Flashlamp-excited dye laser therapy of idiopathic vulvodynia is safe and efficacious

Flashlamp-excited dye laser therapy of idiopathic vulvodynia is safe and efficacious Richard Reid, MD,"b Katherine H. Omoto, MS, c Sheryl L. Precop, RN, NP, c Nancy R. Berman, RN, CS, MSN, c Lisa H. Rutledge, BA, c Steven M. Dean, MD, d and Mark Pleatman, MD e Detroit, Southfield, and Royal Oak, Michigan, and Rochester, Minnesota OBJECTIVE: The management of chronic vulvovaginal pain, not explicable on specific histologic grounds, presents a major problem in referral centers for lower genital tract diseases. STUDY DESIGN: This article reports on a two-step protocol in a sample of 175 medical nonresponders, drawn from a 2-year cohort of 725 women with vulvovaginal pain. The first maneuver was the use of a flashlamp-excited dye laser to selectively photocoagulate symptomatic subepithelial blood vessels in 168 women; the second was the microsurgical removal of chronically painful Bartholin's glands in 52 women not responsive or not suited to fiashlamp-excited dye laser photothermolysis. RESULTS: Dye laser response rates were independent of whether patients manifested macroscopic foci of painful erythema ("vestibular adenitis") or just colposcopically apparent hyperemia-ectasia of the individual blood vessels ("pruritic papillomatosis") (56% vs 45% after a single surgical procedure; 76% vs 65% after serial retreatment; p not significant). Conversely, response rates were much lower among women in whom pressure on the Bartholin's glands produced sharp, lancinating pain (15% vs 66% after a single surgical procedure; 22% vs 93% after serial retreatment; p < 0.001). Forty-two (85%) of 50 patients with fiashlamp-excited dye laser failure had deep pain; however, the impasse to progress was broken by gland removal. Final response rates were 92.5% (complete response 62%; partial response 30%) in the "surface-only" group and 80.3% in the "surface-plus-deep" group (×2 = 14.9; p < 0.001). The major complication was acute bacterial cellulitis, occurring in the first postoperative week. Modification of the treatment protocol to include topical antibiotics with an occlusive dressing reduced the cellulitis rate from 17.2% to 2.5%. In four women (1.8%) Koebner-like exophytic condylomas also developed within 1 month of flashlamp-excited dye laser surgery. CONCLUSION: The availability of a safe, efficacious, and relatively noninvasive treatment should reduce the need for resective surgery in most patients with idiopathic vulvodynia. (AM J OBSTETGYNECOL 1995; 172:1684-701 .)

Key words: Flashlamp-excited dye laser, vulvodynia, Bartholin's gland

Historically, chronic vulvar discomfort was generally attributable to a specific diagnosis: (1) cutaneous vulvar infections (cyclic candidiasis, tinea cruris); (2) secondary irritation from a vaginal discharge (bacterial vaginosis, trichomoniasis); (3) chemical or drug irritations (contact dermatitis, bullous erythema multiforme); (4) vulvar dermatoses (lichen planus, psoriasis, eczema, pemphigus); (4) nonneoplastic epithelial disorders (lichen sclerosus, lichen simplex chronicus); (6) neoplastic

From the Department of Obstetrics and Gynecology, Sinai Hospital, = the Department of Obstetrics and Gynecolog'~ Wayne State University School of Medicine, b The Reid Institute for Research and Education/ the Department of Obstetrics and Gynecology, William Beaumont Hospital, d and the Department of Surgery, Crittenton Hospital.' Community Hospital Award, presented at the Sixty-second Annual Meeting of The Central Association of Obstetricians and Gynecologists, Memphis, Tennessee, October 13-15, 1994. Reprint requests: Richard Reid, MD, 29355 Northwestern Hwy., Suite 210, Southfield, MI 48034. Copyright © 1995 by Mosby-Year Book, Inc. 0002-9378/95 $3.00 + 0 6/6/64183 1684

epithelial disorders (squamous neoplasia, Paget's disease, melanoma); or (7) vulvar dysesthesia (causalgia, pudendal neuralgia). Over the last decade there has been a dramatic increase in the number of women seen with vulvar burning and introital dyspareunia, not explicable by one of these specific diagnoses. Traditionally, these women with idiopathic vulvodynia have been subdivided into two groups: vulvar vestibulitis and pruritic papillomatosis. The term vulvar vestibulitis syndrome was introduced by Freidrich' to describe women with a triad of clinical features: acquired introital dyspareunia, painful erythema at the hymenal sulcus, and intense tenderness on gentle palpation with a cotton-tip swab. Pruritic papillomatosis was coined by McKay, 2 to describe patients with introital burning and dyspareunia, in whom vulvar inspection with the unaided eye gives essentially normal results. However, with the better lighting and resolution of the colposcope, the individual blood vessels within the vulvar vestibule are seen to be diffusely hyperemic and ectatic, and the overlying

Volume 172, Number 6

Am J Obstet Gynecol

Reid et al.

1685

Fig, 1. A, An intensely painful focus of vestibular erythema, arising adjacent to the site of hymenal . resection. (From Reid R. Colposcopic findings in women with vulvar pain syndromes. J Reprod Med 1988;33:525-32. Reproduced by permission.) B, Appearance 6 months after argon photocoagulation showing complete resolution. The patient has been in stable clinical remission since fall 1987.

epithelium shows prominent irritative acetowhitening after vinegar soaking? It is not yet clear whether these clinical patterns reflect two distinct etiologic entities or just spectral differences in the severity of a single disease. There are no specific therapies and no effective symptom-controlling antinflammatory agents. Topical 5-fluorouracil cream is often curative in pruritic papillomatosis but seldom helps established vestibultis, s Success has been reported within an uncontrolled trial of interferon alfa, injected three times weekly into the vulvar connective tissues over 4 weeks. 4 However, these injections are painful, and clinical benefits are often transient. Prevention of episodic hyperoxaluria, by avoidance of oxalate-rich foods and use of calcium citrate to reduce crystal formation in the urine, was effective in a single case, 5 but the efficacy of this regimen has not yet been established by randomized clinical trial. Hence the mainstay of conventional treatment for patients with macroscopically visible foci of painful erythema has remained cold knife resection of the minor vestibular glands and the adjacent hymen, with closure by downward advancement of the vaginal mucosa. ~ Woodruffs localization of the main sites of pain to the minor vestibular glands and his recognition that excision could cure some patients were valuable advances. However, vestibulectomy has several unsatisfac-

tory aspects: Cosmetic appearances are disfiguring, success rates approximate 50%, and symptoms can be dramatically worsened by phenomena such as postoperative neoangiogenesis, Bartholin's duct obstruction, or symptomatic scarring. In search of a more reliable, less mutilating surgical approach we have explored a variety of laser therapies. 6 In the mid-1980s we treated 36 patients with vulvodynia with the carbon dioxide laser. Two strategies were used: (1) Irritative acetowhite vestibular epithelium, showing low-grade koilocytotic atypia on biopsy, was photovaporized to the second surgical plane7; (2) erythematous lamina propria surrounding painful vestibular and Skene's glands were "cylinderized" to a depth of about 1 cm. Lasting clinical remission was achieved in 22 (61.1%) instances. However, these successes were overshadowed by the onset of exquisitely painful vesfibular hyperemia in 9 (25%) women (Fig. 1, A)? In 1987 foci of proliferating telangiectatic surface blood vessels were eradicated by argon laser photocoagulation in five such patients (Fig. 1, B)? However, continuous wave blue-green argon energy has poor selectivity for hemoglobin; hence, damage to the adjacent stroma was almost as severe as that within the ectatic vessels, s' 9 leading to severe postoperative pain, protracted healing, and considerable vulvovaginal cicatrization. Nonetheless, this observation had one important corollary.

1686 Reid et al.

June 1995 Am J Obstet Gynecol

Fig. 2. A, A 16-year-old virginal student with interval vulvar pain severe enough to disrupt school attendance. Naked eye inspection shows coalescent foci of painful erythema occuping most of the vestibular mucosa. The erythema also involves the hairless skin of the interlabiai sulci. B, Appearances 4 months after the second flashlamp-excited dye laser photocoagulation of these chronically hyperemic blood vessels. Symptoms are approximately 75% resolved.

