[78] Foran P, Mohammed N, Lisk G, et al. Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A. Journal of Biological Chemistry. 2002;**278**(2):1363-1371. DOI: 10.1074/jbc. m209821200

[79] Neale E, Bowers L, Jia M, Bateman K, Williamson L. Botulinum neurotoxin a blocks synaptic vesicle exocytosis but not endocytosis at the nerve terminal. The Journal of Cell Biology. 1999;**147**(6):1249-1260. DOI: 10.1083/ jcb.147.6.1249

[80] Najib A, Pelliccioni P, Gil C, Aguilera J. Clostridium neurotoxins influence serotonin uptake and release differently in rat brain synaptosomes. Journal of Neurochemistry. 2008;**72**(5):1991-1998. DOI: 10.1046/j.1471-4159.1999.0721991.x

[81] Lucioni A, Bales G, Lotan T, McGehee D, Cook S, Rapp D. Botulinum toxin type A inhibits sensory neuropeptide release in rat bladder models of acute injury and chronic inflammation. BJU International. 2008;**101**(3):366-370. DOI: 10.1111/j.1464-410x.2007.07312.x

[82] Grando SA, Zachary CB. The nonneuronal and nonmuscular effects of botulinum toxin: An opportunity for a deadly molecule to treat disease in the skin and beyond. British Journal of Dermatology. 2018;**178**(5):1011-1019. DOI: 10.1111/bjd.16080

[83] Kim Y, Kim J, Lee K et al. Botulinum neurotoxin type A induces TLR2-mediated inflammatory

responses in macrophages. PLoS One. 2015;**10**(4):e0120840. DOI: 10.1371/ journal.pone.0120840

[84] Williamson LC, Neale EA. Syntaxin and 25-kDa synaptosomalassociated protein: differential effects of botulinum neurotoxins C1 and A on neuronal survival. Journal of Neuroscience Research. 1998;**52**(5):569- 583. DOI: 10.1002/(SICI)1097- 4547(19980601)52:5<569::AID-JNR9>3.0.CO;2-A

[85] Eleopra R, Tugnoli V, Quatrale R, et al. Botulinum neurotoxin serotypes A and C do not affect motor units survival in humans: An electrophysiological study by motor units counting. Clinical Neurophysiology. 2002;**113**(8):1258-1264. DOI: 10.1016/s1388-2457(02)00103-7

[86] Cohen JL, Scuderi N. Safety and patient satisfaction of AbobotulinumtoxinA for aesthetic use: A systematic review. Aesthetic Surgery Journal. 2017;**37**(suppl 1):S32-S44. DOI: 10.1093/asj/sjx010

[87] Sätilä H. Over 25 years of pediatric botulinum toxin treatments: What have we learned from injection techniques, doses, dilutions, and recovery of repeated injections? Toxins. 2020;**12**:440. DOI: 10.3390/toxins12070440

[88] Dressler D. Botulinum toxin drugs: Brief history and outlook. Journal of Neural Transmission. 2016;**123**:277-279. DOI: 10.1007/s00702-015-1478-1

[89] Thirunavukkarasusx N et al. Microarray analysis of differentially regulated genes in human neuronal and epithelial cell lines upon exposure to type A botulinum neurotoxin. Biochemical and Biophysical Research Communications. 2011;**405**(4):684-690. DOI: 10.1016/j.bbrc.2011.01.102

**Chapter 4**

## Botulinum Neurotoxin Uses in Overactive Bladder

*Mohamed H. Zahran, Ali Abdel Raheem, Ibrahim Alowidah and Diaa-Eldin Taha*

#### **Abstract**

Botulinum neurotoxin has been approved for use in different urologic disorders, especially overactive bladder (OAB). OAB is highly prevalent, with a relevant impact on patients' quality of life and the available health resources. The prevalence of OAB is 11.8% with no significant difference between male and female. Botulinum neurotoxin is now approved as a treatment of choice for refractory overactive bladder (ROAB) after the failure of behavioral and pharmacological therapy. It is associated with improvement of urgency and urge urinary incontinence in 60–70% of patients. Yet the effect is not long-standing and fades out in a mean of 6-months duration and repeated injection is warranted. Moreover, its associated side effects are not uncommon, especially urinary tract infection and urine retention. New modifications have been studied to make it less invasive, effective, and tolerable by the patients through injection-free mode. The subject to be explained in the book chapter is the role of botulinum neurotoxin in ROAB, including the mechanism of action, different types of botulinum toxin used, the accepted dose, associated side effects, and comparison of the outcome to other available treatment modalities. In addition, a close look at the new accepted approaches for intravesical administration of botulinum toxin in the bladder will be done.

**Keywords:** botulinum neurotoxin, overactive bladder, refractory overactive bladder, outcomes

#### **1. Introduction**

The International Continence Society (ICS)/International Urogynecological Association (IUGA) defines overactive bladder (OAB) as urgency with or without urge incontinence (UUI), associated with urinary frequency and nocturia in the absence of pathological (e.g. UTI, stones, bladder tumor) and metabolic factors (e.g. diabetes) [1]. The diagnosis is made by exclusion. Whether there is nerve damage or not, OAB might be classified as neurogenic or idiopathic. The prevalence of OAB is 11.8% with no significant difference between male and female and the incidence increases with age [2]. The prevalence of OAB in adults aged ≥18 years was 16% in men and 16.9% in women in the USA, and in adults aged ≥40 years, it was 15.6% for men and 17.4% for women in Europe. In Asia, the prevalence of OAB was lower, but it was still 6.0% with no differences between male and female [3].

As a result, proper understanding and management of OAB is mandatory to improve patients' quality of life and decrease its socioeconomic burden. Behavioral therapy, bladder retraining, and pelvic floor exercise represent the first line of management of OAB. Pharmacotherapy is the second line of treatment. Anticholinergics and β3 agonists have been shown to be clinically effective in people with OAB [4]. Yet, it has many side effects such as dry mouth, dry eyes, constipation, blurred vision, dyspepsia, urine retention, and reduced cognitive function, which limit their use especially in elderly. More than 70% of patients discontinue medication within 6 months to 3 years due to side effects [5]. Refractory OAB (ROAB) develops when both behavioral therapy and oral medications become no longer effective [5]. The AUA/SUFU guidelines describe ROAB as a failure of behavioral therapy after 8–12 weeks and failure of at least one anticholinergic agent used for 4–8 weeks [6]. ROAB has an unknown prevalence rate, but it is not uncommon among the OAB population [7]. Third-line treatment should be considered when patients fulfill the ROAB diagnostic criteria. Sacral neuromodulation (SNM) and Botulinum neurotoxin-A (BoNT-A) have been recently demonstrated to be successful, with success rates reaching up to 60% and 70%, respectively [6].

BoNT-A is frequently used for cosmetic purposes and is used to treat strabismus, blepharospasm, muscle dystonia, hyperhidrosis, and migraine [8]. Carpenter was the first to prove that botulinum neurotoxin inhibits bladder contractility in rats in 1967. In 2011, BoNT-A was licensed for the treatment of urine incontinence (UI) caused by neurogenic overactive detrusors. The US Food and Drug Administration (FDA) approved it for the treatment of OAB in 2013 [9].

#### **2. Pathophysiology and management of OAB**

OAB is a chronic condition of urgency, frequency, nocturia with or without UUI. It is sub-classified into dry and wet type based on the absence or presence of the UUI. The exact cause of OAB is not well-understood. The pathophysiology varies between neurogenic, myogenic, or idiopathic factors [10]. The imbalance between the excitatory and inhibition neural pathway to the bladder is one of the underlying mechanisms. Also, the increased sensitivity of bladder muscle receptors and muscarinic receptor upregulation plays a role in OAB pathophysiology [11]. Another potential cause is the myogenic dysfunction secondary to structural or functional alteration of the detrusor smooth muscle. Idiopathic detrusor instability of undetermined underlying cause is another mechanism [10].

Proper history taking and at least a 3-day bladder diary are indicated for initial evaluation of patients in order to quantify OAB symptoms. Urodynamic evaluation is essential for establishing the diagnosis. The hallmark urodynamic feature of OAB is detrusor overactivity (DO). Yet, it may not be demonstrated in some patients due to the inability to reproduce symptoms during the urodynamic [12]. It is worth mentioning that urodynamic diagnosis has no proven predictive value for the treatment response [13]. And EAU guidelines recommended against routine urodynamic evaluation before starting the first line of treatment for uncomplicated OAB [14].

The first line of management is conservative treatment in the form of lifestyle modification (fluid restriction, decrease caffeine intake, weight reduction, and stop smoking), behavioral therapy, bladder retraining, timed voiding, and pelvic floor muscle exercise [14]. Bladder retraining and timed voiding work by setting a target time for using the toilet before it patient should not void. Once this is achieved the

*Botulinum Neurotoxin Uses in Overactive Bladder DOI: http://dx.doi.org/10.5772/intechopen.102396*

time can be lengthened. Thus the central control can be re-learned as in infancy. Pelvic floor muscle training; described by Kegel, aims at strengthening and rehabilitating the pelvic floor muscle, increasing its tone, and increasing urethral resistance [15].

The second recommended line of treatment is pharmacotherapy. It can be initiated together with conservative treatment or postponed till the failure of conservative treatment based on the OAB symptoms severity. The EAU and AUA guidelines recommended anticholinergics and β3 agonists as a pharmacological treatment of OAB [6, 14]. Anticholinergics are competitive muscarinic receptors antagonists. They prevent cholinergic muscarinic receptors activation in the urinary bladder and consequently reduce spontaneous detrusor muscle activity during the filling phase and decrease detrusor pressure. Many anticholinergics have been used in clinical trials and none proved to be superior to the others in OAB management. Dose escalation may be appropriate in certain patients and increases the response [16]. The efficacy of anticholinergics varies between 50% and 75%. They help to reduce urgency and UUI episodes along with reducing frequency of micturition. However, adherence to anticholinergic treatment is low and decreases over time because of lack of efficacy, adverse events, and/or cost and a significant number of patients will stop anticholinergic agents within the first 3 months [17, 18].

When anticholinergics are ineffective, non-tolerated, or contraindicated, β3 agonist (mirabegron) can be used. It activates the β-3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity helping the bladder to fill and store urine. Yet, it is not free of side effects. Tachycardia, hypertension, dyspepsia, palpitations, atrial fibrillation, joint swelling, rash, and pruritus were reported with mirabegron use [19].

Patients who are refractory to behavioral and pharmacologic therapy should be properly reevaluated. If the diagnostic criteria of ROAB are fulfilled, a third-line treatment should be offered. Third-line therapy recommended by guidelines is intradetrusor injection of BoNT-A or sacral neuromodulation [6, 14].

