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

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

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

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Abstract

“Differential Diagnosis: Is It Herpes or Aphthous?”

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

Volume 3 Number 1 February 15, 2002

© Seer Publishing

2The Journal of Contemporary Dental Practice, Volume 3, No. 1, February 15, 2002

IntroductionRecurrent aphthous stomatitis (RAS) and recur-rent intraoral herpetic (RIH) lesions are commonoral disorders that are often mistaken for oneanother. The confusion associated with develop-ing an accurate diagnosis is somewhat under-standable since these two very different lesionsshare some common characteristics. However,since they do differ in a variety of parameters, thewell-informed clinician should be able to differenti-ate between these distinctly separate conditions.

The patient history, the physical examination, andthe results of any indicated tests are important tothe diagnostic process. A complete and accuratepatient history is a critical component of develop-ing a working diagnosis. Information regarding

initiating factors, frequency of lesions, relievingfactors (including any previously prescribed orover-the-counter medications), and aggravatingfactors provides historically important data. It hasoften been said that if you listen to the patient, heor she will give you the diagnosis.

If the patient history is accurate and the physicalexamination allows the clinician to see thelesion(s), other tests may not be necessary. Inmost cases, the clinician should be able to differ-entiate herpetic lesions from aphthous ulcers.

Lesion Identification: How Accurate Are You?Review the following images of mucosal lesions toassess your skills at differentiating between apht-hous ulcers and RIH lesions. (Figures 1 A-D)

Figure 1a Figure 1b

Figure 1c

Figure 1d

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The high prevalence and often-painful presenta-tion of these lesions suggests that patients willfrequently seek out the oral health professional fordiagnosis and treatment. Since the lesions arealmost always self-limiting, one might questionthe importance of being able to distinguish onefrom the other. What then is the rationale for thedifferential diagnosis?

Table 1 summarizes some of the features of RIHand RAS.

Rationale for Differential DiagnosisDeveloping an accurate diagnosis for herpes andaphthous is critical to the treatment plan becausethe recommended treatment approaches are verydifferent for herpetic lesions and aphthous ulcera-tions. Treating a herpetic lesion with topicalsteroids (as appropriate for an aphthous ulcer)can have serious sequelae. Telling a patient withan active herpes infection that he or she has anaphthous ulcer and that it is not potentially conta-gious is simply bad healthcare. Additionally, the

accompanying peace of mind that occurs withproviding a name and treatment for what mayhave been a long-standing condition can havepsychological advantages for the patient.

Prodromal SymptomologyBoth herpetic and aphthous lesions often presentwith prodromal symptoms which can provideimportant clues to the development of a diagnosis.However, the indications of an impending herpeticlesion are generally more descriptive than for adeveloping aphthous ulcer.

Awareness of the initiation of the aphthous lesionis generally indicated by local discomfort at thelesion site. The degree of pain can vary fromslight to severe and is frequently described as outof proportion to the size of the lesion.

The prodromal symptomology for herpes mayseem confounding to the patient at initial occur-rence, but for those experiencing frequent out-breaks of herpetic lesions, the symptoms areoften recognizable. The first indication of a

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recurrent herpetic outbreak may be an unusualsensation of the affected tissue that may manifestas a lack of tactile or sensory perception. Thismay progress to a tingling, burning, or throbbingsensation. The development of vesicles (smallblisters) within 24-48 hours will help to validatethe occurence of a recurrent herpes outbreak.

Lesion LocationThe site of the initial lesion can provide importantclues concerning the presenting condition.Recurrent aphthous ulcerations are usuallydescribed as occurring on non-keratinized, orgland-bearing tissues. Common sites for recur-rent aphthous ulcers include labial and buccalmucosa, floor of the mouth, oropharynx, vestibule,and lateral tongue. With the exception of sites offrequent trauma, there appears to be no predilec-tion for aphthous ulcers to recur at a previouslocation.

In contrast, RIH generally appears on keratinizedtissues such as the vermillion borders of the lips,hard palate, attached gingivae, and alveolarridges. The initial lesion can be at any of theselocations with subsequent outbreaks often mani-festing at or very near the original site.

Appearance of LesionsThe clinician is not always able to view a lesion atthe initial stage when most easily diagnosed.Therefore, eliciting a detailed description of thecourse of the eruption becomes essential. Inmost cases the combination of the history of thelesion and viewing the current stage can allow fora working (presumptive) diagnosis.

