Ross Pagano FRCOG, FRACOG

Vulvar Disorders Clinic, Royal Women's Hospital, Melbourne, Victoria

Summary: Vulvar vestibulitis syndrome (VVS) is an easily identifiable cause of entry dyspareunia. The aetiology is unknown although there is a strong association with Candida infection. The condition represents a focal area of hyperaesthesia within the vulvar vestibule. A management protocol for patients with this condition is presented; 230 patients with VVS were managed and followed-up over a. 5-year period. Spontaneous resolution or improvement occurred in 21 % of patients following initial explanation and use of simple local measures. In 21 %, there were positive Candida cultures and long-term antifungal therapy resulted in a 7 1 % cure. In Candida-negative patients, lown-dose amitriptyline was used (up to, 75 mg daily) with a 60% positive response rate. Carbamazepine was of little benefit (13% response). Surgical vestibulectomy was offered when conservative measures failed and this was performed in 22 patients (10%) with a beneficial result in 20 patients (91%).

Patients with vulvar pain and severe entry dyspareunia have been managed poorly for many years primarily because of a lack of understanding of the. aetiology of the symptoms -and failure to recognize that these patients have distinct pathology within the vulvar vestibule. The condition was first described by Skene in 1889 as excessive sensitivity of the vulva and he called it 'vulvar hyperaesthesia' (1). The condition was then ignored in the literature for almost 100 years except for a brief reference by Kelly in 1928 who simply described exquisitely sensitive red spots in the mucosa of the hymenal ring that could make intercourse painful and even impossible (2). Nothing was mentioned again until 1976 when Pelisse and Hewitt described a syndrome of superficial dyspareunia with 'erythematous vulvitis en plaques' (3). Woodruff described a similar condition in 1983 and attributed it to infection of the vestibular glands (4) and proposed a purely surgical approach to the problem (5).

The condition was finally defined and given the name 'vulvar vestibulitis syndrome' (VVS) in 1987 by Friedrich who described the features seen in an increasing number of women presenting with varying degrees of entry dyspareunia (6). The 3 criteria required to make a diagnosis of VVS were: (1) severe pain on vestibular touch or attempted entry, (ii) tenderness localized to the vulvar vestibule and (M) physical findings confined to vulvar erythema of varying degree. This condition results in a hyperaesthesia of the vulvar vestibule, particularly at the base of the hymenal remnant (around the opening of the minor vestibular glands) and extending anteriorly to the paraurethral gland areas, and even subclitorally.

Patients with VVS present with varying degrees of vulvar pain and tenderness. Initially this results in patients experiencing pain on insertion of tampons and entry dyspareunia, eventually rendering some patients apareunic. Occasionally the presenting symptom may be dysuria and these patients are often treated repeatedly and needlessly for supposed urinary tract infection. In severe cases, patients will have vulvar pain just from sitting and from the pressure of clothing. The cause of this condition is unknown and in the majority of patients will eventually resolve spontaneously, although it may persist for many years. The most important aspect in the diagnosis of this condition is an awareness of it by the attending clinician. Unfortunately, due to an ignorance of the existence of this condition by the practitioner and the often lack of gross physical findings, these patients have often been labelled incorrectly as suffering primarily from a psychosexual disorder. Understandably, these patients are often frustrated and angry when they present to a Vulvar Disorders Clinic, often having seen multiple doctors before a correct diagnosis is made.

The vestibule consists of that area of the vulva bound anteriorly by the clitoris, posteriorly by the fourchette and laterally by Hart's line (the mucokeratinous junction on the medial aspect of the labia minora). Embryologically, the vestibule is the only part of the vulva that is endodermal in origin. As the bladder mucosa and the vulvar vestibule are both derived from the urogenital sinus, this could explain why patients with vestibulitis may have associated bladder symptoms. The minor vestibular glands are confined to a narrow segment of skin located at the base of the hymen. In contrast to the major vestibular glands (e.g. Bartholin glands) whose main function is providing lubrication for sexual intercourse, the function of the minor vestibular glands is unknown. Even although their anatomical distribution is confined exactly to the area of tenderness found in VVS, their role in the aetiology of this condition is uncertain.

