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Differential Diagnosis of Acute and Chronic Symptomatic Oral Ulcerations

Differential Diagnosis of Acute and Chronic Symptomatic Oral Ulcerations

DIFFERENTIAL DIAGNOSIS OF ACUTE AND CHRONIC SYMPTOMATIC ORAL ULCERATIONS

Acute and chronic ulcerations represent the most common symptomatic mucosal pathoses encountered by oral health care practitioners. Every clinician should have an organized approach to these problems which will be encountered frequently. The first step in all cases should be to divide and conquer. The ulcerations can be classified as acute or chronic, and this will cut in half the number of diseases in the differential diagnosis. Acute lesions arise rapidly (1 or 2 days), normally heal in 10-14 days and may recur at varying intervals. In some cases, the lesions may take longer than a month to heal, but this is not typical. Recurrences are highly variable. Some may never recur, while others may recur before the first crop has healed.

On the other hand, chronic erosions tend to slowly evolve and become more problematic over an extended period of time. Instead of crops of lesions interspersed with periods of remission, the chronic erosions tend to persist with variable levels of intensity. Patients rarely present to their health care professional when these lesions first arise; the vast majority of chronic ulcerations have been present for months when the patients present for diagnosis and treatment. Normally, the distinction between acute and chronic ulcerations is made easily; but like everything else, there are gray areas.

Prior to the development of a differential diagnosis, the patient’s medical history should be evaluated thoroughly. The presence of any extraoral lesions must be documented. A listing of all utilized prescription and “over-the-counter” medications is mandatory. The following is a list of common symptomatic oral ulcerations:

ACUTE CHRONIC

Recurrent aphthous Erosive Hand, foot & disease vulgaris Behçet's syndrome erythematosus Drug reaction Herpes zoster Contact reaction multiforme Graft-versus-host disease Necrotizing sialometaplasia Cinnamon reaction

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ACUTE ORAL ULCERATIONS

1. Recurrent

Recurrent aphthous stomatitis (RAS) is the most common pattern of oral ulcerations encountered by the health professional. Approximately 20 percent of the general population has a positive history for these ulcerations. Prevalence as high as 55% has been reported in populations under stress (professional school students).

Numerous studies have indicated an immunologic cause. Although the humoral system is involved, the cell mediated immune response has received the most attention and is thought to be responsible for the initiation of the ulceration. Early lesions do show similarity to a delayed hypersensitivity reaction. Investigators theorize RAS is the result of bacterial toxins, foods, and other substances acting as allergens or haptens which initiate an immune response. A variety of allergens most likely is responsible. In addition, mucosal thickness and immunodysregulation appears involved in many patients. Elimination of one allergenic source often resolves RAS in some patients but not in others. Since discovery of the causative agent is most difficult, therapy has been directed toward decreasing the immune reaction.

The prototypical and most common form is the minor aphthous stomatitis (MiRAS). These arise almost exclusively on nonkeratinized movable mucosa and exhibit yellow fibrinopurulent membranes surrounded by erythematous halos. The ulcerations vary from 2-10 mm (majority approximately 5 mm) and usually heal without scarring within 10-14 days. The recurrence rate is highly variable. The lesions may number from one to a hundred at a time. Several systemic medical problems can result in lesions clinically identical to RAS and must be ruled out in all cases which are severe or nonresponsive to therapy. A number of systemic disorders such as blood dyscrasia (esp. leukopenia), nutritional deficiencies (low zinc, iron, B12 or folate), Behçet's syndrome, Crohn's disease, celiac sprue and AIDS are associated with an increased prevalence of aphthous-like ulcerations. In addition, every one of the other acute ulcerative conditions may resemble RAS and must be ruled out prior to therapy. Topical steroids appear to be the most consistently efficacious; chemical cautery is contraindicated. Most over- the-counter medications produce more problems than they solve. If clinical contraindications to steroids exist (children, pregnancy, nursing, hypertension, diabetes, granulomatous infectious disease, G.I. ulcerations, blood dyscrasia, previous malignancy, etc.), permission for corticosteroid utilization must be obtained from the attending physician or utilize antimicrobials such as tetracycline or chlorhexidine. In all severe cases and those resistant to normal therapy, a systematic evaluation for the underlying trigger or any related systemic disorders should be performed.

THERAPY Localized -Lidex gel (Sore Mouth [SMS] 1-1). Easy to apply but slightly bitter -Diprolene ointment (SMS 1-2). Thicker than gel but tasteless. Also available as gel but slightly bitter. Often prescribed generically due to difficulty to obtain 15gram tube. Diffuse -Dexamethasone (SMS 1-6) Damm Sore Mouth 3

Another type which exhibits significantly more morbidity is the major aphthous stomatitis (MaRAS). This variant also has been called periadenitis mucosa necrotica recurrens or Sutton’s Disease. These ulcerations are similar to MiRAS but are significantly larger, deeper, take longer to heal and result in scarring. The lesions are seen predominantly on movable mucosa, vary in size from one to several centimeters and often take up to six weeks to heal. It is not uncommon for a new lesion to arise before the current has healed. Long periods of remission are difficult to obtain. The usual topical steroids normally are ineffective. More potent local steroids (Kenacort® tablets, Kenalog 40® , dexamethasone solution) or systemic often are required for temporary control. All MaRAS patients should be thoroughly evaluated to rule out a systemic basis for their ulcerations.

THERAPY Accessible (vestibule, buccal mucosa, etc.): Kenacort tablets (SMS 1-9) Inaccessible (soft , , etc.): Compounded dexamethasone solution (SMS 1-7) Extension past wet line: Kenalog 40 injection (SMS 1-10)

A relatively rare variant is the herpetiform aphthous stomatitis (HeRAS). These ulcerations appear similar to MiRAS but generally are smaller in size, more numerous and can be found on movable or bound mucosa. The typical size is 2 mm or less, and it is not uncommon for patients to exhibit more than 100 lesions at one time. The recurrences are spaced so closely that the patients are seldom free of these very painful lesions and often have the ulcerations continuously for several years. The lesions frequently cluster and superficially may resemble a primary herpetic ; the lack of a painful and intensely erythematous gingiva combined with the recurrence history allows separation. Therapy with 2% tetracycline rinse has proved efficacious but, on occasion, is not effective or becomes ineffective with time. A topical corticosteroid is the treatment of choice.