The aphthous ulcer does not transition throughspecific discernable stages as does the herpeticlesion. It may, however, increase in size from firstdetection to maturity. Aphthous ulcers are usuallydivided into two general categories: aphthousmajor and minor. Amore uncommon form,herpetiform aphthousstomatitis, mimics her-petic lesions in appear-ance but is found in thesame areas as theother forms of aphthousstomatitis.

In the aphthous minor form of aphthous stomati-tis, the ulcer is shallow and 0.5-2 cm in size. Itusually appears as a single lesion, although 1-5ulcers may be present. The initial lesion maybegin as an erythematous macule, but it quicklyprogresses to an ulcer characterized by a white toyellow or gray center of necrosis surrounded by asmooth, symmetrical, round or elliptically shapederythematous perimeter often described as a "redhalo." Within 10-14 days of the initial presentation,the aphthous ulcer should usually be fully healed.

Major aphthae typically are larger, last longerthan aphthous minor, and may heal with scarring.Clinicians should remember that HIV/AIDSpatients can present with ulcers demonstrating aclinical appearance similar to or indistinguishablefrom major aphthae due to their immunocompro-mised health status.

Following the characteristic prodromal stage pre-viously described, the herpetic lesion manifestsas a cluster of small grey to white vesicles thatrupture to form small punctate ulcers that areusually 1 mm or less in diameter. These ulcersmay coalesce into one larger ulcer up to 1.5 cmin size. A red halo effect may be visible, but willappear scalloped in contrast to the smooth haloseen in aphthous ulceration. The next stage is'crusting,' which precedes the healing process.From prodrome to crusting takes up to 96 hourswith pain resolution over 96-120 hours and complete healing by 8-10 days. Since "crusting"does not occur intraorally, this feature is noted primarily in labial or cutaneous lesions.

Comparing the two lesions, it is apparent thatboth become ulcerative, but the progression tothe ulcer stage differs widely, as does the appear-ance of the mature lesions associated with herpes and aphthous.Thus, the history, loca-tion, and appearance ofthe lesions should allowthe knowledgeable clini-cian to establish a pre-sumptive diagnosis.Regarding transmissibili-ty, it is important to notethat while the aphthous ulcer is not contagious,the herpetic lesion is transmissible to a suscepti-ble host. Herpes is communicable throughout thecourse of the outbreak, particularly during thevesicle and ulceration phases.

Aphthous Ulcer

Herpetic Lesion

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Etiology, Prevalence, and Pathogenesis

Aphthous StomatitisThe term 'aphthous' originated with Hippocratesas far back as 460-370 BC in reference to disor-ders of the mouth.1 In general usage, the word'aphthae' refers to the presence of an otherwiseundefined ulcer.2 Despite the fact that aphthousstomatitis is the most common human oralmucosal disease, the cause is poorly understood.Although symptomatic treatment is available, aphthous is not preventable.3 Since the etiologyof aphthous ulcers is indeterminate, research hasfocused upon a variety of potentiating factors.Until the etiology is clarified, the focus has shiftedtoward the notion of 'precipitating factors.'Studies of these are not conclusive, but precipitat-ing factors that have been identified include:stress, nutritional deficiencies, trauma, hormonalchanges, diet, and immunologic disorders. Othercontributors that have received attention are:foods, allergies, progesterone levels, psychologicfactors, and a familial history. Despite extensiveresearch, no conclusive etiology has been deter-mined. For some time it was thought that aphthous ulcerations were due to an L-form ofStreptococcus since this organism was often isolated from the lesions. A more common beliefis that the lesions may become secondarily infected with streptococci. Since the lesions areoften suppressed by steroid therapy, which affectsthe immune response, it is more likely that thelesions are a manifestation of the immuneresponse, perhaps a hypersensitivity to strepto-cocci or another oral phenomenon.4 RAS is currently characterized as an idiopathic disorderwhose fundamental etiology is unclear. It is, how-ever, widely recognized as immunologically mediated.

RAS is a common oral disorder. The prevalenceamong 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 systemicdisorders that are associated with chronic gas-trointestinal malabsorption disturbances such asCrohn's disease and celiac disease. Another systemic disorder associated with aphthous ulcer-ation is Behcet syndrome that is characterized byrecurrent attacks of genital and oral ulcers.

Aphthous stomatitis is divided into three clinicalpresentations. It is unclear whether these presentations are manifestations of one diseaseor represent other oral disorders characterized byrecurrent ulcers. The three designations are apthous minor, apthous major and herpetiformulcers.

