromatic anticonvulsants, any of them can cause it. For topiramate, the dosage margin is wide. In migraine prophylaxis, the dosage is 25 mg/day, while as an antiepileptic drug the dosage can be as high as 600 mg/ day with a maximum of 1,600 mg/day. The list of side effects is shorter than for other anticonvulsants, but there are still many cases with a wide variety of manifestations. eosinophilia (drug reaction with eosinophilia and systemic symptoms; DRESS syndrome) had to be ruled out. The patient reported unquantified fever, but this could not be corroborated, since whenever we saw the patient he was found normothermic. The complete blood cell count was within normal ranges except for eosinophils that were reported as slightly elevated. The liver function tests were unremarkable, and consequently, an atypical DRESS syndrome was diagnosed. So, the final diagnosis was a drug reaction, with a score of 7 on the Naranjo Adverse Drug Reaction Probability Scale (Table 1). As the dermatosis was asymptomatic, he was conservatively treated with soap substitutes and skin moisturizer, with which the lesions very slowly regressed, and he required no further drugs for the dermatologic condition. Case Report We present the case of a 35-year-old man with the only relevant condition of chronic migraine unmanageable with analgesics. He initiated treatment with 25 mg topiramate daily as a prophylactic migraine treatment with good therapeutic response. After 10 weeks of treatment, he sought dermatological attention for an asymptomatic rash spread over the trunk and received prednisone 50 mg daily for 2 weeks, tapering the dosage. The lesions resolved but soon reappeared after steroid discontinuation. Now, the lesions were spread over the trunk and extremities. They appeared as erythematous papules, some confluent and with eczematous appearance (Fig. 1, 2), and continued to be asymptomatic. This time, a punch biopsy was performed, and the histological report was of a vacuolar interface dermatitis with superficial lichenoid infiltrate by lymphocytes and eosinophils (4.2%, with a normal range of 1–4%), for which hypersensitivity syndrome with 26 Skin Appendage Disord 2018;4:25–28 DOI: 10.1159/000477742 Conclusions Despite the fact that this drug has almost ideal pharmacokinetic properties (the same as gabapentin and vigabatrin) as it is rapidly absorbed and excreted by urine and as there are no intermediate metabolites and fewer drug reactions in comparison with older anticonvulsants [5], still, several reports of side effects mention kidney stones, heatstroke [6], metabolic acidosis, respiratory alkalosis, increased metabolism of ethinylestradiol and progestogens, possibly a teratogenic effect, acute myopia and angle closure glaucoma, impaired concentration, dizziness, emotional lability, and psychosis [7, 8]. Among the dermatological complaints are urticaria and angioedema as well as photosensitivity and pigmentary changes that return to normal after the discontinuation of the drug. Also, alopecia cases have been reported, although in a lower Bello-Hernández/Espinoza-Hernández/ Moreno-Coutiño Table 1. Naranjo Adverse Drug Reaction Probability Scale 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Question Yes No Do not Score know Are there previous conclusive reports on this reaction? Did the adverse event appear after the suspected drug was administered? Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? Did the adverse event reappear when the drug was re-administered? Are there alternative causes (other than the drug) that could on their own have caused the reaction? Did the reaction reappear when a placebo was given? Was the drug detected in blood (or other fluids) in concentrations known to be toxic? Was the reaction more severe when the dose was increased or less severe when the dose was decreased? Did the patient have a similar reaction to the same or similar drugs in any previous exposure? Was the adverse event confirmed by any objective evidence? +1 +2 +1 +2 –1 –1 +1 +1 +1 +1 0 –1 0 –1 +2 +1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Total score 1 2 1 0 2 0 0 0 0 1 7 According to Naranjo et al. [16]. percentage than for other mood stabilizers. The drug causes nonscarring alopecia that may be localized or generalized and is apparently associated with telogen effluvium and, thus, reversible. Exanthema, pruritus, fixed drug eruption, acneiform eruptions, and hyperhidrosis can also be related [9, 10]. Mild adverse effects might not even be reported by the patients; however, pruritus has warranted case reports [11, 12]. So, we conclude that topiramate is a mood stabilizer and notably has fewer side effects than other drugs in the same group, such as carbamazepine or lamotrigine. Nevertheless, it apparently accounts for almost 2% of the skin rashes caused by this group of drugs, which is often really