2. Herpangina

This is a specific viral infection which can be caused by any one of a number of strains of . It normally is seen in young children but may occur in older patients. Once infected, permanent immunity to the infecting strain develops, but an individual can have the disease several times from different strains. By adulthood, most individuals exhibit immunity to several strains. Affected patients present with , low-grade fever, headache, sometimes vomiting and abdominal pain. The lesions closely resemble RAS and most commonly occur on the , pharyngeal wall and tonsillar pillars. They normally heal within a week.

THERAPY OTC ibuprofen and Sucrets® with dyclonine

3. Hand, Foot & Mouth Disease

This is another clinical presentation of enterovirus infection which can be caused by one of several strains. The majority of the cases arise in young children but can present in adulthood. Damm Sore Mouth 4

It is characterized by an erythematous maculopapular of the which most frequently involves the hands, feet, legs, arms and buttocks. Anorexia, low-grade fever, coryza, sometimes lymphadenopathy, diarrhea, nausea and vomiting can occur. Oral lesions are invariably present and are the principal symptoms in over 90% of the patients. The lesions resemble RAS and occur primarily on the palate, tongue and buccal mucosa. The infection resolves within 10-14 days. Treat like herpangina.

4. Behçet's Syndrome

This is a systemic abnormality which most likely is autoimmune and usually arises be- tween the ages of 10 and 45. It is 5-10 times more common in males. Oral, genital, skin and ocular lesions are seen. The oral lesions present as RAS, and the genital ulcers often are small and occur on the scrotum, root of penis, labia majora or perianally. Ocular lesions range from conjunctivitis to uveitis to hypopyon. The skin lesions usually present as pustules on the trunk, limbs or genitalia. A number of other systemic complications may occur also. Classic triad: oral ulcers, genital ulcers and ocular inflammation. If discovered, refer to an experienced dermatologist.

5. Herpes Simplex

Classically, herpes simplex is divided into type I in which the infections arise above the waist and type II which is seen below the waist. With the current changing sexual practices, a widespread translocation of the two types has occurred. Type I infection is extremely common, and 70-90% of the adult population has circulating against the . The following comments will be limited to infections of the perioral areas and oral cavity.

When exposed to the virus, patients without circulating antibodies may luckily develop a subclinical infection. Those not so blessed (<10%) develop the primary herpes infection, and the most common pattern is acute herpetic gingivostomatitis. Primary herpes normally develops only once, but it must be remembered that types I and II are different with each capable of producing its own primary infection.

These highly symptomatic cases typically begin with high fever and lymphadenopathy which are followed in a few days by diffuse oral lesions. In all of the cases, the gingiva is painful and demonstrates enlargement and an intense erythema. Ulcerations of the midfacial free marginal gingiva are not uncommon. These ulcerations along with the pain help separate this form of from those which are plaque-related. Multiple fragile vesicles develop and rapidly ulcerate; observation of an intact vesicle is rare. The lesions frequently cluster and coalesce. The ulcerations vary in size from a few millimeters to a centimeter and may resemble RAS closely, especially the herpetiform variety. The involvement of bound mucosa, especially the gingival changes, is the clue to the diagnosis. The lesions can extend past the wetline and involve the vermilion border of the . If the diagnosis is in question, a cytologic smear can be beneficial if performed within the first 3-5 days. Intraoral culture is not worthwhile.

Therapeutic attempts most often are directed toward palliation. Benadryl solution or dyclonine can be utilized as a short-term anesthetic and can be complemented by a non-steroidal Damm Sore Mouth 5 anti-inflammatory medication such as Motrin®. Tetracaine work great in this situation. If the patient is diagnosed prior to day three of the ulcerations, acyclovir has been shown to be highly effective in reducing the severity of the infection. Without therapy, the ulcerations normally heal in 10-14 days.

THERAPY Acyclovir (SMS 3-1), ibuprofen (SMS 3-8), tetracaine lollipops (SMS 3-6)

After the initial infection, the surviving virus is sheltered in the nerve ganglia which innervate the area. The virus is contained in that location by the cell mediated immune response. Any reduction of containment can result in reactivation of the virus and a recurrent infection known as secondary herpes. Old age, pregnancy, allergy, trauma, respiratory illnesses, menstruation, and underlying or malignancy have been associated with an increased frequency of the recurrent infection. Involvement of the lips and perioral skin is common and known as .

The clinically evident portion of the infection frequently is preceded by prodromal symptoms which include burning, stinging, soreness, paresthesia and/or redness of the affected area. Shortly thereafter, vesicles appear. These vesicles are filled with clear fluid, subsequently rupture and lead to formation of a brown crust. The vesicles are a few millimeters in diameter but tend to cluster and coalesce. Significant edema and occasional secondary infections may complicate the course. Most cases are unilateral, but bilateral examples are not rare. The fluid within the vesicles is contagious and can cause spread of the lesions if allowed to contact other open wounds. Patients with active lesions should be dismissed prior to dental therapy. In addition, it must be remembered that the virus can survive up to five hours in a damp gauze; all health care personnel must maintain barrier protection until all contaminated instruments and disposable materials have been eliminated. The virus may infect any unprotected finger and result in very painful recurrences to the affected digit (herpetic ).

A number of therapeutic medications have been utilized, most of which work well in some patients but not in the majority. Idoxuridine, vidarabine, and lysine have demonstrated limited usefulness in certain patients. Systemic antiviral capsules (acyclovir, valacyclovir, famciclovir) have demonstrated clinical efficacy, but only valacyclovir has been studied extensively in clinical trials. Although individual patients exhibit varying results, acyclovir ointment has demonstrated no statistically significant clinical benefit for herpes labialis in the immunocompetent patient. In contrast, penciclovir has demonstrated a measurable reduction in the intensity and duration of the lesions. Although rare in immunocompetent patients, viral resistance to acyclovir has been reported in immunocompromised patients and should warn against over use. High-dose short-term systemic therapy with valacyclovir has been proven to the highly effective in aborting or minimizing attacks.