#### **3. Mechanism of action of botulinum neurotoxin**

Botulinum toxin is a neurotoxin derived from Gram-positive, spore-producing bacteria (*Clostridium botulinum*). The bacteria produce seven serotypes (A–G) of botulinum toxin each with different antigenic profiles and biochemical actions; however, they all have a similar pharmacological effect [20]. Botulinum toxin types A (BoNT-A) and B (BoNT-B) have been developed for clinical use. BoNT-A has the longest duration of action which makes it more suitable for clinical use.

BoNT-A is synthesized as a single polypeptide chain (150 kDa) which is cleaved into a light chain (50 kDa) and a heavy chain (100 kDa) held together by a fragile disulfide bond and noncovalent bonds. The available formulations of BoNT-A are BOTOX (onabotulinumtoxin A) (Allergan, United States), Dysport (abobotulinumtoxin A) (Ipsen, United Kingdom), and Xeomin (incobotulinumtoxin A) (Merz, Germany). Each formulation of BoNT-A has its own dosing regimen which is not interchangeable. BOTOX is most commonly used followed by Dysport (the former is five times more potent than the latter) [20].

Although fibroblast growth factor receptor 3 has been mentioned as a potential BoNT-A receptor, two forms of BoNT-A cell-surface receptors have been identified: gangliosides and the synaptic vesicle-associated protein 2 (SV2) family [21]. BoNT-A's heavy chain attaches to SV2 on the nerve terminals' surface, followed by endocytic internalization of the toxin within the nerve terminal. The toxin is broken within the synaptic vesicle after translocating into the cytoplasm, leaving the light chain of BoNT-A as the actual active moiety. BoNT-A light chain can then cleave synaptosomeassociated protein (SNAP25) off the SNARE proteins, a complex protein that when intact forms the core of the neuroexocytosis machinery. This disrupts the fusion of neurotransmitter-containing vesicles with the neuronal cell membrane, inhibiting neurotransmitter release [22].

SV2-immunoreactive and SNAP25-immunoreactive nerve fibers are found in the sub-urothelium and muscle layer of the human bladder, but not in the urothelium. Almost all parasympathetic nerves express SV2 and SNAP25, while only about half of sensory and sympathetic nerves do [23]. Cleaved SNAP25 is the final product of the BoNT-A light chain's enzymatic activity. It is regarded as an appropriate marker of BoNT-A's action and, thus, an essential target in future research [24].

#### **3.1 Motor effect of BoNT-A**

Intradetrusor injection of BoNT-A temporarily blocks the presynaptic vesicular release of acetylcholine (ACh) at the neuromuscular junction of the parasympathetic nerves supplying the detrusor muscles and decreases detrusor pressures and phasic contractions in both idiopathic and neuropathic bladders. However, patients also report a significant decrease in urgency and hence, it is hypothesized that botulinum toxin also modulates the sensory pathways [20].

#### **3.2 Sensory effects of BoNT-A**

BoNT-A suppresses bladder sensations by processes unrelated to its effects on ACh release. Transient receptor potential vanilloid subfamily 1 (TRPV1) and P2X3 immunoreactive fibers can be seen throughout the sub-urothelium of the human bladder [25]. BoNT-A injection reduces TRPV1 and P2X3 activity in sensory nerve fibers with subsequent reduction in the frequency of urgency episodes [26]. Also, intravesical BoNT-A injections have been demonstrated to reduce ATP and neurotrophin release from urothelial cells and increase NO release [27]. ATP has been shown to play a role in the pathophysiology of OAB by mediating the sense of bladder fullness [27].

#### **4. Techniques of administration of BoNT-A**

Intradetrusor injection of BoNT-A should be offered to carefully-selected and thoroughly-counseled patients with ROAB not responding to the previous two lines of treatment. Patients should be able and willing to maintain close follow-up and frequent PVR estimation and accept the possibility of self-catheterization [6].

Patients should be given enough written and verbal peri-procedure instructions, as well as information regarding urinary tract infection (UTI) and urine retention. Prophylactic antibiotics are recommended for all patients and continue for 1–3 days postoperatively. Urinalysis should be performed before the procedure to rule out active infection. Administration of intradetrusor BoNT/A injections has been described in an office setting under local anesthesia or in the operating room with regional or general anesthesia using a flexible or rigid cystoscopy.

*Botulinum Neurotoxin Uses in Overactive Bladder DOI: http://dx.doi.org/10.5772/intechopen.102396*

For idiopathic detrusor overactivity typically 100–200 units of BOTOX (diluted in 20 mL of normal saline) or 750–1000 units of Dysport have been used. BOTOX 100 U is licensed in Europe to treat OAB with persistent or refractory UUI in adults of both genders [14]. Similarly, the AUA guidelines recommended 100 U of BOTOX as a third-line of treatment of OAB [6].

There is no consensus on the ideal injection technique. The location of injections, the depth of injections, the number of injection sites, and the volume at each site vary in literature. Kuo et al. looked back at injection sites and discovered that success rates were the same whether they were in the bladder body alone, the trigone alone, or the bladder body and trigone together [28]. In a subsequent meta-analysis of OAB patients, no significant differences in efficacy between trigonal sparing and nontrigonal sparing injection techniques were found with short-term cure rates of 52.9% and 56.9%, respectively [29].

The injection depth varies as well and is influenced by the length of the needle tip (available tips range between 2 and 8 mm) used for injections. Some authors added a trace amount of indigo carmine or methylene blue to the injection solution to facilitate observation of the procedure and assessment of drug distribution [30]. Even among the same surgeons, there is likely to be some variation, and no study has determined whether sub-urothelial or intradetrusor injection is preferable. However, intradetrusor injections, as opposed to submucosal injections, with sparing of the trigone are favored. Again, there is no consensus on the number of injection sites and the dilution of the toxin but generally, 20 sites are injected and the volume per injection is usually 0.5–1 mL (**Figure 1**) [31].

#### **4.1 Precautions during injection**

#### **5. Efficacy of BoNT-A injection in ROAB**

In a multicenter double-blinded randomized trial compared the efficacy of 50, 100, and 150 U onabotulinum toxin A to placebo in OAB patients, at 3 months >50% improvement in urgency and UUI was reported by 37% of the 50 U patients, 68% of 100 U patients and 58% of 150 U. Only the 100 U groups was statistically significant compared to the placebo group. Frequency was statistically significant, reduced in 100 and 150 U groups and complete continence at 3 months was significantly greater in the 100 U group (55%) and the 150 U group (50%) compared to the placebo group (11%). At five-months post-treatment, these differences were maintained [32].

A phase III trial randomized 557 OAB-wet patients; whose symptoms were not responded to anticholinergics to receive bladder wall injections with BoNT-A (100 U) or saline. At week 12, in patients treated with BoNT-A, UUI episodes were halved and the number of micturitions reduced by more than two. A total of 22.9% of the patients in the BoNT-A arm were fully dry, against 6.5% in the saline arm [33]. Tincello and colleagues published the results of the RELAX study including 240 women with refractory OAB to compare 200 U BoNT-A and placebo injections. At 6 months, voiding frequency, urgency, and incontinence episodes per day were significantly reduced in patients receiving BoNT-A injection. Continence was also significantly higher in the treatment group (31% vs. 12%, p = 0.002) with subsequent statistically significant improved patients' QOL [34].

In early systematic review assessing the efficacy and safety of botulinum toxin in the management of OAB, Anger et al. reported that BoNT-A treatment improved incontinence episodes and patients' QOL scores, as shown by a 15-point drop in Urinary Distress Inventory scores compared to placebo-injected patients [35]. In a recent systematic review and network meta-analysis, BoNT-A (100 U) had associated with the greatest reductions in urinary incontinence (UI) episodes, urgency episodes, and micturition frequency, and the highest odds of achieving decreases of 100% and ≥50% from baseline in UI episodes/day. In comparison to other pharmacotherapies, BoNT-A was more superior in reduction of UUI episodes, urgency,

*Botulinum Neurotoxin Uses in Overactive Bladder DOI: http://dx.doi.org/10.5772/intechopen.102396*

and frequency and was associated with higher odds of achieving a 100% and ≥50% decrease in UUI episodes/day than most other treatments in the network [36].

Moreover, pre-treatment with BoNT-A improved patients' response to anticholinergic treatment. One hundred pre-treated patients with intravesical injections of 100 IU of BoNT-A and the effect faded, were randomized to receive 10 mg solifenacin and placebo for 12 weeks. After 12 weeks of follow-up, all overactive bladder symptom score items, including the total score, had improved significantly (P < 0.0001) in solifenacin group. Also, urodynamic parameters including frequency and amplitude of detrusor contractility and detrusor leak point pressure decreased significantly with increased cystometric capacity and improved incontinence quality of life parameters with solifenacin re-treatment [37]. This was explained by the possibility that repeated BoNT-A injections increased bladder capacity and restored the normal numbers and function of M3 receptors, potentially restoring patients' responsiveness to anticholinergic drugs [37]. This was based on the clinical findings and immunohistochemical assays which evidenced that BoNT-A injections could restore the number and efficacy of intra vesical urothelial and suburothelial receptors [38].

The effects of BoNT-A injection last for 4–10 months (mean 6 months). The median time to request re-treatment in the pooled analysis of the two RCTs was 24 weeks [33, 39]. Follow-up over 3.5 years showed the consistent or increasing duration of effect for each subsequent injection, with a median of 7.5 months [14].

#### **6. Botulinum toxin injection-related adverse events**

Intradetrusor injection of BoNT-A is still an invasive procedure and associated with a considerable incidence of adverse events. The local side effects include pain, UTI, bleeding, no benefit, need for further injections, need for temporary self-catheterization. The generalized side effects include flu-like symptoms, dry mouth, and malaise. Bauer et al. focused on side effects with botulinum toxin injection and reported that 54% of patients reported at least one side effect [40].  However, symptoms other than urinary retention and UTI were transient and resolved without the need for further treatment [40].

The reported rate of UTI ranged from 3.6% to 54.5% from different RCTs [6] and some reported increased rates of UTI with increases in the dose [41].

Increased PVR and the need for self-catheterization is not uncommon adverse event after botulinum toxin injection. The rate of urinary retention in published studies ranges from 5.4 to 43%, depending on how retention is defined [6, 20, 33, 39]. An interim analysis of a long-term extension study found that the proportions of patients requiring CIC remained stable at 4.6%, 4.1%, and 4.7% after one to three BoNT A treatment cycles, respectively [20]. The onset of urinary retention usually coincides with the onset of clinical efficacy, which occurs between 5 and 10 days after injection and the duration of retention varies, with some patients only requiring CIC for a few days, while others require CIC for the duration of the drug's effects [42–44]. Multivariate analysis revealed that preoperative PVR ≥ 100 ml and preoperative bladder capacity were associated with postoperative urinary retention for the first BoNT-A treatment. Preoperative PVR, BoNT-A units injected, and retention after the first injection were all associated with an increased rate of postoperative retention in those who received a second BoNT-A treatment [45].