Long-term control in these 5 patients suggested that the blood vessels within these fields of reactive erythema were actual mediators of the chronic pain rather than nonspecific sentinels of some other underlying process. On the basis of these observations we hypothesized that the flashlamp-excited dye laser, an instrument designed specifically for the photocoagulation of small blood vessels within the superficial dermis of facial and upper-body port-wine stains, 1°' ~ might offer an efficacious but nonmorbid alternative to the bare fiber argon laser. Study objectives were (1) to determine the safety and efficacy of selective flashlamp-excited dye laser photothermolysis as treatment for vulvar p a i n syndromes not responsive to a trial of medical therapy, (2) to compare outcomes of serial flashlamp-excited dye laser therapy within different clinical subsets of idiopathic vulvodynia, and (3) to evaluate the role for resective surgery in patients who were not suited for or did not respond to a trial of flashlamp-excited dye laser photothermolysis. Material and methods

Study design. Our research design was a linear analysis of flashlamp-excited dye laser selective photothermolysis and/or microsurgical removal of Bartholin's

glands as treatment for vulvodynia. The study sample of 177 volunteers was recruited from a large cohort of patients with vulvar pain seen in our office between January 1988 and December 1990. Data analysis was conducted in two parts: First, the effect of sequential flashlamp-excited dye laser therapy as initial treatment was evaluated within a sample of 168 women; second, flashlamp-excited dye laser photothermolysis was reevaluated in 52 women after microsurgical removal of chronically painful Bartholin's glands. Therapeutic maneuvers were assigned by physician judgment and patient accord, not by experimental allocation. Obviously, because we could not identify an acceptable surgical alternative to flashlamp-excited dye laser therapy, it was not possible to incorporate a control arm into this study. Nonetheless, the risks of susceptibility, performance, or detection bias were limited by several safeguards: The study subjects were a consecutive sample of patients who were refractory to medical therapy over a 2-year period; host decision-making conformed to a protocol approved by the Sinai Hospital Institutional Review Board in 1988; outcome was assessed by four semiobjective pain scales; patient's responses have been followed up for a median of 2.6 years. Study population. The study sample was drawn from

Volume 172, Number 6 Am J Obstet Gynecol

Reid et al.

1687

T a b l e I. Functional assessment schema for assessing impact of chronic gynecologic pain on "day-to-day activities" and "ability to have intercourse" Day-to.day activities How do your day-to-day symptoms presently affect your life ? 10. Incapacitating pain destroying most facets of your life (e.g., unemployable, socially withdrawn, sense of personal desperation) 9. Severe burning or actual pain dominating your daily thoughts and severe enough to cause regular absenteeism (e.g., 1 day/too). Regular suspension of household tasks and frequent restriction of social outings (e.g., 7 days/no) 8. Severe burning or actual pain dominating your daily thoughts but not severe enough to cause more than occasional absenteeism, suspended housework, or social disruption 7. Moderate vulvar discomfort (e.g., burning rather than pain). Severe enough to frequently break your concentration but not severe enough to dominate your whole day's thoughts. Can be severe enough to restrict your personal activities (e.g., exercise, shopping, social outings) 6. Moderate vulvar discomfort, frequently breaking your concentration but not dominating your thoughts. Severe enough to restrict your choice of clothing or sitting posture (but not enough to disrupt your personal activities) 5. Moderate vulvar discomfort constant or almost constant. Severe enough to break your concentration but not severe enough to limit your choice of clothing or sitting posture. Present at least 20 days/mo (even if severity varies from week to week) 4. Moderate vulvar discomfort intermittent but severe enough to break your concentration when present. Does not limit clothing or sitting. Present less than 20 days/mo 3. Moderate vulvar discomfort (intermittent or constant). Present less than 10 days/no. Not usually severe enough to break your concentration when you are busy doing other things 2. Nuisance-level vulvar symptoms (e.g., rawness, dryness, or stinging rather than distressing burning) 1. No vulvar discomfort Sexual dysfunction How does your pain with intercourse affect your sex life? 10. Cannot have intercourse under any circumstances 9. Intercourse extremely painful. Often have to discontinue and have several days of subsequent pain. Frequency drastically reduced (less than once a month) 8. Intercourse always painful. Tolerable only at a much reduced frequency (e.g., 1 or 2 times/mo) and often have to discontinue 7. Intercourse almost always painful. Tolerable only at a much reduced frequency (e.g., 1 or 2 timesdmo) and often have to discontinue 6. Intercourse always painful. Tolerable only at an average frequency (e.g., 1 or 2 times/wk) if topical local anesthetic ointments are used. Often followed by postcoital pain or burning 5. Intercourse almost always painful throughout. Tolerable at average frequency (1 or 2 times/wk without topical anesthesia). Often followed by postcoital pain or burning 4. Intercourse not painful (e.g., at entry) and becomes partly pleasurable. May be followed by short period of postintercourse burning 3. Intercourse not painful during the act but is followed by prolonged (-> 2 days) flare-up of burning discomfort 2. Intercourse not painful during the act but is followed by short ( < 1 day) flare-up of burning discomfort (generally minor) 1. No pain with intercourse or tampon use

a population of 725 women seen in our office because of vulvar pain, burning, rawness, or superficial dyspareunia within a 2-year period. Geographically, these patients were referred from a large population base: 34% from the northwestern Detroit suburbs adjacent to our office, 27% from other townships in southeastern Michigan, 18% from provincial Michigan cities, 19% from other states, and 2% from Canada and other countries. Specific diagnoses were made in 48 instances: exophytic condyloma acuminatum, 8; irritation caused by chronic vaginitis, 12; lichen sclerosus, 4; lichen simplex chronicus, 8; symptomatic vulvar intraepithelial neoplasia, 8; and causalgia, 4. An additional 4 women had symptoms attributable to epithelial damage and/or painful vulvovaginal scarring, after previous cold knife or laser surgery. The remaining 677 patients were designated as having idiopathic vulvodynia and were prescribed a 6-month trial of topical corticosteroids (betamethasone 0.1%) and topical 5-fluorouracil (either 1% or 5% cream, depending on

complexion type). 9 Ninety-two women with clinical features suggestive of concomitant candidiasis received a 6-month regimen of oral ketoconazole, 1~ and 56 with a suspected dysesthetic component were treated with tricyclic antidepressants (amitriptyline 25 to 75 rag/day)? ~ Finally, in 48 of the more severe cases the patients were given an empiric trial of systemic interferon alfa (1 million units three times weekly for 20 weeks)) 4 Of 677 women initially diagnosed as having idiopathic vulvodynia, 156 had complete or major partial responses to these various medical therapies. Of 521 medical nonresponders, 177 were recruited into this trial. Each received a written and verbal explanation of the rationale, potential benefits, risks, and treatment alternatives and signed an institutional review board informed consent form. Median age was 30 years, with a range of 14 to 74 years. Ninety-nine percent of the sample was white; moreover, 76% had type I or type II sun tolerance. Socioeconomic and education levels tended to be high: 98% had graduated

1688

June 1995

Reid et al.

Am J Obstet Gynecol

Table IiA. Initial response to first flashlamp-excited dye laser treatment in 168 women categorized according to disease pattern

Disease category

Complete response (No.)

Significant partial response (No.)

Pruritic papillomatosis Vuivarvestibulitis TOTAL

17 (26.6%) 25 (24.0%) 42 (29.2%)

19 (29.7%) 22 (21.2%) 41 (24.4%)

l

lnitial failure (No.)

]

Total (No,)

28 57 85

64 104" 168

X~ = 2.26; p not significant. *Seven women with vulvar vesdbulitis began therapy with microsurgical resection of Bartholin's glands, followed by subsequent flashlamp-excited dye laser photothermolysis as needed.

Table l i B . Initial response to first flashlamp-excited dye laser treatment categorized according to surface versus deep pain

Disease category

Complete response (No.)

Significant partial response (No.)

Initial failure (No.)

Surface-only Surface-plus-deep TOTAL

41 (36%) 1 (1.9%) 42 (29.2%)

34 (29.8%) 7 (13%) 41 (24.4%)

39 46 85

I

] ]

Total (No.) 114 54 168

X2 = 40.2; p < 0.001.

Table I l i A . Eventual response among 163 fully assessable patients sequentially treated by flashlamp-excited dye laser photothermolysis until an end point (success, patient withdrawal, or a decision for resective surgery) was attained

Disease category

Complete response (No,)

Significant partial response (No.)

Persistentfailure (No.)

Total (No.)

Pruritic papillomatosis Vulvar vestibulitis TOTAL

27 (45.8%) 43 (43.3%) 70 (42.9%)

18 (30.5%) 25 (24%) 43 (26.4%)

14 36 50

59 104 163"

x 2 = 2.21; p not significant. Patients are subcategorized as having papillomatosis versus vestibulitis. *Five patients with pruritic papillomatosis from Table II defaulted after just one flashlamp-excited dye laser treatment, thus reducing n = 168 to n = 163.

Table IIIB. Same data as in Table IIIA, analyzed according to presence or absence of Bartholin's gland involvement

Disease category

Complete response (No.)

Surface-only Surface-plus-deep TOTPa~

68 (62.4%) 2 (3.7%) 70 (42.9%)

I

[ ]

Significantpartial response (No.)

Persistentfailure (No.)

T0ta/

33 (30.3%) 10 (18.5%) 43 (26.4%)

8 42 50

109 54 163

(No.)

×2 = 89.0; p < 0.001. from high school, and 38% completed a baccalaureate degree. Comparable rates for the State of Michigan are 77% and 17.3% respectively (U.S. Census Bureau). Thirty-four (19.2%) gave a history of chronic yeast infections, and 46 (26%) had either concurrent or preexisting vulvovaginal condylomas. Two of these 177 original volunteers never returned for a postoperative visit after the initial laser treatment and therefore were excluded from the data set. Of the 175 women for whom at least one surgical procedure could be assessed, 168 began treatment with

flashlamp-excited dye laser phototherrnolysis of symptomatic surface blood vessels and 7 began with microsurgical removal of chronically painful Bartholin's glands, with a superpulsed carbon dioxide laser? Five women in the flashlamp-excited dye laser group defaulted before a prescribed second flashlamp-excited dye laser surgery (three withdrawals, two lost to followup). These 5 women were retained as failures for the analysis of the first surgery. Hence Tables IIA and IIB describe 168 partially assessable women. Thereafter, these 5 defaulters were assigned in either of two ways.

