Vet Dermatol 2015; 26: 391–e89
DOI: 10.1111/vde.12237
Erythema multiforme associated with zonisamide in a dog Amanda L. Ackermann*, Linda A. Frank*, Michael F. McEntee† and Elizabeth R. May* *Department of Small Animal Clinical Sciences, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA †Department of Biomedical and Diagnostic Sciences, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA Correspondence: Amanda L. Ackermann, Department of Small Animal Clinical Sciences, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA. E-mail: [email protected]
This report describes a dog that developed erythema multiforme in temporal association with administration of the sulphonamide-based anticonvulsant drug zonisamide. Similar adverse drug reactions have been associated with sulphonamide antimicrobial drugs. Caution should be exercised when prescribing this medication for dogs with known hypersensitivity to sulphonamides.
Introduction Cutaneous Adverse Drug Reaction (CADR) is defined as any unintended effect of a therapeutic drug on the skin. The most common drugs associated with idiosyncratic CADRs in dogs are antimicrobial medications.1 Clinical presentations may range from urticaria to erythema multiforme (EM) and toxic epidermal necrolysis (TEN).2 Differential diagnoses may be extensive as CADRs can mimic many other dermatoses. Suspicion of CADR is based on clinical presentation, current or recent drug administration corresponding with the onset of lesions, supportive histopathology and exclusion of differential diagnoses. Clinical resolution following drug withdrawal supports the diagnosis; however, absolute confirmation requires rechallenge with the drug. This is seldom done due to ethical concerns.2
A complete blood count revealed mild normocytic, normochromic anaemia (haematocrit 39%, reference range 41–60%). Serum chemistry revealed elevated liver enzymes [alkaline phosphatase (ALP) 671 l/L (reference range 15–164 l/L) and alanine transaminase (ALT) 158 l/ L (reference range 21–97 l/L)]; however, these values were similar to those obtained prior to onset of the dermatologic disease and were presumed to be secondary to chronic phenobarbital administration. Cytological evaluation of lesional skin revealed many neutrophils and occasional cocci. Aerobic culture yielded >100 colonies of Staphylococcus pseudintermedius susceptible to all antibiotics tested. Histopathological examination of skin biopsy specimens revealed individual keratinocyte apop-
a
Case Report A nine-year-old, castrated male, 11 kg miniature dachshund was presented to the dermatology service at the Small Animal Hospital of the University of Tennessee College of Veterinary Medicine with a one week history of a progressive dermatitis. The dog was lethargic and severely lame upon presentation, with crusting and ulceration of the interdigital skin and surrounding the paw pads. There were multifocal to coalescing areas of erythema, erosion, ulceration and crusting on the ventral abdomen and prepuce (Figure 1a), and focal areas of ulceration on the hard palate. The dog had no previous history of dermatological disease. He was receiving three different drugs for poorly controlled idiopathic epilepsy: phenobarbital (Qualitest Pharmaceuticals; Huntsville, AL, USA) for 2 years’ duration, potassium bromide (PRN Pharmacal; Pensacola, FL, USA) for 1 year duration and zonisamide (Glenmark Generics; Mahwah, NJ, USA) for 2 months’ duration.
Accepted 30 May 2015 Source of funding: This study was self-funded. Conflicts of interest: No conflicts of interest have been declared. © 2015 ESVD and ACVD, Veterinary Dermatology, 26, 391–e89.
b
Figure 1. (a) Multifocal to coalescing areas of erythema, erosion, ulceration and crusting on the ventrum on the day of presentation. (b) Healing of lesions 72 h after discontinuation of zonisamide.
391
Ackermann et al.
