Feline Gingivitis-Stomatitis-Pharyngitis

FELINE INFECTIOUS DISEASES

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FELINE GINGIVITISSTOMATITIS-PHARYNGITIS Kelly Diehl, DVM, MS, and Rod A.W. Rosychuk, DVM

Inflammatory conditions of the feline oral cavity are common. 8· 17• 51 Gingivitis-periodontitis related to dental plaque and calculus formation appears to be the most frequently encountered. 8 The next most common diagnosis variously has been called chronic gingivitis-stomatitis, feline gingivitis-pharyngitis, plasmacytic-lymphocytic gingivitis-pharyngitis, 17 or the primary gingivitisstomatitis complex. 13 The authors prefer the term gingivitis-stomatitis-pharyngitis complex for this syndrome. This term emphasizes the fact that the inflammatory, ulcerative, and proliferative changes noted often are both nonspecific and multifactorial. The process of diagnosing and treating this disease complex is one of the most difficult challenges in feline medicine. Autoimmune/immunemediated diseases, the eosinophilic granuloma complex, neoplasia, and other miscellaneous diseases round out the differential diagnoses to be considered for inflammatory conditions of the feline mouth. A thorough dental examination, complete blood count, biochemical profile, urinalysis, viral serology, diagnostic radiography, cultures, and biopsies are valuable tools in establishing a diagnosis and appropriate treatment. The more routine performance of these diagnostics on cats with significant oral disease would greatly contribute to the data available for study. Such data is notably deficient in the veterinary literature at this time. DENTAL DISEASE

Dental disease is the most common cause of gingivitis and periodontitis in the cat,S Dental-related gingivitis is usually first noted in adulthood. 55 The accumulation of plaque (a constantly changing bacterial flora incorporating other organic debris and inorganic substances such as calcium and phosphorous) and calculus (mineralized plaque) 18 can have direct pathogenic effects on From the Department of Clinical Sciences, Colorado State University College of Veterinary Medicine and Biomedical Sciences, Fort Collins, Colorado

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 23 • NUMBER 1 • JANUARY 1993

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the gingiva or initiate an inflammatory response that is itself destructive. 45• 55 As plaque matures, its bacterial flora changes from predominantly gram-positive cocci mixed with a few gram-negative rods, to a more motile, anaerobic gramnegative rod population with a few cocci. Spirochete numbers increase. 17• 18 Gram negative anaerobes (e.g. , Actinobacillus and Bacteroides sp.) have been incriminated as the major cause of gingivitis and periodontitis in most species studied to date. 55 Some bacteria associated with plaque produce toxins that are irritating to the gingiva. 17 Several bacteria also produce hyaluronidase and lysosomal enzymes, which contribute to gingival inflammation. 17 The gingiva become swollen, edematous, and friable. Periodontal pocket (sulcus) depth increases, and the sulcus becomes more permeable to bacteria and their by-products. The vasculature to the gingival papillae increases, allowing a greater influx of inflammatory cells. Plasma cells and lymphocytes become the predominant cell types found in chronically inflamed gingival tissues.45 Plasma cells produce antibodies against bacterial endotoxins, and these antigen/antibody complexes activate complement. Anaphylatoxins are elaborated when complement is activated . These substances mediate neutrophil chemotaxis, increase phagocytosis, damage cell membranes, increase vascular permeability, and cause smooth muscle contraction, all of which may potentiate the destruction of gingival cells. 45 Gingivitis may lead to periodontitis and the necrosis of supporting tissues and alveolar bone.45 In turn, periodontitis may perpetuate gingivitis. Odontoclastic tooth resorption is a common problem in cats and is reported in as many as 74% of cats over 6 years of age.• Siamese and Oriental Shorthairs may be predisposed.•· 8 The etiology of this disorder is not known but is likely multifactorial. The various inciting causes hypothesized include an extension of periodontal disease, viral induction, nutritional imbalance, exposure to low pH in association with regurgitation of hairballs, 21 and hypervitaminosis A. 46 A recent report showed a significant positive correlation with increasing calcium deficiency in the diet. 59 The premolars and molars are most commonly affected, with most lesions .located on the buccal surface.• There is a progressive resorption of the tooth root beginning in the neck region. Gingivitis is frequently associated with root resorptive lesions.8 Hyperplastic gingival tissue may grow into and obscure the lesions.8 Whether the inflammatory response initiates or is a product of the resorptive lesions is controversial. 8 • 30• 59 Early lesions are often covered by normal gingiva. 8 In our experience, patients with extensive gingivitis may not have resorptive lesions. Others59 have also reported that although all patients with such lesions have gingivitis, severe gingivitis is not always associated with resorptive lesions. These resorptive lesions may be very painful and result in anorexia, ptyalism, and dysphagia .30 Extensive resorption may result in crown loss, leaving root remnants imbedded in the jaw. The gingiva may heal over the root, and the remnant can be a source of persistent inflammation. 30 Root remnants are difficult to detect without dental radiographs. Remnant root segments should always be considered a differential diagnosis for chronic gingivitis in the cat.8 • 30 A juvenile onset gingivitis and periodontitis has also been described .55 Affected cats generally are younger than 9 months of age . Siamese, Maine Coon, and Domestic Shorthair cats may be predisposed. Affected cats frequently are of small stature and have histories of chronic upper respiratory infections. Clinical signs begin immediately before eruption of adult teeth. There is rapid accumulation of plaque and calculus, gingival edema/inflammation and recession, and periodontitis with neck and root resorptive lesions and bone loss. 55