Etiology, Prevalence, and PathogenesisAphthous minor is the most common varietyaccounting for 80%1 to 95%5 of all RAS lesions.The lay term for this lesion is canker sore.

During an attack of minor aphthous, lesions mayoccur singly or up to five or more concurrentulcers. Each lesion typically lasts 10-14 days.Lesions may continually appear and heal sponta-neously during a 3-4 week period.

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Aphthous major, which accounts for about 10% ofcases of aphthous stomatitis1,5 is characterizedby large lesions which vary from 5-20 mm ormore in size. Usually only 1-2 lesions occur at atime and primarily in two locations, lip mucosaand posterior palate/anterior fauces area.

The lesions are much more severe than that ofminor aphthae and are associated with severepain. The lesions are crateriform and deep,involving much tissue necrosis, often resulting inscarring upon healing. Aphthous major can last 6 weeks or more and can become secondarilyinfected with bacterial and fungal organisms.Lesions of aphthous major can become intra-ctable in those with immunodeficiency disorderssuch as HIV and AIDS, resulting in weight lossdue to painful deglutition.

Herpetiform aphthous is the least common varietycomprising about 10% of occurrences. The nameis misleading since it suggests a herpetic infec-tion. Rather it is the similar appearance of theulcers that can mimic the appearance of primaryherpetic gingivostomatitis. Additionally, althoughmost commonly occurring on non-keratinized surfaces, herpetiform aphthae can infrequentlyappear on keratinized mucosa as can primaryherpetic gingivostomatits.

Herpetiform aphthous is characterized by multiplerecurrent crops of 10 or more small crateriformulcers of variable size. The episodes may lastseveral weeks or months with individual ulcershealing after 1-2 weeks. The lesions are shallow,like aphthous minor, and heal without scarring.

The age of onset of herpetiform aphthous is laterthan with the other types, with the initial episodeusually presenting in the second or third decadeof life.

TreatmentOnce a diagnosis of aphthous is reached, the clinician must decide whether to provide morethan palliative care. As part of informed consent,the patient should receive instruction about thecondition, treatment options, and the expectedoutcome from each of the various treatment plansoffered. Patients with frequent or severe out-breaks of aphthae should be counseled regardingthe advisability of a medical screening for dia-betes, various forms of anemia, gastrointestinaldisease, food "allergies," and other diseases

potentially affecting the immune system. It maymay also be wise to rule out Behcet's diseasethrough questioning about the presence of lesionsof the genital mucosa. Suggested supportivecare includes rest, increased fluid intake, ade-quate nutritional intake, multi-vitamin and mineraltherapy, and reassurance that aphthae are notcommunicable.

When conservative, palliative care such as elimi-nating trauma (where possible), avoiding expo-sure to identified causative factors, and stressreduction are not enough, steroids of varioustypes can be utilized. Aphthae that are localizedor in small numbers can often be effectively treated with a topical steroid. For single (or few)shallow lesions, a mild steroid ointment or gel isusually adequate. Kenalog (triamicinalone acetonide 0.1%) in Orabase can be used onmany mild aphthae cases. Larger lesions, whenaccessible, can be treated with a more potentsteroid like Lidex (0.05%) or Temovate (0.05%)gels or ointments. When the lesions are more diffuse, difficult to access (i.e., orophaynx), or inlarger numbers, a steroid rinse is more helpfulthan a topical ointment or gel. Decadron (dexam-ethasone) elixir 0.5 mg/5 ml can be consideredwhen treating these lesions. If the lesion(s) arelarge and accessible, combining dexamethasonewith a topical ointment or gel can reduce thesigns and symptoms.

Although topical steroids used appropriately on alimited basis rarely cause untoward effects,patients should be counseled regarding thepotential for candidal overgrowth when steroidrinses are used for extended periods. The morepotent steroids (i.e., Temovate) when appliedmore than twice per day for more than two weekscan lead to mucosal thinning and erosions.

Aphthae are expected to respond quickly tosteroid therapy. It must be emphasized that whenan intraoral ulcer does not heal after potentialcauses have been addressed and/or after steroidtherapy, the lesion should be re-assessed andbiopsied. Oral malignancy and other diseaseprocesses should be considered as part of thedifferential diagnosis for lesions that do notrespond to conservative therapy. Other immune-mediated disease may also mimic aphthae andrequire an accurate diagnosis before an adequatetreatment plan can be developed.