Volume 172, Number 6 Am J Obstet Gynecol

Reid et al.

1689

Table IVA. Source of failures among 59 patients with pruritic papillomatosis

Disease category

Complete response (No.)

Significant partial response (No.)

Pe~tentfailure (No.)

Surface-only papillomatosis Surface-plus-deep papillomatosis TOTAL

27 (56.3%) 0 27 (45.8%)

17 (35.4%) 1 (9.1%) 18 (30.5%)

10 14

4

To~l

(No.) 48 11 59

Fisher's exact test: p < 0.001. Table IVB. Source of failures among 104 patients with vulvar vestibulitis

Disease category

Complete response (No.)

Significant partial response (No.)

Pers~tentfa~u~ (No.)

To~l (No.)

Surface-only vestibulitis Surface-plus-deep vestibulitis TOTAL

41 (37.5%) 2 (4.7%) 43 (41.3%)

16 (26.2%) 9 (20.9%) 25 (24%)

4 32 36

61 43 104

×2 = 57.7;p < 0.001. Under the rules of an intention-to-treat plan, '5 they were retained as failures, to give crude response rates based on a sample size of 175. Alternatively, under the rules of actuarial analysis, 15 these 5 women were removed in decrements from both numerator and denominator. Little difference was seen between crude and actuarial rates. However, because decremental analysis represents the preferred statistical method, ~ only the actuarial results are reported in detail within this article. Thus flashlamp-excited dye laser sample size in Tables IIIA and IIIB equaled 163, and final outcome sample size in Table VI was 170. The sample size of 52 in Tables VA and VB derived from the fact that 7 women began with microsurgical resection of Bartholin's glands and 45 patients had gland removal after failed initial flashlamp-excited dye laser surgery. For the purposes of internal comparison, the study sample of 175 completely or partly assessable women was subdivided in two different ways. Papillomatosis versus vestibulitis. First, the patients were subdivided, according to traditional wisdom, into prnritic papiUomatosis (n = 64) and vulvar vestibulitis (n = 111). Subtracting the 7 women who began treatment with resective surgery and the 5 who defaulted after just one treatment application reduced subset sizes in the flashlamp-excited dye laser-treated patients to 59 for prnritic papillomatosis and 104 for vulvar vestibulitis. Analysis of variance showed no differences with resepct to the distribution of demographic or possible etiologic associations for either clinical variant (data not shown). Nor did this schema prove useful in forecasting therapeutic response. Surface versus deep. Because the mucosal portion of the vulvar vestibule and the vestibular glands (major and minor) share a common embryologic origin from the endodermal portion of the cloaca, it is not surprising that these chronic pain syndromes can affect either

site. Determination as to whether pain extends into Bartholin's fossae can only be made with the patient in a standing position. With the patient in the erect position gravity draws the vulvar soft tissues away from the pubococcygeus, thereby opening enough space for a probing fingertip. The patient is asked to stand on the right leg, with the right hip facing the right-handed examiner, the left hip flexed to 90 degrees, and the foot resting on the stirrup. The physician first palpates the hymen and then applies gentle pressure just distal to this epithelial fold, at a point corresponding to the left minor vestibular glands and Bartholin's duct. The patient is asked to grade the severity of any tenderness and to describe the quality of the pain. The examining finger is then passed above the hymenal fold, to identify the fossa bounded by the hymen and bulbocavernosus muscle (inferiorly), the puborectalis muscle (superiorly), the pubic ramus (anteriorly), and the perineal body (posteriorly). Penetration into this fossa is aided by having the patient contract the pelvic floor; the application of digital pressure is then synchronized with muscle relaxation. A positive result is signaled by two observations. First, pressure on Bartholin's fossae must evoke a sharp lancinating pain that is qualitatively distinguishable from the mucosal burning felt around the vestibular ducts. Second, the severity of this bruising pain in Bartholin's fossae must equal to exceed the surface tenderness. In performing this examination the gynecologist must differentiate Bartholin's fossa tenderness from myofascial pain as a result of levator myalgia. On the basis of this examination, the 175 patients were subdivided into "surface only" (n = 114) versus "surface plus deep" (n = 61). Measure o f outcome. Measure of outcome was the degree to which the symptoms of day-to-day vulvar pain ("interval pain") and pain at attempted vaginal penetration during coitus or tampon insertion Cdyspareu-

1690

Reid et al.

June

]995

Am J Obstet Gynecol

Table VA. Immediate response to Bartholin's gland removal in 52 women who underwent this surgery

Completeresponse (No.)

Disease category Surface-plus-deep papillomatosis Surface-plus-deep vestibulitis TOTAL

2 (22.2%) 4 (9.3%) 6 (11.5%)

Signifieantpartial response (No.)

I

Persistentfailure (No.)

2 (22.2%) 16 (37.2%) 18 (34.6%)

[

5 23 28

Total (No.) 9 43 52

×2 = 1.68; p not significant.

Table VB. Eventual response to Bartholin's gland removal plus re-treatment by flashlamp-excited dye laser photothermolysis

Completeresponse (No.)

Disease category Surface-plus-deep papillomatosis Surface-plus-deep vestibulitis TOTAL

3 (33%) 15 (34.9%) 18 (34.6%)

Significantpartial response (No.)

I [

Persistentfailure (No.)

Total (No.)

2 8 10

9 43 52

4 (44.4%) 20 (46.5%) 24 (46.2%)

×~ = 0.08; p not significant.

Table VI. Final outcome with either serial flashlamp-excited dye laser and/or microsurgical resection of Bartholin's glands in 170 fully assessable women

Disease category

Completeresponse (No.)

Significant partial response (No.)

Persistentfailure (No.)

Surface-only Surface-plus-deep TOTAL

68 (62.4%) 20 (32.8%) 88 (51.8%)

33 (30.3%) 29 (47.5%) 62 (36.5%)

8 12 20

I

[ ]

Total (No.) 109 61 170

×~ = 14.9; p < 0.001.

nia") were altered by surgery. To limit the subjectivity inherent to the clinical task of quantifying pain, any reductions in symptom intensity were assessed separately from any reductions in functional impairment. Intensity was gauged principally by use of a visual analog score. '6 This test is administered by drawing a 10 cm line and asking the patient to place the pain intensity somewhere on this visual scale. Zero is explained as no pain and 10 as the most intolerable pain imaginable. Severity is then gauged by measuring with a millimeter ruler. Differences of -> 2 cm indicate a clinically significant change. Functional impairment scores were quantified on an ordinal scale with approximately equal differences between each gradation point. In contrast to the wide applicability of intensity measures, a pair of reasonable objective ordinal scales had to be constructed specifically for these patients (Table 1). '7 Checking that interval pain and dyspareunia scored within one or two grades of each other provided some degree of quality assurance. Success was defined as either complete remission or an improvement to the point that significant additional surgery would no longer be justifiable. Success meant restoration of the ability to have pleasurable intercourse

(visual analog score < 3 cm, functional impairment score less than response 3 on the "dyspareunia" questionnaire) and reduction of day-to-day vulvar discomfort to nuisance levels on most days of the month (visual analog score < 3 cm, functional impairment score less than response 3 on the "interval pain" questionnaire). Significant partial response was strictly defined to mean a reduction of symptoms from severe (visual analog score and functional impairment score >_.6) to moderate (visual analog score and functional impairment score of 4 or 5). Lesser degrees of improvement were judged to be too subjective for acceptance as a definite response to treatment and hence were scored in the same category as failures. Instrumentation. Traditionally, lasers have been used in one of two roles: shallow, layered tissue removal and deep hemostatic incisions. However, the temporal and absorptive characteristic of the laser beam can be manipulated such that heating of "target" chromosomes (e.g., oxyhemoglobin) greatly exceeds that of "competing" chromophores (e.g., melanin). Under these circumstances the surgeon can produce selective destruction of pigmented deep structures yet cause negligible disturbance to the intervening surface epithelinm. 9 Hence the safety and efficacy of the

Volume 172, Number 6 Am J Obstet Gynecol

Reid et al.