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Prevention is perhaps the most important aspect in the management of gingivitis related to dental disease. Appropriate client education is imperative. Feeding hard, dry foods may be beneficial. Routine brushing or daily mouth rinses with .1%-.2% chlorhexidine will assist in controlling plaque and calculus formation. Routine dental prophylaxis (scaling and polishing) is mandatory, especially in prone individuals. Tetracycline and metronidazole, with and without cleansing, have been useful in reducing tartar and preventing its reformation. 75000 IU of spiramycin (not presently available in the United States) and 12.5 mg/kg of metronidazole given daily for 10 days has been reported to dramatically reduce plaque and gingivitis in the cat.59 The use of antibiotics alone should not supplant the use of procedures intended to provide good oral hygiene . Therapy of gingivitis associated with established dental disease involves scaling and polishing, gingivectomy, restorative procedures for resorptive lesions, tooth extraction, 16 and administration of systemic antibiotics (clindamycin, amoxicillin-clavulanic acid, metronidazole, amoxicillin, ampicillin). The duration of antibiotic therapy is usually 10 to 21 days. Adult onset gingival-periodontal disease usually responds well to these methods of management. However, gross anatomic changes such as gingival recession, pockets, bone loss, and root exposure may predispose to a rapid return of signs. 55

GINGIVITIS-STOMATITIS-PHARYNGITIS COMPLEX

This common disease of cats appears to be a relatively nonspecific reaction pattern associated with a number of underlying etiologies. Purebred cats, including Siamese, Abyssinians, Persians, Himalayans, and Burmese appear predisposed. Cats of all ages may be affected, but the syndrome most commonly begins at less than 2 years of age and is gradually progressive. 8• 51 Lesions may be restricted to the gingiva and are characterized by erythema, increased friability, and a tendency for the gingiva to bleed easily. Inflammation also may involve the adjacent mucosa and glossopalatine arch area. Inflamed tissues may be proliferative. In more severe cases, ulceration may be noted, most commonly over the glossopalatine arch region. Severely affected cats have marked inflammatory and proliferative or ulceroproliferative changes, which are usually oriented towards the caudal oropharynx (glossopalatine arches, pharynx, palate), and the gingiva, cheeks, tongue, and/or lips may also be involved. 8• 13• 17 More severe gingivitis-stomatitis cases frequently have concurrent periodontitis. Many etiologic factors have been incriminated as causative or contributory elements in this disease complex. They are discussed in the following sections. These factors may directly initiate inflammation or may do so indirectly by altering the equilibrium between normal bacterial flora and host tissue defenses or both. Dental disease, diet, oral conformation, and other genetically related characteristics (e.g., immunologic makeup) may also be contributing factors . Unfortunately, owing to a lack of adequate epidemiologic studies correlating medical and dietary histories with serologic, culture, and histologic data, major gaps remain in our understanding of the significance of each. 17 In many cases, a cause cannot be defined.

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Bacterial Disease

Bacteria are rarely, if ever, primary causes of gingivitis-stomatitis-pharyngitis in the cat. This is supported by the observation that systemic antibiotic therapy only transiently improves a relatively small percentage of affected cats. 13• 17• 54 However, as discussed in the section on dental disease, once certain bacteria are allowed to proliferate or are given access to sensitive tissues, even normal flora may cause inflammatory changes through the production of various toxins, enzymes, and immunologic-response modifiers. 55 The aerobic and anaerobic bacteria isolated from the gingival crevice of cats with gingivitis and periodontitis has been reported to predominantly consist of Bacteroides spp. (gram-negative anaerobes) and Peptostreptococci. 17 Cats with severe oral inflammation have been noted to have significantly elevated antibody titers to Bacteroides gingival is and Bacteroides intermedius .17 In another study, the gingival flora in cats with gingivitis did not differ significantly from that of normal cats. 13 Aerobes predominated. They included (in order of decreasing incidence) Streptococci spp., Pasteurella spp., Moraxella spp., Flavobacterium spp. , Pseudomonas sp. , Corynebacterium spp., Group II J Nocardia spp. and Actinomyces spp. Anaerobes included Bacteroides spp., Fusobacterium spp. and small numbers of Clostridium perfringens and anaerobic streptococci.13 Fusobacterium nucleatum was cultured with an increased frequency in cats with severe periodontal disease in a small number of cases examined. This bacteria has been associated with periodontal disease in a number of species. 17 An apparently new species of Bacteroides has been isolated only from cats with gingivitis. Its significance awaits further study. 13 Spirochetes and fusiform bacilli have been incriminated as a cause of acute ulceromembranous stomatitis in otherwise immunocompromised cats55 (see the section on ulceromembranous stomatitis). Although bacteria appear to be opportunists in the gingivitis-stomatitispharyngitis complex, they may potentiate inflammatory disease. Attention is therefore usually given to a trial antibiotic regimen early in the course of therapy to assess the relative importance of bacterial infection to the disease process. Systemic antibiotics are generally chosen empirically, based on their known broad-spectrum aerobic and anaerobic effects. Emphasis is placed on the latter. Bacterial cultures are not routinely performed. Depending on the culture technique, areas sampled, and the laboratory performing the tests, culture results can vary tremendously, The significance of the organisms cultured must also be questioned. The most frequently recommended antibiotics include clindamycin (5-10 mg/kg per os BID), .amoxicillin-clavulanic acid (13.75 mg/kg per os BID), metronidazole (10 mg/kg per os BID), and amoxicillin (10 mg/kg per os BID). 44 Spiramycin is a macrolide antibiotic excreted in high concentrations in saliva. Reports from Europe suggest it may prove very useful in the treatment of oral infections. 59 It is not available in the United States at this time. Trial antibiotic therapies are usually maintained for 14 to 21 days. Viral Diseases

Several viruses have been implicated as etiologic agents in the pathogenesis of the feline gingivitis-stomatitis-pharyngitis complex, including the feline leukemia virus (FeL V), feline immunodeficiency virus (FIV), and feline calicivirus (FCV). The feline herpes virus and panleukopenia virus may cause oral