THERAPY During prodrome Valtrex (SMS 4-2) After bubbles appear Denavir (SMS 4-5) Prior to dental care Valtrex (SMS 4-3)

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Secondary herpes also can occur within the oral cavity and is known as recurrent herpetic stomatitis. Once you have crossed over the wetline and entered the oral cavity, recurrent herpes is seen in the immunocompetent patient only on keratinized mucosa which is bound to bone. This is really nice, because it is exactly opposite from MiRAS which occurs almost exclusively on movable mucosa. The lesions begin as small pin point areas of erythema which, with time, develop central yellow zones of fibrin. Intact vesicles are rare. The lesions tend to cluster and coalesce. Most areas are localized and unilateral. The majority of the cases are associated with mild symptoms and do not require therapy. The ulcerations tend to heal in 5- 7 days. These lesions are not unusual following dental procedures, even in patients who have not had a history of primary herpes.

In the immunocompromised patient, recurrent herpes can appear very atypical clinically (chronic or aggressive HSV infection). Many patients initially present with herpes labialis and subsequently develop an intraoral ulceration with an elevated brownish cap (necrotic ). Instead of healing, the lesions spread laterally as superficial erosions which often exhibit a raised white border. The lesions may occur on any mucosal surface. Treatment is to resolve the cause for the immunocompromised status and treat with one of the effective systemic antiviral medications. This unusual pattern has been seen in everything from asthma patients using steroid inhalers to leukemia patients. If recurrent herpes is found on movable mucosa in a “healthy patient” or becomes chronic and spreads laterally, immunosuppressive causes should be investigated.

6. Herpes Zoster

This viral infection is produced by the varicella-zoster virus and is much like recurrent herpes in that it is a recurrence of a previously received infection: . The virus resides in sensory nerve ganglia and upon reactivation causes vesicular eruptions of the affected skin or mucous membranes. The disease usually affects adults and presents with fever, malaise and pain along the course of the involved nerves. The vesicles follow the nerves and usually are unilateral and anatomic. Initially, intraoral lesions present as white, opaque vesicles that ultimately rupture and form ulcerations that may resemble RAS. Many attacks begin for no apparent reason but may be related to underlying trauma, tumor, malignancy or immunosuppression. Systemic antivirals (acyclovir, valacyclovir, famciclovir) are efficacious, with topical capsaicin utilized for residual neuritis. Prevention through vaccination remains the best approach (Varivax for chickenpox; Zostavax or Shingrix (preferred) for herpes zoster).

THERAPY Chickenpox Acyclovir suspension (SMS 5-1). Acetaminophen should be as antipyretic. NSAIDS associated with increased prevalence of secondary skin infections. Zoster Valtrex (SMS 5-3) Damm Sore Mouth 7

7.

Erythema multiforme (EM) is an acute diffuse ulcerative condition of unknown cause which can involve the skin and any mucosal surface. In about half the cases, a triggering event can be found. A number of viral infections, the most common of which is herpes simplex, precede the attack by one to three weeks. Other patients can trace the outbreak to an allergen exposure, often one of a large number of possible medications. Rare cases have been associated with underlying internal malignancies. The ulcerations may arise at any age but are most commonly seen in young adult males.

The dermatologic manifestations characteristically present with erythematous macules, and/or vesicles which are distributed on the extremities, face and neck. The classic lesion is a macule which exhibits alternating rings of varying shades of erythema, the so-called “bull’s eye” or “target” lesion. Oral lesions are common and occasionally can be seen in the absence of other lesions. Out of all of the acute oral ulcerative conditions, primary herpes and EM produce the most severe symptoms. It is not unusual for patients with oral EM to bring a relative to speak for them.

The oral lesions present predominantly on movable mucosa but are not limited to that location. The individual areas appear as a large zone of irregular epithelial necrosis. The epithelium rapidly sloughs, leaving a large painful erosion. The lesions often are numerous and diffuse. Involvement can extend past the wetline onto the vermilion border of the lips.

Because EM is self-limiting, some clinicians do not feel the necessity to treat the lesions. In those patients receiving therapy, systemic steroids normally are utilized. Patients with significant oral lesions should receive therapy. With appropriate therapy, the pain and duration of their suffering can be diminished dramatically. Although systemic steroids are occasionally required, those with only oral involvement often can be resolved with 0. 1 % dexamethasone or Prelone® syrup. Patients with diffuse dermatologic and oral involvement, which are treated with systemic steroids, rarely exhibit failure of the oral lesions to resolve in a timely fashion. This problem can be circumvented through use of Prelone® in a “swish and swallow” pattern in the same dosages as that utilized with systemic prednisone. In patients with recurrent EM limited to mucosal surfaces, prophylactic acyclovir should be prescribed to rule out a viral trigger. If a medication is involved, STOP THE MED.

Stevens Johnson syndrome and Toxic Epidermal Necrolysis were thought to be variations of erythema multiforme, but subtle differences do exist. In EM, the skin lesions typically begin on the extremities, while SJS and TEN usually involve the trunk initially. In addition, the initial skin lesions in EM usually are elevated and indurated while those with SJS/TEN tend to be flat (prior to bullae formation). All patients with SJS/TEN demonstrate skin lesions, and mucosal involvement also is present in virtually all patients, particularly oral. SJS and TEN are separated by the degree of skin involvement. SJS usually demonstrates less than 10% involvement, while TEN effects greater than 30% of the skin surface. Although SJS often is treated with steroids, this approach is contraindicated in patients with TEN due to the chance of secondary infection. Most patients with TEN are referred to burn units. Pooled human immunoglobulins have proven successfully in several studies of patients with severe TEN. Damm Sore Mouth 8

THERAPY Restricted to mouth Compounded ultrapotent dexamethasone solution (SMS 1-7) Vermilion border Betamethasone gel or ointment (SMS 1-2)

8. Necrotizing Sialometaplasia

This entity is different from the other types of acute sore mouth because it most often is confused with a salivary gland and generally not included in a discussion of acute ulcerations. The disorder may occur in serous or mucous glands of the oral, nasal or respiratory areas but usually occurs in minor salivary glands of the palate. The changes mimic a mucoepidermoid both clinically and histologically, but the appropriate diagnosis can be made by those with previous experience with these changes.