Mild hematuria is expected to occur transiently after the procedure due to the injection technique, but severe hematuria requiring intervention or hospitalization for bladder irrigation occurs infrequently [44]. Not all patients benefit from treatment, and many patients discontinue injections outside of clinical trials due to a lack of efficacy or intolerable side effects, such as the need for catheterization [43].

#### **7. Botulinum toxin versus SNM for ROAB**

The choice between both BoNT-A and SNM for the management of ROAB is influenced by many factors. BoNT-A is a straightforward day case or outpatient procedure, which could be performed with local anesthesia or intravenous sedation. But it is still an invasive procedure. Also, due to the self-limited duration of action, reinjection every 6 months may be necessary. Whereas, SNM is more complex that necessitates a two-step procedure. However, its effect can last for 4–6 years or even longer. Currently, SNM associated risk of injury and surgical complexity are more tolerable due to the standardized and popularity of the technique. As a result, patients may prefer treatment with a longer duration [46]. Safety and effectiveness are critical factors to consider when making a decision. Efficacy and safety of BoNT-A injection and SNM are often assessed using successful treatment rates (symptoms of OAB improvement >50%) and adverse events,

#### **Table 1.**

*Comparison of the sacral neuromodulation and botulinum toxin treatment.*

*Botulinum Neurotoxin Uses in Overactive Bladder DOI: http://dx.doi.org/10.5772/intechopen.102396*

respectively. In A multicenter randomized trial that compared the 2-years outcome of BoNT-A and SNM, no difference in mean UUI episodes reduction was found (*p* = 0.15), with no differences in UUI resolution, ≥75% or ≥50% UUI episodes reduction [46]. Others reported that SNM had a better success rate than BoNT-A after 6 months of follow-up [47]. In a recent systematic review, no significant difference was found in successful treatment between BoNT-A and SNM at 6 months after procedures [48].

The injection of BoNT-A is associated with a significant rate of side effects, particularly urinary retention. Local discomfort and infection are prevalent in SNM and are easily managed. As a result, compared to SNM, BoNT-A injection has a safety disadvantage. Both options have opposing viewpoints on their efficacy.

The suggestion would be reconsidered if we introduced cost-effectiveness. BoNT-A injection would be a cost-effective choice over a two-year period. The results of the ROSETTA randomized trial identified that two-year costs were higher for sacral neuromodulation than for BoNT-A and persisting through 5 years [49]. While at 10 years, SNM provides a considerable possibility of symptom and quality-of-life improvement and is more cost-effective compared to BoNT-A [50]. As a result, in the long run, SNM would be the better alternative.

In the case of the non-responder who was initially treated with SNM or BoNT-A injection, we do not know whether we can switch to another therapy or how effective it will be. BoNT-A can be used in SNM non-responders with a success rate of 43.4% but is associated with a high long-term discontinuation rate (55%) [51].

Furthermore, the success rate in ROAB patients who used SNM therapy after failed BoNT-A therapy was 58.5%. There was no significant difference between ROAB patients who chose SNM as replacement therapy after failed BoNT-A therapy and those who used SNM therapy as first (**Table 1**) [52].

#### **8. Future perspectives**

As mentioned before, intra-detrusor injection of BoNT-A is still an invasive procedure that requires anesthesia and is associated with specific complications especially UTI and urine retention. Also, the efficacy and safety of intra-detrusor injection are sensitive to injection volume and depth, and this issue has motivated researchers to study injection-free modes of drug delivery into the bladder [53]. Therefore, intravesical instillation rather than injection of BoNT-A seems to be a sound idea. Nevertheless, BoNT-A delivery to the bladder tissue after intravesical instillation is hampered by toxin degradation by urine proteases, dilution by urine at the time of instillation, and poor uptake due to the urothelium impermeability, which results from the watertight barrier located at the umbrella cells in the superficial layers of bladder urothelium that are augmented by glycosaminoglycan and uroplakins [54].

To overcome this barrier, intravesical instillation of BoNT-A formulated with liposome (lipo-botulinum toxin) to enhance its absorption was evaluated in two studies; one pilot study and a 2-center, double-blind, randomized, placebo-controlled trial. After 1-month, lipo-botulinum toxin instillation was associated with a statistically significant reduced urinary frequency and urgency; however, the treatment did not reduce UUI episodes. Furthermore, onabotulinum toxin complexed with liposomes did not result in urinary retention [55, 56].

Another method tested was to add a chemical agent that enhances drug delivery into the bladder tissue. Dimethyl sulfoxide (DMSO) is an organic solvent that has been used to facilitate the delivery of several anticancer drugs into animal bladders. Petrou et al. studied 25 women with ROAB that were given BoNT-A (300 U) mixed

with 50% DMSO. Efficacy and toxicity were assessed at baseline, 1 and 3-months after treatment. The median number of UUI episodes decreased at 1 month (p = 0.004) and then increased back at 3 months. Also, a significant reduction in symptom scores from baseline was noted. The Impact Questionnaire short form improved from 13 to 7 at 1 month (p = 0.007), and the Urogenital Distress Inventory improved from 10 to 5 at 1 month (p = 0.003). No serious side effects or urinary retention were noted [57].

Kodama et al. stated that low energy shock waves (LESWs) increase tissue permeability and drug delivery into cells by the shear force generated by the movement of liquid relative to cells, which temporarily affects the permeability of the plasma membrane. So, it can deliver macromolecular drugs into the cell cytoplasm without toxicity [58]. In the OAB-rat model, intravesical instillation of BoNT-A plus LESW group showed statistically significant lower amplitude.

(p = 0.001) and lower frequency of detrusor contractions (p = 0.01). Histologically, combined treatments significantly reduced submucosal edema and inflammatory cell infiltrate scores. Moreover, BoNT-A plus LESW significantly increased tissue expression of antioxidant marker (superoxide dismutase) and suppressed oxidative stress marker (malondialdehyde) and inflammatory cytokines (tumor necrotic factor-α and interleukin-6) [59].

In preliminary clinical study, including 15 patients with ROAB, Intravesical instillation of 100 IU of BoNT-A was done followed by LESWs (3000 shocks over 10 min) exposure to the suprapubic area was tested. Patients were followed-up by urine analysis, urine culture, PVR, and Overactive Bladder Symptom Score (OABSS) at 1, 2, and 3 months. Patients showed statistically significant improvements in all OABSS domains and the total score after 1 and 2 months of treatment (P < 0.05). Whereas, only the nocturia domain remained significantly improved after 3 months (P = 0.02). Seven (46.6%) and 12 (80%) patients were totally dry at 1 and 2 months, respectively. Also, treated patients had no significant increase in PVR throughout the study period (P > 0.05), and none of the patients required clean intermittent catheterization [60].

Further research to optimize the procedure of injection to be less invasive, more effective, and improve the injection-free mode is mandatory and expected in the near future.

### **9. Conclusion**

*Botulinum Neurotoxin Uses in Overactive Bladder DOI: http://dx.doi.org/10.5772/intechopen.102396*

#### **Conflict of interest**

Authors have no conflict of interest to disclose.

### **Author details**

Mohamed H. Zahran1,2\*, Ali Abdel Raheem3,4, Ibrahim Alowidah4 and Diaa-Eldin Taha4,5

1 Urology Department, Urology and Nephrology Center, Mansoura University, Egypt

2 Urology Department, King Salman Armed Force Hospital, Tabuk, Saudi Arabia

3 Urology Department, Tanta University, Egypt

4 Urology Department, King Saud Medical City, Riyadh, Saudi Arabia

5 Urology Department, Kafr Elsheikh University, Egypt

\*Address all correspondence to<EMAIL_ADDRESS><EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 5**

## Gummy Smile and Treatment with Botulinum Toxin Type A (Botox)

*Imad Katbeh, Mohammad Osama Makkeiah, Tamara Kosyreva and Lada Saneeva*

#### **Abstract**

A smile plays an important role in determining a person's initial impression, and its assessment has become integral to clinical evaluation. A smile with an esthetic appearance should be symmetrical and should reveal less than 2 mm of gums when smiling. A gingival smile, gummy smile, or high smile line, is defined as the number of excess gums on the upper jaw exposed. This may have some serious psychological repercussions on the patient, which may sometimes lead them to conceal their smile to avoid "embarrassment." One of the most common methods of treating a gingival smile resulting from an overactive lip is lip reposition as a surgical procedure and the injection of type A (Botox) toxin as an injectable inhibitor of muscle action. However, many patients refrain from surgical treatment because of fear of complications and pain. In this case, injections of botulinum toxin group A are an excellent alternative to surgery. The injection of botulinum toxin takes less time and with the correct dosage and compliance with the protocol of its administration causes much fewer complications. The study presented here is devoted to the disclosure of the potential of this tool in esthetic dentistry.

**Keywords:** lip repositioning, gummy smile, hyperactive upper lip, excessive gingival display, botulinum toxin type A

#### **1. Introduction**

Since facial expression and smile are the main components of nonverbal communication, as they play an important role in creating an initial favorable impression in business and friendly communication; therefore, they are given such importance when conducting a clinical evaluation. It should be borne in mind that when the facial expression changes, it can show pleasure, sympathy, indifference, approval or disgust, amazement or fright, thus various facial defects, including a gummy smile (excessive gingival display), can make it difficult for the patient to build relationships with other people, and if he/she is suspicious, deprive him/her of psychological comfort and contribute to the emergence of various psychological complexes.

In modern society, great importance is attached to the esthetics of appearance, this is what greatly contributed to the development of the elite direction of esthetic dentistry and cosmetology, the patient's smile has become an important marker of their viability and activity, not to mention its influence of this parameter on the patient's self-confidence, which we mentioned earlier. Various structures of the face and the dentoalveolar system are involved in the formation of a smile, respectively, any defect in them will cause a change in the smile and, most likely, will require correction, that is, certain medical procedures.

A smile that meets high esthetic standards should be symmetrical, it is believed that with a beautiful smile, less than 2 mm of gums should be exposed, not every patient meets this standard, so recently, it has become common for many people to hide their smile when they are happy or photographed. This phenomenon is known as a "gummy smile," which is a large exposure of the gums when smiling, creating an appearance far from pleasant or desirable in the eyes of others.

#### **2. Gummy smile**

This excessive exposure of the gums in a full smile occurs as a result of an imbalance in the interaction of the three main components modeling the smile mentioned above—lips, gingiva, and teeth.

Hulsey pointed out that the most attractive smiles were those in which the upper lip reached the level of the gingival edge of upper incisors [1].

Chiche and Pinault concluded that exposure of up to 3 mm of the gingival tissue could still be considered satisfactory [2]. Hunt et al. argued that the acceptable range of gingival exposure was between 0 and 2 mm, with the ideal situation being no exposure at all [3]. Geron and Atalia found that any maxillary gingival exposure above 1 mm would be considered unesthetic [4].