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disease, but it is usually of a more acute nature and is discussed later in this article. The incidence of FeL Y infection in cats with chronic gingivitis-stomatitis is low (0-28%). 25· 26· 51.53 Most studies have failed to show a strong relationship between FeLY infection and oral disease. 25· 26· 51 · 53 In one study,S1 cats infected with FeL Y alone had a similar prevalence and severity of oral lesions as did noninfected cats. Coinfection with FCY did not increase this incidence. However, FeLY infection did synergize with FlY infection to enhance the severity of lesions. 51 The gingivitis associated with FeL Y infection has been described as low-grade and proliferative. 38 Ulcerations can occur on the gingiva, mucous membranes, tongue, and caudal to the molars. 45 Histologic changes have only rarely been reported. Predominant lymphocytic-plasmacytic infiltrates have been noted.54 The pathogenesis of inflammation in affected cats is likely due to immunosuppression and predisposition to bacterial infection. A syndrome of rapidly developing, severe, necrotic stomatitis has been seen in a group of specific pathogen-free cats infected with a new strain of FeLY. 22 Treatment involves supportive care, appropriate dental management, and systemic antibiotics (see the section on dental disease). Lymphocytic-plasmacytic infiltrative disease may be significantly palliated with immunosuppressive drug therapy (e.g. corticosteroids or gold salts). These drugs must be used with great caution in these potentially immunocompromised individuals. Oral inflammation is reportedly the most common clinical abnormality seen in FlY-infected cats, with 50% to 80% having some kind of oral disease. 14· 23• 26· 48· 56• 57· 58 The reported incidence in cats with chronic gingivitis-stomatitis varies from 8% to 80%. 23• 26· 51 In most studies, the incidence and severity of oral disease in FlY-infected cats has been significantly increased when compared to controls. 14· 23· 26· 48· 56· 57· 58 FCY and/or FeL Y coinfection greatly increased the severity of lesions. 51 Inflammatory changes are both ulcerative and proliferative and may affect the gingiva, periodontal tissue, cheeks, glossopalatine region, and tongue. 6 Gingivitis is most common.6 The progression of disease may take years. 38 It remains unclear whether FlY causes these lesions or whether the immunosuppressive effects of the virus result in secondary infections; 38 both may be true. Histopathologic changes have only rarely been reported. Predominant lymphocytic-plasmacytic infiltrates have been noted .54 The use of reverse transcriptase inhibitors AZT (3'-azido-2'3' dideoxythimidine) and PMEA (9-2phosphonomethoxyethyl adenine) have had some success in treating FlYassociated stomatitis. Clinical improvement (occasionally remarkable) was noted during therapy, but signs recurred when the drug was discontinued. 6 The stomatitis associated with FlY may otherwise be resistant to therapeutic measures.6 Emphasis is placed on good dental hygiene. Transient improvement may be obtained with systemic antibiotics and dental management (see the section on dental disease). Patients with lymphocytic/plasmacytic infiltrative disease may improve significantly with administration of anti-inflammatory, immunosuppressive drugs (e.g., corticosteroids, gold salts, progestagens), but these must be used with great caution in these potentially immunocompromised patients. 6· 54 The incidence of FCY infections in cats with chronic gingivitis-stomatitispharyngitis is reported in most studies to be high (20%-90%) and significantly elevated when compared to controls. 26· 51 · 56 However, in one study,S1 FCY infection itself did not increase the prevalence or severity of oral lesions. Inoculation of calicivirus isolated from cats with chronic stomatitis into specific pathogen-free cats produced acute oral ulcerations, but none became viral carriers or developed chronic stomatitis. 27 These data did not support the

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hypothesis that FCV is a primary cause of oral disease in cats. However, it has been noted that FCV synergizes with FIV infection to produce more severe oral disease. 51 It was suggested that FCV may only cause disease in immunocompromised cats. 51 Histopathologic changes have only rarely been reported. Predominant lymphocytic-plasmacytic infiltrates have been noted.13• 26 • 53• 54

Systemic Disease

The normal integrity of the oral mucosa is dependent on the maintenance of an equilibrium between oral bacteria and host tissue defenses. 55 Whereas primary bacterial infections of the mouth are rare, 13• 17 diseases that compromise host defenses are common. In these later instances, normal bacterial flora become pathogenic, or opportunist disease-causing organisms are allowed to proliferate. Any debilitating disease is capable of predisposing to oral inflammation! infection. Protein:calorie malnutrition commonly associated with such diseases may result in oral ulceration because of depressed epithelial cell turnover. 3 Malnutrition also depresses both cell-mediated immunity and other components of the immune system.' Many of these debilitating diseases are capable of directly suppressing normal immunologic responses. 55 Hypothyroidism and diabetes mellitus have been associated with an increased severity of oral inflammatory disease, but the incidence of oral disease apparently is not higher in these patients. 3 Liver and respiratory disease have been associated with oral ulceration. 45 Uremia secondary to renal disease commonly causes oral ulceration. Irritation caused by ammonia coupled with dehydration and blood-clotting defects contribute to ulceration.' Stress acts as an immunosuppressant in humans and has amongst other things, been associated with decreased salivary secretion of IgA. Stress may play a role in the development of acute ulceromembranous stomatitis in the cat by similar mechanisms (see the section on ulceromembranous stomatitis). Chediak-Higashi syndrome is a genetic disease characterized by neutrophil and monocyte functional defects. Affected cats may develop oral ulcerations, periodontal disease, and rapid tooth loss. 55 Idiopathic immunoinsufficiencies (congenital or acquired) may be present in patients with recurrent, usually antibiotic-responsive, gingivitis-stomatitis when there is no other apparent cause. Affected patients often have cyclic or chronic leukopenias or normal or low globulins in spite of severe inflammatory oral disease. 55 On occasion, the gingivitis-stomatitis may be characterized by lymphocytic-plasmacytic infiltrates. 55 In general, therapy for these disorders is aimed at managing and resolving underlying systemic illnesses. Dental therapy and systemic antibiotics for secondary infections should be considered. If the gingivitis-stomatitis can be well controlled on antibiotic therapy, but is recurrent and all immunocompromizing diseases have been ruled out or managed as well as possible, consideration should be given to the use of long-term antibiotics to maintain control; or the immunomodulator staphylococcal phage lysate (Delmont Laboratories Inc., Biological Specialties, Swarthmore, PAY can be used. However, few patients respond well enough to antibiotics to warrant these considerations. Because these patients may be very prone to disease caused by plaque-associated anaerobes, routine professional dental prophylaxis and even total mouth extractions have been recommended.

