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Home , Aphthous stomatitis, Herpes simplex

Volume 3 Number 1 February 15, 2002 “: Is It Herpes or Aphthous?”

Abstract

Recurrent aphthous (RAS) and recurrent intraoral herpes (RIH) are the two most commonly presenting oral lesions in the dental setting. It is critical that the oral health professional be able to accurately discriminate between these disorders. To facilitate the differential diagnosis between RAS and RIH, important components of assessment are discussed. These include: prodromal , lesion location, and appearance of the initial and mature lesion. The comparative etiology, prevalence, pathogenesis, and treatment considerations for these lesions are presented. A familial case report is provided.

Keywords: Herpes, lesion, primary herpetic gingivostomatitis, , RIH, RAS, recur- rent intraoral herpes, recurrent aphthous stomatitis, , canker sore, cold sore, .

Citation: Tilliss TSI, McDowell JD. "Differential Diagnosis: Is It Herpes or Aphthous?" J Contemp Dent Pract 2002 Feb;(3)1: 001-015.

© Seer Publishing 1 The Journal of Contemporary Dental Practice, Volume 3, No. 1, February 15, 2002 Introduction Recurrent aphthous stomatitis (RAS) and recur- initiating factors, frequency of lesions, relieving rent intraoral herpetic (RIH) lesions are common factors (including any previously prescribed or oral disorders that are often mistaken for one over-the-counter ), and aggravating another. The confusion associated with develop- factors provides historically important data. It has ing an accurate diagnosis is somewhat under- often been said that if you listen to the patient, he standable since these two very different lesions or she will give you the diagnosis. share some common characteristics. However, since they do differ in a variety of parameters, the If the patient history is accurate and the physical well-informed clinician should be able to differenti- examination allows the clinician to see the ate between these distinctly separate conditions. lesion(s), other tests may not be necessary. In most cases, the clinician should be able to differ- The patient history, the physical examination, and entiate herpetic lesions from aphthous . the results of any indicated tests are important to the diagnostic process. A complete and accurate Lesion Identification: How Accurate Are You? patient history is a critical component of develop- Review the following images of mucosal lesions to ing a working diagnosis. Information regarding assess your skills at differentiating between apht- hous ulcers and RIH lesions. (Figures 1 A-D)

Figure 1a Figure 1b

Figure 1c Figure 1d

2 The Journal of Contemporary Dental Practice, Volume 3, No. 1, February 15, 2002 The high prevalence and often-painful presenta- accompanying peace of mind that occurs with tion of these lesions suggests that patients will providing a name and treatment for what may frequently seek out the oral health professional for have been a long-standing condition can have diagnosis and treatment. Since the lesions are psychological advantages for the patient. almost always self-limiting, one might question the importance of being able to distinguish one Prodromal Symptomology from the other. What then is the rationale for the Both herpetic and aphthous lesions often present differential diagnosis? with prodromal symptoms which can provide important clues to the development of a diagnosis. Table 1 summarizes some of the features of RIH However, the indications of an impending herpetic and RAS. lesion are generally more descriptive than for a developing aphthous ulcer. Rationale for Differential Diagnosis Developing an accurate diagnosis for herpes and Awareness of the initiation of the aphthous lesion aphthous is critical to the treatment plan because is generally indicated by local discomfort at the the recommended treatment approaches are very lesion site. The degree of pain can vary from different for herpetic lesions and aphthous ulcera- slight to severe and is frequently described as out tions. Treating a herpetic lesion with topical of proportion to the size of the lesion. steroids (as appropriate for an aphthous ulcer) can have serious sequelae. Telling a patient with The prodromal symptomology for herpes may an active herpes that he or she has an seem confounding to the patient at initial occur- aphthous ulcer and that it is not potentially conta- rence, but for those experiencing frequent out- gious is simply bad healthcare. Additionally, the breaks of herpetic lesions, the symptoms are often recognizable. The first indication of a

