OBJECTIVE: To investigate whether botulinum neurotoxin type A improves vaginismus and study its efficacy with repeated treatments.
METHODS: Outpatients were referred because standard cognitive–behavioral and medical treatment for vaginismus and vulvar vestibular syndrome failed. From this group, we prospectively recruited consecutive women (n=39) whose diagnostic electromyogram (EMG) recordings from the levator ani muscle showed hyperactivity at rest and reduced inhibition during straining. These women were followed for a mean (±standard deviation) of 105 (±50) weeks. Recruited patients underwent repeated cycles of botulinum neurotoxin type A injected into the levator ani under EMG guidance and EMG monitoring thereafter. At enrollment and 4 weeks after each cycle, women were asked about sexual intercourse; underwent EMG evaluation and examinations to grade vaginal resistance according to Lamont; and completed a visual analog scale (VAS) for pain, the Female Sexual Function Index Scale, a quality-of-life questionnaire (Short-Form 12 Health Survey), and bowel and bladder symptom assessment.
RESULTS: At 4 weeks after the first botulinum neurotoxin type A cycle, the primary outcome measures (the possibility of having sexual intercourse, and levator ani EMG hyperactivity) both improved, as did the secondary outcomes, Lamont scores, VAS, Female Sexual Function Index Scales, Short-Form 12 Health Survey, and bowel–bladder symptoms. These benefits persisted through later cycles. When follow-up ended, 63.2% of the patients completely recovered from vaginismus and vulvar vestibular syndrome, 15.4% still needed reinjections (censored), and 15.4% had dropped out.
CONCLUSION: Botulinum neurotoxin type A is an effective treatment option for vaginismus secondary to vulvar vestibular syndrome refractory to standard cognitive–behavioral and medical management. After patients received botulinum neurotoxin type A, their sexual activity improved and reinjections provided sustained benefits.
LEVEL OF EVIDENCE: III
In patients with treatment-resistant vaginismus secondary to vulvar vestibular syndrome, levator ani botulinum neurotoxin-A injections (followed by periodic reinjection if necessary) relieve symptoms and allow intercourse.
From the 1Department of Neurological Sciences and Vision, Section of Clinical Neurology, University of Verona, Italy; Departments of 2Neurology and 3Management Control, ULSS15 Cittadella Hospital, Padua, Italy; and 4Centre of Gynaecology and Medical Sexuology, San Raffaele Resnati Hospital, Milan, Italy.
Corresponding author: Dr. Emma Frasson, Neurological Department, Hospital, Via Casa di Ricovero, 40, Cittadella, Padua, 35013, Italy; e-mail: email@example.com.
Financial Disclosure The authors did not report any potential conflicts of interest.
The term vulvar vestibular syndrome refers to pain evoked on touch, particularly at 5 and 7 o’clock if the vaginal introitus is considered as a clock face, or during intercourse (introital dyspareunia) and accompanied by variable degrees of vulvar erythema.1,2 Vaginismus is a sexual pain disorder, indicating persistent or recurrent difficulty in allowing vaginal entry of the penis, a finger, or any object, despite the woman’s expressed wish to do so. The term vaginismus often encompasses (phobic) avoidance and anticipation, fear or experience of pain, along with variable involuntary pelvic muscle contraction.3 The prevalence of vulvar vestibular syndrome is 10–15% of women of fertile age, with a lower percentage (1–2%) reported after the menopause.4 Mild-to-moderate vaginismus is estimated to affect 10% of the population, of whom 1% suffer from severe vaginismus leading to unconsummated marriages, although systematic epidemiologic studies are lacking.5 Previous research from our group6,7 has shown that vulvar vestibular syndrome is associated with hyperactivity of the pelvic floor and vaginismus, as already described by Abramov et al.8 In some patients, vaginismus manifests as a lifelong condition associated with a fear of penetration or variable degrees of phobia for intercourse that satisfies the criteria for primary vaginismus and precedes vulvar vestibular syndrome. Acquired, secondary vaginismus manifests after months or years of normal intercourse. Vulvar vestibular syndrome usually develops after repeated episodes of chronic Candida vaginal infection and chronic vestibular inflammation, leading to upregulated mast cells.9–11 The infection causes increasing introital pain that develops spontaneously or is provoked during physical examination or intercourse, thus eliciting a defensive levator ani muscle contraction.5 The levator ani hyperactivity, a feature contributing to lifelong and to acquired vaginismus, is clinically classified according to the Lamont classification and graded into four degrees of intensity (I to IV).12 In vaginismus, electromyographic (EMG) recordings from the levator ani muscle show hyperactivity at rest and paradoxical activity during straining.7,13–15 Another neurophysiologic feature typical of vaginismus is hyperexcitability of the late oligosynaptic response of the bulbocavernosus reflex and the abnormal cortical pudendal somatosensory evoked potential recovery cycle.7