In VVS, there is pinpoint tenderness in the area of the minor vestibular glands and this can be easily evaluated by the gentle application of a cotton-tipped applicator (figure 1). The tenderness is precisely confined to the base of the hymen, often focal and sometimes involving the paraurethral tissues and occasionally can extend to the area between the urethra and clitoris (figure 2). Application of the cotton tip several millimetres away elicits no tenderness at all. The area around the openings of the Bartholin glands is often the site at which the symptoms start. Erythema is usually present although this can be minimal and focal and the cause of this inflammation is not known.

The aetiology of this condition is uncertain although in a significant number of these patients (approximately 60%), the symptoms start following a severe or repeated episodes of vulvovaginal candidiasis. The role of human papilloma virus (HPV) infection is yet to be established. Racial differences appear to be important as the condition is very rarely seen in women of the Negroid race (6). Management involves a careful explanation of the condition to the patient, reassurance as to the self-limiting nature of the condition, use of local analgesic agents, eradication of any candidiasis, use of systemic neuronal membrane stabilizing agents and finally, for refractory cases, surgical vestibulectomy with vaginal advancement. Intralesional interferon injections have been tided with equivocal results (7,8), and also because of the expense and discomfort involved, have virtually been abandoned.

Marinoff and Turner (9) devised a grading system for dyspareunia so that results could be standardized. Three grades were proposed: Grade 1 where intercourse is painful but the degree of discomfort does not prevent penetration; Grade 2 where the pain prevents intercourse from taking place on most occasions; and Grade 3 where pain results in total apareunia.

This paper presents the findings of a prospective study of 230 patients who presented with the features of VVS. Possible aetiological factors and the response to a proposed treatment protocol are evaluated.

METHODS AND MANAGEMENT PROTOCOL

Over a 5-year period (from 1992 to 1996), 230 patients presenting with features consistent with the vulvar vestibulitis syndrome were seen in the Vulvar Disorders Clinic, Royal Women's Hospital, Melbourne and in private practice. Follow-up of these patients was - between 12 months and 5 years. A careful history was taken, the vulva examined with a cotton tipped applicator to map out areas of tenderness and skin scrapings taken for culture on Sabauraud medium for possible Candida infection. All patients had a

colposcopic assessment of the vulva with 5% acetic acid applied and a biopsy taken only if there were abnormal colposcopic features suggesting associated pathology.

At the initial visit an explanation of the condition was given to the patient and the importance of using an oil-based lubricant during intercourse was stressedThe patient was instructed to take the dominant role during intercourse and also to apply a small. amount of xylocaine 5% cream to the introital area prior to attempted penetration.

Upon review, if the skin cultures were positive for Candida, or if there were features in the history or examination strongly suggestive of recurrent vulvovaginal candidiasis, a long-term course of oral antifungal treatment was commenced. Ketoconazole 200 mg daily or fluconazole 150 mg weekly were used. The course of treatment was for 6 months, as proposed by Sobel (10). If the skin cultures were Candida negative, the patient was commenced on low dose amitriptyline. The starting dose was 10 mg nocte and increased by 10 mg nocte every 2 weeks until a therapeutic response was obtained. The dosage never exceeded 75 mg nocte. If there was a positive response, treatment was continued for 6 months and then gradually withdrawn. If there was no response, a trial of carbamazepine 100 mg tds was commenced. If no response was obtained, patients were further counselled and offered surgical vestibulectomy.

RESULTS

The average age of the 230 patients presenting with the vulvar vestibulitis syndrome was 29 years with the distribution ranging from 16 to 71 years. The average duration of symptoms was 21 months with the longest history being 10 years.

At presentation, 79 patients (34%) were completely apareunic (Grade 3 dyspareunia) and had been so for 6 months or more. Grade 2 dyspareunia was present in 40% (92 patients) and Grade 1 in 41% (59 patients).

In 5 patients, the condition started after C02 laser treatment to the vulva for wart virus infection and in 4 patients, the condition started immediately after delivery. During the study period, 5 patients became pregnant and in all of these patients. the symptoms improved during the pregnancy. However not enough follow-up time has elapsed to assess the rate of recurrence, after delivery.