3 The Journal of Contemporary Dental Practice, Volume 3, No. 1, February 15, 2002 recurrent herpetic outbreak may be an unusual In the aphthous minor form of aphthous stomati- sensation of the affected tissue that may manifest tis, the ulcer is shallow and 0.5-2 cm in size. It as a lack of tactile or sensory perception. This usually appears as a single lesion, although 1-5 may progress to a tingling, burning, or throbbing ulcers may be present. The initial lesion may sensation. The development of vesicles (small begin as an erythematous macule, but it quickly ) within 24-48 hours will help to validate progresses to an ulcer characterized by a white to the occurence of a recurrent herpes outbreak. yellow or gray center of necrosis surrounded by a smooth, symmetrical, round or elliptically shaped Lesion Location erythematous perimeter often described as a "red The site of the initial lesion can provide important halo." Within 10-14 days of the initial presentation, clues concerning the presenting condition. the aphthous ulcer should usually be fully healed. Recurrent aphthous ulcerations are usually described as occurring on non-keratinized, or Major aphthae typically are larger, last longer gland-bearing tissues. Common sites for recur- than aphthous minor, and may heal with scarring. rent aphthous ulcers include labial and buccal Clinicians should remember that HIV/AIDS mucosa, floor of the , oropharynx, vestibule, patients can present with ulcers demonstrating a and lateral . With the exception of sites of clinical appearance similar to or indistinguishable frequent trauma, there appears to be no predilec- from major aphthae due to their immunocompro- tion for aphthous ulcers to recur at a previous mised health status. location. Following the characteristic prodromal stage pre- In contrast, RIH generally appears on keratinized viously described, the herpetic lesion manifests tissues such as the vermillion borders of the , as a cluster of small grey to white vesicles that hard , attached gingivae, and alveolar rupture to form small punctate ulcers that are ridges. The initial lesion can be at any of these usually 1 mm or less in diameter. These ulcers locations with subsequent outbreaks often mani- may coalesce into one larger ulcer up to 1.5 cm festing at or very near the original site. in size. A red halo effect may be visible, but will appear scalloped in contrast to the smooth halo Appearance of Lesions seen in aphthous ulceration. The next stage is The clinician is not always able to view a lesion at 'crusting,' which precedes the healing process. the initial stage when most easily diagnosed. From to crusting takes up to 96 hours Therefore, eliciting a detailed description of the with pain resolution over 96-120 hours and course of the eruption becomes essential. In complete healing by 8-10 days. Since "crusting" most cases the combination of the history of the does not occur intraorally, this feature is noted lesion and viewing the current stage can allow for primarily in labial or cutaneous lesions. a working (presumptive) diagnosis. Comparing the two lesions, it is apparent that The aphthous ulcer does not transition through both become ulcerative, but the progression to specific discernable stages as does the herpetic the ulcer stage differs widely, as does the appear- lesion. It may, however, increase in size from first ance of the mature lesions associated with detection to maturity. Aphthous ulcers are usually herpes and aphthous. divided into two general categories: aphthous Thus, the history, loca- major and minor. A tion, and appearance of more uncommon form, the lesions should allow herpetiform aphthous the knowledgeable clini- stomatitis, mimics her- cian to establish a pre- petic lesions in appear- sumptive diagnosis. ance but is found in the Herpetic Lesion Regarding transmissibili- same areas as the Aphthous Ulcer ty, it is important to note other forms of aphthous that while the aphthous ulcer is not contagious, stomatitis. the herpetic lesion is transmissible to a suscepti- ble host. Herpes is communicable throughout the course of the outbreak, particularly during the vesicle and ulceration phases.