Since other researchers have recently discovered that 3 mm of gum exposure worsen the appearance of the patient, which does not meet the esthetic expectations of modern society, thus 2 mm of gum exposure would be the maximum for an esthetically acceptable smile, and therefore, it can be said that the ideal amount of gum exposure with a full smile is 0–2 mm. In other words, an exposure of up to 3 mm can still be considered esthetically acceptable, but if it is over 3 mm with a full smile, then such a smile should be called a "Gummy smile" or "Gingival smile" [4–6].

The prevalence of a gummy smile is 10–15% at the age of 20–30 years, but with age, due to sagging muscle tissue of the upper lip and its covering with gingival tissue along with part of the teeth of the upper jaw, the incidence decreases. The prevalence of gummy smile varies according to gender. A study found that the amount of gingiva exposed when smiling in females was 1.5–2 mm greater than males, at a rate of 7% in males and 14% in females [7].

#### **3. Treatment of gummy smile caused by dentoalveolar factors**

#### **3.1 Treatment of gummy smile caused by shortening the clinical crown length of maxillary anterior teeth**

Here, the distinction should be made between the two cases.

If shortness in the clinical length is caused by the gums covering the crowns of maxillary anterior teeth, it is treated with a traditional gingivectomy [8].

If there is a shortening in the clinical crown length of maxillary anterior teeth with normal gingival growth, here it is necessary to remove an amount of the bone as well as treat this case by surgically lengthening the teeth.

One of the criteria that should be followed before starting to lengthen the crowns is the availability of a sufficient amount of attached gingiva of no less than 3 mm to reduce postoperative gingival recession and maintain vital presentation [9].

#### **3.2 Treatment of gummy smile caused by dentoalveolar eruption**

Treatment is through orthodontic work, correction of the axis of maxillary anterior teeth, and orthodontic intrusion. Sometimes, surgical intervention might be necessary in cases of deep bite and excessive overjet following a comprehensive clinical and radiographic study.

In other words, bone, periodontal ligament, and soft tissues move with teeth movement, so intrusion helps to improve gummy smiles. On the other hand, with the emergence of orthodontic implants, which are known as temporary anchorage devices, anterior teeth intrusion has become a possibility.

#### **3.3 Treatment of gummy smile caused by gingival hyperplasia**

Gingival hyperplasia accompanied by periodontal pockets is treated with conventional surgical resection of the gum, necessary to achieve optimal periodontal condition and reduce the depth of periodontal pockets so that they do not exceed the mucosal-gingival junction.

#### **3.4 Treatment of gummy smile caused by soft tissue factors**

Shortening of the upper lip and hyperactivity of levator labii superioris muscle. Traditional orthodontic surgical methods of treating gummy smile are perceived by patients to be painful and unacceptable methods. Therefore, it was necessary to devise less invasive and more patient-acceptable methods to fulfill esthetic demands. These methods include surgical lip repositioning, injection of botulinum toxin type A (Botox), and maxillary anterior nasal spine implants.

#### *3.4.1 Surgical repositioning of the lip*

This is a surgical technique performed under local anesthesia to reposition the lip, which helps to reduce gingival exposure by limiting muscle tension of the levator labii superioris muscle by decreasing the depth of the vestibule. This is achieved through the removal of a spindle-shaped strip of the vestibular fold either with cutting insertions of the levator labii superioris muscle (fully thick slice) [10] or without (partly thick slice) [11].

*Indications for surgical repositioning of the lip:*

4.Sufficient amount of attached gingiva no less than 3 mm.

*Contraindications for surgical lip repositioning:*

#### *3.4.2 Anterior nasal spine implants*

Maxillary anterior nasal spine implantation obstructs lifting of the upper lip, which helps to reduce gingival exposure when smiling.

Austin describes this technique; a pocket is created by bilaterally incising and raising the periosteum from the maxillary anterior nasal spine by 10 mm. The pocket is then filled with silicone and the latter is left to solidify and take on the shape of the area. It is then removed, the hard edges trimmed, re-implantation performed, and the pocket sutured. Results were good and patients were fully satisfied. However, during such interventions, infection of the periodontal pocket may occur, and in this case, it will be necessary to remove all its contents and administer antibiotics [12].

#### *3.4.3 Botox injection*

#### *<IP_ADDRESS> Botox: concept and history*

It is considered one of the non-surgical alternatives to reduce gummy smile caused by the hyperactivity of the levator labii superioris muscle. This technique has become a part of clinical practice [13].

The term Botox is a combination of two words—botulinum and toxin, where the first refers to the name of the microbes from which this substance is extracted, and the second means poison in English. Thus, it consists of substances extracted from the bacterium clostridium botulinum [14, 15].

The Botox known to us today was developed by US ophthalmologist Alan Scott in 1970, who said the following about his product: "When I developed it, I knew that it could do miracles with regard to neurological problems, but I never knew that it might work as a cosmetic substance" [16].

At first, Alan Scott and his colleague Schantz used low doses of serotype BTX A to treat cases of "strabismus" and cases of blepharospasm. Thus, initially, since the 1970s, this drug was used to treat strabismus and then found its application in cosmetology and esthetic medicine.

In 1989, FDA approved Allergan's BTX A as an effective and safe treatment for blepharospasm, strabismus, hemifacial spasm, and 7th cranial nerve disorders. In April 2002, it obtained approval to treat glabella lines associated with corrugator supercilii and procerus muscles activity. In 2004, it was approved as a treatment for axillary hyperhidrosis [17].

#### *<IP_ADDRESS> Biochemical and physical properties of Botox*

Clostridium botulinum, which is a gram-positive, anaerobic spore-forming bacterium, produces multiple exotoxins.

The most stable and potent exotoxin is BTX A. Its median lethal dose in monkeys is 39 U/kg—approximately 2500–3000 U/kg in humans.

BTX A has a neurotoxic effect by suppressing synaptic transmission in cholinergic nerve endings. When it overlaps with presynaptic terminations, it prevents the extracellular release of acetylcholine, that is, it can be used to reduce skeletal muscle tone by binding to a synaptosomal protein (SNAP-25), which inhibits the release of acetylcholine from motor neurons and activates presynaptic repolarization [18]. Side effects are limited to the peripheral nervous system and mainly occur through the neuromuscular junction (NMJ), but it should be noted that the nerve endings of the ganglia can also be affected.

When it affects NMJ's nerve endings, BTX A causes denervation of muscle fibers and triggers reversible paralysis. It should be noted that denervated muscles can atrophy after BTX A administration, but they restore sensitivity to neurotransmission by producing acetylcholine receptors outside the compound. Motor neurons also develop new endings, so if given enough time to recover, they will eventually reverse the paralysis. When BTX A is administered for therapeutic purposes, its effectiveness is limited to a few months [19].

#### *<IP_ADDRESS> Therapeutic applications*

The number of therapeutic applications of BTX A has significantly expanded after years of study on humans, for whom local injection of BTX A is the primary treatment for blepharospasm, spastic dysphonia in addition to strabismus and hypersalivation, myoclonus, stuttering, nystagmus, tremor, and focal hyperhidrosis.

#### *<IP_ADDRESS> Botox cosmetic indications*

Botox treatment can be recommended to a patient of any age since the appearance of wrinkles is usually associated with high activity of facial muscles, and not with age-related skin changes in patients. Therefore, it is possible to come across patients who are in their twenties. It is worth noting that its result will be much better if Botox is used before the formation of deep wrinkles, which are difficult to remove even during the facelift. The complexity of the procedure depends on the severity, depth and location of wrinkles, and primarily on the quality and thickness of the skin. It should be noted that the use of Botox is limited in the area of the circular muscle of the mouth due to its active participation in the processes of eating and speech formation.

#### *<IP_ADDRESS> Contraindications*

*Absolute contraindications:* Botox is not used in the following cases:

*Relative contraindications:*

*Gummy Smile and Treatment with Botulinum Toxin Type A (Botox) DOI: http://dx.doi.org/10.5772/intechopen.102341*

*Disadvantages of Botox*

Botox is used in dentistry and maxillofacial surgery in the following cases:

#### *<IP_ADDRESS> Gummy smile and treatment with type A botulinum toxin injection*

In a pioneering study by Polo [22], botulinum toxin injection to treat gummy smile showed promising results, as it did not require either surgery or anesthesia. Instead, a high cosmetic effect was achieved by reducing the amount of gum exposure by inhibiting and partially blocking by introducing Botox type A into the projection area of the following muscles—the levator labii superioris and the zygomatic muscle [22].

In another study by Polo [23] that involved 30 patients, two points were injected with five units of Botox bilaterally above the levator labii superioris alaeque nasi and zygomaticus minor muscles. Gingival exposure improved by 0.09 mm two weeks after injection.

Hwang [16] performed measurements on corpses to determine the Yonsei point for a single injection of targeted muscles, including the levator labii superioris alaeque nasi. The Yonsei point was determined to be at the center of a triangle formed by the intersection of the muscle's levator labii superioris, levator labii superioris alaeque nasi, and zygomaticus minor muscles, laterally located 1 cm on the transverse plane, and 3 cm above the lip line on the frontal plane in both men and women.

In a 2010 study, Mazzuco and Hexcel classified patients with a gummy smile into three categories:

*Anterior gummy smile*—a single injection point in the lateral nasolabial fold 1 cm below the levator labii superioris alaeque nasi.

*Posterior gingival smile*: two injection points—the first in the nasolabial fold at the point of maximum contraction when smiling; the second, 2 cm lateral to the first point at the level of the tragus of the ear (zygomaticus minor and major).

*Mixed anterior and posterior gingival smile*—both anterior and posterior injection points (levator labii superioris alaeque nasi and zygomaticus minor and major muscles).

*Asymmetrical gingival smile*—two posterior injection points on the side of the greater gingival exposure and only in the lowest point on the opposite side (zygomaticus minor and major) [15].

Sucupira and Abramovitz [24] used only one injection point 3–5 mm lateral to the nostril, targeting the levator labii superioris alaeque nasi muscle. They reported 84% improvement rate.

As for Suber, he used three injection points: 2 mm lateral to the pterygopalatine fossa at the level of the nasal passage, followed by another 2 mm lateral to the first at the same transverse level, and a third injection 2 mm below and between the first and second sites. The resulting injection sites were drawn as an inverted triangle [25].

Dinker et al. used Botox type A to manage the problem of gummy smile [26].

Aly and Hammouda [27] proposed combining Botox injection and lip repositioning for cases of gummy smile resulting from vertical maxillary excess.

Similarly, Pedron and Mangano [28] discussed the benefit of combining gingivectomy and Botox injection in the management of cases of the gingival smile. They used graded 1 mL 30 G insulin syringes, and, as for type A botulinum toxin, a 100-U vial, along with sodium chloride solution (serum), cotton, and alcohol.

#### *<IP_ADDRESS>.1 Type A botulinum toxin injection technique*

Injection sites are to be determined in three places on each side through muscular activity (smiling) and probing the extent of contraction to ensure accurate muscle position before injection, given that there might occur minor anatomical site variations with no local anesthesia performed.