The cause of vaginismus secondary to vulvar vestibular syndrome is poorly understood, and despite intense research efforts vulvar vestibular syndrome remains difficult to diagnose. The possible causes of vulvar vestibular syndrome include multifactorial biologic, psychosexual, and relational factors.4,16 As a multisystemic disease, it involves the mucous structure of the vulvar vestibule and the immune, muscular, vascular, and nervous systems, including pain fibers and centers.17,18 The local and generalized decrease in the tactile and pressure pain thresholds in patients with vulvodynia suggests a central sensitization component.19
Vulvar vestibular syndrome also remains difficult to treat. Tailored multimodal treatment includes oral drugs (antimycotic agents, myorelaxants, antidepressants and pain modulators such as amitriptyline, and γ-aminobutyric acid-ergic inhibitors), local anesthetic nerve blockade,20–23 and surgical treatments including vestibulectomy.23 Despite the various medical and surgical options proposed over the years, a subset of patients, in whom levator ani hyperactivity persists, remain ineffectively treated and have a poor quality of life.16,24 Vulvar vestibular syndrome can also be associated with constipation and micturition problems,2,4,25 ranging in severity to interstitial cystitis, especially when levator ani hyperactivity is not diagnosed in time or patients fail to respond satisfactorily to EMG biofeedback aimed at increasing a woman’s ability to voluntarily relax the tightened pelvic floor.26–28
Botulinum neurotoxin type A is a polypeptide that inhibits binding of intracellular acetylcholine vesicles to the cell membrane at presynaptic level. Botulinum neurotoxin injected into the affected muscles decreases muscle spasms and pain through various mechanisms.29 Botulinum neurotoxin type A is a new therapeutic tool for pelvic pain syndromes, such as lifelong vaginismus10,30–33 and chronic genital pain syndromes.24,33–35 Botulinum neurotoxin type A treatment also improves vulvodynia associated with hyperactive levator ani muscle.36–39 More information is needed on botulinum neurotoxin type A injections for vaginismus secondary to vulvar vestibular syndrome.
Prompted by the need to extend the treatment options for patients with vaginismus secondary to vulvar vestibular syndrome attending our outpatient clinic, in a medium-term prospective study we assessed the effectiveness of botulinum neurotoxin type A injected into the levator ani muscle in a group of patients with vulvar vestibular syndrome accompanied by vaginismus, all of whom had EMG-documented pelvic floor muscle dysfunction. As primary outcome measures we studied the effectiveness of treatment with botulinum neurotoxin type A injected into the levator ani muscle in allowing sexual intercourse without pain and reducing pelvic floor EMG hyperactivity at rest and paradoxical activity with straining. Secondary outcome measures included the effectiveness of botulinum neurotoxin type A in reducing vaginal spasm as measured with the Lamont classification, reducing local pain as measured by a visual analog scale (VAS), improving sexual function as measured by the Female Sexual Function Index score, and improving quality of life scores in the Short-Form 12 Health Survey (SF-12) for physical and mental health, and last, improving bowel and bladder symptoms.
PATIENTS AND METHODS
In a prospective, open-label study, from January 2003 to January 2007 we enrolled 39 consecutive patients with vaginismus secondary to vulvar vestibular syndrome. The patients were recruited in our specialist referral center for a wide area in Northern Italy set up in collaboration with the Gynecology Center. We prospectively recruited 39 patients whose diagnostic EMG recordings from the levator ani muscle showed muscular hyperactivity at rest and reduced inhibition during straining, both defined by reduced or full EMG interference pattern.7 We collected follow-up data over 39.5 months. Before entering the study and already receiving cognitive–behavioral treatment, all patients had been periodically treated unsuccessfully with antibiotics, antimycotics, γ-aminobutyric acid-ergic inhibitors and antidepressant drugs that reduced pain but induced only transient benefit because levator ani hyperactivity persisted and attempted intercourse caused vulvar vestibular syndrome to relapse. Patients’ clinical and demographic characteristics are listed in Table 1. None of the patients had other gynecologic diseases. The Ethical Committee of the Institute of Clinical Neurology, University of Verona approved the protocol and subjects gave their informed consent.