4 The Journal of Contemporary Dental Practice, Volume 3, No. 1, February 15, 2002 Etiology, Prevalence, and Pathogenesis Aphthous stomatitis is divided into three clinical presentations. It is unclear whether these Aphthous Stomatitis presentations are manifestations of one The term 'aphthous' originated with Hippocrates or represent other oral disorders characterized by as far back as 460-370 BC in reference to disor- recurrent ulcers. The three designations are ders of the mouth.1 In general usage, the word apthous minor, apthous major and herpetiform 'aphthae' refers to the presence of an otherwise ulcers. undefined ulcer.2 Despite the fact that aphthous stomatitis is the most common human oral Etiology, Prevalence, and Pathogenesis mucosal disease, the cause is poorly understood. Aphthous minor is the most common variety 1 5 Although symptomatic treatment is available, accounting for 80% to 95% of all RAS lesions. aphthous is not preventable.3 Since the etiology The lay term for this lesion is canker sore. of aphthous ulcers is indeterminate, research has focused upon a variety of potentiating factors. During an attack of minor aphthous, lesions may Until the etiology is clarified, the focus has shifted occur singly or up to five or more concurrent toward the notion of 'precipitating factors.' ulcers. Each lesion typically lasts 10-14 days. Studies of these are not conclusive, but precipitat- Lesions may continually appear and heal sponta- ing factors that have been identified include: neously during a 3-4 week period. stress, nutritional deficiencies, trauma, hormonal changes, diet, and immunologic disorders. Other contributors that have received attention are: foods, , progesterone levels, psychologic factors, and a familial history. Despite extensive research, no conclusive etiology has been deter- mined. For some time it was thought that aphthous ulcerations were due to an L-form of since this organism was often isolated from the lesions. A more common belief is that the lesions may become secondarily infected with streptococci. Since the lesions are often suppressed by steroid therapy, which affects the , it is more likely that the lesions are a manifestation of the immune response, perhaps a hypersensitivity to strepto- cocci or another oral phenomenon.4 RAS is currently characterized as an idiopathic disorder whose fundamental etiology is unclear. It is, how- ever, widely recognized as immunologically mediated.

RAS is a common oral disorder. The prevalence among differing populations has been document- ed as 5-66%3 and 50%.4 World-wide, approxi- mately 15-20% are afflicted with RAS.5 It is especially common in North America.3,5 RAS also occurs in association with some systemic disorders that are associated with chronic gas- trointestinal disturbances such as Crohn's disease and celiac disease. Another systemic disorder associated with aphthous ulcer- ation is Behcet syndrome that is characterized by recurrent attacks of genital and oral ulcers.