1691

Fig. 3. A refractory pain loop, located deep within the right Bartholin's gland.

flashlamp-excited dye laser are predicated on several distinctive physical properties. First, with a wavelength of 585 nm, energy emitted from the flashlamp-excited dye laser has strong selectivity for the third oxyhemoglobin absorption peak? °' ]~ Second, peak powers are high enough to allow single-pulse destruction of the target blood vessels. 9' J0 Third, because the ultrashort pulse widths are shorter than the thermal relaxation time, thermal conduction from the heated vessels is kept to a minimum. 8 Last, the high pulse energy permits the use of very large spot sizes, thus nullifying the problems caused by intense scattering of incident laser light within the dermis? °' ~J Treatment protocol. The treatment protocol was modeled on the use of the Candela SPTL-1 (Candela Lasers, Wayland, Mass.) to selectively photocoagnlate superficial blood vessels within cutaneous port-wine stains. The essential concept is to fractionate therapy into a series of treatments, so as to keep irradiation and delivered energy for each operation below the level at which epidermal necrosis might occur. Flashlamp-excited dye laser photothermolysis of these nonpainful pigmented lesions is generally performed without anesthesia. However, we found it necessary to treat patients with vulvodynia in the operating room, while they were under general or regional anesthesia, for a number of reasons. First, obtaining sufficient exposure for effective energy delivery required extreme eversion of the vestibular epithelium (with the use of a series of traction sutures). Second, targeting the deep dermal vessels required firm compression of the surface microcirculation within these tender lesions, with the use of specially constructed transmissive spatulas. Third, repeated impact of laser light on areas of symptomatic hyperemia is quite painful. Erythematous tissues were sequentially lased with a hand probe that delivered a

5 mm spot. Energy dosage was judged against two clinical end points. Within areas containing dilated stem vessels, power was adjusted to the point at which a palpable vibration could be felt through the compressive spatula. For areas without visible stem vessels the clinical end point was a dark purpuric change, appearing within 5 minutes of irradiation. Through experience, irradiation levels were narrowed to a range of 6.5 to 10 J/cm ~ (depending on anatomic location and complexion type). Because 10% of the incident energy was reflected or scattered by the spatula, these settings correspond to about 6.0 to 8.25 J/cm 2 at the tissue surface. Median energy delivery was 300 pulses (range 50 to 630 pulses) at 8.0 J/cm 2. Once the intended target area had been systematically treated, the same field was reexamined under magnification, and any secondarily dilated vascular channels were retreated at the same power. Results

Efficacy of flashlamp-excited dye laser surgery. A single flashlamp-excited dye laser surgical procedure essentially abolished the painful vestibular hypervascularity in 42 (29%) of the 168 women whose therapy began with selective photothermolysis (Tables IIA and IIB). Complete or significant partial response was invariably associated with objective reduction in surface hypervascularity (Fig. 2). No differences were seen with respect to papillomatosis versus vestibulitis (×~ = 2.25, p not significant in Table IIA). Conversely, the presence or absence of deep pain was highly significant (X2 = 40.2, p < 0.001 in Table IIB). The protocol offered repeat laser therapy until a response was attained or until clinical assessment suggested adopting a different approach. Hence the remaining 126 women with partial response and no

1692 Reid et al.

June 1995 Am J Obstet Gynecol

lOO 8oCumulative " Success soRate (%)

Surface Only G r o ~ ¢ •

Barfs Group

<>j~

/

2O o

-7"*,"7°'7 -* $1

$2

S3

$4 ~

I

Pl

I

P2

I

P3

I

P4

[

P5

P6

No. of Surgeries

Fig. 4. Sequential response rates for surface-onlyversus surface-plus-deep disease. Bart's, Removal of Bartholin's glands. response were serially re-treated, elevating the final flashlamp-excited dye laser response rates to 113 (69.3%) of the 163 suitable patients (complete response 43%; partial response 26%) (Tables IIIA and IIIB). Again, the likelihood of success was independent of disease pattern (Table IIIA) but was profoundly affected by the presence or absence of a deep pain loop (Table IIIB). Forty-two of 50 flashlamp-excited dye laser failures occurred in women with severe Bartholin's fossa pain (×~ = 89.0, p < 0.001). Specifically, there were no flashlamp-excited dye laser complete responses among the 11 pruritic papillomatosis patients with "surfaceplus-deep" disease, compared with 27 (56.3%) complete responses among the 48 women with "surfaceonly" patterns (Table IVA). Likewise, of the 104 vulvar vestibulitis patients who began treatment with flashlamp-excited dye laser surgery, complete response rates were 2 of 43 (5%) for the deep subset versus 41 of 61 (67%) with surface pain (Table IVB). At reexamination of Table IIIB, it can be seen that sequential flashlamp-excited dye laser surgical procedures done while Bartholin's glands remained in situ produced a clinically valuable response in only 12 of 54 (22%) women versus 99 of 109 (91%) in the "surface-only" group. Role of resective surgery. The presence of a deep pain loop presented an impasse to progress, despite serial repetition of fla,shlamp-excited dye laser treatments (Fig. 3). However, utilizing the microsurgically adapted carbon dioxide laser, we were able to remove Bartholin's glands through paired 15 mm vestibular incisions. Gland removal, in itself, produced clinical remission in 6 of 52 (12%) and significant partial response in another 13 (25%) instances (Table VA). More important, serial flashlamp-excited dye laser retreatment after gland removal raised response rates in

the previously refractory "surface-plus-deep" subset to 81% (Table VB). Plotting cumulative success rate against the number of surgical procedures done yielded a pair of sigrnoid curves (Fig. 4). Notably, after Bartholin's gland removal, the hitherto refractory "surface-plus-deep" group responded almost as well as the "surface-only" subset. The importance of Bartholin's gland involvement is also reflected in the regression analyses of the severity of "day-to-day pain" and "dyspareunia" scores (Figs. 5 and 6). When we evaluated final outcome in all treated patients, response rates were excellent. With an intentionto-treat plan, wherein the five defaults would be counted as failures, complete or partial response rate was at least 150 of 175 (85.7%). With the statistically preferable actuarial method, final response rates rose to 150 of 170 (88.2%) (Table VI). The final clinical audit is diagrammed in Fig. 7. Total numbers of treatments were 198 in the "surface-only" group (average 1.8 per patient) and 239 in the "surface-plus-deep" group (average 3.9 per patient).

Complications of flashlamp-excited dye laser therapy and Bartholin's gland resection. The major complication of flashlamp-excited dye laser therapy was acute mixed bacterial cellulitis, occurring in the first postoperative week. During the initial 8 months, 17.2% of surgical procedures (10 of 58) were followed by an infection severe enough to require inpatient intravenous antibiotics (generally ampicillin, clindamycin, and gentamicin). In January 1990 the treatment protocol was modified in several ways: (1) pretreatment with topical intravaginal antibiotics, consisting of either 2% clindamycin phosphate suppositories in polyethylene glycol (taken for 3 days before surgery) or 100 mg oxytetracycline vaginal tablets (taken 5 days before and

Reid et al. 1693

Volume 172, Number 6 Am J Obstet Gynecol

10 9

Surface + Deep Pain

8

7 6

Surface Pain Only

[G L A N D , R E M O V A L [

*-...,

A v e r a g e Pain 5 Score 4 3 2

1 0 0

~ 1

I

2

I

3

~ 4

Number

I

5

I

6

I

7

I

8

~ 9

I 10

of Operations

Fig. 5. Regression analysis of severity of day-to-day symptoms, with serial re-treatment.

10 9

#

Surface + Deep Pain

8

\

7

.C,~

\'"

6 Average Dyspareunia Score

5

Surface Pain Only

--<>

{GLAND REMOVAL]

t

4 3 2 1 0 0

I

1

I

2

I

3

I

Number

4

I

5

I

6

I

7

~

8

I

9

I

10

of Operations

Fig. 6. Regression analysis of dyspareunia severity, with serial re-treatment. 5 days after surgery), (2) intravaginal instillation of 30 gm of polymyxin-bacitracin ointment at the conclusion of surgery, and (3) three daily postoperative dressings with a specially formulated zinc oxide paste (bacitracin powder 1.7 gin, polymyxin B powder 0.32 gin, lidocaine powder 4.8 gm, and zinc oxide up to 240 gm). After the introduction of these preventive measures, the mixed bacterial cellulitis rate fell to 2.5%. The only other laser complication has been the occurrence of exophytic condylomas in 4 patients, within a few weeks of flashlamp-excited dye laser photothermolysis. This observation appears to represent a Koebner phenomenon, wherein a preexistent field of latent human papillomavirus infection transforms into active viral expression during healing from the local tissue injury. 9 Complications of Bartholin's gland removal included

hematoma (1.9%), wound breakdown (3.7%), and pain on stretching an otherwise well-healed circumferential incision scar (29.6%). This latter problem generally resolved with steroid injection and/or local releasing incision. Comment

Idiopathic vulvodynia is a chronic and distressing problem that has increased in prevalence over the last decade. Disability varies markedly from person to person. Patients with milder cases suffer nuisance-level (but persistent) vulvar burning and loss of sexual pleasure. Those with severe cases report severe sexual restriction or even total inability to have vaginal intercourse. The constant vulvar pain can also be severe enough to dominate daily life, even to the point of forcing with-

