Immune‐mediated polyarthritis and anterior uveitis secondary to zonisamide administration in a dog with refractory epilepsy

Abstract The objective of this article is to describe a case of suspected zonisamide‐induced immune‐mediated polyarthritis (IMPA) and anterior uveitis in a dog. A 7‐year‐old male neutered Siberian Husky with a history of refractory idiopathic epilepsy was presented for cluster seizures. Following the addition of zonisamide to the antiepileptic regime, the dog developed new IMPA and anterior uveitis. Within a few weeks of discontinuation of the zonisamide, the dog's IMPA and anterior uveitis resolved. These immune‐mediated conditions were thus presumed to be an idiosyncratic reaction to zonisamide. To our knowledge, this is the first report of IMPA and anterior uveitis in dogs associated with zonisamide administration at its recommended dose.

ambulatory, which improved to ambulation with ataxia by the time of admission to the ICU approximately 2 h later.The remainder of the neurologic examination was normal.The dog was hospitalized for monitoring, and zonisamide (Glenmark; 3.0 mg/kg, PO, q12h) was added to the treatment regime.After 24 h without seizures the potassium bromide dose was increased to 13.1 mg/kg, PO, q12h and the zonisamide dose was doubled to 6.0 mg/kg, PO, q12h.The levetiracetam and phenobarbital were kept at the previously prescribed doses.The dog remained seizure-free for an additional 24 h and was then discharged.
Additionally, the dog developed polyuria, possibly secondary to intravenous fluid administration, steroid therapy and/or historic polyuria.The dog's bodyweight reduced from 33.9 kg at admission to 31.4 kg.
On day 4 of hospitalization, the dog was transitioned from dexamethasone sodium phosphate to prednisone (Jubilant Cadista; 1.2 mg/kg, PO, q24h) and from methadone to gabapentin (Markasas Pharm Ltd; 9.5 mg/kg, PO, q8h The dog remained seizure-free.