Following local ischemia of undetermined origin, coagulative necrosis develops within the affected gland. Intraorally, the most common site is the palate, and the presentation is so distinctive that the diagnosis often can be made secondary to the unique clinical pattern. The affected area begins as an enlarged, tender and erythematous zone which arises over a couple of days. Subsequently, the overlying mucosa breaks down with the formation of a well- circumscribed and deep ulceration. Bilateral lesions can occur. Pain often is mild considering the size of the defect, which may be large with healing taking as long as 10 weeks. often is utilized to confirm the clinical impression.

CHRONIC ORAL ULCERATIONS

1. Oral Lichen Planus

Lichen planus (LP) is a very common chronic disorder which may affect skin or mucosal surfaces. The cause is idiopathic, but the cell mediated immune response is known to attack the basal cell layer of the affected epithelium. As in aphthous ulcerations, the primary event could be a delayed hypersensitivity reaction to an as yet unknown antigen(s). The inciting antigen could vary from patient to patient, thereby making the final discovery more difficult. Chronic drug reactions can produce a mucosal reaction which can mimic lichen planus and should be ruled out thoroughly. Dental restorative materials have been implicated as a source of the antigens for LP, but only a minority of those studied exhibit a reaction to the dental materials. Removal of the dental restorative materials also has failed to resolve the lesions. In spite of this, amalgam is known to produce a mucosal reaction which is similar to, but not, LP (see later section).

The clinical presentations of the early lesions can be described best utilizing the “3 Ps”. On skin, the early lesions can be described as purple polygonal plaques. The involved skin is sharply demarcated and often intensely pruritic. The early oral lesions can be described as porcelain pinhead papules (papular pattern). These small papules can become confluent and Damm Sore Mouth 9 form striae (reticular pattern). Beware of any isolated and nonmigratory plaque diagnosed as “plaque-type of lichen planus”; most of these represent epithelial with a lichenoid immune reaction. With progression, areas of painful erythema (atrophic pattern) or ulceration (bullous or erosive patterns) may develop.

Any mucosal surface may be involved, but the gingiva and buccal mucosa are affected most frequently. In the majority of the cases, patients with oral LP do not present with skin lesions. If skin lesions are present or develop in the future, they should be investigated to rule out the possibility of . Oral lupus erythematosus can resemble closely LP clinically and histopathologically, and this separation is best made via .

The possibility of LP representing a premalignant condition remains an area of hot debate. Patients with LP are not immune to development of ; the question is whether they are disposed to its development. In investigations of LP in which more than 100 patients were studied, the rate of arising in LP varied from 0.0% to 5.3%.

The classification of generic oral LP as a premalignant lesion does not seem justified for several reasons. There is significant disagreement as to the frequency of malignant transformation among the authors of the numerous studies. This is not surprising because of the clinical and histopathologic similarities between dysplasia and LP. Many reports of LP developing into carcinoma actually may represent dysplasia with a lichenoid mucositis, not true LP. A literature review of 223 reported cases of cancer arising in LP revealed only 15 with sufficient evidence. The patients included in these studies are most frequently those with symptomatic LP who are not representative of LP as typically seen in the general population. In one of the larger studies, 75% of those included had complaints of pain and/or ulceration.

In conclusion, cancer occasionally develops in patients with LP, but the true occurrence of carcinomatous development in the general LP population currently is not known. Patients with asymptomatic reticular lichen planus should be followed like any other dental patients receiving routine care. In contrast, patients with chronic, severe atrophic lichen planus should be followed closely with biopsy of any unusual areas. Long-term atrophy of the oral cavity should be considered premalignant, whether it is occurring in a process such as Plummer-Vinson syndrome or poorly controlled lichen planus. This is most challenging due to the clinical similarities between atrophic LP and erythroplakic dysplasia. Beware of a histopathologic diagnosis of LP in a patient with an isolated white or red patch. Beware of an LP patient who develops an atypical erythematous area which is resistant to normal interventions. NEVER let patients with atrophic lichen planus smolder; control of the disease process is mandatory.

Asymptomatic LP requires no therapy. Symptomatic, atrophic and erosive LP is best treated with topical corticosteroids. When widespread, the lesions may be treated with topical corticosteroids in a liquid or gel formulation. Difficult cases may resolve with 0.1% dexamethasone or Prelone® syrup; but on occasion, systemic steroids (swallow Prelone®) are required to obtain control. The patients should be told this is not a cure and should expect the lesions to recur and require future treatment. Secondary is not rare and can be controlled with Nizoral®, Mycelex® or Mycostatin® or by mixing clotrimazole or nystatin into the topical corticosteroid gel. Damm Sore Mouth 10

LICHEN PLANUS THERAPY Steroid Temovate gel (SMS 1-3). For gingival involvement use trays as occlusive dressings. Steroid Dexamethasone solution (SMS 1-6 & 1-7) Tacrolimus Aqueous oral rinse (SMS 1-15) or Protopic ointment (SMS 1-11) Systemic Tx Systemic prednisolone (SMS 1-14) Bottom Line Pray. Repeat after me. I HATE LICHEN PLANUS. I HATE LICHEN PLANUS.

2. Oral Pemphigoid

Pemphigoid is a chronic epithelial vesiculoerosive process secondary to autoimmune destruction of a portion of basement membrane zone (BMZ) with the formation of a subepithelial separation from the underlying connective tissue. This disease presents in two different patterns: (BP) and cicatricial mucosal pemphigoid (CP). In the past, the two types have been thought to be variations of the same disease, but recent work suggests the autoimmune destruction may be occurring at different sites within the BMZ. At least eight different clinical variants have been documented.