Surface facial marks used for locating injection sites according to Suber [25]. The resulting injection sites were drawn as an inverted triangle. The bone marker was the forefront of the maxilla attached to the muscles covering it—levator labii superioris alaeque nasi and zygomaticus minor [25].

The amount of botulinum toxin used for each target muscle was 2.5 units. A 100 unit bottle of dried botulinum toxin type A dissolved by adding 2 mL chloride saline serum under sterile conditions so that the dilution ratio was ½, as each grade on the syringe indicated 1 unit of diluted and injectable Botox.

About 1 mL insulin syringes with 30 G needles to be used for injection [29]. Grover et al. confirmed that 1 mL insulin syringes with 26–30 G needles are preferred for Botox injection since the bevel is much thinner, sharper, and long enough to enable injection in facial muscles. Additionally, the mL-graded syringe makes unit distribution easier [30].

After identifying the three injection sites and without performing local anesthesia, the area to be wiped with cotton moistened with alcohol for cleansing, and then 2.5 units should be injected frontally and bilaterally into each of the three muscles, according to Polo and Sumaya [31].

#### **4. Conclusion**

Carrying out injections of botulinum toxin type A for the correction of the gingival smile is a promising direction of esthetic dentistry. Of course, the method is not without individual drawbacks—partial relapses of this condition, requiring repeated administration, edema, the occurrence of compensatory wrinkles, and compensatory facial expressions or allergic reactions. Nevertheless, this method should be recognized as less traumatic compared to surgical intervention, which also has several complications and does not guarantee the absence of relapses of this pathology.

In addition, this method is usually recommended for patients who need correction of the gingival smile for esthetic purposes, who refuse surgical intervention for psychological reasons (fear of the sight of their own blood, the occurrence of pain, fear of notwithstanding a long surgical operation).

We believe that the development of esthetic dentistry will follow the path of developing minimally invasive interventions that achieve a great therapeutic effect with simple techniques such as the implementation of botulinum toxin type A injection.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Botulinum Toxin - Recent Topics and Applications*

### **Author details**

Imad Katbeh1 \*, Mohammad Osama Makkeiah2 , Tamara Kosyreva1 and Lada Saneeva1

1 Peoples' Friendship University of Russia (RUDN University), Medical Institute, Moscow, Russia

2 Damascus University, Damascus, Syria

\*Address all correspondence to<EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Gummy Smile and Treatment with Botulinum Toxin Type A (Botox) DOI: http://dx.doi.org/10.5772/intechopen.102341*

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[2] Chiche GJ, Pinault A. Smile rejuvenation: A methodic approach. Practical Periodontics and Aesthetic Dentistry. 1993;**5**(3):37-44. quiz 44. 38

[3] Hunt O, Johnston C, Hepper P, Burden D, Stevenson M. The influence of maxillary gingival exposure on dental attractiveness ratings. European Journal of Orthodontics. 2002;**24**(2):199-204

[4] Geron S, Atalia W. Influence of sex on the perception of oral and smile esthetics with different gingival display and incisal plane inclination. The Angle Orthodontist. 2005;**75**(5):778-784

[5] Bynum J. Treatment of a "gummy smile": Understanding Etiology is key to success. Compendium of Continuing Education in Dentistry (Jamesburg, N.J.: 1995). 2016;**37**(2):114-122

[6] Ezquerra F, Berrazueta MJ, Ruiz-Capillas A, Arregui JS. New approach to the gummy smile. Plastic and Reconstructive Surgery. 1999;**104**: 1143-1150

[7] Zardawi FM, Gul SS, Fatih MT, Hama BJ. Surgical procedures reducing excessive gingival display in gummy smile patients with various etiologic backgrounds. Clinical Advances in Periodontics. 2020;**10**(3):130-134

[8] Trushkowsky R, Montalvo Arias D, David S. Digital smile design concept delineates the final potential result of crown lengthening and porcelain veneers to correct a gummy smile Int. Journal of Esthetic Dentistry. 2016;**11**(3):338-354

[9] Mahn DH. Elimination of a "gummy smile" with crown lengthening and lip repositioning. The Compendium of Continuing Education in Dentistry. 2016;**37**(1):52-55

[10] Abdullah WA, Khalil HS, Alhindi MM, Marzook H. Modifying gummy smile: A minimally invasive approach. The Journal of Contemporary Dental Practice. 2014;**15**:821-826

[11] Simon Z, Rosemblatt A, Dorfmann W. Eliminating a gummy smile with surgical lip repositioning. Journal of Cosmetic Dentistry. 2007;**23**:100-108

[12] Austin HW. Correction of the gummy smile--a plastic surgeon's view. Dentistry Today. 1990;**9**(2):28

[13] Araujo JP, Cruz J, Oliveira JX, Canto AM. Botulinum toxin type-a as an alternative treatment for gummy smile: A case report. Dermatology Online Journal. 2018;**24**(7):13030/qt75f0h8kz

[14] De Maio M, Rzany B. Botulinum toxin in aesthetic medicine. Berlin, Heidelberg: Springer; 2007. 141 p. DOI: 10.1007/978-3-540-34095-9

[15] Mazzuco R, Hexsel D. Gummy smile and botulinum toxin: A new approach based on the gingival exposure area. Journal of the American Academy of Dermatology. 2010;**63**(6):1042-1051

[16] Hwang W-S, Hur M-S, Hu K-S, Song W-C, Koh K-S, Baik H-S, et al. Surface anatomy of the lip elevator muscles for the treatment of gummy smile using botulinum toxin. The Angle Orthodontist. 2009;**79**(1):70-77

[17] Chen S. Clinical uses of botulinum neurotoxins: current indications,

limitations and future developments. Toxins (Basel). 2012 Oct;**4**(10):913-939. DOI: 10.3390/toxins4100913. Epub 2012 Oct 19. PMID: 23162705; PMCID: PMC3496996

[18] Meunier FA, Schiavo G, Molgó J. Botulinum neurotoxins: From paralysis to recovery of functional neuromuscular transmission. Journal of Physiology Paris. 2002 Jan-Mar;**96**(1-2):105-113. DOI: 10.1016/s0928-4257(01)00086-9. PMID: 11755789

[19] Aoki K. Evidence for Antinociceptive activity of botulinum toxin type A in pain management. Headeach. 2003;**43**(suppl. 1):S9-S15

[20] Makkeiah MO, Harfoush M, Makkiah A, Saneeva L, Tuturov N, Katbeh I. Comparative efficacy of Botox and surgical lip repositioning in the correction of gummy smile. Dentistry Stomatologiia. 2021;**100**(3):47-54. (In Russ.). DOI: 10.17116/ stomat202110003147

[21] Jaspers GWC, Pijpe J, Jansma J. The use of botulinum toxin type A in cosmetic facial procedures. International Journal of Oral and Maxillofacial Surgery. 2011;**40**:127-133

[22] Polo M. Botulinum toxin type A in the treatment of excessive gingival display. American Journal of Orthodontics and Dentofacial Orthopedics. 2005;**127**(2):214-218 quiz 261

[23] Polo M. Commentary on: Botulinum toxin for the treatment of excessive gingival display: A systematic review. Aesthetic Surgery Journal. 2016;**36**(1):89-92

[24] Sucupira E, Abramovitz A. A simplified method for smile enhancement: Botulinum toxin injection for gummy smile. Plastic and Reconstructive Surgery. 2012;**130**(3): 726-728

[25] Suber JS, Dinh TP, Prince MD, Smith PD. Onabotulinumtoxin A for the treatment of a "gummy smile". Aesthetic Surgery Journal. 2014;**34**(3):432-437

[26] Dinker S, Anitha A. Management of gummy smile with botulinum toxin type-A: A case report. Journal of International Oral Health. 2014;**6**(1): 111-115

[27] Aly LA, Hammouda NI. Botox as an adjunct to lip repositioning for the management of excessive gingival display in the presence of hypermobility of upper lip and vertical maxillary excess. Dental Research Journal (Isfahan). 2016;**13**(6):478-483

[28] Pedron IG. Comment on "botulinum toxin type-A as an alternative treatment for gummy smile: A case report". Dermatology Online Journal. 2019;**25**(6):13030/qt1qk3183b

[29] Amin V, Swathi, Jabir, Shetty P. Enhancing the smile with Botox – Case report. Global Journal of Medical Research. 2013;**13**(2):14-18

[30] Grover S, Malik V, Kaushik A, Divakar R, Vadav P. A future perspective of botox in dentofacial region. Journal of Pharmaceutical and Biomedical Research. 2014;**04**(5):525-531

[31] Polo M. Botulinum toxin type a (Botox) for the neuromuscular correction of excessive gingival display on smiling (gummy smile). American Journal of Orthodontics and Dentofacial Orthopedics. 2008;**133**(2):195-203

## Quality of Life in Neurogenic Bladder Patients and Improvement after Botulinum Toxin Injection

*Giovanni Palleschi and Antonio Cardi*

#### **Abstract**

Various neurogenic conditions may determine an altered function of the bladder and urethral sphincters leading to urinary symptoms. Among these symptoms, loss of urine is considered the most bothersome, and recent literature has proposed that urinary incontinence and poor quality of life should be considered as associated conditions. Urinary incontinence is responsible for reducing the enjoyment of life, including loss of self-confidence and limitation of social activity; it is also associated with anxiety, depression, and deterioration in sexual life, and reduced physical activity. Conservative treatments represent a first-line therapeutic approach to neurogenic urinary disorders, followed by oral medications. However, these treatments often do not provide complete recovery from symptoms, especially from urinary incontinence. Onabotulimun toxin A has proven to be safe and effective for treating neurogenic urinary incontinence and its use is associated with a strong improvement of patients' quality of life. Furthermore, this treatment lowers the risk of severe complications to the upper urinary tract, reducing the need for hospitalization. Quality of life improvement as well as clinical efficacy must be considered targets of the therapy, and the use of onabotulimun toxin A for treating neurogenic urinary incontinence reaches both these goals.

**Keywords:** neurogenic urinary incontinence, quality of life, onabotulinum toxin A

#### **1. Introduction**

Various neurogenic conditions are responsible for lower urinary tract symptoms (LUTS) which further worsen the quality of life (QoL) of patients. In most cases, LUTS onset follows a neurogenic diagnosis by several years, while in certain disorders (i.e., parkinsonism) the urologic disease can sometimes precede neurogenic symptoms. However, in all cases, LUTS represent a significant problem for neurogenic patients, especially for those suffering from physical limitations, such as spinal cord injured (SCI) ones. In addition, LUTS of neurogenic origin is often secondary to a bladder-sphincteric dysfunction which can lead to severe complications and, therefore, must be early and properly managed. The aim of treatment is to restore adequate bladder filling and emptying processes, preventing severe complications, especially to the upper urinary tract (renal failure), and improving QoL. Various therapeutic

options are today available for neurogenic LUTS, varying from conservative approaches (behavioral treatment, physical therapy) to pharmacologic oral medications (antimuscarinics, beta-3- agonists, alpha-blockers). Among LUTS, urinary incontinence (UI) is the most bothersome and, in the neurogenic bladder (NGB), is often severe because it is the consequence of neurogenic detrusor overactivity (NDO), which is characterized by involuntary bladder contractions. Conservative treatments and first-line therapeutic options often fail to provide complete recovery from neurogenic UI. In these cases, the international guidelines therapeutic algorithms suggest the use of mini-invasive treatments, including onabotulinum toxin A (BoTA) which has proven to be effective in restoring urinary continence, improving urodynamic parameters, and ameliorating QoL. This chapter aims to report the current knowledge about the relationship between neurogenic disorders and LUTS, their impact on patients' QoL, and how they improve after administration of BoTA, as shown by large cohort studies provided by literature.