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Plasmacytic-Lymphocytic, Gingivitis-Stomatitis-Pharyngitis

Cats of all ages and breeds appear susceptible to this disease. Clinical presentations most commonly include inappetence, anorexia, or difficulty prehending or chewing food. Less commonly, there is halitosis, ptyalism, weight loss, and dehydration. 25• 54 • 55 Erythema, swelling, ulceration, and proliferation (raspberry-like appearance) of the gingiva or the glossopalatine arches are most commonly noted in the mouth. 44 Less commonly involved areas are the pharynx, tongue, buccal mucosa, hard palate, and lips. 25• 54• 55 The severity of disease may wax and wane over time. Rarely, other areas of the skin or feet may be involved. Variable degrees of dental disease are common (e.g., plaque, calculus, resorptive lesions). In the majority of cases (approximately 70% ), histopathologic examination of tissues shows a diffuse, dense lymphocytic and plasmacytic infiltrate in the mucosa and submucosa. 54 In approximately 30% of cases, the infiltrate is predominantly plasmacytic. 54 The most common clinicopathologic finding is a polyclonal hyperglobulinemia, which is present in about 50% of cases. 25• 54 The etiology of this disease remains unclear. Although dental disease may in itself produce lymphocytic-plasmacytic infiltrates, many cats with significant gingivitis-stomatitis fail to have significant dental problems or are not significantly improved by dental therapy. However, dental disease appears to contribute to the inflammatory process, and affected cats do appear to be comparatively plaque intolerant. 55 Both hypersensitivities and immunoinsufficiences have been suggested to result in similar lymphocytic-plasmacytic infiltrates. 55 The nature of the infiltrates, presence of hyperglobulinemias, and observed responses to immunosuppressive drug therapies suggests that hypersensitivity disorders are most common. Similar lymphocytic-plasmacytic inflammatory disease of the feline bowel50 and footpads 32 are also thought to be immunologically mediated. Both immediate and delayed hypersensitivity reactions to oral bacteria may play a role. Interestingly, the bacterial flora of normal versus affected gingiva may not differ. 13 It is possible that certain cats are hyperresponsive to even normal bacterial antigens because of genetic tendencies or acquired immune dysfunctions. The fact that only approximately 30% of affected cats will show some transient response to systemic antibiotic therapy suggests that bacteria produce, at best, opportunistic infections. 54 FeLV, FIV, and FCV infections have all been noted in cats with this syndrome. FeLV and FIV infections were noted in 16% and 23% of cases, respectively. 54 In one study, 13 all but one of the FCV-infected cats from which gingival biopsy specimens and oropharyngeal swabs were taken had heavy plasma cell infiltrates. The one case without FCV had a predominantly neutrophilic infiltrate. The number of cats biopsied and their FIV status were not noted in this study. Although much more data is available regarding the carriage of these viruses in cats with chronic stomatitis-gingivitis (see the section on viral diseases), histologic data has not been reported in most studies. The role viral infections play in affected cats remains speculative. Their immunosuppressive potential may be most contributory. Some FeLV- and FlYinfected cats with this syndrome may respond to immunosuppressive drug therapy (e.g., corticosteroids, progestagens, gold salts). This may suggest that more than one immunologic phenomenon are operative in affected cats. Immunosuppressive therapies should be used with great caution in such patients.

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Food hypersensitivities have been rarely incriminated as causes of a Iymphocytic-plasmacytic stomatitis in the cat.55 The diagnosis is made on the basis of response to a strict hypoallergenic diet (e.g., lamb baby food). Immunoinsufficiencies (nonviral) have been theorized to result in chronic gingivitis-stomatitis characterized by Iymphocytic-plasmacytic infiltrates. 55 Genetic defects (congenital or acquired) may compromise host defenses and allow normal flora of the mouth to initiate an inflammatory response. Affected patients are often noted to have cyclic or chronic leukopenias or normal or low globulins in spite of severe inflammatory diseases. Immunosuppressive therapies should be used with great caution in such patients. 55 The standard workup for patients suspected of having this syndrome includes a complete blood count, serum chemistry panel, urinalysis, FeLV, FIV serology, dental radiographs, and biopsy specimens of affected tissues . Cytologic examinations and viral and bacterial cultures usually are not rewarding. Attention should be given to maintenance of a well-balanced diet. Although the routine administration of multivitamins (especially Vitamins A and C) have been suggested, there is no data to support their benefit. 13 Treatment should always begin with thorough dental management (scaling, polishing, restorations, or extractions). Special emphasis is placed on removing anatomically compromised teeth, retained root tips, or bony sequestra. Because affected individuals tend to plaque intolerant, thorough dental prophylaxis should be performed every 4 to 12 months and, when possible, may be followed up with aggressive home care. 55 Because home care often is difficult to manage and of questionable value, greater emphasis is placed on routine professional dental prophylaxis. Systemic antibiotics produce transient responses in about 30% of cases. 54 Those that have proved most effective include clindamycin, amoxicillin-clavulanic acid, metronidazole, or amoxicillin. See the section on bacterial diseases for dosages. The trial treatment period is 14 to 21 days. Corticosteroids have produced the most consistent therapeutic responses.54 Best initial results have been obtained with methylprednisolone acetate (DepoMedrol, Upjohn, Kalamazoo, MI) (86% of cases responding; n = 15). 54 2 to 5 mg/kg intramuscularly or subcutaneously is given every 14 days until significant response is noted (usually 4-6 weeks); this dose is then given as necessary but, ideally, no more frequently than every 6 to 8 weeks. Oral prednisone or prednisolone have yielded good responses when started at immunosuppressive dosages of 1 to 2 mg/kg BID (73% of cases responding; n=11). 54 Emphasis is placed on gradually reducing this dose to the lowest every-other-day dose required to control the symptomatology. Oral triamcinolone or dexamethasone may prove of benefit in cases refractory to control with reasonable dosages or oral prednisone or prednisolone. Oral triamcinolone is given at a dose of .3 to .6 mg/kg/day or 4 mg/cat every 24 hours initially, followed by 4 mg every other day and then the lowest every-other-day dose required to control the symptomatology. Dexamethasone is given at a dose of .1 to .2 mg/kg/day or 2 to 4 mg/ cat/day. 44 Overall, cats appear to tolerate these potent, longer-acting steroids quite well, but there is still the potential for iatrogenic hyperadrenocorticism. It is not uncommon for the effectiveness of corticosteroid therapy to diminish over a period of several months. Gold salts (chrysotherapy) have been noted to benefit approximately 75% of patients treated. 44 • 54 Their effectiveness is likely related to their antiinflammatory and immunomodulatory effects. Aurothioglucose (Solganol, Schering, Kenilworth, NJ) is given at a dose of 1 mg/kg intramuscularly every 7 days for