The same neurologist and gynecologist examined the patients when the study began (baseline) and at week 4 of each botulinum neurotoxin type A treatment cycle, the time when most patients reported receiving the maximal benefit from the treatment cycle. To ensure that botulinum neurotoxin type A was injected into the levator ani muscle, injections were given under EMG guidance (monopolar needle, 0.46 mm in diameter).
During the study, the 39 patients received repeated botulinum neurotoxin type A treatment cycles. Patients were considered responders after at least 1 year free of symptoms. Patients in whom botulinum neurotoxin type A treatment failed to allow sexual intercourse or who reported persisting introital dyspareunia on attempted intercourse or severe penetration pain tested by progressive vaginal molds or who had benefit lasting less than 1 year followed by symptom return were considered partial responders and eligible for retreatment. All patients underwent clinical and EMG assessment before each treatment cycle began and at week 4 of each cycle. As primary outcome measures, we assessed the effectiveness of treatment with botulinum neurotoxin type A injected into the levator ani muscle in allowing sexual intercourse and reducing pelvic floor EMG hyperactivity and paradoxical activity with straining. Secondary outcome measures included its effectiveness in reducing vaginal spasm, considering vaginal resistance as measured with the Lamont classification, reducing local pain as measured by a VAS, improving sexual functions as measured by the Female Sexual Function Index scale, and improving quality of life scores for the Short Form 12 Health Survey (SF-12) for physical and mental health, and last, improving bowel and bladder symptoms.
To examine vaginal residual introital resistance, secondary to the muscle contraction, we used the Lamont classification for grading the severity of vaginal spasms: grade 1, perineal and levator spasm, relieved with reassurance; grade 2, perineal spasm, maintained throughout the pelvis; grade 3, levator spasm and elevation of buttocks; grade 4, levator and perineal spasm, elevation; adduction and retreat.12
Electromyogram activity was recorded with a concentric needle (diameter 0.46 mm) inserted perpendicularly into the levator ani muscle between the anal and vaginal orifices. Motor unit potentials were collected and analyzed by a standard EMG system (Keypoint, Dantec Medical, Park Ridge, IL; filter settings 5–10 kHz, gain 100–500 microvolt/division, sweep speed 10–20 ms/division). The EMG recording was evaluated for baseline tonic activity at rest, voluntary activity, and straining, and classified as score 0, no activity; 1, physiologic tonic activity (sustained low-rate firing of isolated motor unit potentials at rest); 2, EMG with a reduced interference pattern (some motor units can still be identified on the baseline EMG recording); and 3, EMG activity with a full interference pattern (the baseline is completely obscured by motor unit activity).40,41 This analysis generated separate trials for the three experimental conditions, baseline tonic activity, maximal voluntary activity, and straining. During EMG, participants lay on the right side with hips and knees flexed and were asked to fully relax the sphincters when spontaneous activity was evaluated at rest and to attempt straining the sphincters when recruitment patterns were tested. Electromyogram data were recorded before botulinum neurotoxin type A (Dysport, Ipsen Ltd, UK) was injected into the levator ani and at week 4 of each treatment cycle, when the patients reported receiving the maximal benefit from the treatment cycle.
When the study began (baseline) and at week 4 of each treatment cycle, the patients completed the following tests: a VAS pain assessment for vulvar pain; the vulvar pain on touch (Q-tip) rest done by touching the area with a cotton swab and noting any pain2 (for this test we considered a mean pain value in the 5 o’clock and 7 o’clock position); a VAS pain assessment was used also to evaluate dyspareunia and dysmenorrhea; the Female Sexual Function Index, a questionnaire relating to sexual activity42,43; the SF-12 for physical and mental health, a questionnaire relating to quality-of-life scores44; the Wexner score, a questionnaire relating to bowel symptoms—obstructive constipation—graded from 0 to 30 (0 normal, 1–5 mild, 6–11 moderate, 11–15 severe, 16–30 very severe constipation)45; a VAS pain assessment was used also to evaluate pain during urination, including bladder and urethral pain after intercourse and burning pain in general during micturition (10–30 mild, 40–60 moderate, 70–100 severe).
