Introduction:Botulinum neurotoxins (BoNT) are proteic neurotoxins produced by an anaerobic sporulated bacteria of the Clostridium genus. Once introduced in the body, they cause flaccid muscle paralysis by inhibiting the release of acetylcholine neurotransmitters from the nerve endings. [1] BoNT consists of two chains: a heavy chain of 100 kDa and a light chain of 50 kDa linked by a non-covalent bond and by a disulfide bridge which is extending from the heavy chain and surrounding the light chain like a belt. [2] Botulinum neurotoxin has seven different serotypes, designated A, B, C, D, E, F and G. Although the mechanism of action of these serotypes is similar, their potency varies. BoNT-A and BoNT-B are the only ones used in clinical purposes and BoNT-A was the most studied for therapeutic purposes. Clinical trials on this topic have defined the safety and tolerability profile of BoNT-A. The incidence of adverse effects was approximately 25% in the BoNT-A treated group compared to 15% in the control group. Of the side effects after treatment with BoNT-A, the most frequently mentioned was focal weakness and after local treatment, erythema, edema and a slight hyperesthesia may occur. [3] Botulinum toxin type A is used in dermatology, motion disorders, ophthalmic disorders , gastrointestinal disorders, but it is also useful in uro-gynecological pathology, having high efficacy with minimal adverse effects. Among the gynecologycal pathologies treated with BoNT-A it have been mentioned in the literature: chronic pelvic pain, vaginism, dyspareunia and urinary incontinence with overactive bladder or sphincterian dissinergia. This article is a review of the current published data on the administration of botulinum toxin in gynecological pathology, but in order to recommend the wider use of this treatment, it is essential to carry out more research to add extra data to our current knowledge.
II. Off-label use of BoNT-A in Gynecology
II.1. Use of BoNT-A in the treatment of vaginism
The term "vaginism" was initially used in 1862 by Dr. Marion Sims to describe the involuntary, recurrent or persistent contraction of the perineal muscles that surrounds the outer third of the vagina when when occurs the penetration of the vagina with the penis, with a swab or with the vaginal speculum during the gynecological examination. This involuntary contraction of the perineal muscles can aggravate or even make sexual life impossible. Vaginism may have different degrees of severity, there are cases when penetration with vaginal swabs or vaginal speculum is allowed, but in the worst cases they are not allowed and too, sexual intercourse is impossible. [4] Kegel exercises, relaxation, exercise, self-satisfaction and physical examination play an important role in the management of these patients. Also, voluntary control of perineal muscle contraction is a key factor in the successful treatment of vaginism. [5] Anxiolytic therapeutic agents and local treatments (lubricants, anesthetic creams) have been used for the pharmacological treatment of this pathology, but about 10% of patients do not find healing or amelioration. [4]
Botulinum Toxin A (Botox) is a neurotoxin produced by a bacteria of the Clostridium genus and it is used in medicine in a wide range of muscular dysfunctions because it acts on nerve endings and inhibits the release of acetylcholine in synaptic spaces preventing the occurrence of muscle spasm. A series of studies have been conducted in the literature based on the use of BoNT-A in the treatment of vaginism. A study [4] included 24 women aged 19-34 years who had 3-4 grade vaginism (62.5% had severe vaginism), with no previous treatment. Prior to injection, 500 U BoNT-A was diluted with 1.5 ml of saline solution. A total dose of 150-400 U was injected equally into levator ani muscles, in 3 points on each side, under sedation with Midazolam and with Oxygen administration. For the first cases, 150-200 U BoNT-A was used, then the dose gradually increased to the following patients, up to 400 U. Patients were followed on average for 12 months and the results were satisfactory: 95.8% of the patients did not show any resistance or showed reduced resistance to post-injection vaginal examinations, 75% achieved satisfactory sexual relations after the first injection and 16.7% had mild pain at penetration after the first injection. Also, recurrent vaginism in patients treated with BoNT-A was not detected.
Shafik et al. [6] have also developed a case-control study based on the efficacy of botulinum toxin use in the treatment of vaginism. The cohort consisted of eight cases of vaginism suffering women aged 26.6-1.2 years and five women with vaginism, of the same age category, which were included as controlers. The patients were injected with 25 IU of BonNT diluted in 1 ml of saline in each bulbospongiosus muscle. The controlers were injected with saline solution. After the injection, the patients were followed for an average of 10.2-3.3 months. The results obtained were encouraging: an improvement was observed in all cases, recurrences have been described and the sexual life of the cases became posible or satisfactory. There were no improvements in the control group.
The vaginism may be primary, when the sexual penetration is impossible from the beginning and secondary vaginism appears when involuntary contraction of vaginal and pelvic muscles occurs secondary to other conditions. [4] To illustrate the utility of botulinum neurotoxin in the treatment of vaginismus secondary to vulvar vestibulitis syndrome, Bertolasi L. et al. [7] recruited 39 women whose EMG recordings in the levator ani muscle had reduced resting and reduced inhibition during exercise and injected BoNT-A into repeated cycles under the guidance of EMG. Then, he followed the patients for an average of 105 (+/- 50) weeks. Four weeks after each cycle, the women underwent EMG evaluations, vaginal examinations, completed a visual analogue scale (VAS) for pain, the female sexual function index scale, a quality of life questionnaire and the evaluation of bowel and bladder symptoms. Four weeks after the first injection of BoNT-A, the results of the questionnaires were satisfactory and the results maintained with the increase in the number of subsequent injections. After the end of the follow-up period, 63.2% of the patients were completely cured, 15.4% needed re-injections and 15.4% gave up.
Peter T. Pacik [8] is another author who shares his experience based on the results of vaginism treatment with BoNT-A. It has made a cohort of 20 patients who have been treated with Botox injections during 2005-2009. The severity of vaginism was as follows: 12 women-primary vaginism, 5 female- secondary vaginism and 3 women showed severe dyspareunia. Initially, low doses of Botox were used then the doses increased from 100U to 150U of Botox, diluted in 2ml saline solution, injected under sedation (15-20 ml of bupivacaine 0.25% with epinephrine 1: 200,000 ) in several points along each side of the vagina (into the bulbocavernosus, pubococcygeus, and puborectalis muscles).
At the time of the study, 16 patients managed to have sexual intercourse in 2 weeks to 3 months after the injection; 3 patients are still in treatment and a patient is considered a failure because neither the smallest penetration dilator could ever be used. Patients continued to have a low degree of discomfort and vaginal burns during early sexual intercourse attempts, but this problem was resolved within a few weeks of completing the treatment.