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Herpes Etiology,Prevalence, Pathogenesis The herpes infection has ahistory dating back to ancientGreece. The word 'herpes'was used by Hippocrates todescribe lesions that 'creep' or'crawl.' Although previouslywell characterized, it was notuntil 1893 that the transmissi-bility was recognized.6

The herpes family of viruses currently is thoughtto consist of herpes simplex 1 (HSV-1), herpessimplex 2 (HSV-2), varicella-zoster, Epstein-Barr,cytomegalovirus, and human herpes virus VI, VII,and VIII.5 All are capable of entering and replicat-ing in epithelial cells, while some of the herpesfamily is neurotropic and others are lymphotropic.HSV-1 and HSV-2 are neurotropic, infecting sen-sory nerve fibers and have been demonstrated toreproduce in epithelial cells. HSV-1 and HSV-2are lytic to human epithelial cells and latent inneural tissue at the site of regional ganglions.Usually the virus initially enters the body througha break in the mucous membrane integrity,although there is evidence that it may penetrateintact skin. In either case, transmission resultsfrom mucocutaneous contact with infected secre-tions and aerosols. When reactivated, the virustravels along the nerve axon to the surfaceepithelial cells and can cause a recurrent epithe-lial outbreak.

Often the initial herpes infection goes undetected.However, in a small percentage of cases, the ini-tial oral infection with HSV-1 or HSV-2 is acutelysymptomatic causing many signs and symptomsdetected by the patient. When the patient demonstrates systemic signs, symptoms, and hasperioral and intraoral vesicular lesions, it isreferred to as primary herpetic gingivostomatitis.Although the condition most often occurs in chil-dren, it can also affect adolescents and adults.Fever and lymphadenopathy may occur, lastingfrom 2-10 days. Pharyngitis, malaise, myalgia,fiery red gingival, and mucosal tissues associatedwith painful swallowing are hallmarks of the pri-mary infection. Intraorally, many small punctateulcers may form on keratinized and nonkera-tinized mucosa as well as at the nasopharynx.Perioral tissues can also be affected.

Another manifestation of acuteprimary herpetic stomatitis is anacute inflammation of the mar-ginal and attached gingiva with-out accompanying vesicularlesions. It has been reportedthat only 12% of those with RIHremember an initial infection.7,8

After the initial infection, thevirus will remain dormant untilactivated. The frequency of

reactivation with clinical recurrence has beenreported as occurring in 40%9 and 10-15%4 ofthose with the latent virus.

Reactivation can occur as a result of several fac-tors that suppress the immune system. Theseinclude but are not limited to emotional stress,trauma, cold, sunlight, extreme fatigue, fever, andmenstrual cycle.

The recurrent vesicular/ulcerative lesions havebecome known as 'cold sores' or 'fever blisters'because people may notice activation following anillness such as upper respiratory infection. Somepatients may report an outbreak following animmunosuppressive experience.

The incubation period between infection or reacti-vation and the appearance of vesicles is about 7-8 days but may range from 1-26 days. Duringthis pre-emergence period and during the vesicu-lar stage, secretions are highly contagious.6

Additionally, there is evidence that those withrecurrent HSV-1 shed the virus in the saliva even when asymptomatic. People with genitalHSV-2 shed the virus about 10% of the dayswhen they are asymptomatic, although thisdeclines over time.9

HSV-1 and HSV-2 are both different and alike.HSV-1 generally is described as occurring abovethe waist, with HSV-2 occurring below the waist.In reality, either variety can reside at either loca-tion. HSV-1 usually establishes latency in thetrigeminal or other ganglion. HSV-2 is usuallylatent at the sacral ganglion at the base of thespine. Usually at its alternate site, the virus caus-es milder infection as well as less asymptomaticshedding. It is much more common for HSV-1 tospread genitally than for HSV-2 to occur orally.Overall 80%-90% of the adult human populationhave been infected with HSV.

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Treatment for RecurrentIntraoral HerpesAs with aphthae, an accuratediagnosis of RIH must bedeveloped prior to initiatingdefinitive treatment for theviral lesions. Patients shouldbe informed that there ispotential for self-inoculationand transmission of the virusto other susceptible hosts.Patients or their caregiversshould be warned aboutpotentially transmitting the virus to the eye, geni-tals, or hands through direct contact with saliva orvesicular fluid containing the virus.