The Female Sexual Function Index is a 19-item validated questionnaire that was designed to evaluate female sexual dysfunction, especially female sexual arousal disorder.42 The scale is divided into six domains: desire, arousal, lubrication, orgasm, satisfaction, and pain. Each item is scored with a 5- or 6- point Likert scale. The scales for each domain are variable, and the total score ranges from 4 to 95. Because our study began in 2003, questionnaires were adapted from the subsequently published Italian version of the Female Sexual Function Index.43
Before being referred to our center, all patients had already completed the standard EMG biofeedback rehabilitation and self-stretching program with incomplete or absent improvement in levator ani hyperactivity. After botulinum neurotoxin type A injections, they were asked to do pelvic muscle training exercises, including pelvic floor self-stretching and daily use of progressive vaginal molds at home.
For statistical analysis, we used a non parametric repeated measures analysis of variance to compare EMG data, vaginal resistance scores, Female Sexual Function Index score, VAS, and Short-Form 12 Health Survey questionnaires and data related to bowel symptoms before and after botulinum neurotoxin type A treatment. We considered median and interquartile range confidence intervals or specified mean and standard deviation. Spearman correlation test was used to compare the relationship between sociodemographic variables (age, educational level, disease duration, marital status, parity) and dependent measures (VAS score, Lamont classification, EMG, and treatment cycle numbers). We calculated Kaplan-Meier curves to estimate patients’ survival. Repeated-measures analysis of variance was used through cycles 0–4, because the sample size thereafter was small. Missing data were excluded from the statistical analysis. P<.05 was considered indication of statistical significance.
Of the 41 patients with vulvar vestibular syndrome and vaginismus considered eligible for the study, two declined to participate, leaving 39 for study. Of the 39 patients who were initially included, 33 patients completed the study. Of these 33 patients, 27 (63.23%) completely recovered from vaginismus and vulvar vestibular syndrome; their sexual intercourse normalized after a mean±standard deviation of 2.7±1.5 treatment cycles (range 1–7), range 4–94 weeks, and the benefit persisted over the ensuing months (mean 23.75±7.3, range 13–35.25). The proportion of responder patients varied at each cycle (Fig. 1). Conversely, six patients (15.38%) recovered from vaginismus, and vulvar vestibular syndrome and sexual intercourse had normalized after 4.5±2. 3 cycles (range 1–8), but they remained eligible for botulinum neurotoxin type A reinjections within the 1-year symptom-free observation period (censored patients) (Fig. 1). A total of six patients (15.38%) were lost to follow-up (dropouts) after 1.16±0.37 cycles, five patients for unknown reasons and one patient because she complained that she received no benefit on vulvar pain and spasms and could not have sexual intercourse (Fig. 1). A mean botulinum neurotoxin type A dose of 0.12±0.06 mL (0.1 mL=20 international units) was used in each session; the benefit began 8.28±6.56 days after the first botulinum neurotoxin type A injection. Treatment cycles lasted a mean 35±34 weeks (range 4–120 weeks) (Fig. 2). The mean follow-up was 105±50 weeks (range 4–168 weeks, 1–39.5 months). The interval elapsing between cycles varied, and the duration peaked at cycle 4 (Figs. 3–5). None of the patients reported major adverse events, but one patient reported transient urinary incontinence. Finally, three patients became pregnant during the study (two deliveries, one cesarean and one natural, and one abortion).
Before botulinum neurotoxin type A treatment (cycle 0), all patients’ EMG recordings from the levator ani muscle showed baseline hyperactivity at rest and paradoxical activity with straining. Conversely, after botulinum neurotoxin type A treatment scores for EMG hyperactivity at rest improved significantly. The improvement began after cycle 1 (Fig. 3A and B). Scores for EMG paradoxical hyperactivity also improved significantly improved after cycle 1 (Fig. 3A and B). Electromyogram recordings showed this typical pattern also in the six patients who withdrew before finishing the study. Because levator ani hyperactivity tended to reappear after the first botulinum neurotoxin type A injection cycle, most patients (28 of 39) needed reinjection, and repeated cycles led to sustained improvement throughout treatment cycles (Fig. 3A and B). Whereas levator ani EMG trials before botulinum neurotoxin type A treatment (Fig. 3C) showed increased activity at rest and paradoxic muscle activation during correct attempted straining, recordings after botulinum neurotoxin type A treatment showed only physiologic tonic activity at rest and no EMG activity during correct attempted straining, implying that both EMG abnormalities had normalized (Fig. 3C). No difference was found in maximal voluntary EMG activity before and after botulinum neurotoxin type A treatment cycles.