5 The Journal of Contemporary Dental Practice, Volume 3, No. 1, February 15, 2002 Aphthous major, which accounts for about 10% of potentially affecting the . It may cases of aphthous stomatitis1,5 is characterized may also be wise to rule out Behcet's disease by large lesions which vary from 5-20 mm or through questioning about the presence of lesions more in size. Usually only 1-2 lesions occur at a of the genital mucosa. Suggested supportive time and primarily in two locations, mucosa care includes rest, increased fluid intake, ade- and posterior palate/anterior area. quate nutritional intake, multi-vitamin and mineral therapy, and reassurance that aphthae are not The lesions are much more severe than that of communicable. minor aphthae and are associated with severe pain. The lesions are crateriform and deep, When conservative, palliative care such as elimi- involving much tissue necrosis, often resulting in nating trauma (where possible), avoiding expo- scarring upon healing. Aphthous major can last sure to identified causative factors, and stress 6 weeks or more and can become secondarily reduction are not enough, steroids of various infected with bacterial and fungal organisms. types can be utilized. Aphthae that are localized Lesions of aphthous major can become intra- or in small numbers can often be effectively ctable in those with disorders treated with a topical steroid. For single (or few) such as HIV and AIDS, resulting in shallow lesions, a mild steroid ointment or gel is due to painful deglutition. usually adequate. Kenalog (triamicinalone acetonide 0.1%) in Orabase can be used on Herpetiform aphthous is the least common variety many mild aphthae cases. Larger lesions, when comprising about 10% of occurrences. The name accessible, can be treated with a more potent is misleading since it suggests a herpetic infec- steroid like Lidex (0.05%) or Temovate (0.05%) tion. Rather it is the similar appearance of the gels or ointments. When the lesions are more ulcers that can mimic the appearance of primary diffuse, difficult to access (i.e., orophaynx), or in herpetic gingivostomatitis. Additionally, although larger numbers, a steroid rinse is more helpful most commonly occurring on non-keratinized than a topical ointment or gel. Decadron (dexam- surfaces, herpetiform aphthae can infrequently ethasone) elixir 0.5 mg/5 ml can be considered appear on keratinized mucosa as can primary when treating these lesions. If the lesion(s) are herpetic gingivostomatits. large and accessible, combining with a topical ointment or gel can reduce the Herpetiform aphthous is characterized by multiple signs and symptoms. recurrent crops of 10 or more small crateriform ulcers of variable size. The episodes may last Although topical steroids used appropriately on a several weeks or months with individual ulcers limited basis rarely cause untoward effects, healing after 1-2 weeks. The lesions are shallow, patients should be counseled regarding the like aphthous minor, and heal without scarring. potential for candidal overgrowth when steroid rinses are used for extended periods. The more The age of onset of herpetiform aphthous is later potent steroids (i.e., Temovate) when applied than with the other types, with the initial episode more than twice per day for more than two weeks usually presenting in the second or third decade can lead to mucosal thinning and erosions. of life. Aphthae are expected to respond quickly to Treatment steroid therapy. It must be emphasized that when Once a diagnosis of aphthous is reached, the an intraoral ulcer does not heal after potential clinician must decide whether to provide more causes have been addressed and/or after steroid than palliative care. As part of informed consent, therapy, the lesion should be re-assessed and the patient should receive instruction about the biopsied. Oral malignancy and other disease condition, treatment options, and the expected processes should be considered as part of the outcome from each of the various treatment plans differential diagnosis for lesions that do not offered. Patients with frequent or severe out- respond to conservative therapy. Other immune- breaks of aphthae should be counseled regarding mediated disease may also mimic aphthae and the advisability of a medical screening for dia- require an accurate diagnosis before an adequate betes, various forms of , gastrointestinal treatment plan can be developed. disease, food "allergies," and other

6 The Journal of Contemporary Dental Practice, Volume 3, No. 1, February 15, 2002 Herpes Etiology, Another manifestation of acute Prevalence, Pathogenesis primary herpetic stomatitis is an The herpes infection has a acute of the mar- history dating back to ancient ginal and attached gingiva with- Greece. The word 'herpes' out accompanying vesicular was used by Hippocrates to lesions. It has been reported describe lesions that 'creep' or that only 12% of those with RIH 'crawl.' Although previously remember an initial infection.7,8 well characterized, it was not until 1893 that the transmissi- After the initial infection, the bility was recognized.6 will remain dormant until activated. The frequency of The herpes family of currently is thought reactivation with clinical recurrence has been to consist of 1 (HSV-1), herpes reported as occurring in 40%9 and 10-15%4 of simplex 2 (HSV-2), varicella-zoster, Epstein-Barr, those with the latent virus. , and human herpes virus VI, VII, and VIII.5 All are capable of entering and replicat- Reactivation can occur as a result of several fac- ing in epithelial cells, while some of the herpes tors that suppress the immune system. These family is neurotropic and others are lymphotropic. include but are not limited to emotional stress, HSV-1 and HSV-2 are neurotropic, infecting sen- trauma, cold, sunlight, extreme fatigue, fever, and sory nerve fibers and have been demonstrated to . reproduce in epithelial cells. HSV-1 and HSV-2 are lytic to human epithelial cells and latent in The recurrent vesicular/ulcerative lesions have neural tissue at the site of regional . become known as 'cold sores' or 'fever blisters' Usually the virus initially enters the body through because people may notice activation following an a break in the integrity, illness such as upper respiratory infection. Some although there is evidence that it may penetrate patients may report an outbreak following an intact skin. In either case, results immunosuppressive experience. from mucocutaneous contact with infected secre- tions and aerosols. When reactivated, the virus The incubation period between infection or reacti- travels along the nerve to the surface vation and the appearance of vesicles is about epithelial cells and can cause a recurrent epithe- 7-8 days but may range from 1-26 days. During lial outbreak. this pre-emergence period and during the vesicu- lar stage, secretions are highly contagious.6 Often the initial herpes infection goes undetected. Additionally, there is evidence that those with However, in a small percentage of cases, the ini- recurrent HSV-1 shed the virus in the saliva tial oral infection with HSV-1 or HSV-2 is acutely even when . People with genital symptomatic causing many signs and symptoms HSV-2 shed the virus about 10% of the days detected by the patient. When the patient when they are asymptomatic, although this demonstrates systemic signs, symptoms, and has declines over time.9 perioral and intraoral vesicular lesions, it is referred to as primary herpetic gingivostomatitis. HSV-1 and HSV-2 are both different and alike. Although the condition most often occurs in chil- HSV-1 generally is described as occurring above dren, it can also affect adolescents and adults. the waist, with HSV-2 occurring below the waist. Fever and lymphadenopathy may occur, lasting In reality, either variety can reside at either loca- from 2-10 days. , malaise, , tion. HSV-1 usually establishes latency in the fiery red gingival, and mucosal tissues associated trigeminal or other . HSV-2 is usually with painful swallowing are hallmarks of the pri- latent at the sacral ganglion at the base of the mary infection. Intraorally, many small punctate spine. Usually at its alternate site, the virus caus- ulcers may form on keratinized and nonkera- es milder infection as well as less asymptomatic tinized mucosa as well as at the nasopharynx. shedding. It is much more common for HSV-1 to Perioral tissues can also be affected. spread genitally than for HSV-2 to occur orally. Overall 80%-90% of the adult human population have been infected with HSV.