In 48 patients (21 %), the skin scrapings were positive for Candida, indicating possible ongoing active candidiasis. However, in 147 patients (64%), them was a history that the symptoms commenced immediately following a severe case of candidiasis or there had been recurrent vulvovaginal candidiasis. It a patient had a positive culture for Candida, long-term oral antifungal agents (ketoconazole 200 mg daily or fluconazole 150 mg weekly) were given. In 71% of patients treated, there was complete resolution or significant improvement in symptoms. In patients in whom the Candida cultures were negative but in whom the clinical findings were highly suggestive of recurrent candidiasis (12 patients), long-term oral antifungal agents were given for an initial 6-week trial and continued if a therapeutic response was achieved. In half of this group (6 patients), the response was positive.

In 21 % of the study group (48 patients), spontaneous resolution or improvement occured without any specific treatment given over the follow-up period. In this group, the improvement often occurred after the initial consultation. Of these 48 patients who improved spontaneously, 23 had Grade 1 dyspareunia, 20 had Grade 2 and 5 were completely apareunic (Grade 3).

In patients who were Candida negative or whose symptoms persisted despite long-term antifungal therapy (168 patients), oral amitriptyline was commenced. In 20 patients, it was stopped within the first week because of intolerance. Of the 148. patients who remained on the treatment, there was a significant therapeutic response (i.e. reduction of at least one grading of severity of dyspareunia) in 89 patients (60%). Of these 89 patients who had a positive response, 45 were completely pain free at the end of the 6 months of treatment and the other 44 were improved. In this latter group, a further 6-month course of amitriptyline was given and at the end of this course, 15 were pain free and the rest (29 patients) regarded themselves as stable and requiring amitriptyline on a PRN basis only. Of the patients who failed to respond to amitriptyline. 30 agreed to a trial of carbamazepine. In only 4 patients (13%) was there a positive response to therapy.

Surgical vestibulectomy was performed in 22 patients (10 % of the study group) and in 20 patients (91 %) there was significant improvement. Of these patients, 14 had a complete resolution of the pain and in 6, there was patient perception that there had been a significant improvement. In these patients in whom only a partial cure was achieved' there was extension of the tenderness around the urethral meatus.

In summary, 74% of patients improved with conservative measures only (either spontaneous resolution or use of antifungals amitriptyline or carbamazepine). Of the remaining 26% (59 patients), surgical vestibulectomy was offered as a therapeutic option and performed in 22 patients with the rest (37 patients) deciding to not have any other treatment.

DISCUSSION

Even although the features of vulvar vestibulitis syndrome were first described 100 years ago, the condition has received little mention in the medical literature or in gynaecological textbooks. Since the name was proposed and the condition defined in 1987, the 'incidence' of presentation of this condition has increased, reflecting an increased awareness of the condition by attending gynaecologists. The incidence of vulvar vestibulitis syndrome is not known. In one study where all patients attending a private general gynaecological practice were specifically questioned and examined for the condition ' the incidence was a staggering 15% (11). This figure represented all degrees of severity of the syndrome and clearly the incidence of patients presenting for treatment will be much less. Nevertheless, it is the responsibility of the clinician to he aware that this condition exists and that it is a recognized cause of entry dyspareunia. Any psychosexual disturbance that eventuates (fear of intercourse, loss of libido, pelvic floor muscular spasm etc) is a secondary effect of the syndrome and should not be regarded as the primary problem as so often has been the case.

The condition represents a hyperaesthesia of the vulvar vestibule and the Pinpoint tenderness elicited is confined to the strip of skin in which are located the minor vestibular glands. Even although in this condition a lymphocytic infiltrate is often seen surrounding these glands the cause of the inflammation and redness is not established and no specific infecting organism has consistently been found (9).

The aetiology of this condition is not established. There is probably a noxious stimulus to the nerve endings in the affected area (either by an infective agent such as Candida, trauma etc) and this results in the hypersensitivity of the nerve endings as evident clinically. In the normal vulvar vestibule. there is a lack of specialized nerve endings such as Paccinian corpuscles. Meissner tactile discs etc, and the skin is exclusively innervated by unmyelinated C fibres (12) which are usually responsible for the transmission of painful stimuli. Thus all sensation in the vestibule is transmitted by these pain fibres and so damage to these nerve endings could result in the inappropriate transmission of painful sensations in response to simple tactile stimulation.