Vaginal examinations showed significant improvement in vaginal resistance after botulinum neurotoxin type A treatment and the improvement was sustained after treatment cycles 2 and 3 (Fig. 3D).
Similarly, VAS for vulvar pain improved significantly after botulinum neurotoxin type A treatment and the improvement between cycles remained significant even up to cycle 3. Visual analog scores for dyspareunia also improved significantly after botulinum neurotoxin type A treatment, and the improvement between cycles remained significant up to cycle 4. Visual analog scores for pain during micturition also improved significantly after botulinum neurotoxin type A treatment up to cycle 2. In contrast, VAS for dysmenorrhea remained statistically unchanged (Fig. 4A).
Bowel symptoms (Wexner score) questionnaire scores were also significantly improved after botulinum neurotoxin type A treatment cycle 1 and 2 (Fig. 4C).
All the other secondary outcome measures assessed after botulinum neurotoxin type A treatment showed similar patterns of sustained improvement: Female Sexual Function Index scores (cycle 1 to 3); the Short-Form 12 Health Survey scores mental component scores (cycle 1); and physical component scores (cycle 1 to 3) (Fig. 5A and B).
Spearman test scores disclosed a significant correlation between vaginal resistance (Lamont classification) and VAS for vulvar pain and dyspareunia; the correlation was significant also for the Short-Form 12 Health Survey and VAS (vulvar pain, dyspareunia) and the Short-Form 12 Health Survey and Female Sexual Function Index. Conversely, no significant correlation emerged among disease duration, age, and treatment cycle numbers.
All the women who completed our prospective trial reported that vaginismus secondary to vulvar vestibular syndrome improved after botulinum neurotoxin type A treatment, and most patients who responded had more than 1 year free of symptoms. Evidence documenting the effectiveness of botulinum neurotoxin type A injected into the levator ani muscle came from all our primary and secondary outcome measures, including those measuring the ability to have sexual intercourse, reduced EMG hyperactivity scores, reduced local pain, and improvement in sexual activity and quality of life. Bowel and bladder problems improved as well. In this trial we describe the effectiveness of botulinum neurotoxin type A in a large group of patients with vaginismus secondary to vulvar vestibular syndrome studied with a medium-term follow-up. Botulinum neurotoxin type A injected into the levator ani muscles effectively reduced our patients’ muscular spasms and their pain, so that when the follow-up ended, most patients had apparently recovered permanently from the disease, and their sexual life and quality of life had improved. These encouraging findings in a large population confirm and extend the few reports published in recent years describing the successful use of botulinum neurotoxin type A for the treatment of vaginismus and in small groups of patients with chronic pelvic pain syndromes, vulvodynia, and pelvic floor spasms in placebo-controlled24,30 and open trials29,32,37,39 and case reports.13,15,34–36,38
The benefit most of our patients had from botulinum neurotoxin type A therapy could depend on several factors. First, we selected only patients who had severe vaginismus, a complaint that frequently coexists with vulvar vestibular syndrome6,8 and often responds to botulinum neurotoxin type A injected into the levator ani muscle.30,31 For this reason, we specifically selected patients with documented EMG pelvic floor muscle hyperactivity. Unlike previous studies, which used superficial EMG electrodes and failed to show increased levator ani muscle activity at rest and during a correct attempt at straining in vaginismus,46 in our patients needle EMG recordings showed a pattern of prolonged (100 ms to several minutes) spontaneous muscle activity in the levator ani muscle and a lack of appropriate voluntary inhibition, an EMG pattern already described by Shafik and Sibai12 in their patients with vaginismus and recently by our group.7 The second technical strong point in our study was that injecting botulinum neurotoxin type A with a monopolar needle helped us identify the hyperactive muscle.. The third factor that may have influenced the duration of botulinum neurotoxin type A benefit was the dose. To minimize possible adverse reactions, we used a lower dose than others (20 mouse units compared with 5031 and 150–40030). This difference may explain why vaginismus had a shorter-lasting benefit from botulinum neurotoxin type A in our study sample than in previously reported patients30,31 and needed a larger number of treatment cycles before it responded. Another factor influencing patients’ improved outcome when follow-up ended was that although many patients improved after a few injections, we monitored our patients closely and if necessary repeated injections regularly until vaginismus and vulvar vestibular syndrome improved. An additional feature that probably helped our patients’ vaginismus to improve was the pelvic muscle exercise training they did after botulinum neurotoxin type A injections. Botulinum neurotoxin type A injections also helped to improve obstructive constipation. Our clinical data showing that botulinum neurotoxin type A also improved our patients’ bowel and bladder symptoms are in line with case report studies of vaginismic patients.13,15 Recent evidence on pelvic floor muscle hyperactivity and comorbidity with dyspareunia and vaginismus in women with interstitial cystitis suggests that this condition as well might respond to the botulinum neurotoxin type A approach.47–49 Although in our patients botulinum neurotoxin type A improved urination pain, a bladder symptom often related to vulvar vestibular syndrome,2,50 published information is lacking on coexisting bladder symptoms and pelvic pain syndromes and how they respond to botulinum neurotoxin type A injection. This could be a matter for future research. A possible limitation of the study that might have led us to overestimate the benefit of botulinum neurotoxin type A in our patients through cycles was the open-label rather than placebo-controlled study design.
