Presumed Sulfonamide-Associated Uveitis With Stevens-Johnson Syndrome in a Quarter Horse Mare.

We describe the case of a four-year-old Quarter Horse mare that presented with fever, respiratory infection with productive cough, disorientation, and bilateral anterior uveitis with discharge that had been previously treated with trimethoprim-sulfadiazine (TMPS). Acinetobacter johnsonii was cultured from an endoscopic tracheal wash. Treatment was initiated with cefquinome, systemic flunixin-meglumine, local ocular atropine, and corticosteroids. On subsequent days, the mare exhibited bilateral edematous, painful swelling of the face, primarily affecting the eyelids and lips. There were neither swellings nor pulsations of the metatarsal arteries. On day five of treatment, the facial swelling disappeared, the uveitis improved markedly, and the mare's periorbital skin, muzzle, and vulva began to slough, revealing underlying, nonpigmented skin. Although systemic use of sulfonamides has been associated with bilateral anterior uveitis and Stevens-Johnson syndrome (SJS or erythema multiforme major) in humans, these conditions are rare in horses. Stevens-Johnson syndrome has been associated most commonly with sulfonamide use but also with a range of other medications, including anti-infectives, anti-inflammatories, anticonvulsants, analgesics, and infections. A possible pathway for sulfonamide-induced SJS is discussed. To our knowledge, this is the first reported case of sulfonamide-associated uveitis and SJS in the horse.

Apoptosis as a Mechanism for Keratinocyte Death in Canine Toxic Epidermal Necrolysis.

In humans and dogs, toxic epidermal necrolysis (TEN) is a life-threatening dermatosis characterized by sudden epidermal death resulting in extensive skin detachment. There is little information on the pathogenesis of keratinocyte cell death in canine TEN. We studied the occurrence of apoptosis in skin lesions of dogs with TEN to determine if apoptosis contributes to the pathogenesis of this disease. Immunostaining with antibodies to activated caspase-3 and the terminal deoxynucleotidyl-transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling technique revealed positive apoptotic keratinocytes in basal and suprabasal epidermal compartments in 17 biopsy specimens collected from 3 dogs with TEN and 16 from 3 dogs with erythema multiforme (EM). There was no significant difference in the number of positively stained epidermal cells between TEN and EM. These results suggest that apoptosis of epidermal keratinocytes and lymphocytic satellitosis represent one of the early steps in the pathogenesis of canine TEN, as in the human disease counterpart.

Clinical and microscopic characteristics of canine toxic epidermal necrolysis.

Canine toxic epidermal necrosis (TEN), a rare and life-threatening cutaneous drug reaction, traditionally has been described as full-thickness devitalization of the epidermis with minimal dermal inflammation; however, few reports detail the histologic findings. We characterize the clinical features and histologic variations of 3 canine TEN patients. Clinically, irregular erythematous and purpuric macules evolved into widespread and severely painful erosions. The number of eroded mucosae varied; however, periocular and perilabial mucocutaneous junctions frequently were affected. Thirteen of 17 biopsies were evaluated. Apoptosis at multiple epidermal levels was the most common pattern of epidermal necrosis (12/13 biopsies, 92%). In contrast, full-thickness coagulation necrosis was present less often (7/13 biopsies, 52%). Lymphocytic interface dermatitis was the predominant inflammatory pattern, and intraepidermal lymphocytes, along with fewer histiocytes, were present to some degree in all samples along with lymphocytic satellitosis of apoptotic keratinocytes. The sequence of changes points to lymphocyte-mediated keratinocyte apoptosis as an early step in lesion development with subsequent variation in progression to coagulation necrosis among patients. Histopathologic changes overlapped with those reported for erythema multiforme, in contrast to traditional histologic descriptions of canine TEN. A specific algorithm for assessment of drug causality in epidermal necrolysis (ALDEN) was applied for each patient; carprofen was associated with a probable score for causality in 1 dog. Clinicians should be encouraged to take multiple biopsies in TEN suspect cases as nearly 25% of all biopsies lacked epithelium and were not diagnostic.

Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis: a comparative review.