DISCUSSION
This case report is, to the authors' knowledge, the first description of anterior uveitis and IMPA suspected to be secondary to zonisamide treatment.The presumptive diagnosis was based on the clinical signs, history, exclusion of other concurrent disorders and resolution of clinical signs following the discontinuation of zonisamide.
The mechanism of zonisamide-induced IMPA in this case is unknown.The sulphonamide group in zonisamide's chemical structure may play a role in stimulating immunogenic reactions, as suggested by prior reports documenting drug reactions to sulphonamide antimicrobials (Ackermann et al., 2015;Ghimire et al., 2013) (Ghimire et al., 2013;Madisson et al., 2008;Ovung & Bhattacharyya, 2021;Verdel et al., 2006).3describes a lethal subacute 3 idiosyncratic hepatic necrosis following zonisamide administration to a dog experiencing refractory idiopathic seizures (Miller et al., 2011).The authors of that study report similar clinical presentations between the dogs in the study and people with sulphonamide antibiotic toxicity.Although controversial, multiple case reports in people have suggested cross-reactivity between sulphonamide drug classes (Figure 1a-c) including non-antimicrobials (Charalambous et al., 2016;Dewey et al., 2004;Podell et al., 2016;Schwartz et al., 2011;Verdel et al., 2006).Given the similarities in the chemical structures of sulphonamide antimicrobials and sulphonamide non-antimicrobials (Figure 2), cross-reactivity could potentially explain The drugs in this class feature a sulphonamide chemical structure attached to a benzene ring with amine group attached to the cyclic structure, rather in the N4 position.An example of a drug in this class is furosemide.(c) Sulfonamide moiety: Zonisamide, like other drugs in this class, features a sulphonamide chemical structure that is not connected directly to any cyclic structure (Ghimire et al., 2013;Madisson et al., 2008;Ovung & Bhattacharyya, 2021;Verdel et al., 2006).
In people, sulphonamides are a common drug class associated with allergic reactions, but evidence varies as to whether the sensitivity is due to the chemical structure or whether the patient has increased susceptibility to adverse reactions regardless of chemical structure (Khan & Chow, 2022;Khan et al., 2022;Strom et al., 2003;Verdel et al., 2006).A 2003 report describes that 9% of patients with a history of adverse reaction to sulphonamide antibiotics developed adverse reactions following administration of a non-antibiotic sulphonamide medication (Khan et al., 2022;Strom et al., 2003).There is speculation that either T-cell or IgE mediated responses to reactive metabolites play a role in sulphonamide antibiotic induced hypersensitivity.
Further, there is consideration that the N4 amine ring drives the formation of reactive metabolites (Figure 2).The current consensus from the American Academy of Allergy, Asthma, and Immunology is that patients with a history of prior reaction to sulphonamide antibiotics are at a slightly increased risk for adverse reaction to sulphonamide non-antibiotics.However, this is suspected to be secondary to a predisposition to overall drug hypersensitivities rather than immunologic driven cross-reactivity.Multiple studies have shown that patients with sulphonamide hypersensitivities had a history of allergies to at least one other drug class (Khan et al., 2022).Sulphonamide allergy and cross-reactivity continue to remain a topic of study in human medicine.
To date, there are no studies in veterinary medicine assessing the hypersensitivity of non-antimicrobial sulphonamides in patients with known sulphonamide antibiotic reactions.In this report, the dog had no known historic exposure to sulphonamide antibiotics; thus, predisposition to adverse reactions cannot be ruled out.However, with a reported history of pneumonia and a lack of prior medical records due to recent adoption, the authors cannot confirm this with certainty.
Studies highlighting sulphonamide antibiotic adverse effects in dogs include a report of one dog that developed non-septic polyarthritis secondary to trimethoprim-sulphonamide. This dog's signs were suspected to be due to trimethoprim-sulphonamide because the signs improved in 1-3 days following withdrawal of medication and returned when the dog was re-challenged with the medication (Trepanier et al., 2003).Similarly, a dog receiving zonisamide for idiopathic epilepsy developed polyarthropathy (Dewey et al., 2004).However, this dog also had high titres for Lyme disease, and the associated lameness resolved with doxycycline administration despite no changes in zonisamide dose.It is thus unclear if the use of zonisamide exacerbated the symptoms of Lyme polyathropathy, or if zonisamide had no impact on the dog's clinical picture (Dewey et al., 2004).In the same study of zonisamide use for idiopathic epilepsy, another dog developed transient KCS following zonisamide treatment that improved with topical cyclosporine despite continuation of zonisamide (Dewey et al., 2004).
The authors could not identify other causes aside from the addition of zonisamide or compounding effect of multiple medications (Dewey et al., 2004).
In this report, the potential reasons for this dog's ocular pathology, including anterior uveitis and decreased tear production, are direct toxicity and immune-mediated mechanisms (Trepanier et al., 2003).
Sulphonamide-induced KCS has been identified with sulphasalazine, which is cytotoxic to the lacrimal gland.With regards to an immunemediated mechanism, the presence of antibodies to platelets and T-cells has been shown in dogs with sulphonamide hypersensitivity.
The adaptive immune system has been implicated in the development of KCS and uveitis and may contribute to the ocular changes described in this study (Trepanier et al., 2003).
Like zonisamide, dorzolamide's sulphonamide group is not attached to the benzene ring; however, despite this, it has been reported to cause idiosyncratic reactions similar to other sulphonamides (Cawrse et al., 2001;Ghimire et al., 2013;Trepanier et al., 2003).Several case reports in people document sulphonamide-induced uveitis, more specifically non-granulomatous anterior uveitis (Tilden, 1991).One study describes patients developing non-granulomatous anterior uveitis within 1 week of initiating trimethoprim-sulphamethoxazole (TMS), and after re-exposure, clinical signs of uveitis developed within 24 h (Tilden, 1991).Some patients re-challenged with a sulphonamide medication developed other sulphonamide-induced adverse effects such as erythema multiforme, stomatitis and abnormal liver function (Tilden, 1991).All patients had resolution of anterior uveitis with discontinuation of TMS and topical steroid use (Tilden, 1991).The exact mechanism of sulphonamide-induced uveitis is unknown as it is less frequently seen in comparison to other sulphonamide-induced reactions in people.In this report, the dog was not re-challenged with zonisamide to assess for recurrence of signs, so a definitive diagnosis of drug reaction cannot be confirmed.However, given the temporal association, drug class and lack of alternative explanation despite extensive investigations, there is strong suspicion that the uveitis was secondary Most importantly, re-challenge with zonisamide and recurrence of the clinical signs would be required to definitively prove the role of zonisamide.In a 2021 case report where dogs receiving zonisamide developed aggression, behaviour was improved and resolved within a week of discontinuing medication (Kanazono et al., 2021).Similarly, in a 2022 case series, four dogs developed febrile neutropenia, which began to resolve within a few days of discontinuing zonisamide (Brandifino et al., 2022).In both studies, the dog's symptoms improved, and extensive diagnostics, including bone marrow aspirates in the latter study, did not identify any other cause for symptoms (Brandifino et al., 2022;Kanazono et al., 2021).Many parallels can be drawn between these studies and the current study, particularly the improvement to resolution of clinical symptoms with the discontinuation of zonisamide.The symptoms in these two studies as well as the current study were presumed to be associated with zonisamide; thus, the medication was discontinued.Although supportive care was provided, alleviation of symptoms occurred sooner than anticipated, and no other underlying conditions were identified on diagnostics performed.The authors in the 2022 case series acknowledged that re-challenge with zonisamide would definitively confirm hypothesis; however, there were humane concerns with re-exposure (Brandifino et al., 2022).In the current study, as the dog's seizure control was adequate at follow-up visits, reintroduction of additional antiseizure medications was not required.Additionally, given the severity of the dog's clinical symptoms, there were ethical concerns with re-exposure.