Pemphigoid is diagnosed from an incisional biopsy which includes an area of separation in addition to a portion of the adjacent normal epithelium. Rubbing the affected area prior to surgery is recommended as in aid in biopsy site selection. The initial histopathologic diagnosis should be confirmed with immunofluorescence (IF). Direct IF almost always is positive and demonstrates IgG and/or C3 in a linear band along the BMZ. Indirect IF is not highly beneficial, since the titers do not correlate to the severity and there is a significant number of false negatives. As with any chronic vesiculoerosive process, prior to definitive therapy, all patient medications should be screened for a possible relationship.

Bullous pemphigoid typically presents with large tense bullae most commonly seen in the groins, axillae and forearms. The disease usually arises in elderly adults but has been seen in all ages. Oral involvement is not a prominent part of the process but has been reported in 11-45 % of the cases. In healthy patients, the disease usually runs a benign course and subsides after months or years. Low dose systemic prednisone with or without is the first line therapy. On occasion, LP and BP may occur concurrently and has been termed lichen planus pemphigoides.

Cicatricial pemphigoid also is known as mucous membrane pemphigoid and is a more unremitting chronic disorder which may involve any mucosal surface. Oral involvement is very common and the percentage of involvement varies according to practitioner type. Multiple oral sites may be involved, but the vast majority demonstrate gingival involvement. The term “” (DG) has been applied to the diffuse vesiculoerosive changes that may be seen in pemphigoid. It must be emphasized that DG is a clinical diagnosis and must be investigated. Although many cases do represent CP, similar lesions have been seen in lichen planus, pemphigus and several other less common vesiculoerosive processes. Palatal, labial and buccal mucosae also are affected frequently. Oral lesions present as areas of painful erythema, scattered intact vesicles and/or superficial erosions. Typically, scarring is not seen. Damm Sore Mouth 11

CP may remain isolated to the oral cavity, but management of this disease requires a multidisciplinary approach. Nasal, vaginal, genital, anal, laryngeal, esophageal and ocular involvement is seen. Any patient presenting with oral lesions diagnostic of CP should be thoroughly evaluated for involvement of these sites. In addition, thorough dermatologic evaluation also is mandatory. Lesions located in the , and ocular mucosa do frequently exhibit significant scarring which can result in serious debilitation and rarely death. Every patient is different; and the type, amount and duration of medication required to obtain satisfactory control is variable. The patients require long-term follow-up to maintain control of discovered lesions and to provide surveillance for additional sites of involvement.

THERAPY Oral only Treat similar to lichen planus (SMS 1-3, 1-6, 1-7). Often beneficial to combine topical steroid therapy with systemic tetracycline and niacinamide (SMS 1-12, requires medical supervision, please contact me for additional handout). If does not respond, refer to rheumatologist or dermatologist for therapy. Extraoral Refer to experienced dermatologist or rheumatologist.

3. Oral

Pemphigus is another chronic immunologic mucocutaneous vesiculoerosive disorder. Most cases arise after the age of 30, but occurrence in children is reported. Four patterns may be seen: vulgaris, vegetans, foliaceous and erythematosus. Pemphigus vulgaris (PV) is the most common type and the only variant to exhibit common oral involvement. Pemphigus is an mediated destruction of the intercellular cement which results in intraepithelial . The diagnosis is obtained secondary to histopathologic examination and IF. The biopsy should include an area of erosion with a margin of normal uninvolved epithelium. Direct IF demonstrates IgG and often C3 in the intercellular spaces. Indirect IF is positive in approximately 90% of the cases, and the titers correlate well to the severity of the disease. In spite of this, indirect immunofluorescence is being replaced by ELISA (enzyme-linked immunosorbent assay) for specific antibodies such as anti- for pemphigus vulgaris. On skin, PV is characterized by rapid development of numerous vesicles or bullae which may cover large areas of the surface. The lesions rupture and result in a denuded surface after loss of the remaining detached surface epithelium.

PV is relatively rare. In an active oral service, LP usually is diagnosed at least once a day, CP four times every month and PV about once every 2-3 months. The initial lesions usually occur on skin, but oral involvement normally is present at some time during the course of the disease. Occasionally, the oral lesions may be seen initially; and rarely, the may be the only site of involvement. As in LP and CP, the patient's medication history should be reviewed thoroughly. In addition, a significant percentage of PV has been associated with food hypersensitivity. Due to the intense therapy required for this disease, it is mandatory to investigate a medication or food-related trigger prior to initiation of treatment.

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The oral lesions develop on any mucosal surface with an average time of seven months between the onset and diagnosis. The vesicles tend to rupture as soon as they form, and most patients present with areas of superficial erosion which are very tender and often bleed upon manipulation. The lesions tend to enlarge peripherally, and often the surface epithelium can be dislodged with manipulation (+Nikolsky’s sign).

If untreated, PV is progressive and can result in widespread infection, electrolyte im- balance, cachexia, toxemia and death. Topical steroids often are not effective. Treatment usually consists of high dose systemic steroids, often combined with azathioprine, methotrexate, , levamisole, Dapsone or gold.

THERAPY All patients should be referred to experienced dermatologist or rheumatologist for Rituximab therapy. The possibility of a chronic food or drug reaction should be ruled out prior to initiation of therapy.

A rare form termed is seen in association with systemic disease, usually or leukemia. These lesions often demonstrate a rapid onset and clinically resemble erythema multiforme. Upon biopsy, histopathologic features of lichen planus, pemphigoid and pemphigus are noted. Direct immunofluorescence reveals IgG in the basement membrane zone and the intercellular areas. Although the antibodies present in typical pemphigus react only with stratified squamous epithelium, those in the paraneoplastic variety are broad spectrum and also react with transitional epithelium (such as bladder epithelium). Therapy in these patients is problematic, and the prognosis is poor.

4. Lupus Erythematosus

Lupus erythematosus is a chronic autoimmune disorder which typically affects the skin and involves the oral mucosa in 10-40% of the cases. Two different variants of lupus are seen. Discoid lupus erythematosus (DLE) affects primarily the skin while systemic lupus erythematosus (SLE) also involves multiple tissues and organs. The skin lesions present as elevated erythematous plaques with a surface scale. The affected areas usually are sun-exposed, and a butterfly rash over the bridge of the nose and malar areas is classic.