1694 Reid et al.

June 1995 Am J Obstet Gynecol

Total 2

year Cohort

725

I Other Diagnosis 48

Vulvodynie

677

¢ 521

Non-Reeponder

Medical Respond er 156

J

I Study 8emple* (*2 excluded immediately) 175 .I

,,

Trial of

FEDL

Began with Resection

168

I & S excluded after first surgery

7 163 fully assessable

70

4~0

l

Mic~osurgica152 Barts

I Fig. 7. Final clinical audit of 177 women recruited into this study. Note that bold figures add to n--- 177. drawal from normal activities. Success rates were independent of whether physical findings were visible to the unaided eye (painful vestibular erythema) or best seen through the colposcope (hyperemia of the individual blood vessels) (Tables IIA and IIIA). Conversely, prospects of cure of major improvement after flashlampexcited dye laser surgery, even with serial treatment, were much lower among women with Bartholin's gland pain (Tables IIB and IIIB). During the initial 8 months, the mixed bacterial cellulitis rate within the first postoperative week was prohibitive. However, this risk of cellulitis was reduced from 17.2% to 2.5%, by preoperative control of the vaginal flora with topical antibiotics and by postoperative dressing with an occlusive paste. From the pragmatic viewpoinL we could find no benefit in separating patients with vulvar vestibular syndrome from those with pruritic papillomatosis. Provided that there was no deep pain on palpation of Bartholin's glands, both clinical variants responded to flashlamp-excited dye laser surgery. No statistically significant differences were seen between the papillomatosis and vestibulitis groups with regard to the prospect of either initial response (56% vs 45%, p > 0.10) or eventual response (76% vs 65%, p > 0.10). Moreover, we found no meaningful differences in demographic profiles (race, complexion type, and education) of these two groups, and similar colposcopic abnormalities (irritative acetowhitening and vascular ectasia) were detectable in both subsets. Finally, 12 cases have been observed to progress from less symptomatic pruritic papillomatosis(characterized by colposcopic signs only) to intensely symptomatic or even disabling vulvar yes-

tibulitis (with flame red patches visible to the naked eye). Our data favor the view that the presence or absence of macroscopic foci of vestibular erythema in patients with vulvar pain syndromes represents spectral diversity rather than differing causes. The only subdivision of practical importance in vulvodynia patients is the decision as to whether Bartholin's glands are involved, because the "surface-plus-deep" group require microsurgical resection~ rather than superficial photothermolysis. Despite the low response rate (complete response 2%, partial response 21%), an initial photothermolysis treatment in the "surface-plus-deep" group is probably a wise prevention-making an incision through areas of prominent painful erythema can provoke rebound hypervascularity (Fig. 1). However, continued photothermolysis in patients with deep pain yielded a response rate of only 22% (Fable IIIB). Conversely, gland removal in itself produced a 36.5% response (complete response 11.5%, partial response 25%) (Table VA), and subsequent retreatment by flashlamp-excited dye laser photothermolysis pushed the success rate to 81% (complete response 35%, partial response 46%) among our 52 most difficult cases (Fable VB). The value of microsurgical Bartholin's resection is perhaps most clearly shown in comparing the cumulative success rates before and after gland removal (Fig. 4). Before gland removal the response curve in the "surface-plus-deep" group essentially followed the X axis; after gland removal the response curve in the "surface-plus-deep" group paralleled that of the "surface-only" group. A similar phenomenon is also reflected in the graphs of interval pain and dyspareunia scores (Figs. 5 and 6). The presence of a deep pain loop

Reid et al.

Volume 172, Number 6 Am J Obstet Gynecol

seemed to nullify the benefits of serial flashlamp-excited dye laser re-treatment, but this damper was removed by gland resection. Although vestibulectomy can produce good results, 4 surgical removal of the hymenal ring and closure by vaginal advancement are best reserved as a treatment of last resort rather than one of first response. The availability of a safe, efficacious, relatively noninvasive treatment heralds an important advance in the management of chronic vulvar pain syndromes. Even when resective surgery is appropriate, reactive hyperemia is an everpresent risk for which there seems to be no effective conventional solution. More important, our results should prompt a reevaluation of the future role of this operation. As a first surgical option, vestibulectomy is more invasive and perhaps less efficacious than selective photothermolysis. In refractory cases vestibulectomy is probably insufficient, because removal of hyperemic surface mucosa does not address the problem of chronically painful Bartholin's glands. The material presented in this article is drawn principally from the years 1989 to 1991. Since that time the protocol has continued to evolve. Several important refinements have been added. First, patients are offered a trial of a low-oxalate diet, augmented by calcium citrate tablets to improve the solubility of these potentially irritative crystals. 5 In the future questions of safety and efficacy of this regimen should be resolved with a placebo-controlled trial. Second, any component of burning perineal pain referred from concomitant levator myalgia is treated with biofeedback-controlled pelvic floor rehabilitative exercises and myofascial release techniques. '8 Many patients, including several partial responders described in this article, have derived major benefit from this regimen. 19 Third, the problem of mixed bacterial cellulitis follow-up flashlamp-excited dye laser treatment has been reduced to about 0.2% by a preoperative protocol of dexamethasone 4 mg, diphenhydramine 25 mg, and ketorolac 60 mg, aimed at reducing the inflammatory effect within the nonpigmented tissues surrounding the target blood vessels. Fourth, patients with refractory "surface-plus-deep" pain are now having only one attempt at photothermolysis before we proceed with gland removal. Finally, the incidence of vaginal pain on stretching the periorificial Bartholin's gland excision scars has been greatly reduced by prophylactic use of a medium or large dilator, beginning in the third or fourth postoperative week (30% to 14%). Because of prominent emotional distress in many patients with idiopathic vulvodynia, some authors 2°'~ have suggested that this syndrome is psychosomatic. However, a dualistic approach to chronic pain (distinguishing somatic from psychogenic elements) is hazardous at any anatomic site. Diagnosing sexual dysfunction

1695

as purely physical or purely psychologic is especially troublesome; difficulties arise from all sides. First, many causes of sexual pain or discomfort are not easily recognized at physical examination. Second, even when there is a purely physical cause, long-term disruption of female sexuality might reasonably be expected to produce some anxiety, irritability, or sadness. Third, organic causes of sexual pain can also evoke marital friction, thereby further fostering secondary pain behavior. Finally, anger, guilt, and despair can exacerbate preexisting neurotic or depressive traits. Hence, in formulating a diagnostic assessment gynecologists must be very sensitive to the interplay of organic, behavioral, and psychiatric factors. Likewise, psychologists must not overlook the presence of a physical disorder simply because of prominent emotional distress. REFERENCES

1. Freidrich EG Jr. Vulvar vestibulitis syndrome. J Reprod Med 1987;32:110-4. 2. McKay M. Vulvodynia: a muhifactorial clinical problem. Arch Dermatol 1989;125:256-62. 3. Reid R. Colposcopic findings in women with vulvar pain syndromes. J Reprod Med 1988;33:525-32. 4. Horowicz BJ. Interferon therapy for condylomatous vulvitis. Obstet Gynecol 1989;73:446,8. 5. Solomons CC, Melmed MH, Heitler SM. Calcium citrate for vulvar vestibulitis: a case report. J Reprod Med 1991; 36:879-82. 6. WoodruffJD, Parmley TH. Infection of the minor vestibular gland. Obstet Gynecol 1983;62:609. 7. Reid R, Elfont E, Zirkin R, Fuller TA. Superficial laser vulvectomy. II. The anatomic and biophysical principles permitting accurate control over the depth of dermal destruction with the carbon dioxide laser. AM J OBSTrT GYNECOI 1985;152:261-71.

8. Walsh JT Jr, Flotte TJ, Anderson RR, et al. Pulsed CO2 laser tissue ablation: effect of tissue type and pulse duration on thermal damage~ Lasers Surg Med 1988;8:108-18. 9. Reid R, Absten G. Lasers in gynecology: why pragmatic surgeons have not abandoned this valuable technology. Lasers Surg Med [In press]. 10. Tan OT, Carney M, Margolis R, et al. Histologic responses of port wine stains treated by argon, carbon dioxide and tunable dye lasers: a preliminary report. Arch Dermatol 1986;122:1016-22. 11. Garden J, Tan OT, Kerschmann R, Boll J, Parrish JA. Effect of pulsewidth on vessel specific changes induced by a pulsed laser radiation. J Invest Dermatol 1986;87:653-7. 12. Sobel JD. Recurrent vulvovaginal candidiasis: a prospective study of the efficacy of maintenance ketoconazole therapy. N EnglJ Med 1986;315:1455-8. 13. McKay M. Subsets ofvulvodynia. J Reprod Med 1988;33: 695-8.' 14. Bornstein J, Pascal B, Abramovici H. Intramuscular [3-interferon treatment for severe vulvar vestibulitis. J Reprod Med 1993;38:117-20. 15. Feinstein AR. Clinical epidemiology. Philadelphia: WB Saunders, 1985:337-45, 691. 16. Huskisson EC. Visual analogue scales. In: Melzack R, ed. Pain measurement and management. New York: Raven Press, 1983:33-7. 17. Reid R, Lininger T. Sexual pain disorders in the female. In: O'Donohue W, Geer J, eds. Handbook of sexual dysfunctions. Needham Heights, Massachusetts: Simon & Schuster, 1993:335-66. 18. Perry JD, Talcott LB. EMG perineometry and myofascial

1696

Reid et al.

release in the treatment of pelvic muscle dysfunction. In: Barnes J, ed. Search for excellence. Paoli, Pennsylvania: MFR Seminars, 1990. 19. Glazer H, Rodke G, Swencionis C, et al. The treatment of vulvar vestibulitis syndrome by electromyographic biofeedback of pelvic floor muscles. J Reprod Med [In press]. 20. Stewart DE, Whelan CI, Fong IW, Tessler KM. Psychosocial aspects of chronic, clinically unconfirmed vulvovaginitis. Obstet Gynecol 1990;76:852-6. 21. Lynch PJ. Vulvodynia: a syndrome of unexplained vulvar pain, psychologic disability and sexual dysfunction. J Reprod Med 1986;31:773-80.