Discussion
Figure 2. Photomicrograph of affected epidermis with scattered shrunken, hypereosinophilic epithelial cells (apoptosis) occasionally flanked by lymphocytes (arrow). The surface in this area is covered by a serocellular crust. (Histological section stained with haematoxylin and eosin; bar = 60 lm)
tosis scattered throughout all layers of the epidermis, with occasional lymphocytic satellitosis suggestive of EM (Figure 2). The superficial dermis contained a mixed infiltrate of lymphocytes, macrophages and plasma cells; neutrophils were more numerous below areas of ulceration and surface bacterial colonization. Based on clinical signs and histopathology the dog was diagnosed with EM presumed secondary to drug administration. In cases of suspected CADR it is advisable to discontinue all possible offending drugs. This dog’s uncontrolled epilepsy precluded this approach. Zonisamide was withdrawn because it was the most recent drug added to the treatment regimen and as a sulphonamide, belongs to a drug class commonly implicated in cases of CADR.3 It was replaced with levetiracetam (Keppra XRâ, UCB; Brussels, Belgium) as an additional antiepileptic agent. The dog was also started on 5 mg/kg cefpodoxime (Simplicefâ, Zoetis; Florham Park, NJ, USA) once daily for 21 days to treat secondary bacterial infection and 4 mg/kg tramadol hydrochloride (Amneal Pharmaceuticals; Bridgewater, NJ, USA) every 8 h for 7 days for pain. Significant improvement of lesions was noted within 72 h of discontinuing the zonisamide (Figure 1b) and resolution was complete within 2 weeks. A complete blood count at the two week recheck showed resolution of the previously noted anaemia (haematocrit 57.5%). Serum chemistry revealed elevated but stable values for ALP (951 l/L) and ALT (135 l/L).
Idiosyncratic reactions to sulphonamide antimicrobials are well described, but this is to the best of the authors’ knowledge the first report of a CADR to zonisamide in dogs. Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) is a sulphonamide-based anticonvulsant with several proposed mechanisms for efficacy against seizures.4,5 Unlike the potentiated sulphonamide antimicrobials, zonisamide is not an aryl amine, and, therefore, is not metabolized to the nitroso molecule that is theorized to be immunogenic in the sulphonamide antimicrobials.6 The mechanism of drug hypersensitivity in this case is unknown. Hypersensitivity may be directed against the parent drug or a reactive metabolite. A case of CADR and a report of zonisamide-associated TEN in two people have been reported,7,8 but no pathogenesis was theorized. With first-time exposure to a drug, the average time from treatment initiation to reaction is 12 days, with a range of 5–36 days.3 In this case the reaction was seen approximately 40 days after starting zonisamide. The dog had been on potassium bromide and phenobarbital for 1 and 2 years, respectively. Although drug reaction to phenobarbital has been documented, it is uncommon in dogs.1 In summary, this report describes a dog with EM that resolved upon withdrawal of zonisamide.
References 1. Scott DW, Miller WH Jr. Idiosyncratic cutaneous adverse drug reactions in the dog: literature review and report of 101 cases (1990-1996). Canine Pract 1999; 24: 16–22. 2. Voie KL, Campbell KL, Lavergne SN. Drug hypersensitivity reactions targeting the skin in dogs and cats. J Vet Intern Med 2012; 26: 863–874. 3. Trepanier LA. Delayed hypersensitivity reactions to sulfonamides: syndromes, pathogenesis and management. Vet Dermatol 1999; 10: 241–248. 4. Dewey CW, Guiliano R, Boothe DM et al. Zonisamide therapy for refractory idiopathic epilepsy in dogs. J Am Anim Hosp Assoc 2004; 40: 285–291. 5. Schachter S. The next wave of anticonvulsants. CNS Drugs 2000; 14: 229–249. 6. Boothe DM, Perkins J. Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs. J Vet Pharmacol Ther 2008; 31: 544–553. 7. Hirose K. A case of drug-induced hypersensitivity syndrome with the features of toxic epidermal necrolysis. Nishinihon J Dermatol 2009; 71: 584–588. 8. Teraki Y, Murota H, Izaki S. Toxic epidermal necrolysis due to zonisamide associated with reactivation of herpesvirus 6. Arch Dermatol 2008; 144: 232–235.