The oral lesions may present as areas of erythema or but often exhibit a strong similarity to lichen planus. The classic intraoral lesions of lupus appear as an area of speckled with a peripheral border of perpendicular radiating white striae and telangiectasia. Histopathologically, classic lupus can be diagnosed on an oral biopsy, but the specimens often closely resemble lichen planus. In addition, occasional lichen planus may exhibit features of lupus. If skin lesions are present, the distinction between these two disorders is best made on skin. Immunofluorescence is beneficial in separating the two diseases when only oral lesions can be found. Lupus should be considered anytime there are skin lesions present in addition to oral lichenoid changes. In addition, lupus should be ruled out anytime the oral lesions demonstrate the classic pattern of peripheral radiating striae and telangiectasia.

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One of the most common drug reactions is lupus-like, mandating investigation of this possibility prior to initiation of therapy. The treatment of lupus varies with the severity and usually consists of antimalarials (lowers circulating ANAs), topical or systemic steroids. The prognosis of DLE usually is excellent with good response to topical steroids; about 5% progress to SLE. Although most cases of SLE can be controlled with proper medication, death can result from severe renal or CNS involvement.

THERAPY All patients should be referred to an experienced rheumatologist or dermatologist.

5. Chronic Drug Reactions

Chronic oral vesiculoerosive lesions related to drug ingestion are second in frequency of occurrence, with lichen planus being the most frequent. The lesions most commonly present on the lateral border of the tongue and/or posterior buccal mucosa and frequently are bilateral. The classic lesion presents as a zone of chronic ulceration which frequently demonstrates radiating white striae. The offending drugs are too numerous to mention and may be either prescription or over-the-counter. All patients with a chronic vesiculoerosive process should be closely questioned concerning all currently used medications. Most offending medications will have a previous history of producing a lichen planus, pemphigoid, pemphigus, lupus-like or non- specific chronic vesiculobullous reaction. Medications can mimic any of the chronic vesiculoerosive disorders with identical clinical, histopathologic and immunofluorescence findings. Treatment includes discontinuation of the medication with a course of topical steroids to insure resolution. If the lesions return after steroids and cessation of the medication, the drug was not the inciting cause.

The PDR is insufficient for investigation. One of the best pharmaceutical guides is Drug Facts and Comparisons. This resource describes all OTC and prescriptions medications legally available in the US. This references is offered in several formats, is not cheap and is available from JB Lippincott (1-800-223-0554). Another useful drug reference system is Clinical Pharmacology (www.clinicalpharmacology.com; 1-800-375-0943; for demo: [email protected] ). This program has the ability to quickly and easily produce an adverse reaction or drug interaction report from a long list of patient utilized medications. My personal favorite (Micromedex) is more difficult to use than Clinical Pharmacology (must investigate each drug one at a time) but provides all of the well known adverse reactions along with individual case reports from the literature (www.micromedex.com; 1-(877) 843-6796). A different kind of useful item is the IDENT- A-DRUG Handbook offered by the Therapeutic Research Center (1-209-931-2923).

Three other problems, xerostomia, dysgeusia and osteonecrosis are not rare and frequently associated with medications. Discussion of bisphosphonate osteonecrosis requires an extended presentation and is a topic for another day.

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Some degree of xerostomia occurs with aging, but a large number are due to medications. In many instances, an association with medications is ignored; and the patients are evaluated for Sjögren Syndrome. Xerostomia is very common and associated with an increased prevalence of cervical caries, candidiasis and orolingual paresthesia.

Dysgeusia is a persistent abnormal taste that is much less common than loss of smell or loss of taste. The pathosis is not well tolerated and often leads to dental consultation. Many cases are related to an underlying systemic disorder or previous radiation therapy to the head and neck. Xerostomia often is associated with a metallic taste. In these patients, hydration and/or oral moisturizers may prove effective. Since 75% of flavor is derived from smell, many perceptions of dysgeusia are not secondary to an alteration of taste. The “jelly bean” test is used by many but is not definitive in many cases. Orange and yellow (lemon) jelly beans taste identical but have different smells.

Appropriate diagnosis is difficult and often involves formal taste/smell testing combined with electrical and chemical analysis of taste bud function. Such an evaluation often is outside the scope of most general practices and mandates a referral to a Taste and Smell Center. Prior to this referral, three possibilities should be investigated: oral foci of infection, asymptomatic post- nasal drip and an adverse drug reaction.

6. Lichenoid Reaction to Amalgam

Amalgam has been blamed for almost every physical and social ailment known to man, but no scientifically sound investigation has ever proven any significant problems associated with its use. It has withstood the passage of time and remains an excellent dental restorative material. In spite of this, one oral pathologic condition has been proven to be related to dental amalgams (and less frequently other metallic restorative materials) in susceptible patients.

Rarely, patients may present with areas of leukoplakia which are in direct contact with large amalgams. The lesions most frequently are present on the lateral border of the tongue or posterior buccal mucosa. The white lesions often have radiating peripheral striae and may closely resemble lichen planus. Biopsy of the lesions presents a pattern very similar to lichen planus. Unlike lichen planus, the lesions do not migrate and remain stationary and adjacent to the amalgam. Periodic atrophy and ulceration may occur and require topical steroid application. Replacement of the adjacent amalgam with resin results in rapid resolution.

7. Oral Mucosal Chronic Graft-Versus-Host Reaction

Patients who have received a bone marrow transplant and subsequently develop graft- versus-host-disease not infrequently demonstrate chronic vesiculoerosive lesions which closely resemble lichen planus. Diffuse erosion and ulceration may occur. Well-developed striae often are seen, and the pattern may become very closely meshed. The vermilion of the lower often is affected frequently, in addition to diffuse oral involvement.

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8. Oral Mucosal Reactions to Cinnamon-flavored Products

In 1981, Allen and Blozis described several patients with chronic oral mucosal lesions associated with the use of cinnamon-flavored gum. This reaction is not a rare occurrence; but because of lack of suspicion, the diagnosis is made infrequently. The clinical presentation is rather distinctive; and once a clinician has seen one case, then many usually are found. Biopsy presents a pattern of mucositis which is not totally diagnostic but can lead to the final answer if a good clinicopathologic correlation is present. The changes most often present bilaterally on the buccal mucosa and/or lateral borders of the tongue. The affected mucosa is erythematous and often exhibits an overlying shaggy hyperkeratosis. The excess keratin presents in a pattern very similar to cheek biting. Cinnamon reactions will present with discomfort and surrounding erythema, while will not. Cinnamon-flavored floss presently is available and may be associated with chronic gingival lesions.