Precisely how botulinum neurotoxin type A benefitted vaginismus secondary to vulvar vestibular syndrome remains unclear. The most likely mechanism is that botulinum neurotoxin type A succeeded in relaxing the otherwise hyperactive pelvic floor that did not respond to conventional EMG biofeedback and self-stretching. Our future research project includes a study designed to compare physical therapy plus botulinum neurotoxin type A with physical therapy plus a placebo injection. The botulinum neurotoxin type A injection procedure we proposed here is simple, easy, and not time-consuming and can be done on an outpatient basis. Most patients tolerate botulinum neurotoxin type A injections well, and adverse effects are rare and transient.29 A disadvantage that calls for future research is the number of patients (15.38% in our study) who need reinjections to maintain consistent benefits.
The observation that vaginismus and vulvar vestibular syndrome commonly coexist raises the question of whether an inflammatory mechanism combined with pain and muscular spasm can cause or maintain the disease. Which of the many structural and functional changes taking place during the disease triggers vulvar vestibular syndrome is unknown. Hence, another problem is that of knowing which disturbance to treat first, inflammation or spasms. This dilemma notwithstanding, our finding that treating our patients’ pelvic spasms effectively helps to reduce and cure their inflammation (acting in synergy with medical treatment and changes in lifestyles) implies that muscular spasms and inflammation depend on a vicious circle and that treating vaginismus can also improve vulvar vestibular syndrome. All the patients we treated had already tried other therapies with only scarce, inconsistent benefit. Our study now suggests that botulinum neurotoxin type A promises to provide long-lasting benefit. We therefore suggest beginning therapy at an early stage of the disease, at least in the subset of patients who present with hyperactive pelvic floor at examination, or respond poorly to standard cognitive–behavioral and pharmacologic treatments. Further controlled studies should investigate whether botulinum neurotoxin type A injections started when vulvar vestibular syndrome and lifelong or acquired vaginismus is first diagnosed might shorten the treatment course and increase the success rate and disease-free follow-up.
1. Friedrich EG Jr. Vulvar vestibulitis syndrome. J Reprod Med 1987;32:110–4.
2. Bergeron S, Binik YM, Khalifé S, Pagidas K, Glazer HI. Vulvar vestibulitis syndrome: reliability of diagnosis and evaluation of current diagnostic criteria Obstet Gynecol 2001;98:45–51.
3. Basson R, Leiblum S, Brotto L, Derogatis L, Fourcroy J, Fugl-Meyer K, et al. Revised definitions of women’s sexual dysfunction. J Sex Med 2004;1:40–8.
4. Munday P, Buchan A. Vulval vestibulitis. BMJ 2004;328:1214–5.
5. Vincenti E, Graziottin A. Sexual pain disorders: dyspareunia and vaginismus. In: Porst H, Buvat J, editors. Standard practice in sexual medicine. Oxford (UK): Blackwell; 2006. p. 342–50.
6. Graziottin A, Rovei V. Sexual pain disorders. In: Tepper M, Owens AF, editors. Sexual health. Westport (CT): Praeger; 2007. p. 287–313.
7. Frasson E, Graziottin A, Priori A, Dall’ora E, Didonè G, Garbin EL, et al. Central nervous system abnormalities in vaginismus. Clin Neurophysiol 2009;120:117–22.