sume – Cet article de crit un chien qui pre sente un e rythe me polymorphe suite Re a l’administration de l’anactions inde sirables similaires ont e te de crites en ticonvulsivant a base de sulfamides : zonisamide. Des re re est ne cessaire lors de prescripassociation avec les sulfamides antimicrobiens. Une attention particulie sentant une sensibilite connue aux sulfamides. tion de ce traitement pour les chiens pre eritema multiforme en asociacio n temporal con Resumen – Este artıculo describe un perro que desarrollo n de un farmaco anticonvulsivante zonisamida del grupo sulfonamidas. Reacciones simila administracio lares adversas han sido asociadas con farmacos antimicrobianos de tipo sulfonamidas. Se debe administrar n en perros sobre todo si hay conocida hipersensibilidad a sulfonamidas. con cautela esta mediacio 392
© 2015 ESVD and ACVD, Veterinary Dermatology, 26, 391–e89.
Presumed erythema multiforme associated with zonisamide in a dog
€bergeZusammenfassung – Dieser Bericht beschreibt einen Hund, der Erythema multiforme nach voru hender Gabe eines auf Sulfonamid-basierenden antikonvulsiven Medikaments namens Zonisamid entwick€ elte. Ahnliche Medikamentennebenwirkungen sind bei Sulfonamid Antibiotika aufgetreten. Es sollte €r Hunde mit bekannter Hypersensibilit€ Vorsicht walten, wenn diese Medikamente fu at auf Sulfonamide verschrieben werden. 要約 – この報告はスルホンアミド系抗痙攣薬のゾニサミドの投与に一時的に関連した多形紅斑が発生したイヌを解説して いる。同様の薬物有害事象はスルホンアミド抗菌剤と関連して生じている。スルホンアミドに過敏症を示すことがわかってい るイヌへこの薬剤を処方する際には注意が必要である。 摘要 – 该报道描述一例多形红斑患犬,发病与临时服用抗惊厥药物唑尼沙胺有关,其基本成分为磺胺类药 物。磺胺类抗菌素也有相似的药物副反应。对于磺胺类药物过敏的犬,需谨慎使用此药。
© 2015 ESVD and ACVD, Veterinary Dermatology, 26, 391–e89.
e89
DOI: 10.1111/vde.12237
Erythema multiforme associated with zonisamide in a dog Amanda L. Ackermann*, Linda A. Frank*, Michael F. McEntee† and Elizabeth R. May* *Department of Small Animal Clinical Sciences, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA †Department of Biomedical and Diagnostic Sciences, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA Correspondence: Amanda L. Ackermann, Department of Small Animal Clinical Sciences, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA. E-mail: [email protected]
This report describes a dog that developed erythema multiforme in temporal association with administration of the sulphonamide-based anticonvulsant drug zonisamide. Similar adverse drug reactions have been associated with sulphonamide antimicrobial drugs. Caution should be exercised when prescribing this medication for dogs with known hypersensitivity to sulphonamides.
Introduction Cutaneous Adverse Drug Reaction (CADR) is defined as any unintended effect of a therapeutic drug on the skin. The most common drugs associated with idiosyncratic CADRs in dogs are antimicrobial medications.1 Clinical presentations may range from urticaria to erythema multiforme (EM) and toxic epidermal necrolysis (TEN).2 Differential diagnoses may be extensive as CADRs can mimic many other dermatoses. Suspicion of CADR is based on clinical presentation, current or recent drug administration corresponding with the onset of lesions, supportive histopathology and exclusion of differential diagnoses. Clinical resolution following drug withdrawal supports the diagnosis; however, absolute confirmation requires rechallenge with the drug. This is seldom done due to ethical concerns.2
A complete blood count revealed mild normocytic, normochromic anaemia (haematocrit 39%, reference range 41–60%). Serum chemistry revealed elevated liver enzymes [alkaline phosphatase (ALP) 671 l/L (reference range 15–164 l/L) and alanine transaminase (ALT) 158 l/ L (reference range 21–97 l/L)]; however, these values were similar to those obtained prior to onset of the dermatologic disease and were presumed to be secondary to chronic phenobarbital administration. Cytological evaluation of lesional skin revealed many neutrophils and occasional cocci. Aerobic culture yielded >100 colonies of Staphylococcus pseudintermedius susceptible to all antibiotics tested. Histopathological examination of skin biopsy specimens revealed individual keratinocyte apop-
a
Case Report A nine-year-old, castrated male, 11 kg miniature dachshund was presented to the dermatology service at the Small Animal Hospital of the University of Tennessee College of Veterinary Medicine with a one week history of a progressive dermatitis. The dog was lethargic and severely lame upon presentation, with crusting and ulceration of the interdigital skin and surrounding the paw pads. There were multifocal to coalescing areas of erythema, erosion, ulceration and crusting on the ventral abdomen and prepuce (Figure 1a), and focal areas of ulceration on the hard palate. The dog had no previous history of dermatological disease. He was receiving three different drugs for poorly controlled idiopathic epilepsy: phenobarbital (Qualitest Pharmaceuticals; Huntsville, AL, USA) for 2 years’ duration, potassium bromide (PRN Pharmacal; Pensacola, FL, USA) for 1 year duration and zonisamide (Glenmark Generics; Mahwah, NJ, USA) for 2 months’ duration.