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a trial period of at least 16 to 20 weeks. Onset of benefit may be noted anywhere from 1 to 16 weeks; the mean is 8 weeks. Once a reasonable response is noted, the frequency of administration is decreased to 14-day intervals for 2 months, then monthly for 6 to 8 months. It is important to note that many cats will not have total resolution of their lesions on this protocol; slight erythema, especially of the gums, will remain. However, these patients usually are dramatically improved clinically. If the problem remains in remission for 6 to 8 months, then the gold salts should be stopped. Approximately 40% of cats have been noted to go into remissions of at least 1 year following discontinuation of the drug. 54 Deleterious reactions to gold salts are rare. In humans, these include dermatitis, stomatitis, thrombocytopenia, leukopenia, anemia, eosinophilia, and nephropathies characterized by proteinuria. A fatal thrombocytopenia has been reported in one cat.>• We have seen one cat develop a pancytopenia and one cat develop renal failure while on this protocol. An association with gold salt therapy could not be proven because of the presence of intercurrent diseases. We have also seen one cat develop an eosinophilia, which, in humans, is thought to herald other drug reaction phenomena. The eosinophilia resolved with discontinuation of the gold salts in this cat. Complete blood counts, platelet counts, blood urea nitrogen and creatinine, and urinalyses are recommended every 2 to 3 weeks during the induction phase of therapy. Thereafter, these tests are run every 2 to 6 months. The authors favor the early consideration of gold salt therapy in the management of this disease because they are well tolerated, circumvent the need to give oral medication, may be used when corticosteroids are not tolerated well (e.g., diabetes), and offer the potential for prolonged drug-free remissions after several months of therapy. Immunosuppressive dosages of corticosteroids can be used initially along with gold salts to hasten the resolution. Corticosteroids are then gradually dropped from the protocol. Corticosteroids and gold salts have been used to successfully manage this disease in FeLV- and FlY-infected cats. However, the use of such drugs in potentially immunocompromised patients must be approached with caution. Megestrol acetate may prove beneficial (80% of cases responding; n = 5)54 because of its anti-inflammatory and immunomodulatory effects. 1 mg/kg is given every other day until remission, then this dose is given once or twice a week for maintenance. Potential side effects (e.g., diabetes mellitus) warrant considering this therapy only for 'last ditch' efforts. Other immunosuppressive therapies to be considered include azathioprine (.3 mg/kg qod; potentially very toxic in cats) as used for treating lymphocyticplasmacytic inflammatory bowel disease,S0 and chlorambucil, .1 to .2 mg/kg/ day per os until significant improvement, and then every other day as used for Pemphigus foliaceus in the cat. 32 The extraction of all teeth behind the canines (premolars and molars) is considered by some to be the treatment of choice for chronic, refractory gingivitis-stomatitis. 9 When significant signs persist, the canines and incisors are also removed. This procedure may be indicated in patients that are considered immune deficient.55 Anaerobes present in plaque may be significant disease-contributing factors in these cats. Immune suppressant drugs may be contraindicated in such patients. 55 This very aggressive procedure may benefit the majority of cats (6 of 9 and 8 of 12 in two studies). 15• 17• 18 However, in our experience, many cats treated in this fashion will have recurrences of their inflammatory disease thereby necessitating other modes of therapy. Radiation therapy (24 Gy given in fractions of 4 Gy, given three times a week for 2 weeks) as an adjunctive treatment to extractions has been shown to

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further reduce the inflammation in the oral and oropharyngeal regions (n = 5). However, four of five cats continued to manifest signs of inflammation in the oral and oropharyngeal regions. 9 FELINE JUVENILE GINGIVITIS

This hyperemic, proliferative (hyperplastic) gingivitis is noted in lines of purebred cats. 55 Abyssinians and Persians may be predisposed. Time of onset is usually associated with eruption of adult teeth. Hyperplastic tissue may cover the crowns of premolars and molars by 1 year of age. The histopathology of this disease has not been reported. Therapy involves gingivectomy, thorough plaque removal, and intensive plaque control through aggressive home care and professional prophylaxis (done as frequently as every 2 or 3 months). As the patient matures, a tendency to spontaneous remission is noted, necessitating less aggressive management. 55 The use of anti-inflammatory or immunosuppressive treatments has not been reported . ULCEROMEMBRANOUS STOMATITIS