difficult to evaluate, as patients usually receive more than one of these drug [13]. We based our final diagnosis of a drug reaction on the clinical aspect and histopathology, supported by the Naranjo Adverse Drug Reaction Probability Scale, which assesses whether there is a causal relationship between an identified adverse clinical event and a drug, using a simple questionnaire to assign probability scores. Total scores range from –4 to +13; the reaction is considered definite if the score is 9 or higher, probable if it is 5–8, possible if it is 1–4, and doubtful if it is 0 or less (Table 1 shows that the patient had a score of 7). The atypical DRESS syndrome was based on the unquantified fever, peripheral eosinophilia, and persistence of symptoms several weeks after the discontinuation of the drug. This syndrome, originally thought to be caused only by anticonvulsants, is known to have a different pathophysiology from that of toxic epidermal necrolysis. In this case, Treg cells appear and downregulate the im- mune response, causing milder lesions than those seen in toxic epidermal necrolysis, although both have participation of CD4 T-cell lymphocytes [14]. It is important to remember that aromatic antiepileptic drugs may cross-react in 40–58% of the cases [15], so patients with a documented rash due to these medications should be prescribed the less likely drug to produce it. This is why we think that this case report is important for further reference. We consider that adverse effects are important to document. This particular case is useful, since this patient only received topiramate and no other medication. Fortunately, this case resolved satisfactorily. Topiramate Rash Skin Appendage Disord 2018;4:25–28 DOI: 10.1159/000477742 Statement of Ethics The patient’s identity will be kept in confidentiality and anonymity at all times. According to the guidelines for human study and animal welfare regulations, the authors state that the patient gave his informed consent for all the tests performed. This is not a protocol, so it has not been submitted to the institution’s committee on human research. This report did not involve any study on animals. Disclosure Statement The authors state that they have no conflicts of interest and ensure the quality and integrity of this report. 27 References 1 Vorsanger MH, Subramanyam P, Weintraub HS, Lamm SH, Underberg JA, Gianos E, et al: Cardiovascular effects of the new weight loss agents. J Am Coll Cardiol 2016;68:849–859. 2 Rezaei F, Ghaderi E, Mardani R, Hamidi S, Hassanzadeh K: Topiramate for the management of methamphetamine dependence: a pilot randomized, double-blind, placebo-controlled trial. Fundam Clin Pharmacol 2016; 30:282–289. 3 Bagnato F, Good J: The use of antiepileptics in migraine prophylaxis. Headache 2016; 56: 603–615. 4 Aurora SK, Brin MF: Chronic migraine: an update on physiology, imaging, and the mechanism of action of two available pharmacologic therapies. Headache 2017;57:109– 125. 5 Natsch S, Hekster Y, Keyser A, Deckers CLP, Meinardi H, Reiner WO: Newer anticonvulsant drugs. Role of pharmacology, drug interactions and adverse reactions in drug choice. Drug Saf 1997;17:228–240. 28 6 Canel L, Zisimopoulou S, Besson M, Nendaz M: Topiramate-induced severe heatstroke in an adult patient: a case report. J Med Case Rep 2016;10:95. 7 Ortinski P, Meador KJ: Cognitive side effects of antiepileptic drugs. Epilepsy Behav 2004; 5:S60–S65. 8 Levy J, Yagev R, Petrova A, Lifshitz T: Topiramate-induced bilateral angle-closure glaucoma. Can J Ophthalmol 2006;41:221–225. 9 Warnock JK, Morris DW: Adverse cutaneous reactions to mood stabilizers. Am J Clin Dermatol 2003;4:21–30. 10 Castela E, Thomas P, Bronsard V, Lacour JP, Ortonne JP, Passeron T: Blue pseudochromhidrosis secondary to topiramate treatment. Acta Derm Venereol 2009;89:538–539. 11 Ochoa JG: Pruritus, a rare but troublesome adverse reaction of topiramate. Epilepsia 2000;41:122. Skin Appendage Disord 2018;4:25–28 DOI: 10.1159/000477742 12 Cutaneous drug reaction case reports: from the world literature. Am J Clin Dermatol 2001;2:267–274. 13 Wang XG, Lang SY, Shi XB, Tian HJ, Wang RF, Yang F: Antiepileptic drug-induced skin reactions: a retrospective study and analysis in 3,793 Chinese patients with epilepsy. Clin Neurol Neurosurg 2012;114:862–865. 14 Balakirski G, Merk HF: Cutaneous allergic drug reactions: update on pathophysiology, diagnostic procedures and differential diagnostic. Cutan Ocul Toxicol 2017, DOI: 10.1080/15569527.2017.1319379. 15 Hirsch LJ, Anif H, Nahm EA, Buchsbaum R, Resor SR Jr, Bazil CW: Cross-sensitivity of skin rashes with antiepileptic drug use. Neurology 2008;71:1527–1534. 16 Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ: A method for estimating the probability of adverse drug reaction. Clin Pharmacol Ther 1981;30:239–245. Bello-Hernández/Espinoza-Hernández/ Moreno-Coutiño