BACKGROUND: Human erythema multiforme (EM) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are separate conditions. There is no consensus on classification criteria for the eponymous diseases in animals. RESULTS: Animal EM is very different from 90% of human EM, which is herpes virus associated (HAEM). Animals lack acrally distributed, typical raised targets. Unlike canine parvovirus 'EM', HAEM is not an active infection. Animal EM is often attributed to drugs, but this is rarely proved. Conversely, human and animal SJS/TEN are almost identical, life-threatening disorders of epidermal necrosis and detachment, typically triggered by drugs (occasionally by infectious agents). Both EM and SJS/TEN are mediated by cytotoxic lymphocyte responses against altered keratinocytes (infectious agents or drugs). Apoptosis results from direct cytotoxicity or through soluble mediators, namely Fas ligand, granzymes, perforin and granulysin. Diagnosis in humans is clinicopathological, with emphasis on clinical lesions; histopathology confirms the pathological process as interface (cytotoxic) dermatitis. Human EM is self-limiting; only recurrent and rare persistent cases require antiviral/immunosuppressive therapies. Drug-induced EM responds to drug withdrawal. Idiopathic canine EM (>40%) is usually chronic, refractory to treatment and may represent heterogeneous conditions. Early identification and removal of the causative drug and high-quality supportive care are critical in SJS/TEN. Mortality rate is nevertheless high. CONCLUSIONS AND CLINICAL IMPORTANCE: (1) Histopathological lesions do not reliably differentiate EM, SJS and TEN. (2) A multicentre study to develop a consensus set of clinical criteria for EM and SJS/TEN in animals is overdue. (3) No adjunctive therapies, including intravenous immunoglobulin and ciclosporin, have met evidence-based standards.

Toxic epidermal necrolysis in two rhesus macaques (Macaca mulatta) after administration of rituximab.

A 2- and a 7-year-old rhesus macaque developed toxic epidermal necrolysis (TEN) after administration of ritux imab. Rituximab, a chimeric monoclonal antibody (mAb) directed against the CD20 antigen on B lymphocytes, is used to treat certain B cell neoplasias. The macaques were part of a gene therapy study that involved administering an adeno-associated viral vector encoding human factor IX (hFIX) to the animals. Both animals developed antibody against hFIX, which eliminated expression of the protein. Rituximab was administered to deplete the population of B cells producing antibodies against the protein. Two days after treatment, the 7-year-old animal developed erythemic skin lesions that rapidly progressed in severity, resulting in epidermal sloughing and ulceration. Despite aggressive treatment with analgesics, antibiotics, and corticosteroids, the animal had to be euthanized 5 days later. The 2-year-old macaque had no reaction to the initial dose of rituximab and received a second infusion 2 weeks later. Two days after drug administration, skin lesions developed; aggressive analgesic, antibiotic, and corticosteroid treatment was initiated, and the lesions resolved. A third rituximab dose was given approximately 2 months after the second. Skin lesions developed and were treated. The animal made a full recovery. In both cases, skin biopsies were taken and histopathologic findings were consistent with TEN. A severe, life-threatening condition, TEN manifests as an intolerance reaction in the skin. The most common cause of TEN is a response to previous drug administration. To our knowledge, this condition has not been reported in association with rituximab administration in macaques.

Successful intravenous human immunoglobulin treatment of drug-induced Stevens-Johnson syndrome in a dog.

A two-year-old, male English springer spaniel developed severe mucocutaneous ulceration following treatment with trimethoprim-potentiated sulphadiazine. The clinical signs were consistent with Stevens-Johnson syndrome (SJS): there were no target or arciform lesions typical of erythema multiforme minor and major; more than one mucosal surface was affected; epidermal detachment affected less than 10 per cent of the body surface area; and there was a clear history of drug exposure. Systemic signs included a severe hepatopathy, dyspnoea, pyrexia and cachexia. Glucocorticoid therapy was associated with secondary infection by Pseudomonas aeruginosa. The clinical signs rapidly resolved following a single intravenous infusion of 0.51 g/kg human immunoglobulin (ivHIG) as a 5 per cent solution. By blocking FAS/FAS ligand (CD95/CD95L) interactions, ivHIG is thought to prevent keratinocyte apoptosis. It also binds to immunoglobulin G Fc receptors, inhibiting cell activation and cytokine synthesis, neutralises autoantibodies and immune complexes, blocks complement activity, is antimicrobial and increases colloid osmotic pressure. To the authors' knowledge, this is the first report of successful treatment of canine SJS using ivHIG, although it has been used to treat erythema multiforme in a cat and toxic epidermal necrolysis in a dog.