SORE MOUTH SOLUTIONS

RAS, ERYTHEMA MULTIFORME, LICHEN PLANUS, LOCALIZED PEMPHIGOID

1-1. Lidex Gel (0.05% Fluocinonide): Apply thin film to affected area three times a day.

1-2. Augmented betamethasone dipropionate ointment 0.05% (Diprolene): Apply thin film to the affected area three times a day.

1-3. Temovate Gel (0.05% Clobetasol Propionate): Apply thin film to the affected area 3 times a day. POTENT. Treatment should be limited to 14 days and amounts greater than 50 grams a week should not be used (unlikely).

1-4. Clobetasol 0.05% and Clotrimazole 0.1% 10 grams compounded in an oral puffer. Use up to five times daily. This custom formulation is used for patients who are having problems with secondary candidiasis.

1-5. Clobetasol 0.05% and Clotrimazole 0.1% compounded in 3% methocel gel. Dispense 30 gram tube and apply thin film to affected area 4-5 times daily. This custom formulation is used for patients who are having problems with secondary candidiasis.

1-6. Dexamethasone Solution (0.5mg/5ml): Rinse and hold for two minutes, then expectorate. Use 1-2 tsp. four times a day.

1-7. Dexamethasone Solution (5mg/5ml): Rinse and hold for two minutes, then expectorate. Use 1-2 tsp. four times a day. Very potent; must expectorate; use with caution. Must be compounded upon request.

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1-8. Prelone Syrup (Prednisolone 15mg/5ml): Rinse and hold for two minutes, then expectorate. Use 1-2 tsp. four times a day. In addition, Prelone utilized as “swish and swallow” is an excellent method for local coverage and systemic administration selected cases (erythema multiforme, pemphigus, etc).

1-9. Kenacort Tablets (8mg Triamcinolone): Dissolve one TID for 3 days; one tablet BID for 3 days and one tablet once a day for three days.

1-10. Kenalog 40 Injection (5cc vials, 40mg/ml Triamcinolone): Inject one cc around border of large ulcers.

1-11. Protopic (topical tacrolimus ointment, 0.1 or 0.03%): Apply thin film to the affected area 2-3 times daily. More potent than cyclosporine. The medication should be used only as a second line therapy in patients who have failed corticosteroid use.

1-12. Tetracycline (500mg QID) and Niacinamide (500mg QID): Use for resistant pemphigoid. Improvement usually seen in 2-6 weeks. After six months, attempt to taper if disease is well controlled. Patients on niacinamide can experience flushing which normally resolves if reduced to 1.5 gms/day. THIS IS COMPLICATED to administer but is worth the effort. Send me an email for a more complete description.

1-13. Dapsone: Use for resistant cases of pemphigoid. Doses ranging from 25-200 mg/day are used. Referral to experienced dermatologist often wise due to significant side effects.

1-14. Systemic Prelone Syrup (Prednisolone 15mg/5ml): Instruct patient to rinse entire daily amount first thing in the morning. Rinse and hold +/-2tsp at a time for AT LEAST two minutes then swallow. First four days: 5tsp. Days 5-8: 4 tsp. Days 9-11: 3 tsp. Days 12- 13: 1.5tsp. Day 14: 1tsp. Patient should be instructed to call at the end of day three. If improving, continue on schedule. If not improving, continue at 5tsp for three more days then call again. If this fails, refer to MD and suggest systemic steroids at 0.75 mg/kg/day until the lesions clear. Use of Prelone formulation will improve response.

1-15 Tacrolimus aqueous oral rinse: Gould: Mix 1mg Prograf in 1000ml of purified water. Dispense 1000ml. Rinse 2 tsp (10ml) of solution for at least two minutes, then expectorate. Repeat four times daily. Store refrigerated. Shelf-life is one month. Some UK contributors have reported greater success with three 1mg capsules rather than one. ActaDerm: Compound 0.03% tacrolimus suspension. Rinse 1-2 tsp twice daily for five minutes. Once controlled, taper to once daily, then once every second day with subsequent attempt at temporary cessation. Expensive.

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CANDIDIASIS

2-1. Mycostatin Oral Suspension (100,000 units of Nystatin per ml): Rinse and hold for two minutes. Use one tsp. four times a day. This is not my favorite due to high sucrose content and expense.

2-2. Mycelex Troches (10mg Clotrimazole): Dissolve one troche five times a day for 14 days. Liver function tests required for course longer than 14 days. Excellent choice but expensive.

2-3. Sporanox Oral Solution (Itraconazole 10mg/ml): Rinse 1-2 tsp for two minutes, then swallow. Repeat twice daily for three weeks.

2-4. Diflucan (200mg Fluconazole): Take one tablet a day for 14 days.

2-5. Clotrimazole 1% cream: This represents the first line therapy against angular . This medication is OTC and surprisingly is effective in cases due to candida and bacteria.

2-6. Mycolog II Ointment (100,000 units of Nystatin and l mg of Triamcinolone per gram): Apply thin film to the affected area four times a day. Works well for in many patients. Will not be beneficial in cases of angular cheilitis due to strep or staph. Difficult to find, but generic equivalent can be obtained.

2-7. Hydrocortisone 1% / Iodoquinol 1% Cream (Generic or Dermazene): Dispense 1 oz (28.4 gram) tube. Apply thin film to the affected area four times a day. This has anti- inflammatory, antibacterial and antifungal actions. Works well for angular cheilitis but tastes like death (helps stops chronic lip lickers). Also available in gel > Alcortin A gel: aloe polysaccharide 1%, hydrocortisone acetate 2%, iodoquinol 1% in 2 gram packets. Packets come individually or in box of 24.