Accepted 30 May 2015 Source of funding: This study was self-funded. Conflicts of interest: No conflicts of interest have been declared. © 2015 ESVD and ACVD, Veterinary Dermatology, 26, 391–e89.
b
Figure 1. (a) Multifocal to coalescing areas of erythema, erosion, ulceration and crusting on the ventrum on the day of presentation. (b) Healing of lesions 72 h after discontinuation of zonisamide.
391
Ackermann et al.
Discussion
Figure 2. Photomicrograph of affected epidermis with scattered shrunken, hypereosinophilic epithelial cells (apoptosis) occasionally flanked by lymphocytes (arrow). The surface in this area is covered by a serocellular crust. (Histological section stained with haematoxylin and eosin; bar = 60 lm)
tosis scattered throughout all layers of the epidermis, with occasional lymphocytic satellitosis suggestive of EM (Figure 2). The superficial dermis contained a mixed infiltrate of lymphocytes, macrophages and plasma cells; neutrophils were more numerous below areas of ulceration and surface bacterial colonization. Based on clinical signs and histopathology the dog was diagnosed with EM presumed secondary to drug administration. In cases of suspected CADR it is advisable to discontinue all possible offending drugs. This dog’s uncontrolled epilepsy precluded this approach. Zonisamide was withdrawn because it was the most recent drug added to the treatment regimen and as a sulphonamide, belongs to a drug class commonly implicated in cases of CADR.3 It was replaced with levetiracetam (Keppra XRâ, UCB; Brussels, Belgium) as an additional antiepileptic agent. The dog was also started on 5 mg/kg cefpodoxime (Simplicefâ, Zoetis; Florham Park, NJ, USA) once daily for 21 days to treat secondary bacterial infection and 4 mg/kg tramadol hydrochloride (Amneal Pharmaceuticals; Bridgewater, NJ, USA) every 8 h for 7 days for pain. Significant improvement of lesions was noted within 72 h of discontinuing the zonisamide (Figure 1b) and resolution was complete within 2 weeks. A complete blood count at the two week recheck showed resolution of the previously noted anaemia (haematocrit 57.5%). Serum chemistry revealed elevated but stable values for ALP (951 l/L) and ALT (135 l/L).
Idiosyncratic reactions to sulphonamide antimicrobials are well described, but this is to the best of the authors’ knowledge the first report of a CADR to zonisamide in dogs. Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) is a sulphonamide-based anticonvulsant with several proposed mechanisms for efficacy against seizures.4,5 Unlike the potentiated sulphonamide antimicrobials, zonisamide is not an aryl amine, and, therefore, is not metabolized to the nitroso molecule that is theorized to be immunogenic in the sulphonamide antimicrobials.6 The mechanism of drug hypersensitivity in this case is unknown. Hypersensitivity may be directed against the parent drug or a reactive metabolite. A case of CADR and a report of zonisamide-associated TEN in two people have been reported,7,8 but no pathogenesis was theorized. With first-time exposure to a drug, the average time from treatment initiation to reaction is 12 days, with a range of 5–36 days.3 In this case the reaction was seen approximately 40 days after starting zonisamide. The dog had been on potassium bromide and phenobarbital for 1 and 2 years, respectively. Although drug reaction to phenobarbital has been documented, it is uncommon in dogs.1 In summary, this report describes a dog with EM that resolved upon withdrawal of zonisamide.