Discussion Da. KENNETH L. NO~ER, Worcester, Massachusetts. During the past several years gynecologists have begun to see an ever-increasing number of women complaining of a variety of idiopathic vulvar symptoms. Whereas vulvar burning without recognizable cause was described nearly 100 years ago, it was a rare event to see a patient with this symptom complex before the 1980s. No explanation for this increase has yet been delineated. Unfortunately, it is not possible to describe the subject of this article, "idiopathic vulvodynia," in specific terms. The symptom complex varies from nuisance vulvar burning and/or minor dyspareunia to nearly constant interruption of daily activities, with total inability to participate in vaginal intercourse. The only common feature in this vaguely described syndrome is that no other cause for the discomfort can be identified. The names essential vulvodynia, idiopathic vulvodynia, chronic vestibulitis, vestibular adenitis, and pruritic papillomatosis are only a few of the many names used to describe this disorder in the literature. Thus it is with great admiration that I have reviewed this article. Dr. Reid has dedicated most of t h e last several years of his professional life to the evaluation and treatment of this disease that has no name, no known cause, and no universally successful treatment. Nonetheless, he has been able to organize his thoughts and approach and h'as presented a thought-provoking and clinically useful manuscript. I believe he has shown, without any doubt, that the flashlamp-excited dye laser has the capacity to successfully treat many women with idiopathic vulvodynia. However, this manuscript cannot be viewed as demonstrating a method of treatment to he used as a first-line therapy for all cases of idiopathic vulvodynia. The study group represents only those women in whom an attempt at medical therapy failed, and the flashlamp-excited dye laser treatment was far from universally successful. In addition, some of the women required surgical excision of the Bartholin's glands, and in some women significant complications from the treatment developed. Nonetheless, flashlamp-excited dye laser may very well represent the therapy most likely to provide complete response for those women in whom medical therapy fails. During the past 3 years more and more of my practice has been devoted to the evaluation and treat-

June 1995 Am J Obstet Oynecol

ment of vulvar diseases, especially idiopathic vulvodynia. After a careful history and physical examination (often lasting > 60 minutes) my approach has been to begin with a course of medical therapy that is simple and safe. With this approach most patients have responded to one or more medical treatments. It is only a few patients who have ultimately required vestibulectomy (partial vulvectomy) or, more recently, flashlampexcited dye laser. I am therefore surprised that only 23% of Dr. Reid's patients had a complete or major partial response to medical therapy. Medical therapy is difficult to manage from a distance, and the large fraction of Dr. Reid's patients who are distant referrals may have resulted in a greater reliance on flashlampexcited dye laser. Thus my first two questions for Dr. Reid are as follows: (1) Have you analyzed your medical therapy results on the basis of each patient's hometown? That is, were these true medical failures or geographic failures? (2) If geography does not explain your poor success with medical treatment, can you explain why your medical results are worse than those of other published series? Dr. Reid describes his study design as "a linear analysis of flashlamp-excited dye laser selective photothermolysis." Unfortunately, primarily because this report represents a preliminary attempt to evaluate a new treatment modality, the multiple and seemingly everchanging treatment regimens make statistical analysis difficult and perhaps meaningless. For example, the volunteers represent women who have had a variety of medical treatments applied for multiple periods of time, therapeutic maneuvers that were assigned by physician judgment and patient accord, varying flashlamp-excited dye laser energy, various surgical procedures, and a continuously evolving postoperative care regimen. I do not believe that the statistical analyses found in this article are appropriate for such a diverse study population. Rather, I believe that a simple presentation of the results without hypothesis testing would be more in concert with the clinical material. After reading the manuscript I was left with the general belief that flashlamp-excited dye laser offers some women relief but cannot yet determine which subset of vulvodynia patients is most likely to respond. Only a careful prospective randomized trial, perhaps with crossover capability, will allow us to make this determination. My third question for Dr. Reid is therefore have you begun or are you planning to perform a prospective randomized trial? If you have begun, do you have any preliminary results? If you are not planning a randomized trial, why not? Dr. Reid is currently performing his procedures with the patients under general or major regional anesthesia. In an attempt to decrese both expense and morbidity we have performed our flashlamp-excited dye laser procedures with the use of a topical anesthetic containing prilocaine and lidocaine (EMLA cream, Astra Pharmaceuticals). Two applications approximately 1 hour before surgery have resulted in anesthesia adequate to perform flashlamp-excited dye laser. A corn-

Volume 172, Number 6 Am J Obstet Gynecol

bination of ice packs, oral analgesics, and silver sulfadiazine cream has resulted in minimal morbidity. I wonder if Dr. Reid has tried this approach? Finally, I fully agree with Dr. Reid that neither vestibulectomy nor flashlamp-excited dye laser should be performed as an initial procedure in patients with idiopathic vulvodynia. I believe these techniques should be reserved solely for those patients in whom a full course of medical therapy has failed. DR. LEO B. TwIGGS, Minneapolis, Minnesota. The authors are to be commended on their excellent work in a difficult clinical situation. Idiopathic vulvodynia is a serious and disabling disease, which, at this point in time, has no known cause. Since the etiology remains speculative, management has been empiric. Empiric management suffers when clear histopathologic, bacteriologic, and symptom complex correlations are not used as a foundation for clinical inquiry. The authors should be commended for bringing to this clinical situation some semblance of rational treatment stratification coupled with an attempt to define treatment outcomes. The authors have titled the manuscript "FlashlampExcited Dye Laser Therapy of Idiopathic Vulvodynia Is Safe and Efficacious." However, the manuscript discusses and evaluates a number of treatment modalities and strategies. The title of the article should reflect its content, which includes the flashlamp-excited dye laser therapy of idiopathic vulvodynia as a component of multimodal therapy. The authors use colposcopy as a diagnostic aid in patients with idiopathic vulvodynia. Unfortunately, the authors add little to the formulation of a clear plan of colposcopic assessment, a talent that Dr. Reid is known for in assessing cervical change. The management of vulvodynia in these particular patients is based on the previous clinical experience with the carbon dioxide laser combined with local resection of the Skene glands. This experience was augmented in selected patients by the use of the argon beam laser. Again, this represents a multimodal approach to this diffficult clinical situation. The authors observed that patients who had been treated previously with argon beam laser photocoagulation had long-term control of vulvodynia but with resultant vulvar scarring. This suggested to the authors that blood vessels within these fields of reactive erythema were actual mediators of the chronic pain rather than nonspecific sentinels of some other underlying process. This hypothesis seems logical but is based on little scientific fact. I suggest to the authors that they reference this important concept with a scientific foundation so as to convince the readers of its validity. On the basis of this hypothesis, the flashlamp dye laser is used for the photocoagulation of small blood vessels. This technique has previously been used by dermatologists in eradicating port-wine staining in other tissues. With this concept the laser is a method to destroy vulvar erythema and ectatic blood vessels that are perceived to act as "mediators of the chronic pain." This observational, noncontrolled study began with a

Reid et al. 1697

population of 795 patients. The authors described the study population geographically and the methods of therapy before the use of this laser. Interestingly enough, of the 521 medical nonrespondents, only 177 were recruited into this trial. One questions the reasoning why > 300 patients were not able to be treated and were not recruited in the trial. Why were they not recruited in the trial? It must be noted that 7 of the original 175 patients began with microsurgical removal of chronically painful Bartholin's glands with a carbon dioxide laser, and it is also interesting to note that 45 patients had gland removal after failed flashlamp-excited dye laser t h e r a p y - a multimodal approach to this clinical situation. The authors should be commended for their attempts to assess vulvar pain with objective measurements. Clinical outcome data with measurements including the visual analog score and functional impairment scores are important ways of assessing treatment methods with objective outcome measurements. Outcome measurements have been lacking in our assessment of a number of treatment methods in gynecology. The authors should be commended for using these types of outcome measures. Three important findings deserve assessment and long-term corroboration by other authors. First, in certain patients a successful decrease in vulvar pain is dependent on resection of vulvar Bartholin's gland and indeed may have a separate cause. Second, the success rates were independent of the physical examination and classification previously defined. Third, colposcopic examination of the vulva showing erythema of individual blood vessels is an important diagnostic adjunct in these patients. These authors believe the data presented here argue for a spectrum of abnormality with colposcopically noted erythema to macroscopically apparent erythema. They are of the opinion that the only subdivision of practical importance is the decision whether to surgically resect Bartholin's glands in patients who have surface and deep pain and the diagnosis to be made by the rather extensive vulvar examination. In the Comment section the authors state that the protocol continues to evolve. They now offer other methods of treatment along with other types of vulvar pain assessments, including biofeedback and controlled pelvic f o o t rehabilitative exercises and other techniques such as myofascial release. I ask the authors if all the patients described in this manuscript, who had objective measurements of vulvar pain, had the evaluation done between the years 1989 and 1991. Are we sure that the efficacy rates of this treatment combined with Bartholin gland resection are germane to this group of patients and no other treatment method was used, leading to bias in the assessment of objective response? The authors state that "a dualistic approach to chronic pain (distinguishing somatic from psychogenic elements) is hazardous at any anatomic site." I agree with the authors that the separation of this abnormality of idiopathic vulvodynia into the classic mind-and-body