Ulceromembranous stomatitis (trench mouth, Vincent's stomatitis, or acute necrotizing ulcerative gingivitis [ANUG]) 16 is an acute form of gingivitis and stomatitis that has been suggested to be relatively common in the cat. 52 Siamese cats may be predisposed. 52 Lesions usually begin on the gingival margin as severe inflammation and necrosis. The gums are painful and may bleed readily. With progressive necrosis, there is ulceration, which may result in bone exposure. 16 Pseudomembrane formation can occur. 52 Similar inflammation and necrosis may spread to involve adjacent oral mucosa. Ulceromembranous stomatitis is thought to be an infection caused by the normal bacterial flora of the mouth (spirochetes and fusiform bacillus) when oral resistance to infection has been compromised. 55 Factors incriminated include psychogenic and physical stress and immunocompromising diseases such as diabetes mellitus, FIV, and FeLV. 55 An underlying disease may not always be delineated . Treatment includes dental therapy, removal of necrotic tissue, and systemic antibiotic therapy (clindamycin, metronidazole, amoxicillin). 55 The ulcerative areas can be flushed one to three times daily with 1% hydrogen peroxide. If possible, underlying predisposing factors should be removed to prevent recrudescence of disease. IMMUNE-MEDIATED AND AUTOIMMUNE DISEASES

Pemphigus vulgaris, systemic lupus erythematosus, hypersensitivity vasculitis, erythema multiforme, and toxic epidermal necrolysis have all been reported to cause oral lesions in the cat. Pemphigus vulgaris produces oral lesions in 90% of affected cats. In 50% of cases, these lesions antedate the development of more generalized mucocutaneous, cutaneous, and systemic signs. 35 Oral lesions are vesicobullous, erosive, or ulcerative and have been noted on the tongue, hard palate, and throughout the mouth. 31 , 35 Systemic lupus erythematosus has been noted to produce an ulcerative glossitis, ulcerative palatine lesions, and oral vesicles in the cat. These cats usually have other concurrent systemic involvement (leukocytosis, leukopenia, neutropenia, lymphopenia, polyarthritis, myopathies, conjunctivitis, dermati-

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tis, subclinical pulmonary disease, hemolytic anemia, and progressive renal failure). 40 A hypersensitivity vasculitis has been noted to produce oral lesions in the cat. Although an etiology is often unknown, the deposition of immune complexes related to infections, drug reactions, neoplasia, or immune-mediated diseases are incriminated. 10 Lesions are most commonly noted on the skin (wheals, urticaria, purpura, bullae, crusty lesions, necrosis, ulceration), mucous membranes of the mouth, and mucocutaneous junctions (ulceration). Diagnosis of these immune-mediated diseases requires a complete history, physical examination, direct smears from unbroken vesicobullous lesions (numerous acanthocytes, neutrophils, and/or eosinophils, no organisms-F. vulgaris), biopsy (with emphasis on including the margins of lesions, especially for P. vulgaris), immunofluorescence or immunoperoxidase testing, antinuclear antibody titer (SLE), and response to treatment. Generally, therapy involves immunosuppressive dosages of corticosteroids (e.g., oral prednisone starting at 2-4 mg/kg/day), or corticosteroids plus cyclophosphamide,35 chlorambucil, 36 azathioprine or gold salts (gold salts for P. vulgaris) .35 Erythema multiforme (EM) and toxic epidermal necrolysis (TEN) are acute eruptions of the skin and mucous membranes. They are thought to be hypersensitivity reaction patterns most commonly associated with various intercurrent diseases or drug reactions (e.g., aurothioglucose and penicillin reported for EM; ampicillin, hetacillin, cephaloridine reported for TEN). 35• 47 They also may be idiopathic. Skin lesions associated with EM are most commonly asymptomatic maculopapular eruptions that enlarge peripherally and heal centrally; oral lesions are maculopapular, erosive, or ulcerative. 35• 47 Skin and oral lesions for TEN are vesicobullous or ulcerative. Systemic signs are common (pain, fever, anorexia, depression). 35• 47 Diagnosis for both EM and TEN is based on history and skin biopsy specimens. 35 • 47 Treatment emphasizes correcting underlying problems and is otherwise supportive. 35• 47 Corticosteroid therapy, beginning at immunosuppressive dosages, is controversial. 35• 47 EOSINOPHILIC GRANULOMA COMPLEX

Indolent ulcers (eosinophilic ulcers, rodent ulcers), eosinophilic plaques, and linear granulomas (collagenolytic granulomas) are only rarely noted within the mouth. When present, they usually are associated with the palate or tongue. Indolent ulcers tend to be circumscribed, red-brown lesions with raised borders or may assume a plaquiform appearance. Eosinophilic plaques are circumscribed, raised, and erythematous. Collagenolytic granulomas are papular to nodular and may appear very proliferative. 35 Concurrent cutaneous involvement is variable. When they affect the skin, all three components of the eosinophilic granuloma complex are thought to be nonspecific reaction patterns, most commonly associated with hypersensitivity disorders (e.g., atopy, food, or drug hypersensitivities). 43 However, when lesions are confined to the mouth, many tend to be idiopathic. Diagnosis is made by biopsy. 35• 43 Treatment involves aggressive corticosteroid administration (methylprednisolone acetate, oral prednisolone/prednisone, triamcinolone or dexamethasone; for dosages, see the section on lymphocytic-plasmacytic gingivitisstomatitis-pharyngitis). Consideration should be given to ruling out food allergy. The authors have not seen atopy manifest as oral lesions. Refractory cases may be treated with megestrol acetate, 2.5 to 5.0 mg total dose every other day until lesions are resolved, then once or twice weekly for maintenance.