The strong association with a past history of recurrent vulvovaginal candidiasis or a particularly severe infection at the commencement of symptoms (64%) is noteworthy. The excellent response of this condition to the treatment of any ongoing candidiasis with long-term oral antifungals is indicative that Candida infection must play a major role in the aetiology of this condition. Treatment with long-term ketoconazole 200 mg daily or fluconazole 150 mg weekly for 6 months as proposed by Sobel (10) results in significant improvement and cure of the vestibulitis in 70% of patients who have positive Candida cultures on skin scrapings. Monitoring of liver function during prolonged therapy with ketoconazole is mandatory.

The role of HPV infection in this condition is unclear. Using polymerase chain reaction on vulvar biopsies to detect DNA evidence of HPV in patients with VVS, reports showing incidences varying from nil (13) to 54% (14) have been published. Thus the exact relationship between vulvar vestibulitis and subclinical HPV infection is yet to be determined. There is no indication for treatment of vulvar HPV by laser vaporization as there is no evidence to suggest this would be effective in treating vestibulitis and in fact, it could make the condition worse (9).

The most important aspect of management is giving the patient an adequate explanation of the condition, stressing that it represents a definite neuronal dysfunction and that it is not primarily a psychosexual problem although this may develop secondary to it. The condition will eventually resolve spontaneously. Simple measures such as local analgesic creams (even though they can initially stimulate the nerve endings) and oil-based sexual lubricants are used in order to help overcome the fear of intercourse that has inevitably developed. Together with explanation, these simple measures will result in a significant improvement or complete resolution of symptoms in 21 % of patients, often after the initial assessment.

Based on the success of McKay in using amitriptyline as a nerve membrane stabilizer in the management of idiopathic vulvar pain disorders such as dysaesthetic vulvodynia (15), it was decided to try this therapeutic approach in this condition. This treatment was used in patients who were Candidanegative on culture or who had persistent hyperaesthesia following the course of antifungal therapy (168 patients). Low dose amitriptyline (up to 75 mg nocte) was found to give significant improvement and even complete resolution of the symptoms in 60% of patients. In these patients, there was an improvement of at least one grade in the Marinoff dyspareunia grading score. If an improvement was achieved, amitriptyline was continued for at least 6 months. In approximately one third of patients, the symptoms recurred on ceasing the drug and a further 6 months course was given. No further treatment was considered necessary in these patients. Patients who failed to respond to amitriptyline were commenced on another membrane stabilizer (carbamazepine) although the response was poor (13%) and probably represented a placebo effect only.

Surgical excision of the medial aspect of the vulvar vestibule (including the hymenal remnants) and vaginal advancement as described by Woodruff (5) was performed on 22 patients (10%) with a significant improvement in 20 patients and a complete cure in 14. In the woman with partial cures, the tenderness extended periurethrally and this area is difficult to excise completely. Summarizing the results Of management options, 20% of patients Improve spontaneously, 60% improve significantly with either long-term therapy for chronic candidiasis or the use of low-dose amitriptyline and the rest would be suitable for surgical excision. In this series, only just over one third of these patients opted for. surgery, the rest accepting their condition in the hope that it will resolve in the long term. ]Ins vestibulectomy should only be necessary in amaximum of 20% of patients with VVS and should only be used as a last resort. At this stage, there have been no recurrences in the patients cured by vestibulectomy with the longest follow-up period being 5 years. In conclusion, VVS is a very real but poorly understood condition causing varying degrees of vulvar pain and entry dyspareunia. Diagnosis can easily be made by careful inspection of the vulva and the patient should be reassured that she is suffering from a definite recognized syndrome. Conservative measures include reassurance, local analgesic agents, eradication of chronic candidiasis and use of membrane stabilizing agents such as amitriptyline. Surgical vestibulectomy is only required in a small proportion of patients and gives excellent results in carefully selected cases.

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