Superficial necrolytic dermatitis in 11 dogs with a history of phenobarbital administration (1995-2002).

The clinical records of 11 dogs with histologically confirmed superficial necrolytic dermatitis (SND) and a history of phenobarbital (PB) administration (SND/PB) were evaluated retrospectively (1995-2002). Historical, clinical, clinicopathologic, ultrasonographic, and pathologic findings were compared with those in dogs with SND without prior PB exposure (SND/No PB; n = 9) and with those dogs with PB-associated hepatotoxicity without skin disease (PB/hepatotoxicity). Dogs in the SND/PB group accounted for 44% of all histologically confirmed cases of SND that were evaluated at The Ohio State University Veterinary Teaching Hospital between 1995 and 2002. Median age of dogs in the SND/PB group was 10 years, and median duration of PB therapy was 6 years. Mean alanine aminotransferase (ALT) activity was 239 U/L, and median duration of abnormally high ALT activity was 6.25 months before SND diagnosis. Plasma amino acid concentrations measured in 1 dog were severely decreased. Ultrasonographic findings of hypoechoic nodules with hyperechoic borders corresponded to pathologic findings of nodular areas of normal hepatic tissue surrounded by zones of collapsed parenchyma with vacuolated hepatocytes. Clinical, clinicopathologic, ultrasonographic, and pathologic features of SND/PB and SND/No PB were similar. PB-associated cirrhosis and overt hepatic failure were not features of SND/PB. Different pathogenic mechanisms might induce SND in dogs. Chronic administration of PB requires further examination as a potential risk factor for the development of SND.

Nine cases of idiopathic toxic epidermal necrolysis in cattle in Israel.

Nine sporadic cases of apparent toxic epidermal necrolysis in nine cattle herds in Israel are presented. The clinical symptoms were characterized by full-thickness epidermal exfoliation. No underlying disease or drug administration could be detected in the affected animals, and so all cases were classified as idiopathic. Recovery was noted in all affected animals. The clinical and histological findings are discussed in the light of the pertinent literature.

Case report: idiopathic toxic epidermal necrolysis in a one-week old calf.

A sporadic case of apparent toxic epidermal necrolysis in a one-week-old calf is presented. The clinical picture was characterized by full-thickness epidermal exfoliation. No underlying disease or drug administration could be detected in the affected animal, therefore, the case was classified as idiopathic. The clinical and histological findings are discussed in the light of the pertinent literature. Recovery was noted within three months.

Toxic epidermal necrolysis associated with flea dips.

A 5-y-old intact female Himalayan cat was dipped with an organophosphate-based compound for flea infestation. The animal subsequently died of organophosphate intoxication. Skin lesions present at necropsy were diagnosed microscopically as toxic epidermal necrolysis. A 5-y-old spayed female Corgi dog was dipped with a d-limonene-based compound for flea infestation. The dog subsequently developed a bullous skin disorder which rapidly progressed to severe coalescing necrotizing dermatitis with large areas of skin sloughing. The dog was treated for a tentative diagnosis of toxic epidermal necrolysis with a short course of corticosteroids and extensive supportive care and recovered completely. Flea dip preparations have the potential to induce severe immune-mediated dermatopathies such as toxic epidermal necrolysis.

Management of cryptococcosis and toxic epidermal necrolysis in a dog.

Generalized cryptococcosis with CNS involvement was diagnosed in a 3-year-old spayed German Shorthaired Pointer. Clinical findings included Horner's syndrome, generalized lymphadenopathy, temporal muscle atrophy, and chorioretinitis. Toxic epidermal necrolysis resulted after 19 days of treatment with 5-fluorocytosine and amphotericin B. After discontinuation of the 5-fluorocytosine and amphotericin B and treatment with cephradine and ketoconazole, the toxic epidermal necrolysis resolved. Treatment was completed without further complication by using amphotericin B and ketoconazole concurrently.