8. Abramov L, Wolman I, David MP. Vaginismus: an important factor in the evaluation and management of vulvar vestibulitis syndrome. Gynecol Obstet Invest 1994;38:194–7.
9. Bohm-Starke N, Hilliges M, Falconer C, Rylander E. Neurochemical characterization of the vestibular nerves in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest 1999;48: 270–5.
10. Bohm-Starke N, Hilliges M, Blomgren B, Falconer C, Rylander E. Increased blood flow and erythema in posterior vestibular mucosa in vulvar vestibulitis(1). Obstet Gynecol 2001;98:1067–74.
11. Graziottin A, Serafini A. HPV infection in women: psychosexual impact of genital warts and intraepithelial lesions. J Sex Med 2009;6:633–45.
12. Lamont JA. Vaginismus. Am J Obstet Gynecol 1978;131:633–6.
13. Brin MF, Vapnek JM. Treatment of vaginismus with botulinum toxin injections [published erratum appears in Lancet 1997;349:656]. Lancet 1997;349:252–3.
14. Shafik A, El-Sibai O. Study of the pelvic floor muscles in vaginismus: a concept of pathogenesis. Eur J Obstet Gynecol Reprod Biol 2002;105:67–70.
15. Bertolasi L, Frasson E, Bottanelli M, Vicentini S, Didonè G, Graziottin A. Coexisting idiopathic cervical dystonia and primary vaginismus: a case report. J Neurol 2008;255:443–5.
16. Graziottin A, Brotto L. Vulvar vestibulitis syndrome: a clinical approach [published erratum appears in J Sex Marital Ther 2004;30:303]. J Sex Marital Ther 2004;30:125–39.
17. Bornstein J, Goldschmid N, Sabo E. Hyperinnervation and mast cell activation may be used as histopathologic diagnostic criteria for vulvar vestibulitis. Gynecol Obstet Invest 2004;58:171–8.
18. Halperin R, Zehavi S, Vaknin Z, Ben-Ami I, Pansky M, Schneider D. The major histopathologic characteristics in the vulvar vestibulitis syndrome. Gynecol Obstet Invest 2005;59:75–9.
19. Giesecke J, Reed BD, Haefner HK, Giesecke T, Clauw DJ, Gracely RH. Quantitative sensory testing in vulvodynia patients and increased peripheral pressure pain sensitivity. Obstet Gynecol 2004;104:126–33.
20. Graziottin A. Dyspareunia and vaginismus: review of the literature and treatment. Curr Sex Health Rep 2008;5:43–50.
21. Vincenti E, Graziottin A. Management by anesthetic blocks. In: Goldstein I. Meston C. Davis S. Traish A, editors. Women’s sexual function and dysfunction: study, diagnosis and treatment. New York (NY): Taylor & Francis; 2006. p. 524–8.
22. Rapkin AJ, McDonald JS, Morgan M. Multilevel local anesthetic nerve blockade for the treatment of vulvar vestibulitis syndrome. Am J Obstet Gynecol 2008;198:41.e1–5.
23. Goetsch MF. Surgery combined with muscle therapy for dyspareunia from vulvar vestibulitis: an observational study. J Reprod Med 2007;52:597–603.
24. Abbott JA, Jarvis SK, Lyons SD, Thomson A, Vancaille TG. Botulinum toxin type A for chronic pain and pelvic floor spasm in women: a randomized controlled trial. Obstet Gynecol 2006;108:915–23.
25. Peters K, Girdler B, Carrico D, Ibrahim I, Diokno A. Painful bladder syndrome/interstitial cystitis and vulvodynia: a clinical correlation. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:665–9.
26. Glazer HI, Rodke G, Swencionis C, Hertz R, Young AW. Treatment of vulvar vestibulitis syndrome with electromyographic feedback of pelvic floor musculature. J Reprod Med 1995;40:283–290.
27. Bergeron S, Binik YM, Khalifé S, Pagidas K, Glazer HI, Meana M, et al. A randomized comparison of group cognitive– behavioral therapy, surface electromyographic biofeedback, and vestibulectomy in the treatment of dyspareunia resulting from vulvar vestibulitis. Pain 2001;91:297–306.
28. Graziottin A. Female sexual dysfunction: treatment. in: Bø K, Berghmans B, Mørkved S, Van Kampen M, editors. Evidence-based physical therapy for the pelvic floor-bridging science and clinical practice. Oxford (UK): Elsevier; 2007. p. 277–287.