Topical steroids applied to intraoral herpeticlesions must be avoided as steroid use allows thevirus to spread. As with aphthae, adequatehydration and nutrition are essential to the healingprocess. Palliative rinses combining equal partsby volume of a topical anesthetic (Lidocaine 2%or Dyclonine 1%), an antihistamine (diphenhyr-damine 12.5 mg/ml), and a coating agent thatbinds to the lesion's surface (Maalox orKaopectate) can relieve the symptoms associatedwith the herpetic lesions. Clinicians might con-sider discussing the mixing of such palliative rins-es with a pharmacist. When using a topical anes-thetic that can potentially affect the swallowingprocess, patients should be counseled to usecaution when drinking and eating. Depending onthe degree of patient discomfort, acetaminophenwith or without a narcotic can also be given forrelief of pain.

Systemic medications interfer-ing with viral DNA synthesiscan be helpful but are not routinely used for mild RIH inthe immunocompetent patient.In the less common case ofan immunocompromised orimmunosuppressed adultpatient, antivirals can be pre-scribed. Sample prescriptionsare listed below for three ofthe more commonly usedantivirals. Dosages may needto be adjusted up or downbased on the size and sys-temic health (especially in the

presence of renal disease) ofthe patient.

Rx: Acyclovir (Zovirax) 200mg capsulesDisp: 50 (fifty) capsulesSig: Take by mouth one capsule five times per dayduring the waking hours forten days.

Rx: Valacyclovir (Valtrex)500 mg tablets

Disp: 21 (twenty one) tabletsSig: Take by mouth one tablet three times per day for seven days

Rx: Famciclovir (Famvir) 250 mg tabletsDisp: 21 (twenty one) tabletsSig: Take by mouth one tablet three times per day for seven days

Case ReportTwo days prior to embarking upon a planned out-of-town trip, a 33-year old woman became awareof vague symptoms of illness in her two children,ages 2 and 5. Symptoms included irritability,anorexia, painful deglutition, and pharyngitis. Thiscombination of symptoms did not appear pathog-nomonic for any particular disorder and were sug-gestive of a non-descript viral disorder, possiblyan upper respiratory infection. The day of depar-ture, upon examining the mouths of the children,a generalized acute inflammation of the gingivaewas apparent. This sign combined with the previ-ous signs and symptoms allowed for a presump-tive diagnosis of primary herpetic stomatitis.

Once this designation wasdetermined, the self-limitingnature of the disorder allowedfor the children to be left with acaretaker and the parents con-tinued with vacation plans. Aspredicted, the children's illnessran its course within 3-5 days.

Approximately 2-3 weeks laterthe maternal parent begin toexperience similar symptoms.The malaise and discomfortwere so severe that she wasbedridden for 3 days. With ahistory of being quite healthy,

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she had no prior recollection of being ill enoughto 'stay in bed'.3 Her gingivae were so severelyinflamed and painful that it was impossible to fol-low her usual oral hygiene regimen. Full recuper-ation ensued within 5-7 days.

Subsequently, the paternal parent, age 35, devel-oped the same disorder. In his case, the palataltissue was so affected that it became denuded tothe bone. Painful deglutition resulted in a weightloss of 15 pounds over a 7-10 day period of time.Full recuperation ensued. Both parents hadexperienced primary herpetic gingivostomatitis,presumably infected by the children who mayhave been exposed in child-care settings.

The oral pathologist who examined the familymembers commented that it was extremely rareto find 2 adults in the same household who hadnot previously experienced the primary episodeearly in life.

At current age 16, the youngest child had not hadsecondary herpes eruptions, while the older, now19, has had several episodes of recurrent herpeslabialis.

The mother has had recurring bouts of non-vesic-ular herpetic gingival inflammation, usually asso-ciated with precipitating factors of stress and/orfatigue and unrelated to any changes in local fac-tors/oral hygiene regimen. The father has had norecurrences.

ConclusionThe oral health professional is viewed as the'expert' when an individual develops mouth sores.These peri-oral or intraoral lesions can be verydisconcerting to the affected individual both dueto pain and fear/confusion about the meaning ofsuch lesions.

Along with performing a thorough and skilledintraoral and extraoral examination at every dentalvisit, the oral health professional must be knowl-edgeable in differentiating between RIH and RAS.

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References

1. Ship, JA. Recurrent aphthous stomatitis. An update. Oral Surg Oral Med Oral Pathol Oral RadiolEndod. 1996 Feb;81(2):141-7. Review.

2. Vincent SD, Lilly GE. Clinical, historic, and therapeutic features of aphthous stomatitis. Literaturereview and open clinical trial employing steroids. Oral Surg Oral Med Oral Pathol. 1992Jul;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. Herpes Simplex Virus. 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.

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