2-8. Peridex (0.12% Chlorhexidine Gluconate): For prevention, rinse capful (1/2 ounce) twice a day. Sold in 16 ounce containers. Avoid in pregnancy and nursing females. May cause staining of teeth, increased supragingival calculus and altered taste.

2-9. Clorox: Dilute 1:5 with water and use as denture soak. Will discolor metallic frameworks. Damm Sore Mouth 18

PRIMARY HERPES

3-1. Zovirax Suspension {200mg/5ml (tsp) Acyclovir}: Rinse and swallow required amount five times a day for five days. For children too young to swallow capsules or in patients with primary herpetic gingivostomatitis. The dosage is 5mg/kg, not to exceed the adult dose.

Weight (KG=2.2 lbs) Required amount

5-10 KG 1/4 TSP 11-15 KG 3/8 TSP 16-20 KG 1/2 TSP 21-25 KG 5/8 TSP 26-30 KG 3/4 TSP 31-35 KG 7/8 TSP >35 KG 1 TSP (adult dose)

3-2. Zovirax Capsules (200mg Acyclovir): Take one capsule five times a day for five days. Avoid in pregnancy and ages 0-12.

3-3. Valtrex (1g Valacyclovir hydrochloride): Take one caplet twice daily for ten days. Therapy is most effective if initiated within 48 hours of initial signs and symptoms.

3-4. Famvir (125mg Famciclovir): Take one tablet twice daily for five days.

3-5. Dyclonine HCL, 0.5%: The brand name Dyclone has been discontinued by manufacturer due to low profits. This active ingredient can be obtained easily by compounder and custom formulated as desired. Rinse, spray or swab on affected areas PRN for pain. Supplied in 1 oz bottles. Also available in 1% strength for severe cases which fail to respond to 0.5%. Excellent topical anesthetic.

3-6. Tetracaine 0.5% lollipops (compound medication): Swab in mouth for 8-10 minutes per hour. Don’t chew and be careful of hot/cold food or drink.

3-7. Sucrets maximum strength oral anesthetic lozenges. These are over-the-counter and contain dyclonine.

3-8. Benadryl solution (12.5mg/5ml diphenhydramine hydrochloride): Rinse and hold for two minutes. Use one tbsp. four times a day. Can be used as an inexpensive but mild topical anesthetic. Search for no alcohol variety.

3-9. Motrin (400-600mg Ibuprofen): Take one tablet every four hours.

3-10. Tylenol (325mg acetaminophen): Take two caplets every 4-6 hours.

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SECONDARY HERPES

4-1. Zovirax Capsules (200mg Acyclovir): Take one capsule five times a day for five days, beginning in the prodrome or prior to known trigger. Avoid in pregnancy and ages 0-12. For maintenance in severe cases, take three capsules a day. Temporarily discontinue every six months to monitor activity of the virus. Therapy often breaks the back of the virus within a couple of years. Females must be sterile or practicing excellent contraception.

4-2. Valtrex (1g Valacyclovir hydrochloride): take two caplets (total of 2 grams) twice daily for 1 day taken about 12 hours apart. Therapy should be initiated at the earliest symptom (tingling, itching, burning, etc.). For suppressive therapy, take 1 caplet daily.

4-3. Valtrex (1g Valacyclovir hydrochloride) for prevention of recurrence associated with dental therapy: take two caplets (total of 2 grams) twice daily for 1 day taken about 12 hours apart, followed by one caplet twice daily for one additional day.

4-4. Famvir (125mg Famciclovir): Take one tablet twice daily for five days.

4-5. Denavir Cream (1% Penciclovir): Dispense 1.5mg tube. Beginning in the prodrome, apply thin film to the affected area every two hours during waking hours for a period of four days. Works best if initiated prior to appearance of vesicles.

4-6. Zovirax Cream (5% Acyclovir): Beginning in the prodrome, apply thin film to the affected area six times a day for seven days. Superior absorption when compared to ointment formulation.

4-7. Zovirax Ointment (5% Acyclovir): Beginning in the prodrome, apply thin film to the affected area six times a day for seven days. Does not penetrate skin well and is of limited usefulness, although some patients respond well.

4-8. Abreva Cream (OTC; 10% topical docosanol): Few published studies. In the early stages of the recurrence, apply sufficient quantity to cover all lesions; rub in gently and completely; repeat five times a day until the lesions are healed.

4-9. Viroxyn Swab (Sold through participating DDS/DMD & MD offices, 0.13% alkylbenzyldimethylammonium chlorides): Single-application treatment system with little available information. Break glass vial and saturate swab. Vigorously rub swab against lesion until are ingredients are dispensed. Do not use soap or other cleansers for 24 hours in the affected area.

4-10. Lysine Tablets (OTC): Beginning in the prodrome, take at least 2000mg per day for seven days; for maintenance, utilize 1000mg per day. This is effective in up to 40% of affected patients.

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4-11. Peridex (0.12% Chlorhexidine gluconate): Rinse and hold one capful for two minutes then expectorate. Repeat twice daily. Good choice for mild recurrent herpetic stomatitis.

VARICELLA & HERPES ZOSTER

5-1. Zovirax Suspension (200mg/5ml Acyclovir): Dispense required amount five times a day for five days. For children with varicella. The dosage is 20mg/kg, not to exceed the adult dose.

Weight (KG = 2.2 lb) Required amount

5-10 KG 1 TSP (5ml) 11-15 KG 1.5 TSP 16-20 KG 2 TSP 21-25 KG 2.5 TSP 26-30 KG 3 TSP 31-35 KG 3.5 TSP >35 KG 4 TSP (Adult dose)

5-2. Famvir (500mg Famciclovir): Take one tablet three times a day for seven days. Appears to decrease time to resolution of pain when compared to acyclovir. In addition, prompt utilization appears to reduce the duration of .

5-3. Valtrex (1g Valacyclovir hydrochloride): Take one caplet three times daily for seven days. Appears to decrease time to resolution of pain when compared to acyclovir. Due to lower cost, Valtrex appears to be a better choice than Famvir.

5-4. Zovirax Capsules (800mg Acyclovir): Take one capsule five times a day for five days.

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