1698

Reid et al.

duality, which emphasizes the mind as opposed to physical abnormality, is a therapeutic foundation that leads to distrust in the therapeutic relationship and a realization that patients may not trust their own sensations. Multimodal therapy, which includes psychologic counseling for these particular patients, is helpful. The clinical psychologist helps to distinguish patients who have problems of which clinicians are not fully aware. In my practice of treatment of vulvodynia the patient is first seen by me but is always seen by a clinical psychologist conversant in this clinical situation within 2 weeks. The clinical psychologist evaluates the reaction of the pain along with the psychological milieu in which the pain exists. Also, we have been extremely gratified with this strategy combined with the use of a simple vaginal dilator. The use of a vaginal dilator and the teaching of this method is important because certain patients need desensitization to the discomfort. Also, patients need to become aware of the vulvar anatomy, and the combined use of teaching this method with the video colposcope has allowed the patient to become more in tune to her body. This combined technique has been very helpful, and patients are continually gratified to be able to have a more visual understanding of their anatomy. A therapeutic relationship with team approach including the patient, the clinical psychologist, and the physician, who all agree that this clinical situation is a real problem for this individual patient, is essential. I would agree in forming a diagnostic assessment that gynecologists must be sensitive to the interplay of organic behavior and psychiatric factors. I have some additional questions for the authors. (1) Suggesting that the appropriate threshold for energy density would be the point at which palpable vibration could be felt through compressive spatula sounds unlikely at best. Practically any pulse will give rise to. "palpable vibration." There are well-established methods for defining this threshold with a particular laser. Which methods did these authors use? (2) Importantly, there is a new 7 mm spot size that is available which effectively doubles the area treated by one pulse. Have the authors had any experience? (3) The authors state that because 10% of the incident energy was reflected or scattered by the spatula, these settings correspond to about 6.0 to 8.25 J/cm 2 at the tissue surface. How do the authors actually determine the degree to which the light was reflected or scattered by the spatula? In summary, these colleagues have entered into an objective assessment of a difficult clinical problem that does plague a number of patients. This clinical problem should be delegated to people who have an interest in dealing with these types of patients in a multimodal fashion. Surgical intervention with any method is only one component of the treatment and should be entered into only after a successful, long, and therapeutic relationship. DR. KEITH REEVES,Houston, Texas. I would ask what percentage of the patients had coexisting or preexisting cervical dysplasia? Also what biopsy pathology proce-

June 1995 Am J Obstet Gynecol

dures were done and were any viral studies done before treatment was initiated? DR. M~TIr4 Scnov.N~at~a, Okemos, Michigan. I personally thank Dr. Reid for successful treatment of many of my patients with this technique. He has helped them considerably. Dr. Reid, if you have an opportunity, could you please discuss your current preference for medical management of this disease? With all the theories concerning etiology and the concomitant plethora of treatment options, which do you use currently? Also, many of us do not have flashlamp-excited dye laser in our hospitals. Could you comment on the new KTP-laser also currently in use for vulvodynia? DR. STEPHENH. CRUIKSHANK,Dayton, Ohio. I just want to ask Dr. Reid one question. The burning, poorly localized pattern of vulvodynia has some similarities to the chronic sympathetic pain that some persons have. Have you thought about this and would you explain it, please? DR. JOSEPHC. SCOTT, Omaha, Nebraska. Was a biopsy diagnosis used in every instance before treatment was implemented? If not, would you please explain. Second, regarding the histologic features of Bartholin's glands that were removed, was there any uniform pattern in these glands? DR. E~O.NU~ P. GAZmNO, Minneapolis, Minnesota. How do you attempt to explain this kind of relative epidemic in vulvar pain syndrome? Second, I wonder if you obtained a sexual history on these patients and if you did a psychologic profile on them before surgical therapy. DR. REID (Closing). Thank you for your interesting and constructive remarks. First, I agree with Dr. Noller that medical regimens should be tried before laser treatment or excisional surgery. There are several reasons why our study showed a low response to medical treatment. Some of the explanation relates to the geographic makeup of our sample. Only 34% of patients came from the county within which my office is located. Twenty-seven percent came from adjacent townships in southeast Michigan, 22% travelled from out of state or Canada, and the remainder were from provincial Michigan cities. Such distances certainly militate against the efficient use of medical treatments. A second reason is that a substantial proportion of our patients were referred from Dr. Jack Sobel's Wayne State University vaginitis clinic. Dr. Sobel is an infectious disease specialist who has pioneered modern concepts of cyclic candidiasis. His clinic thus tended to filter out women who were likely to respond to medical regimens. Third, because this study presented the'cohort from our first 2 years, there was a bias toward severe, long-standing cases, again reducing the likelihood of response to a nonsurgical therapy. In that this article reports on the analysis and reanalysis of accumulating experience, I agree with Dr. Twiggs that the study represents a multimodal trial. Hence, we were especially careful to avoid overinterpretation of our data, such as by the inappropriate use of

Volume 172, Number 6 Am J Obstet Gynecol

Reid et al.

1699

MECHANISM

I Activates

Pain Tissue I Gated in -- [ projection damage -- Nociceptor -- dorsal horn neurons

I

CLINICAL FEATURES Sharp pain, highly localized Proportionate to initiating insult O Specific histologic or biochemical lesion Minimal autonomic efferent activity O Responds to steroids, NSAID's & opiates Resolves with removal of insult Fig. 1. Nociceptive pain.

NSAID's, Nonsteroidal antiinflammatory drugs.

statistics. I am sure that the high ×2 value for the comparison of the "suface" versus "deep" subsets reflects real biologic differnces, rather than type I error. Likewise, I am comfortable that the low X~ value for the comparison of "vestibulitis" versus "papillomatosis" reflects a genuine lack of biologic difference rather than an unrecognized type II error. I agree with Dr. Noller that a multicenter randomized trial would be invaluable. However, randomized controlled trials are expensive and restrictive undertakings, which depend on medical theory and observational studies to define the questions of interest. One of the significant contributions of this study has been to identify the major prognostic parameter in this puzzling disease. Why did the sample deal with only 175 women? The answer is that this was a cohort study, encompassing 1989 to 1990. Hundreds more women have since been treated by flashlamp-excited dye laser therapy, but it has taken us 4 years of serial treatment and ongoing follow-up to even present final results from those first 2 years. Dr. Twiggs also asked about our choice of energy settings. We did go through the complexion testing protocol that dermatologists use for lasting port-wine stains but did not find this to be helpful. Hence, we setded on 8 J / c m as the best general setting but used 6.5 J/cm when we wanted a gentler effect. How did we know that the plastic diascope produced a 10% reflectance? We calculated this energy drop by firing the laser beam through the diascope, into an absorptiometer. No, we haven't yet had the oppotunity to use the 7 mm spot but acknowledge that it would be about twice as fast, on the basis of a comparison of areas within the focal spot (41.7 mm 2 vs 19.6 ram2). In response to Dr. Reeves, who asked about the prevalence of cervical dysplasia, our observations were that, just as in any other group of young women, about 10% showed minor-grade acetowhitening suggestive of acanthotic squamous metaplasia (congenital transformation zone)? We do not believe that vulvodynia pa-

tients show an increased frequency of bona fide cervical intraepithelial neoplasia. In answer to Dr. Scott, we collecied vulvar biopsy specimens from more than 100 of these women. Although many of these samples were originally classified as "low-grade koilocytosis, suggestive of human papillomavirus infection," critical review by two gynecologic pathologists showed the only real abnormality to be low-grade, nonspecific inflammation in the superficial submucosa (Husain M, Selvaggi S, Reid R. Unpublished data). Moreover, many samples were also analyzed by either Southern blot (Reid R, Lorincz A. Unpublished data) or polymerase chain reaction (Reid R, Manos M. Unpublished data). Moreover, many samples were also analyzed by either Southern blot (Reid R, Lorincz A. Unpublished data) or polymerase chain reaction (Reid R, Manos M. Unpublished data) and were found not to contain viral deoxyribonucleic acid. These data are in accord with an exhaustive study by Wilkinson et al., 2 who tested 14 vestibulectomy specimens by histochemical stains for Mycobacterium sp., fungus, spirochetes, and bacteria, with negative results. Immunofluorescent studies for immunoglobulins, complement, and fibrin also failed to document the presence of an immune complex-mediated vasculitis or neuritis. Characterization of the mixed chronic infiltrate by monoclonal antibody testing in eight specimens showed the predominant cell type to be a mixed population of T lymphocytes rather than the eosinophils, mast cells, and monocytes that would be seen in a true allergic response. In view of the absence of any real abnormality within these chronically painful tissues, I would endorse Dr. Cruikshank's suggestion that vulvodynia may be a chronic, sympathetically mediated pain. Acute pain and most chronic pain seen in surgical practice correspond to what is called nociceptive pain. That is to say, some form of tissue damage, (e.g., trauma, infection, or malignancy) activates specialized pain receptors called nociceptors, resulting in the conduction of an impulse

1700

June 1995 Am J Obstet Gynecol

Reid et al.