7 The Journal of Contemporary Dental Practice, Volume 3, No. 1, February 15, 2002 Treatment for Recurrent presence of renal disease) of Intraoral Herpes the patient. As with aphthae, an accurate diagnosis of RIH must be Rx: Acyclovir (Zovirax) 200 developed prior to initiating mg capsules definitive treatment for the Disp: 50 (fifty) capsules viral lesions. Patients should Sig: Take by mouth one be informed that there is capsule five times per day potential for self-inoculation during the waking hours for and transmission of the virus ten days. to other susceptible hosts. Patients or their caregivers Rx: Valacyclovir (Valtrex) should be warned about 500 mg tablets potentially transmitting the virus to the eye, geni- Disp: 21 (twenty one) tablets tals, or hands through direct contact with saliva or Sig: Take by mouth one tablet three times vesicular fluid containing the virus. per day for seven days

Topical steroids applied to intraoral herpetic Rx: (Famvir) 250 mg tablets lesions must be avoided as steroid use allows the Disp: 21 (twenty one) tablets virus to spread. As with aphthae, adequate Sig: Take by mouth one tablet three times hydration and nutrition are essential to the healing per day for seven days process. Palliative rinses combining equal parts by volume of a topical ( 2% Case Report or Dyclonine 1%), an antihistamine (diphenhyr- Two days prior to embarking upon a planned out- damine 12.5 mg/ml), and a coating agent that of-town trip, a 33-year old woman became aware binds to the lesion's surface (Maalox or of vague symptoms of illness in her two children, Kaopectate) can relieve the symptoms associated ages 2 and 5. Symptoms included irritability, with the herpetic lesions. Clinicians might con- anorexia, painful deglutition, and pharyngitis. This sider discussing the mixing of such palliative rins- combination of symptoms did not appear pathog- es with a pharmacist. When using a topical anes- nomonic for any particular disorder and were sug- thetic that can potentially affect the swallowing gestive of a non-descript viral disorder, possibly process, patients should be counseled to use an upper respiratory infection. The day of depar- caution when drinking and eating. Depending on ture, upon examining the of the children, the degree of patient discomfort, acetaminophen a generalized acute inflammation of the gingivae with or without a narcotic can also be given for was apparent. This sign combined with the previ- relief of pain. ous signs and symptoms allowed for a presump- tive diagnosis of primary herpetic stomatitis. Systemic medications interfer- Once this designation was ing with viral DNA synthesis determined, the self-limiting can be helpful but are not nature of the disorder allowed routinely used for mild RIH in for the children to be left with a the immunocompetent patient. caretaker and the parents con- In the less common case of tinued with vacation plans. As an immunocompromised or predicted, the children's illness immunosuppressed adult ran its course within 3-5 days. patient, antivirals can be pre- scribed. Sample prescriptions Approximately 2-3 weeks later are listed below for three of the maternal parent begin to the more commonly used experience similar symptoms. antivirals. Dosages may need The malaise and discomfort to be adjusted up or down were so severe that she was based on the size and sys- bedridden for 3 days. With a temic health (especially in the history of being quite healthy,