#### **1.1 Neurogenic bladder: Definition and epidemiologic data**

Neurogenic bladder refers to bladder dysfunction secondary to neurologic disease affecting any point of the complex neuronal circuit, which can ultimately compromise safe bladder filling and emptying [1]. Various pathologic conditions of the central and peripheral nervous system can lead to altered bladder and urethral sphincter function, and consequently, many people suffering from the neurogenic disease can develop LUTS. Epidemiological data available show that, in the United States, NGB has been found in 40–90% of patients with multiple sclerosis (MS), in 37–72% of patients with parkinsonism, and 15% of patients with stroke [2, 3]. In the same country, it is estimated that 70–84% of patients with SCI have at least some degree of bladder dysfunction, which is also frequently seen in patients with spina bifida, associated with vesicoureteral reflux in 40% of children and UI in 60.9% of young adults [4]. Less common scenarios for NGB may include diabetes mellitus (due to autonomic neuropathy involving the bladder), unintended sequelae following pelvic surgery, and cauda equina syndrome resulting from lumbar spine pathology [5]. More specific epidemiological data are provided by studies on neurogenic UI. A meta-analysis of five studies showed that men who suffered a stroke were at increased risk for UI with a pooled odds ratio 0f 2.68 [6]. Other reports showed that men who had a stroke presented an increased risk for UI with an odds ratio ranging from 7.1 to 8.26 [7, 8]. These studies reported that among UI sufferers, the stroke survivors had a higher prevalence of UI compared to controls (17% vs. 9%). Poorer data are provided by Literature regarding neurogenic UI in women. However, various studies analyzed the association between UI and dementia in females. Even if data in some cases are controversial, in a 9-year follow-up of 1453 women aged 65 years and over enrolled in a US HMO, diagnosed dementia was strongly associated with an incident diagnosis of UI (odds ratio of 3.0, ranging from 2.4 to 3.7, 95% CI) [9]. Given the strength and consistency of association with prevalent and incident UI, and given that treatment for reversible dementia can improve UI, a causal role seems certain [9, 10]. Among NGB patients are those suffering from the non-neurogenic neurogenic bladder (the Hinman syndrome), a pathological condition characterized by the uncoordinated activity of the lower urinary tract muscles. In these patients the contraction of the sphincter during voiding and overactivity of the detrusor muscle may lead to urinary frequency and incontinence, reproducing a neurogenic voiding pattern that can determine complications to the bladder wall like those secondary to NGB [11].

*Quality of Life in Neurogenic Bladder Patients and Improvement after Botulinum Toxin Injection DOI: http://dx.doi.org/10.5772/intechopen.102384*

NGB is responsible for symptoms of both the bladder filling and voiding phase. Symptom association and severity are strongly related to the site of the neural system involved by the pathophysiological mechanisms of the specific neurogenic condition. Therefore, it is important for clinicians, caregivers, and patients, to gain adequate knowledge of bladder neurophysiology and pathophysiology of NGB.

#### **1.2 Neural control of the bladder and pathophysiology of neurogenic bladder**

Bladder dysfunction secondary to a neurogenic disease can be classified considering the location of the neurologic lesion in the nervous system [12]. This type of classification has the most clinical utility to manage patients with NGB from diagnosis to treatment. Neural control of the bladder and urethral sphincters is extremely complex. However, the different areas of the central and peripheral nervous system play specific and highly defined roles during the bladder filling and emptying. Various studies, including urodynamic investigations, neurophysiologic tests, and advanced imaging techniques (PET, functional MRI) allowed the precise identification of the parts of the nervous system that are activated during the different phases of the micturition cycle. The storage phase of the micturition cycle (bladder filling) is maintained by inhibition of parasympathetic activity, and consequent active relaxation of the bladder mediated by the sympathetic system acting on beta 3 adrenoceptors of the detrusor muscle. During the bladder filling, the sympathetic and pudendal nerve mediated contraction of the urethral sphincters prevents urine leakage under normal conditions. Sensory information from the bladder triggers the micturition reflex leading to bladder emptying. This phase is characterized by the inhibition of the pudendal nerve and suppression of sympathetic activity [13]. Consequently, the detrusor muscle contracts while the pelvic floor muscles and the urethral sphincters relax. When the bladder afferent pathways (from the peripheral pudendal nerves to the spinal cord, and through mesencephalus) stimulate the cerebral cortex, the detrusor center of this region allows micturition to begin or delay [14]. The micturition starts with the external urethral sphincter relaxation, induced by the cerebral cortex, and the detrusor contraction stimulated by the sacral micturition center (located at the spinal cord level S2 to S4) through the pelvic nerves which release acetylcholine to the muscarinic receptors of the detrusor muscle [13, 14]. During the micturition, the simultaneous relaxation of the external sphincter, when the detrusor contracts, is under the control of the pontine micturition center. Therefore, various areas of the nervous system, located in different sites, exert specific control on the bladder and urethral sphincters. In the case of neurogenic disorders, functional changes of detrusor-sphincter complex, clinical signs, and symptoms related, will depend on the site involved by the disease and to the loss of its specific function, as reported in the following scheme.

*Lesions above the brain stem:* Specific damage in this area causes the loss of the inhibitory control exerted by the cerebral cortex on bladder reflex. As consequence, the detrusor muscle develops uncontrolled function (detrusor overactivity, onset of detrusor involuntary contractions). This altered function may be responsible for the following symptoms: urinary frequency (increase of number of micturitions), urinary urgency (a sudden, compelling urge to urinate), and UI (loss of urine) [15]. In these patients, bladder sensation can be normal to decreased. The urinary sphincters should be synergistic with the bladder (they normally relax when the bladder contracts). Thus, high bladder pressures should not develop and the risk of kidney damage is low.

*Complete suprasacral spinal cord lesions:* When the lesion is located at the spinal cord above the sacral level, the bladder and sphincter do not receive the control exerted by the cerebral cortex and from the pontine centers. Therefore, the bladder develops uncontrolled activity but, in addition, the urethral external sphincter paradoxically contracts during detrusor activation (dyssynergia), due to the absence of neural mechanisms which provide synergy located in the pontine micturition center [16]. Patients suffering from disorders involving this area may develop the same symptoms of those affected by lesions above the brain stem, but the consequence of sphincter contraction is the high pressure inside the bladder with the risk of vesicoureteral reflux and obstructive bladder voiding with incomplete bladder emptying (poor micturition flow, intermittent flow, urinary retention). Sensation to bladder filling can be normal to decreased. If the lesion is located above T6, the patient may experience autonomic hyperreflexia, which is represented by a constellation of signs/ symptoms in response to noxious or non-noxious stimuli below the injury level, including an increase in blood pressure > 20 mmHg above baseline, and may include one or more of following signs and symptoms: headache, flushing and sweating above lesion level, vasoconstriction below lesion level, or dysrhythmias.

*Sacral spinal cord lesions:* When the sacral level and its micturition center are involved, the bladder reflex is disrupted and patients experience detrusor areflexia. Depending on the type and extent of neurologic injury, decreased bladder compliance may occur during filling. An open smooth sphincter area may result but the striated sphincter may exhibit varied types of dysfunction, although this area usually maintains a resting sphincter tone and cannot be controlled voluntarily [2]. Sensation to bladder filling can be normal to decreased. Therefore, patients express inability to void the bladder with consequent urinary retention, increased risk of urinary infections, bladder stones formation, and hydronephrosis.

*Distal to the spinal cord lesions:* When this part of the nervous system is damaged, also in these patients the functional alteration leads to detrusor areflexia. However, the smooth sphincter is likely incompetent, and the striated sphincter may exhibit a fixed residual tone that cannot be relaxed voluntarily. Sensation to bladder filling can be normal to decrease [2].

The loss of physiological nervous control of the bladder function causes symptoms that may have a negative impact on a patient's lifestyle and quality of life. While symptoms of the voiding phase may benefit from pharmacological treatment or, in severe cases, from catheterization which can be self-administered at specific time intervals, storage bladder symptoms can hardly limit social interaction, especially when UI is present.

#### **1.3 Onabotulinum toxin type A for treatment of NGB**

Treatment of NGB aims to prevent complications to the lower and upper urinary tract secondary to bladder-sphincter dysfunction and consequently improve symptoms and patients' QoL. Major complications of NGB are represented by urinary infections, urinary stones, vesicoureteral reflux, and renal failure. Clinical assessment is based on symptom evaluation, physical examination, renal and bladder ultrasound, and specific instrumental tools, especially flowmetry and urodynamic investigation combined with urethral sphincter electromyography. These tools allow to establish the type and severity of bladder-sphincter dysfunction and to choose treatment. As above reported, UI is the most bothersome symptom. When clinical and urodynamic assessment allows diagnosing NDO as the cause of low bladder