MECHANISM Initial NC sensitization

"Cross-talk" between somatic & sympathetic nerves

Selfsustaining afferent spinal cord efferent reflex

CLINICAL FEATURES r

• • • • • •

Burning pain, hard to localize Idiosyncratic -- Disabling pain from trivial insult Histology = only non-specific change Trophic change, Vasomotor instability & Dysesthesia Responds to tricyclics, CCB's and clonidine Pain persists after removal of insult

Fig. 2. Sympathetically mediated pain. NC, nociceptive; CCB's, calcium channel blockers. from the site of tissue trauma to the interneurons in the dorsal horn. At the interneuron this nociceptive pain signal has to compete with vibration and tactile sensation, thus allowing fox; down-modulation of the amount of pain signal that is transmitted across the "spinal gate." However, some portion (from a minority to a majority) of this signal is then transmitted across the interneuron and up the pain projection neurons to the brain stem and thalamus, where it is recognized as pain (Fig. 1). Such nociceptive pain can have a variety of qualities. Knowledge of various characteristic patterns is the basis for the art of physical diagnosis. In general, most nociceptive pains are sharp and the sites of pain are highly localized. An important fact is that the patient can always point exactly to the site of maximum pain. The degree of pain is proportionate to the initiating insult and worsens as tissue trauma increases. A biopsy specimen from a site of nociceptive pain will usually show a specific histologic process. Research studies have also shown that nociceptive pain impulses result from a specific biochemical cascade involving mediators such as prostaglandins, substance P, histamine, and other vasoactive peptides. This specific inflammatory cascade can be blocked at various points; hence, steroids, nonsteroidal antiinflammatories, and opiates are very effective in alleviating peripheral pain. Although there is a transient hyperesthesia at the site of injury, nociceptive pain is basically associated with minimal autonomic afferent activity. Finally and most characteristically, nociceptive pain always resolves when the eliciting process is removed. There is, however, a completely different system of pain generation, called sympathetically mediated pain. These chronic pain syndromes are poorly understood or even unknown to many gynecologists and dermatologists. However, sympathetically mediated pain syndromes constitute a substantial portion of the cases in chronic pain clinics. The first description of a sympa-

thetically mediated pain dates to S. Wier Mitchell, a military surgeon in the American Civil War, and colleagues? Mitchell coined the term causalgia to describe a disabling, burning pain that can be provoked by partial severance of a major peripheral nerve or sometimes just by "cross talk" between intact somatic and sympathetic nerves. The basic mechanism is that an initial, often trivial tissue injury results in proliferation of ¢x-adrenergic receptors on the C-fiber nociceptors, setting up a self-sustaining pain loop through the afferent sympathetics that accompany blood vessels at the pain site. At the spinal cord this afferent message generates a reinforcing signal that travels back down the efferent sympathetic fibers to sustain the pain loop. Hence, unless the pain loop can be broken, sympathetically mediated pains typically persist for years or a lifetime. The clinical features of sympathetically mediated pains are quite different to those of nociceptive pains and are, in their own way, somewhat characteristic. Sympathetically mediated pains are classically felt as a diffuse burning, which the patient cannot localize unless the physician touches the area of hyperalgesia during examination. Characteristically, sympathetically mediated pains represent a disabling but idiosyncratic response to a trivial insult. In contrast to nociceptive pains, there are no specific histologic abnormalities at the site of pain. In fact, the histologic result is almost normal, apart from nonspecific features such as edema, chronic round cell infiltration, and vascular ectasia. Another important contrast is the presence of diffuse autonomic malfunction, which results in vasomotor instability, dysesthesia, and trophic changes. Vasomotor instability refers to vascular ectasia, chronic vasospasm, or vasodilatation. Dysesthesia refers to the alterations in nerve fiber sensitivity, such as those reflected by hyperalgesic foci that hurt sharply on light touch. Trophic change refers to the atrophy of skin, muscle, and even bone seen at affected sites. Unlike nociceptive pains,

Volume 172, Number 6 Am J Obstet Gynecol

sympathetic pains do not respond to steroids, nonsteroidals, or opiates (because pain is not mediated by a cascade of histamines, prostaglandins, and vasoactive peptides). However, sympathetic pains do respond to drugs that influence the conduction of neurologic impulses within the central nervous system; hence, antidepressants, anticonvulsants, and sympathetic blockers can dramatically suppress sympathetically mediated pains. Finally and most characteristically, sympathetically mediated pain loops persist even after removal of the initiating insult (Fig. 2). The features of vulvodynia resemble those of a sympathetically mediated pain rather than a nociceptive pain. Specifically, vulvodynia begins as a sudden idiosyncratic response to any of a variety of tissue insults (yeast infection, childbirth trauma, or a carbon dioxide laser burn). Once established, the syndrome manifests as a disabling, poorly localized burning pain. Examination readily demonstrates that the pain and tenderness emanate from discrete foci of dysesthetic erythema, generally located proximal to Hart's line. Vasomotor instability is a prominent feature of vulvodynia, especially in areas that "rebound" after vestibulectomy or carbon dioxide laser treatment. Minor trophic changes, such as hymenal fibrosis and contracture of the fourchette, are common. Histologic changes within biopsy specimens from the hyperalgesic Skene's and Bartholin's ducts are completely nonspecific; hence, as would be expected, vulvodynia responds poorly to steroids, nonsteroidals, and opiates. Characteristically, once the pain loop ofvulvodynia is firmly established, it continues long after the initiating insult is removed. Finally, vulvodynia sometimes responds to selective serotonin reuptake inhibitors (Paxil, Zoloft) or traditional tricyclic antidepressants (amitriptyline, nortriptyline). On the basis of these clinical features, we blocked the superior hypogastric plexus ("presacral nerves") under fluoroscopic control in 35 patients with intractable pain. Thirty-two of these women had a positive response to the diagnostic block, confirming that the vulvodynia symptoms were indeed sympathetically mediated. Four individuals with successful blocks were treated by laparoscopic presacral neurectomy, yielding one durable success, two transient remissions (3 months, 6 months) and one nonresponse. We therefore abandoned the endoscopic approach and turned instead to aggressive open dissection. Six patients with disabling vulvar pain (including two who had failure of laparoscopic procedures) have undergone complete pelvic sympathectomy (resection of the superior hypogastric plexus and the

Reid et al.

1701

lateral sympathetic chains). Five have no vulvar pain, and one has a bizarre but generally transient pain known as sympathalgia. In answer to Dr. Schoenmaker, we try to stabilize the irritated, hyperactive epithelium with 1% 5-fluorouracil cream and topical steroids. If there is any clinical suspicion of candidal hypersensitivity, we try to suppress this potentially initiating event with long-term ketoconazole or fluconazole. We also use medical therapy to break adjacent pain l o o p s - s u c h as biofeedback-supervised Kegel's exercises for levator myalgia. However, the mainstay of one therapy has been flashlamp dye or Hexascan-adapted KTP laser destruction of the sensitized vestibular vasculature, as a means of trying to down-regulate ct-adrenergic receptor expression within sensitized nociceptors. Dr. Gaziano asked why, over the last decade, we have experienced a virtual epidemic of vulvodynia. There is no firm answer to this question, but a reasonable generalization can be offered. Vulvodynia appears to be a sympathetically mediated pain syndrome affecting cloacogenic remnants (the vulvar vestibule, Bartholin's glands, urethra, and bladder walls). Pain is initiated in susceptible women by some environmental factor that has reappeared in Western society, after a half-century hiatus. My speculation is that the eliciting agent is m i c r o b i a l - p e r h a p s a fungus, probably not a papillomavirus. 4 Finally, I agree that many of these women admit to profound sexual dysfunction. However, any chronic disabling pain, let alone chronic pain of the genitalia, will disrupt marital relationships and evoke emotional problems. I am cautious about assuming that the sexual dysfunction and emotional problems caused the genital pain, rather than vice versa. REFERENCES

1. Coppleson M, Monaghan JM, Morrow CP, Tattersall MH, eds. Gynecologic oncology. In: Volumes 1 and 2: fundamental principles and clinical practice. London: Churchill Livingston, 1992. 2. Wilkinson EJ, Guerrero E, Daniel R, et al. Vulvar vestibulitis is rarely associated with human papillomavirus infection types 6, 11, 16 or 18. IntJ Gynecol Pathol 1993;12:344-9. 3. Mitchell SW, Morehouse GR, Keen WW. Gunshot wounds and other injuries of nerves. Philadelphia: JB Lippincott, 1864. 4. Marks TA, Schroyer KR, Markham NE, et al. A clinical histologic a/ad DNA study of vulvodynia and its association with human papillomavirus. J Soc Gynecol Invest 1995 [In press].