CONCLUSION
In conclusion, this case report describes IMPA and anterior uveitis, presumed to be secondary to zonisamide.This complication has not been previously documented; however, other immune-mediated and idiosyncratic reactions have been reported.Though more information is needed to fully understand potential reactions to zonisamide, this case report suggests that zonisamide use in dogs with known immune-mediated diseases, hypersensitivities to sulphonamides or at risk of sulphonamide reaction should be monitored closely.At this time, sulfadiazine is the only sulpha drug in the United States listed with a warning for cross reactivity in people with sulphonamide hypersensitivity (Ghimire et al., 2013).

ETHICS STATEMENT
The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to.No ethical approval was required as this is a review article with no original research data.

F
Classification of sulphonamide drugs and structural differences between the classes with focus on sulphonamide structure.Purple circle denotes position of sulphonamide structure in each class.(a) Sulfonylarylamines: In this group of drugs, which includes sulphadiazine, the sulphonamide chemical structure is attached directly to the benzene ring via an amine group (-NH2) at the N4 position.(b) Non-sulfonylarylamines: to zonisamide.The similarities in the development and resolution of anterior uveitis in this case and previously documented sulphonamideinduced anterior uveitis provide further support to this claim.To the authors' knowledge, there have been no reports of zonisamide induced uveitis despite the reports of sulphonamide-induced uveitis.There are several limitations in this case report.The first is the administration of glucocorticoids.The dog experienced improvement after discontinuation of zonisamide; however, glucocorticoids were started concurrently raising the question of whether resolution of the clinical signs was purely due to discontinuation of zonisamide, or whether improvement would have occurred with glucocorticoids irrespective of zonisamide discontinuation.Nevertheless, in the case of an idiopathic immune-mediated aetiology, long courses of glucocorticoid treatment are invariably required for successful treatment, so recurrence would have been expected following the very short 10-day course used in this dog.A second limitation is the use of antibiotics.The administration of two doses of ampicillin sulbactam prior to sampling could have prevented the identification of bacteria on synovial fluid, and several days of subsequent treatment with doxycycline and enrofloxacin may have then eradicated an inciting infection.Moreover, synovial fluid cytology is not a sensitive test for the detection of infectious arthritis and synovial fluid cytology and PCR testing for infectious causes was not performed.It is therefore possible that resolution of clinical signs is correlated with effective infection control rather than discontinuation of zonisamide.Nevertheless, with the exception of tickborne diseases, infectious causes of polyarthritis are rare, and, considering the absence of reported tick exposure and negative serology results, the former is unlikely.The patient also received only a very short course of antibiotics, which would usually be considered insufficient for effective treatment of infectious polyarthritis.Third, the lack of an initial STT value makes it difficult to determine if poor tear production was significant enough to include KCS as a potential adverse effect of zonisamide.This could have provided further support for the cross-reactivity of sulphonamide medications.
The findings of the canine respiratory disease RealPCR comprehensive panel l from a conjunctival swab.The results of fungal serologic testing s .Serial bloodwork highlighting key findings from complete blood cell count m and serum biochemistry n from day 1 hospitalization, day 2 hospitalization and 10 days post-discharge.