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Consideration should be given to the many deleterious side effects potentially associated with progestagen therapy in the cat. Other treatments reported for the ECG complex have not been used by the authors to treat oral manifestations but could be considered, especially in refractory cases. Recently, some success has been achieved in treating indolent ulcers of the lip with oral antibiotics (trimethoprim-sulfadiazine, 120 mg BID; cefadroxil, 100 mg BID; amoxicillin trihydrate plus clavulanate potassium, 32.5 mg twice daily)Y It was not known if the response was due to antibacterial effects or the antiinflammatory effects at times associated with these antibiotics. Levamisole, 5 mglkg per os given three times per week, has produced incomplete remission in some cases of ECG. C0 2 laser therapy has been beneficial in the management of some refractory eosinophilic ulcers of the lips. Radiation therapy has also proved to be of some benefitY NEOPLASIA

Neoplasms of the oropharynx comprise 20 to 54% of alimentary tumors in cats. 45 The majority(> 80%) are malignant. 45 The mean age of onset is 10 to 11 years of age, although odontogenic tumors have been reported in cats younger than 1 year of age. Squamous cell carcinoma is the most common oral tumor, accounting for 70% of oral neoplasms. 2• 45 Fibrosarcoma is the second most common tumor, comprising 10 to 20%. 45 Hemangiosarcoma, adenocarcinoma, osteosarcoma, lymphoma, fibrous histiocytoma, tonsillar carcinoma, melanoma, and undifferentiated tumors have all been described. Benign oral tumors are unusual in cats, although hemangiomas, epulitides, odontogenic tumors, sebaceous adenomas, papillomas, polyps, and basal cell tumors have been reported .2• 45 Oral squamous cell carcinoma most frequently involves the gingiva and tongue, particularly near the lingual frenulum. Extensive bony involvement is common and occurs rapidly. The metastatic potential of oral squamous cell carcinoma in cats is unclear, because most cats die or are euthanized because of the severity of local disease. In general, squamous cell carcinoma is locally invasive, with a low rate of metastasis. Metastases to local lymph nodes and lungs occurs late in the course of the disease. 2• 45 Therapy of oral squamous cell carcinoma can be frustrating. Cats with these neoplasms are often anorectic and cachectic. Their nutritional needs must be addressed . Surgery may be considered if the lesions are localized. Radiation and chemotherapy are not successful. In a retrospective study of 52 cats with oral squamous cell carcinoma treated with various combinations of surgery, radiation, chemotherapy, and hyperthermia, median survival time was 2 months; only two cats lived longer than 1 year. 42 Oropharyngeal fibrosarcomas most commonly affect the gingiva and palate. They are locally invasive and rarely metastasize. Radical surgery probably is the treatment of choice. Fibrosarcomas are considered radiation-resistant, although there may be benefit if radiation therapy is used as an adjuvant to surgery. 45 Inductive fibroameloblastomas are rare odontogenic tumors usually seen in young cats. The tumors are locally invasive, slow growing, and have a predilection for the upper canine teeth and maxilla. Small lesions can be treated by debulking surgery and cryotherapy. Large masses can be irradiated. Control rates are good with aggressive therapy. Metastasis has not been reported. 5• 20 Nasopharyngeal polyps are pedunculated masses that originate in the bullae or auditory tube. They probably arise secondary to chronic upper respiratory inflammation, although there is recent evidence that some polyps

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may be congenital. They can be visualized on oral examination of the caudal pharynx or in the external ear canal. Young cats are most commonly affected. Complete removal of the mass is necessary to eliminate recurrences. 1• 19• 20 MISCELLANEOUS

Oral ulcerations can be seen with FCV or, less commonly, feline viral rhinotracheitis (FVR). Lesions caused by FVR are more severe and widespread than those seen with FCV.'5 Feline panleukopenia virus can also cause extensive ulceration of the gingiva, tongue, and palate. 12• 44• 45 The lesions associated with FVR, FCV, and panleukopenia virus are usually acute. Most infected cats also show signs of systemic illness. Therapy is reviewed elsewhere. 12• 41 Candidiasis is a rare infection of the mucous membranes and skin. 34 Both localized superficial infections and systemic infections have been suggested to occur in the cat. Candida are considered to be part of the normal microflora of the gastrointestinal tract. 34 Infections usually develop in immunocompromised patients (e.g., those treated with corticosteroids or other immunosuppressive drugs), 34 or in sites of chronic nonhealing ulcers of the oral cavity. Lesions are characterized by nonhealing ulcers convered with whitish-grey plaques with hyperemic margins . 11 Organisms (budding cells) can usually be seen in exudate stained with new methylene blue or Diff-Quik. The organism is usually readily cultured.U· 34 Oral infections have been treated with gentian violet, 1:10,000 in 10% alcohol daily; potassium permanganate 1:3,000 in water daily; or nystatin suspension four times daily. 34 Oral ketoconazole is effective, 34 as is intravenous amphotericin B. 11 Ingestion of plants such as dieffenbachias, pointsettias, and pine needles can irritate the oral mucous membranes. Burns from biting electric cords are not uncommon.<'· 47 Foreign bodies or masses dorsal to the soft or hard palates may result in incessant rubbing of the tongue over the palatine areas to cause oral ulcerations. Thallium toxicosis may cause oral ulceration in addition to the erythema, crusting, necrosis, and ulceration noted to affect the face, ears, axilla, groin, and feet. 33 Dilantin therapy has been noted to produce a hyperplastic gingivitis in cats. 24

