**4. Urethral Sphincter BoNT-A Injections in Children with Dysfunctional Voiding**

DV is characterized by an intermittent or fluctuating flow rate, owing to intermittent contractions of the periurethral striated muscles or pelvic floor muscles during voiding in neurologically normal patients [56]. In 1973, Hinman and Baumann first described the symptom complex including enuresis, daytime wetting, UTI, and upper tract dilatation in 14 boys without neurologic defects and suggested that the condition is a functional discoordination between detrusor contraction and external sphincter relaxation [57]. This syndrome was then described by other authors as Hinman syndrome, occult neuropathic bladder, non-neurogenic neurogenic bladder, learned voiding dysfunction, and dysfunctional voiding [58–60]. In children, the typical symptoms of DV include urinary incontinence, recurrent UTI, voiding difficulty, urinary retention, and hydronephrosis [61]. To establish the diagnosis, uroflowmetry with an EMG is required to confirm that a sudden change in flow rate in the form of a staccato or intermittent pattern is related to sphincter contraction. Also, a "spinning-top" urethra can also be seen in a video-urodynamic study (vUDS) or voiding cystourethrography, indicating discoordination of the EUS and detrusor contraction during voiding [56].

The conventional treatments for children with DV include non-pharmacological urotherapy [62,63] and alpha-blockers [64]. Since DV and DSD share similar pathophysiology in terms of abnormal sphincteric activity during voiding, applying BoNT-A to the EUS seems to be a reasonable therapeutic option. A sphincteric BoNT-A injection was first introduced as a novel treatment for children with DV by Steinhardt et al. [65], who successfully improved incontinence and recurrent UTI in a 7-year-old girl, and also demonstrated a marked improvement in the degree of urethral dilatation.

Several case series with small samples also discussed the therapeutic outcome of BoNT-A in children with DV who failed traditional urotherapy and medical management [66–70]. According to these data, 80–85% of patients showed improvement in daytime incontinence or enuresis [68,69], total dryness was found in 45–80% of patients after sphincteric BoNT-A injections [67–70], and approximately 45–75% of patients were free from recurrent UTI even without prophylaxis antibiotics [68–70]. A small case series reported by Mokhless et al. [66] revealed that nine children who were catheterized preoperatively experienced recovery of spontaneous voiding after sphincteric BoNT-A injections. In the case of urodynamic parameters, PVR improvement was found in most of the studies, and a flow pattern changed to bell-shaped curve was also reported [69,70]. Unlike the usual dose of 50 to 100 units of Botox in pediatric sphincter injections, Franco et al. [67] used a higher dose ranging from 200 to 300 units in 16 children with DV. They reported long-lasting improvements in PVR at six months, and the majority of their patients did not require repeated injections. The authors hypothesized that BoNT-A could block sensory feedback of overactive guarding reflex, making it possible to retrain these children to void appropriately. No acute complications, including nausea, dysphagia, respiratory distress, or paralysis, were found in any of these studies. Clinical studies of sphincteric BoNT-A injections for children with DV are summarized in Table 2.

Although the effects and safety of BoNT-A use in children with DV seem to be convincing, we should remember that all these study designs were nonrandomized, without controlled variables, and comprised small samples. Further better-designed trials with longer follow up are necessary to arrive at an accurate conclusion.


*Toxins* **2019**, *11*, 728

injection group for patients with DV.

#### **5. Urethral Sphincter BoNT-A Injections in Adults with Dysfunctional Voiding**

The precise prevalence of DV in the adult population is still unknown. In a urodynamic database review of 1015 adults who were evaluated for voiding symptoms, around 2% could be defined as having DV using strict vUDS criteria [60]. Adult DV may come from persistent disease since childhood or adult-onset symptoms due to non-neurological etiologies [72]. Although adults and children with DV share similar characteristics and are defined similarly [56,73], the clinical characteristics of these two groups are quite different. Unlike children, adult patients typically present with obstructive symptoms, followed by frequency, nocturia, and urgency. Recurrent UTI and urinary incontinence are less prominent in adults [60].

Data discussing the therapeutic effect of sphincteric BoNT-A injections in adults with DV are limited and are mostly provided by Kuo and his colleagues [48,55,71]. In a prospective nonrandomized study without controlled variables, the authors performed sphincteric injections using 50 to 100 units of Botox in 20 adults with DV and reported a subjectively excellent outcome in 30% of the patients, where the remaining 70% showed improvement [48]. Liao and Kuo also reported an overall success rate of 86.7% in adults with DV by sphincteric injections with 50 to 100 units of Botox in a five-year retrospective review. DU with low abdominal straining pressure, spastic EUS, and bladder neck obstruction were the most common causes of treatment failure [55].