29. Dressler D, Adib Saberi F. Botulinum toxin: mechanisms of action. Eur Neurol 2005;53:3–9.
30. Ghazizadeh S, Nikzad M. Botulinum toxin in the treatment of refractory vaginismus. Obstet Gynecol 2004;104:922–25.
31. Shafik A, El-Sibai O. Vaginismus: results of treatment with botulinum toxin. J Obstet Gynaecol 2000;20:300–2.
32. Bertolasi L, Frasson E, Graziottin A. Botulinum toxin treatment of pelvic floor disorders and genital pain in women. Curr Womens Health Rev 2008;4:180–7.
33. Jarvis SK, Abbott JA, Lenart MB, Steensma A, Vancaillie TG. Pilot study of botulinum toxin type A in the treatment of chronic pelvic pain associated with spasm of the levator ani muscles. Aust N Z J Obstet Gynaecol 2004;44:46–50.
34. Romito S, Bottanelli M, Pellegrini M, Vicentini S, Rizzuto N, Bertolasi L. Botulinum toxin for the treatment of genital pain syndromes. Gynecol Obstet Invest 2004;58:164–7.
35. Thomson AJ, Jarvis SK, Lenart M, Abbott JA, Vancaillie TG. The use of botulinum toxin type A (BOTOX) as treatment for intractable chronic pelvic pain associated with spasm of the levator ani muscles. BJOG 2005;112:247–9.
36. Brown CS, Glazer HI, Vogt V, Menkes D, Bachmann G. Subjective and objective outcomes of botulinum toxin type A treatment in vestibulodynia: pilot data. J Reprod Med 2006;51:635–41.
37. Dykstra DD, Presthus J. Botulinum toxin type A for the treatment of provoked vestibulodynia: an open-label, pilot study. J Reprod Med 2006;51:467–70.
38. Gunter J, Brewer A, Tawfik O. Botulinum toxin a for vulvodynia: a case report. J Pain 2004;5:238–40.
39. Yoon H, Chung WS, Shim BS. Botulinum toxin A for the management of vulvodynia. Int J Impot Res 2007;19:84–7.
40. Binnie CD, Cooper R, Fowler CJ, Mauguière F, Prior PF. Electromyography and nerve conduction. In: Osselton JW, editor. Clinical neurophysiology: EMG, nerve conduction and evoked potentials. 1st ed. Oxford (UK): Butterworth-Heinemann; 1995. p. 43–322.
41. Kimura J. Electrodiagnosis in diseases of nerve and muscle: principles and practice. 3rd ed. New York (NY): Oxford University Press; 2001. p. 380.
42. Rosen R, Brown C, Heiman J, Leiblum S, Meston C, Shabsigh R, et al. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther 2000;26:191–208.
43. Nappi RE, Albani F, Vaccaro P, Gardella B, Salonia A, Chiovato L, et al. Use of the Italian translation of the Female Sexual Function Index (FSFI) in routine gynecological practice. Gynecol Endocrinol 2008;24:214–9.
44. Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996;34:220–33.
45. Agachan F, Chen T, Pfeifer J, Reissman P, Wexner SD. A constipation scoring system to simplify evaluation and management of constipated patients. Dis Colon Rectum 1996;39:681–5.
46. van der Velde J, Laan E, Everaerd W. Vaginismus, a component of a general defensive reaction. An investigation of pelvic floor muscle activity during exposure to emotion-inducing film excerpts in women with and without vaginismus. Int Urogynecol J Pelvic Floor Dysfunct 2001;12:328–31.
47. Peters KM, Killinger KA, Carrico DJ, Ibrahim IA, Diokno AC, Graziottin A. Sexual function and sexual distress in women with interstitial cystitis: a case–control study. Urology 2007;70:543–7.
48. Giannantoni A, Porena M, Costantini E, Zucchi A, Mearini L, Mearini E. Botulinum A toxin intravesical injection in patients with painful bladder syndrome: 1-year followup. J Urol 2008;179:1031–4.
49. Ramsay AK, Small DR, Conn IG. Intravesical botulinum toxin type A in chronic interstitial cystitis: results of a pilot study. Surgeon 2007;5:331–3.
© 2009 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
50. Kennedy CM, Nygaard IE, Bradley CS, Galask RP. Bladder and bowel symptoms among women with vulvar disease: are they universal? J Reprod Med 2007;52:1073–8.