8 The Journal of Contemporary Dental Practice, Volume 3, No. 1, February 15, 2002 she had no prior recollection of being ill enough At current age 16, the youngest child had not had to 'stay in bed'.3 Her gingivae were so severely secondary herpes eruptions, while the older, now inflamed and painful that it was impossible to fol- 19, has had several episodes of recurrent herpes low her usual regimen. Full recuper- labialis. ation ensued within 5-7 days. The mother has had recurring bouts of non-vesic- Subsequently, the paternal parent, age 35, devel- ular herpetic gingival inflammation, usually asso- oped the same disorder. In his case, the palatal ciated with precipitating factors of stress and/or tissue was so affected that it became denuded to fatigue and unrelated to any changes in local fac- the bone. Painful deglutition resulted in a weight tors/oral hygiene regimen. The father has had no loss of 15 pounds over a 7-10 day period of time. recurrences. Full recuperation ensued. Both parents had experienced primary herpetic gingivostomatitis, Conclusion presumably infected by the children who may The oral health professional is viewed as the have been exposed in child-care settings. 'expert' when an individual develops mouth sores. These peri-oral or intraoral lesions can be very The oral pathologist who examined the family disconcerting to the affected individual both due members commented that it was extremely rare to pain and fear/confusion about the meaning of to find 2 adults in the same household who had such lesions. not previously experienced the primary episode early in life. Along with performing a thorough and skilled intraoral and extraoral examination at every dental visit, the oral health professional must be knowl- edgeable in differentiating between RIH and RAS.

9 The Journal of Contemporary Dental Practice, Volume 3, No. 1, February 15, 2002 References

1. Ship, JA. Recurrent aphthous stomatitis. An update. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996 Feb;81(2):141-7. Review. 2. Vincent SD, Lilly GE. Clinical, historic, and therapeutic features of aphthous stomatitis. Literature review and open clinical trial employing steroids. Oral Surg Oral Med Oral Pathol. 1992 Jul;74(1):79-86. Review. 3. Scully C, Porter SR. Recurrent aphthous stomatitis: current concepts of etiology, pathogenesis and management. J Oral Pathol Med. 1989 Jan;18(1):21-7. Review. 4. Baughman RA. Recurrent aphthous stomatitis vs. recurrent herpes: do you know the difference? J Ala Dent Assoc. 1996 Winter;80(1):26-32. Review. 5. Sapp JP, Eversole LR, Wysocki, GP. Contemporary Oral and Maxillofacial Pathology. Mosby: St. Louis, 1997, pp. 245. 6. Whitely RJ, Kimberlin DW, Roizman B. . CID 1998 26:541-553. 7. Langlais RP, Miller CS. Color Atlas of Common Oral Diseases. Lippincott Williams and Wilkins: Philadelphia. pp. 128. 8. Juretic M. Natural history of herpetic infection. Helv Paediatr Acta. 1966 Sep;21(4):356-68. No abstract available. 9. (On-line journal) http://www.herpes.com/hsv1-2.html.

About the Authors

10 The Journal of Contemporary Dental Practice, Volume 3, No. 1, February 15, 2002