References 1. Scott DW, Miller WH Jr. Idiosyncratic cutaneous adverse drug reactions in the dog: literature review and report of 101 cases (1990-1996). Canine Pract 1999; 24: 16–22. 2. Voie KL, Campbell KL, Lavergne SN. Drug hypersensitivity reactions targeting the skin in dogs and cats. J Vet Intern Med 2012; 26: 863–874. 3. Trepanier LA. Delayed hypersensitivity reactions to sulfonamides: syndromes, pathogenesis and management. Vet Dermatol 1999; 10: 241–248. 4. Dewey CW, Guiliano R, Boothe DM et al. Zonisamide therapy for refractory idiopathic epilepsy in dogs. J Am Anim Hosp Assoc 2004; 40: 285–291. 5. Schachter S. The next wave of anticonvulsants. CNS Drugs 2000; 14: 229–249. 6. Boothe DM, Perkins J. Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs. J Vet Pharmacol Ther 2008; 31: 544–553. 7. Hirose K. A case of drug-induced hypersensitivity syndrome with the features of toxic epidermal necrolysis. Nishinihon J Dermatol 2009; 71: 584–588. 8. Teraki Y, Murota H, Izaki S. Toxic epidermal necrolysis due to zonisamide associated with reactivation of herpesvirus 6. Arch Dermatol 2008; 144: 232–235.
sume – Cet article de crit un chien qui pre sente un e rythe me polymorphe suite Re a l’administration de l’anactions inde sirables similaires ont e te de crites en ticonvulsivant a base de sulfamides : zonisamide. Des re re est ne cessaire lors de prescripassociation avec les sulfamides antimicrobiens. Une attention particulie sentant une sensibilite connue aux sulfamides. tion de ce traitement pour les chiens pre eritema multiforme en asociacio n temporal con Resumen – Este artıculo describe un perro que desarrollo n de un farmaco anticonvulsivante zonisamida del grupo sulfonamidas. Reacciones simila administracio lares adversas han sido asociadas con farmacos antimicrobianos de tipo sulfonamidas. Se debe administrar n en perros sobre todo si hay conocida hipersensibilidad a sulfonamidas. con cautela esta mediacio 392
© 2015 ESVD and ACVD, Veterinary Dermatology, 26, 391–e89.
Presumed erythema multiforme associated with zonisamide in a dog
€bergeZusammenfassung – Dieser Bericht beschreibt einen Hund, der Erythema multiforme nach voru hender Gabe eines auf Sulfonamid-basierenden antikonvulsiven Medikaments namens Zonisamid entwick€ elte. Ahnliche Medikamentennebenwirkungen sind bei Sulfonamid Antibiotika aufgetreten. Es sollte €r Hunde mit bekannter Hypersensibilit€ Vorsicht walten, wenn diese Medikamente fu at auf Sulfonamide verschrieben werden. 要約 – この報告はスルホンアミド系抗痙攣薬のゾニサミドの投与に一時的に関連した多形紅斑が発生したイヌを解説して いる。同様の薬物有害事象はスルホンアミド抗菌剤と関連して生じている。スルホンアミドに過敏症を示すことがわかってい るイヌへこの薬剤を処方する際には注意が必要である。 摘要 – 该报道描述一例多形红斑患犬,发病与临时服用抗惊厥药物唑尼沙胺有关,其基本成分为磺胺类药 物。磺胺类抗菌素也有相似的药物副反应。对于磺胺类药物过敏的犬,需谨慎使用此药。
© 2015 ESVD and ACVD, Veterinary Dermatology, 26, 391–e89.
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