A randomized, double-blind, placebo-controlled study was conducted in 31 adults with DV to compare the therapeutic effect of 100 units of Botox with normal saline [71]. Even though the detrusor voiding pressure and voided volume were significantly improved in the BoNT-A group, there were no significant between-group differences in the subjective success rate. The author hypothesized that the local injection itself might have some unknown therapeutic effects on the relaxation of the EUS [71]. This concept is similar to the dry needling effect on myofascial trigger point pain, which can relax the actin-myosin bonds and normalize muscle tone [74]. Additional well-designed studies to enroll more adult patients with DV are necessary to elucidate the therapeutic effect of sphincteric BoNT-A injections, normal saline injections, or even the dry needle effect. Clinical studies of sphincteric BoNT-A injections for adults with DV are summarized in Table 2.

#### **6. Urethral Sphincter BoNT-A Injections in Patients with Fowler Syndrome**

Fowler's syndrome (FS), a specific cause of unexplained urinary retention in young women, was first described by Fowler in 1986 [75]. The condition is characterized by EUS relaxation failure with unique components of complex repetitive discharges and decelerating bursts presented in concentric needle EMG [3]. The typical feature of FS in vUDS include a large bladder capacity, reduced bladder sensation in the storage phase, decreased or no detrusor contraction with a patent bladder neck, and narrowing in the midurethra with or without ballooning of the proximal urethra [76]. The decrease in sensation and motor function in the bladder were thought to be a result of abnormally strong urethra afferent activity, which inhibits the bladder afferent signals to reach the brain as a spinal 'pro-continence' mechanism [77]. These findings are different from the pattern of the typical pattern of high-pressure low-flow in DV also caused by involuntary EUS or pelvic floor muscle contraction during voiding [78]. Whether FS is a subgroup of DV or a totally different entity remains currently unanswered.

Few studies have evaluated the effect of BoNT-A on the management of FS [55,79,80]. The first study was performed by Fowler and colleagues in 1992, where six women with FS were enrolled [79]. Two hundred units of BoNT-A (Division of Biologics, Porton Down, Salisbury, UK) were given to one side of the EUS under EMG guiding via a hollow cannula electrode. No improvements in voiding function were noted in any of the patients. One patient even developed transient stress urinary incontinence. In 2007, Liao and Kuo also reported no restoration of efficient voiding in two patients suspected to have FS with high MUP lacking a typical abnormal needle EMG pattern after injections with 100 units of Botox in four to eight EUS sites [55]. However, decreases in MUP and abdominal voiding pressure by 20 to 25 cm H2O after injections were noted by vUDS during follow up. In contrast to the poor outcome in the aforementioned studies, a 10-patient open-level pilot study in 2016 did find

promising outcomes in the management of FS using BoNT-A [80]. The injections were done with 1 mL 2% lidocaine on either side of the external urethral meatus, followed by 100 units of Botox equally divided on either side of the EUS under EMG guidance. Four of five women with complete urine retention could void spontaneously four weeks after injections. Seven of the 10 women stopped CIC ten weeks after injections. Significant improvement in the Qmax, PVR, International Prostate Symptom Score (IPSS), and urethral pressure profile were also noted at ten weeks. No serious adverse effects were reported. Clinical studies on sphincteric BoNT-A efficacy and adverse FS events are summarized in Table 3.

Due to the rarity of the disease, the difficulties associated with arriving at a definitive diagnosis that needs special equipment, the techniques required for performance, and interpretation of concentric needle EMG, these studies were all limited to a small number of patients without adequate control groups. Further large cohort studies are needed to validate these outcomes. The contradictory findings might be the result of different BoNT-A injection techniques or the different etiology behind this disease. Compared to sacral neuromodulation, BoNT-A urethra injections might serve as a less invasive, low resource, safer alternative to other methods used to treat this disease.


**Table 3.** Summary of clinical studies using sphincteric BoNT-A injections for patients with Fowler's syndrome (FS) and poor relaxation of the external urethral sphincter(PRES). BoNT-A = Botulinum toxin A; CIC = Clean intermittent catheterization; F = Female; FS = Fowler's syndrome; IPSS = international prostate symptom score; M = Male; MUP = Maximalurethral pressure; NA = data not accessible from the study; Nil = none; No. = number; Pdet = Detrusor contraction pressure; PRES = Poor relaxation of the external urethral sphincter;PVR = Post-void residual urine volume; Qmax = Maximal flow rate; QoL = Quality of life index; SUI = Stress urinary incontinence; UDS = Urodynamic study. None of these studieswere randomized or controlled. Sphincteric injections were given with preparation other than typical BoNT-A commercial form including Botox or Disport denoted as "BoNT-A". a The subjects enrolled were not typical FS patients. They had a very high baseline MUP but did not have typical patterns of FS presented in a concentric needle electromyographic study.bData were analyzed using combined groups. Individual results for specific disease groups were not available.