References 1. Bradley RL, Noone KE, Saunders GK, et al: Nasopharyngeal and middle ear polypoid masses in five cats. Vet Surg 14:141-144, 1985 2. Bradley RL, Sponenberg DP, Martin RA: Oral neoplasia in 15 dogs and four cats. Semin Vet Med Surg (Small Anim) 1:33-42, 1986 3. Burrows DF, Miller WH, Harvey CE: Oral medicine. In Harvey CE (ed): Veterinary Dentistry. Philadelphia, WB Saunders, 1975, p 34 4. Coles S: The Prevalence of buccal cervical root resorptions in Australian cats. J Vet Dent 7:14-16, 1990 5. Dubielzieg RR, Adams WM, Brodey RS: Inductive fibroameloblastoma: an unusual dental tumor of young cats. JAm Vet Med Assoc 174:720-722, 1979 6. Egberink HF, Horzinek MC: Feline immunodeficiency and oral cavity disease. In Proceedings of the Second Veterinary Dental Congress, Vienna, Austria, 1991 7. Eisenmenger E, Zetner K: Veterinary Dentistry. Philadelphia, Lea & Febiger, 1985, p 146 8. Frost P, Williams CA: Feline dental disease. Vet Clin North Am Small Anim Pract 16:851-873, 1986

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9. Goldstein GS, King G, Venner M: Radiation as adjunct therapy in treating plasmacytic lymphocytic stomatitis in cats. In Proceedings of the Second World Veterinary Dental Congress, Vienna, Austria, 1991 10. Gorman JT, Werner LL: Immune mediated diseases. In Sherding RG (ed): The Cat: Diseases and Clinical Management. New York, Churchill Livingstone, 1989, pp 15291600 11. Greene CE: Candidiasis. In Infectious Diseases of the Dog and Cat. Philadelphia, WB Saunders, 1990, pp 723-727 12. Greene CE, Scott FW: Feline panleukopenia. In Greene CE (ed): Infectious Diseases of the Dog and Cat. Philadelphia, WB Saunders, 1990, pp 291-299 13. Gruffydd-Jones TJ: Gingivitis and stomatitis. In August JR (ed): Consultations in Feline Internal Medicine. Philadelphia, WB Saunders, 1991, pp 397-402 14. Hardy WM: Feline T-Iymphotropic lentivirus: Retrovirus induced immunosuppression in cats. JAm Anim Hosp Assoc 24:241-243, 1988 15. Harvey CE: Effect of extraction of cheek teeth in cats with gingivitis-stomatitis. Veterinary Dentistry 3:2, 1986 16. Harvey CE: Inflammatory oral diseases of the cat. In Harvey CE, Orr SH: Manual of

Small Animal Dentistry. Cheltenham, British Small Animal Veterinary Association, 1990, pp 49-54 17. Harvey CE: Oral inflammatory diseases in cats: JAm Anim Hosp Assoc 27:585-591, 1991 18. Harvey CE: Periodontal disease. In Proceedings of the Eastern States Veterinary Conference (Kal Kan Foods Inc) 5:338-342, 1991 19. Harvey CE, Goldschmidt MH: Inflammatory polypoid growths in the ear canal of cats. J Small Anim Pract 19:669-677, 1978 20. Hawkins CD, Jones BR: Adamantinoma in a cat. Aust Vet J 59:54-55, 1982 21. Holstrom SE: External osteoclastic resorptive lesions. Feline Pract 20:7, 1992 22. Hoover EA, Mullins Jl, Quackenbush SL, et al: Experimental transmission and pathogenesis of immunodeficiency syndrome in cats. Blood 70:1880--1892, 1987 23. Ishida T, Washizu T, Toriyabek K, et al: Feline immunodeficiency virus infection in cats of Japan. JAm Vet Med Assoc 194:221-225, 1989 24. Ishikawa J, Glickman 1: Gingival response to the systemic administration of sodium diphenylhydantoin (Dilantin) in cats. J Periodontol 32:149-158, 1961 25. Johnessee JS, Hurvitz AI: Feline plasma cell gingivitis-pharyngitis. J Am Anim Hosp Assoc 19:179-181, 1983 26. Knowles JD, Gaskell RM, Gaskell CJ, et al: Prevalence of feline calicivirus, feline leukemia virus and antibodies to FIV in cats with chronic stomatitis. Vet Rec 124:336338, 1989 27. Knowles JD, McArdle F, Dawson S, et al: Studies on the role of feline calicivirus in chronic stomatitis in cats. Vet Microbiol 27:205-219, 1991 28. Kummel B: Treatment of autoimmune skin disease. Dermatology Dialogue 4:2, 1985 29. Lyon KF: An approach to feline dentistry. Compend Contin Educ Pract Vet 12:493497 30. Lyon KF: Feline dental disease-Classification and treatment. In Proceedings of the Second World Veterinary Dental Congress, Vienna, Austria, 1991 31. Manning TO, Scott DW, Lewis RM: Pemphigus diseases in the feline: Seven case reports and discussion. JAm Anim Hosp Assoc 18:432-443, 1982 32. Medleau L, Kaswan RL, Lorenz MO, et al: Ulcerative pododermatitis in a cat:

immunofluorescent findings and response to chrysotherapy. JAm Anim Hosp Assoc 18:449-451, 1982 33. Muller GH, Kirk RW, Scott DW: Environmental Diseases. In Small Animal Dermatology. Philadelphia, WB Saunders, 1989, pp 427-574 34. Muller GH, Kirk DW, Scott DW: Fungal diseases. In Small Animal Dermatology, Philadelphia, WB Saunders, 1989, pp 315-317 35. Muller GH, Kirk RW, Scott DW: Immunologic diseases. In Small Animal Dermatology, Philadelphia, WB Saunders, 1989, pp 427-574 36. Mundell AC: New therapeutic agents in veterinary dermatology. Vet Clin North Am Small Anim Pract 20:1544-1545, 1990 37. Parker NR, Binnington AG: Nasopharyngeal polyps in cats: Three case reports and a review of the literature. JAm Anim Hosp Assoc 21:473-478, 1985

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Address reprint requests to Rod A.W. Rosychuk, DVM Department of Clinical Sciences Colorado State University College of Veterinary Medicine and Biomedical Sciences Fort Collins, CO 80523