#### *Quality of Life in Neurogenic Bladder Patients and Improvement after Botulinum Toxin Injection DOI: http://dx.doi.org/10.5772/intechopen.102384*

compliance and symptoms such as urinary urgency and UI, treatment has the goal to reduce involuntary bladder contractions thus achieving a stable detrusor function (also inducing bladder areflexia). When treatment is effective, intravesical pressure is reduced, and consequently, the risk of vesicoureteral reflux and UI is lower or completely recovered. Various therapeutic options are today available to cure NDO. Based on International Consultation on Incontinence (ICI) algorithms, a conservative approach, followed by oral administration of drugs is recommended as initial management for UI of neurogenic origin, associated with CIC in case of significant post-void residue [17]. Recommended oral drugs are considered antimuscarinics and beta-3-agonists. However, when these therapeutic options fail, the ICI specialized management algorithm suggests BoTA injections into the detrusor muscle for NDO and into the urethral sphincter for bladder-sphincteric dyssynergia. Botulinum toxin causes muscle relaxation (flaccid paralysis) because it binds, at presynaptic level, high-affinity sites on the cholinergic nerve terminals decreasing the release of acetylcholine. After its administration, presynaptic vesicles cannot release the acetylcholine in the synaptic space and consequently, the muscle does not contract. Currently, four different formulations of botulinum toxin, three BTX-A and one botulinum toxin B (BTX-B) are commercially available in Europe and USA: onabotulinumtoxin A / BoTA (Botox, A, Allergan Inc., Irvine, USA) abobotulinumtoxinA (Dysport, Ipsen Limited, Paris, France), incobotulinumtoxinA (Xeomin, Merz Pharmaceutical Raleigh, USA) and rimabotulinumtoxinB (Neurobloc/Myobloc, Solstice Neuroscience Inc., San Francisco, USA). However, adequate clinical data are available only on both BoTA and abobotulinumtoxin B as a treatment option for NDO [18]. Therefore, Literature and international guidelines provide recommendations only for these two formulations to treat NGB, specifically NDO [19]. These two formulations are not interchangeable and of course have different dosing [20], as it's generally accepted that a dosage of 200–300 U of BoTA is comparable with 500–750 U of abobotulinumtoxin [21]. However, further studies have clearly shown that there are no better outcomes comparing both 750 U of abototulinumtoxin and 300 U of BoTA to 500 U abobotulinumtoxin or 200 U BoTA respectively [21, 22]. Although comparative studies are rare and no studies are available comparing different BTX types in the field of urology, in one small non-randomized cohort study on 26 patients, replacement with abobotulinum after the failure of the first injection with BoTA has been proven to be effective [23]. For this reason, a conversion factor between BoTA and abobotulinumtoxin of 1:2.5 has been suggested by Grosse et al., even if this assumption was not scientifically proven and it's believed that a variable conversion rate of the two toxins between 1:2 and 1:3 is applicable [24]. Although both these products are commonly used in real clinical practice, the only FDA-approved dose and formulation for urological application is 200 U of BoTA. Intradetrusor administration of BoTA is performed under local or general anesthesia, using a rigid or flexible cystoscope. A special needle (maximum depth 4 mm) allows to perform the administration of the toxin, usually subdividing the total dose (200 U) in twenty different sites of the bladder, avoiding the bladder dome (to prevent the risk of extra-vesical diffusion) and the trigone (to prevent the risk of vesicoureteral reflux). Large evidence of the safety and efficacy of BoTA on NDO is provided by the literature. A recent review performed by L.F. Cooley and S. Kielb reported long-term data from clinical trials and real-life studies, which show that patients with NDO and detrusor sphincter dyssynergia benefit significantly from intradetrusor BoTA injection with regard to the following parameters: improved voided volume, improved bladder pressure and urodynamic outcomes, reduced incidence of urinary tract infections, and improved QoL [1]. The most important studies

providing high-quality data are those from Cruz (2011) and Ginsberg (2012) [25, 26]. In these placebo-controlled protocols, the population in both trials was represented by patients suffering from MS and SCI, with urodynamic evidence of NDO, and submitted to BoTA intradetrusor injections (200 or 300 U). The positive results shown by these studies were confirmed by Kennelly et al. who conducted a 3-year prospective study in 396 patients with SCI and MS to assess long-term efficacy of BoTA injections for NDO [27]. Data on detrusor-sphincter dyssynergia are not so strong and consistent as seen with NDO because outcomes come from low-powered studies. However, a recent meta-analysis of BoTA use in SCI patients suffering from detrusor-sphincter dyssynergia did point to the potential efficacy of this approach with an average decrease from 251.8 mL to 153 mL of post-void residue up to 6 months post-BoTA injection as well as a reduction in sequelae of urinary tract infections and need for CIC in some studies [28]. BoTA is injected on the external urethral sphincter usually through the transperineal way under transrectal ultrasound guidance, and in some cases using electromyography support.

#### **1.4 Quality of life in patients with NGB and improvement after BoTA injection**

Restoring the adequate quality of life should be considered a goal of treatment as significant as the recovery from the disease. QoL is what patients experience on a day-to-day basis and is one of the key considerations when they are involved in choices about their medical care [29]. Quality of life was defined in 1947 by the World Health Organization as a "state of complete physical, mental and social well-being, and not merely the absence of disease and infirmity" [30]. In neuro-urology, treatments aim to correct bladder-sphincteric dysfunction to both prevent severe complications to the urinary tract and improve QoL. However, in daily clinical practice (even more so in the past) QoL has been wrongly interpreted as a secondary consideration with respect to the treatment of bladder dysfunction with serious urologic complications and the preservation of renal function. In recent years, especially since 2010, various studies have been published reporting objective data collected by specific patient-reported outcome measures. These studies clearly show how QoL changes during neurologic diseases when bladder symptoms develop [29]. It is important to assess and understand how a person's life is affected by bladder changes that can accompany the neurologic disease, especially UI because this evaluation is directed to target the therapy most effectively. Despite it being one of the fundamental aspects of neuro-urology, there has been not much research on QoL differences across bladder management choices; this fact may represent a limit for the assessment of specific therapeutic algorithms which optimize the relationship between clinical success and QoL improvement for the patient [31]. In fact, while literature provides considerable data to support the improvement of functional outcomes of treatments for NGB (i.e. bladder augmentation), there is a much smaller body of studies supporting objective improvements in QoL [31]. A large amount of research has been focused on the identification of specific QoL tools for neurogenic bladder function after SCI. Best et al. conducted a systematic review of literature published from 1950 to 2015 on this topic and found 42 studies including 24 QoL outcome tools (ten objective, fourteen subjective) [32]. This important review concluded the existing outcome measures representative of the three major domains of QoL as "Achievements", "Utility", and "Subjective well-being". The Authors explain that both objective and subjective measures are important in SCI, concluding that the only validated condition-specific outcomes that show sensitivity to NGB are the QLI-SCI (Quality of Life in Spinal Cord Injury) and Qualiveen, while the SF-36

#### *Quality of Life in Neurogenic Bladder Patients and Improvement after Botulinum Toxin Injection DOI: http://dx.doi.org/10.5772/intechopen.102384*

questionnaire provides a valid assessment of objective QoL in SCI. There are some specific studies regarding QoL of neuro-urologic patient sub-categories. In these papers, the authors point out the importance of using dedicated and validated tools to investigate objective and subjective aspects, including psychometric evaluations. Catherine Browne et al. in 2015 provided a report on QoL for people with MS [33]. Bladder dysfunction has been described in approximately 75% of people with MS [34] and therefore, in this study, participants were recruited from one branch of the Multiple Sclerosis Society of Ireland using purposive sampling techniques [35]. Patients from this cohort (19 subjects, 11 females and 8 males) suffered from at least one urinary symptom: involuntary leakage of urine, voiding frequency (>8), nocturia, voiding dysfunction such as hesitancy, straining, poor stream. Outcomes from this investigation showed that bladder dysfunction creates a sense of disruption and loss for people with MS, interfering with daily activities. One of the most important factors conditioning lifestyle was the unpredictability of bladder symptoms, especially urinary urgency which drives UI. In patients suffering from MS, as other people are affected by neurological impairment, bladder dysfunction is magnified due to other co-occurring symptoms; specifically, physical limitations heighten LUTS in terms of mobility issues creating problems in managing urinary frequency and urgency, often leading to UI. In fact, this study showed that also in MS patients, UI represents the most bothersome symptom associated with emotional consequences also because fear of leaking urine in public may be greater than the distress caused by the leakage of urine itself [36]. Urinary incontinence is prevalent also in SCI individuals. In fact, more than 80% of these subjects experience NGB resulting from neurological impairments that determine NDO +/− sphincter dyssynergia or detrusor areflexia [37]. Spinal cord injury patients are at high risk of complications due to the development of vesicoureteral reflux (in case of detrusor-sphincter dyssynergia and consequent high intra-vesical pressures) or high bladder residual volumes (due to areflexia). These conditions may be responsible for urinary infections, hydronephrosis, finally leading to chronic renal failure, thus requiring strong medical intervention which also can contribute to lifestyle changes. For this reason, NGB remains the most important issue in QoL of patients with SCI, apart from physical movement, and it requires an aggressive attitude towards urinary management in order to improve QoL. As previously reported generically for NGB and SCI patients, the Qualiveen questionnaire has proven to adequately assess disease aspects of limitations, constraints, fears, and feelings [38]. Lundqvist et al. found that UI reduced self-reported QoL among individuals with SCI [39]. The same findings were reported by Westgren and Levi, who described lower QoL in SCI subjects with bladder problems with respect to controls [40]. When the bladder is properly managed, LUTS improve, renal function is preserved, and the person with SCI can enjoy a much healthier life [41]. This outcome has been seen especially when significant improvement in urinary continence has been restored and reported as better body image perception and independence [28]. A significant rate of SCI patients practices self-catheterization to void the bladder due to areflexia, which can be a direct consequence of the spinal lesion or the effect of treatment (antimuscarinics or bladder injections with BoTA). Long-term clean intermittent catheterization (CIC) was first promoted in the 1970s by Lapides et al. [42] and became the standard procedure for managing the NGB of SCI patients [43]. Studies on QoL of patients using CIC show that it has many beneficial effects, which include reduced morbidity and mortality, improved body image, and guaranteed improved self-esteem [44]. These outcomes are even more positive when the use of CIC is associated with a complete recovery of UI (when patients are totally dry), as provided in a large rate of

SCI patients by BoTA administration [45]. These outcomes in SCI submitted to CIC are supported by other studies. Fuminicelli et al. showed that in the Brazilian and Portuguese populations of SCI patients, QoL scores improved in those using CIC because of better independence, self-confidence, social relationship, and access to work activities [46]. The same authors performed a review on the topic including 13 high-quality studies (from the initial 2945 examined) examining QoL assessment in patients with NGB secondary to different disorders (SCI, MS, Parkinson's disease, cerebrovascular accident, brain tumors, infection by HTLV-I, neuroschistosomiasis). The report concluded that CIC offers considerable changes in the NGB patients' living activities, modifying social routines, professional activities, and sexuality, among other areas. However, also in this review, an important concept is the significant role of the recovery from UI to achieve a "dry-status" of the patient using CIC, therefore enhancing the role of proper treatments for the neurogenic UI, as BoTA injections [46]. Intravesical BoTA is a safe and generally well-tolerated procedure because it can be performed under local, regional, or general anesthesia and it requires short operative time. This aspect is important for ensuring good patient acceptance of this treatment which can generally be repeated over time. Quality of life outcomes in patients injected with BoTA has been considered in the most important trials since 2011. Francisco Cruz et al. reported a significant reduction of UI episodes and improvement of urodynamic parameters in 275 patients with NDO after BoTA injection during a multicenter, double-blind, randomized, placebo-controlled trial [47]. This cohort was interviewed during the study by means of Incontinence Quality of Life (I-QOL) questionnaire. Final results showed that among patients submitted to BoTA, 38% and 39,6% respectively submitted to 200 and 300 U were fully dry versus only 7,6 of those in the placebo arm. This clinical finding was associated with a significant improvement of I-QOL total summary scores at 6 weeks from treatment in patients injected, despite the incidence of adverse events (urinary tract infections and urinary retention). Specifically, the total I-QOL score improved from 24.4 to 25.1 in subjects injected with 200 BoTA U, and from 24.3 to 25.9 in those injected with 300 U, while subjects in the placebo group presented a worse score (decreased from 11.7 to 8.6). In the long-term, multi-center, double-blind, randomized, placebo-controlled trial conducted by Ginsberg et al., patients were followed up to 52 weeks. In this protocol, patients were evaluated every 6 weeks after the first 3 months from the first injection of 200 or 300 U, until re-treatment [48]. As shown in the previous trial, also in this study good QoL outcomes were associated with urodynamic improvement. Cystometric measures improved both in SCI and MS subjects, without significant difference between the active dose groups (200 or 300 U). Each BoTA dose significantly improved the I-QOL summary score at week 6 compared with placebo and this result was maintained through week 12 in the overall population with increases from baseline of 9 in the placebo arm, 31 and 33 points in the BoTA 200 and 300 U groups (p < 0.001). The most important side effects reported in this trial were UTI and the need of CIC. However, the change from baseline I-QOL score was analyzed in patients who did not perform CIC at baseline to determine whether subsequent initiation of CIC influenced QoL. In these patients, the I-QOL improvement was similar whether they did or did not begin CIC after treatment. The authors commented in the discussion that the onset of BoTA action was rapid and sustained with a duration of effect time approximately of 9 months, probably influencing the positive effect also on I-QOL scores. Particularly, the positive effect of BoTA on recovery of continence is crucial for these patients. Satisfaction with life has been shown to be significantly lower among neurogenic patients with continence problems and the use of BoTA is often required by these

#### *Quality of Life in Neurogenic Bladder Patients and Improvement after Botulinum Toxin Injection DOI: http://dx.doi.org/10.5772/intechopen.102384*

subjects because they frequently discontinue antimuscarinics due to failure of response, side effects, or unmet treatment expectations [47]. Sussman et al. in 2012 randomized patients to intradetrusor placebo or BoTA 200 and 300 U. The Patient Report Outcomes included I-QOL to assess Health Related Quality of Life, the 16-item modified Overactive Bladder-Patient Satisfaction with Treatment Questionnaire (OAB-PSTQ ) to assess treatment satisfaction, and Patient Global Assessment to assess treatment goal achievement [48]. Patients of the 200 and 300 U groups had improvement of I-QOL scores significantly greater compared with placebo. Improvements were reported in the avoidance/limiting behavior, psychosocial impact, and social embarrassment domain (*p* < 0.01). As observed in other trials, there were no clinically relevant differences between BoTA dose groups for the effects on total I-QOL domain scores. A significant association was then found between UI frequency and improvement of HRQoL. Also, OAB-PSTQ showed that patients treated with BoTA were somewhat or very satisfied with treatment compared to unsatisfied patients of the placebo group. These results were observed in patients regardless of the need for CIC after BoTA injection. Consequently, the final PGA measures indicated that the majority of patients treated with BoTA improved in symptoms, QoL, activity limitations, and overall emotions related to their bladder problems at weeks 6 and 12, and this improvement was maintained or continued to improve during the follow-up. Good outcomes can be achieved in NGB when proper assessment is performed (based on standardized symptoms and QoL questionnaires, clinical assessment, instrumental evaluation by urodynamics). In addition, it is important to follow international guidelines to establish treatment starting as soon as possible to prevent complications and worsening of the bladder-sphincteric dysfunction. In fact, a positive effect of continuous care intervention on the QoL of NGB patients with SCI was observed [49]. The goal of continuous care intervention is to maintain continence, prevent urological complications, and preserve upper urinary tract function to make bladder management compatible with the person's lifestyle and environment [50]. In patients submitted to BoTA injections, continuous care intervention may be an important method of re-assessment over time to suggest the need of instrumental re-evaluation and retreatment. A significant part of continuous care is represented by training for CIC and adequate suggestions which prevent infections. It was observed that continuous care interventions contribute to improve the QoL of patients after 3 months. This is the consequence of better bladder management with regard to urinary system complications.

#### **2. Conclusions**

Patients suffering from neurogenic disorders adapt to physical and social limitations. The effect of physical disability of illness cannot be understood if QoL aspects of importance for the individual are not taken into consideration. When urinary symptoms and bladder-sphincteric dysfunction develop, these patients have a significant worsening of their QoL. This report clearly shows that UI is the most bothersome symptom to manage in this population and that it is associated with a hard negative impact on QoL. Recovery of continence allowed by intradetrusor injection of BoTA provides a great QoL improvement which is parallel to the bladder-sphincteric functional modification. This result is supported by various multicentric, randomized, placebo-controlled trials with a specific evaluation of QoL by means of standardized and highly recommended patients' report outcomes. These studies guarantee

that good outcomes are maintained over time despite the need to start CIC. For this reason, BoTA injections are strongly recommended by International Guidelines in these patients. In the future, the authorized use of different types of botulinum toxin for urological use is expected, extending the indication to the pediatric population. Furthermore, large multi-center studies are warranted to design specific protocols which should guide clinicians in managing NGB patients who need re-treatments (in terms of time intervals and BoTA dosing), and which can support the management of subjects who are refractory to BoTA, replacing it by different toxins. However, considering that QoL can be influenced by diverse factors and not only by treatments, it is important to remember that family support, adjustment and coping, productivity, self-esteem, financial stability, education, and physical and social environments must also be assessed and considered in NGB individuals.

### **Author details**

Giovanni Palleschi1 \* and Antonio Cardi2

1 Medica San Carlo Nephrology, Urology and Hemodialysis Center, Frascati (Rome), Italy

2 San Giovanni Addolorata Hospital, Rome, Italy

\*Address all correspondence to<EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Quality of Life in Neurogenic Bladder Patients and Improvement after Botulinum Toxin Injection DOI: http://dx.doi.org/10.5772/intechopen.102384*

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#### **Chapter 7**

## Clinical Relevance of Neutralizing Antibodies in Botulinum Neurotoxin Type A

*Harald Hefter and Sara Samadzadeh*

#### **Abstract**

The precise definition of prevalence of neutralizing antibodies (NABs) affords cross-sectional testing of a cohort. But in most studies, only selected patients are tested. This leads to gross underestimation of NAB-prevalence, and the opinion that induction of NABs is a rare phenomenon in botulinum neurotoxin (BoNT)/A-therapy. However, recent cross-sectional studies report annual incidences between 1 and 2% in patients being treated with a complex protein (CP)-containing preparation. This implies that NAB-prevalence above 10% has to be expected in patients being treated for more than 10 years. High dose per session and long duration of treatment are relevant risk factors for induction of NABs. In patients exclusively treated with the CP-free incobotulinumtoxin A (incoBoNT/A) preparation Xeomin® no NABinduction has been reported so far. In patients with NABs switching to incoBoNT/A may lead to a decline of NAB-titers. In patients with NABs under treatment with a CP-containing BoNT/A-preparation it may take years of treatment until a second treatment failure (STF) becomes clinical manifest. In a cohort of 59 patients with partial STF patients' reports on the reduction of BoNT-activity predicted the presence of NABs better than treatment related data produced by the treating physicians.

**Keywords:** botulinum neurotoxin, neutralizing antibodies, immunogenicity, long-term treatment, treatment failure, secondary nonresponse

#### **1. Introduction**

Botulinum neurotoxins (BoNTs) are bacterial products and large molecules which are usually embedded into even larger complex proteins (CPs) [1–4]. In clinical practice, BoNTs have to be applied by injection. This causes activation of local dendritic cells, elicits hit-shock proteins, and leads to local inflammation. Therefore, the induction of antibodies (ABs) can hardly be avoided [5]. The analysis of lymphocytes in BoNT/A or BoNT/B long-term treated patients with movement disorders indicates that in most of these patients, T-cells have responded to the BoNT application [6].

Induced antibodies target epitopes of CPs and BoNT. Some of the ABs do not influence the biological activity of BoNTs, and others reduce or neutralize BoNT action [7]. Neutralizing antibodies (NABs) in immune-resistant patients target epitopes of the heavy [8] or the light chain [9] of the BoNT molecule.

In clinical practice, the relevant question arises whether a partial or complete secondary treatment failure (pSTF or cSTF) results from NAB induction.

#### **2. The problem of precise determination of the prevalence of ABs and/or STF**

For the determination of the presence of NABs, clinical as well as laboratory tests can be used (for a recent discussion, see [10]). Regardless of which test is addressed, little is known about the test-retest liability or variability of repeated measurements of a single serum or serial measurements within a single patient. Nevertheless, the precise determination of the prevalence of ABs heavily depends on the quality (sensitivity and specificity) of NAB testing.

Furthermore, by definition of prevalence, it is necessary to test all members of a cohort if the prevalence of a certain feature in a special cohort has to be determined. Thus, precise determination of the prevalence of neutralizing antibodies in a cohort of BoNT-treated patients implies that a cross-sectional NAB study has to be performed in this cohort.

In the majority of studies reporting on the prevalence of NABs, no crosssectional testing has been performed. Instead, antibody rates or antibody frequencies (= number of NAB-positive patients/number of patients in the cohort) are determined resulting from NAB testing of selected patients. This procedure crossly underestimates the presence of NABs (comp. [11]).

In their meta-analysis of NABs in BoNT therapy, Fabbri et al. report on an overall NAB frequency of 3.5% in clinically responding patients. In responding patients with spasticity, only 0.7% were reported to be NAB-positive, in patients with dystonia 6.5%. These data are at clear variance with cross-sectional studies reporting 31 positive patients among 212 responding patients with cervical dystonia who were tested by means of the mouse hemidiaphragma assay (MHDA) (= 14.6%; [12]) and 14.3% MHDA-positive patients in long-term treated patients with spasticity [13].

An even more challenging problem is the determination of the temporal development of NAB prevalence. Antibody rates or antibody frequencies do not give any information on the temporal development of NABs, since this ratio between NABpositive patients and all members of the cohort does not take into account the duration of BoNT treatment.

To analyze the temporal development of NAB formation, the Kaplan-Meier survival analysis has to be performed, calculating the prevalence of NAB-positive patients among those patients with a given duration of treatment. This approach demonstrates that up to 50% of the patients will become NAB-positive when treatment durations exceed 25 years or higher doses are used. In **Figure 1**, the probability to remain AB-negative is plotted against the duration of treatment in 595 patients. The prevalence of NABs was 82 out of 594 patients (= 13.8%) in the entire cohort, 7 out of 186 patients (= 3.8%) being treated with doses <500 uDU, 49 out of 312 patients (= 15.7%) being treated with doses between 500 and 1000 uDu, and 26 out of 96 patients (= 27%) when doses larger than 1000 uDU were used. To compare doses of different BoNT/A preparations and to determine unified dose units (uDU), aboBoNT/A doses were left unchanged and ona- and incoBoNT/A doses were multiplied by 3. These conversion ratios have been used by Fabbri et al. 2016 [11] and have been discussed by Contarino et al. [14]. The Kaplan-Meier analysis clearly reveals

*Clinical Relevance of Neutralizing Antibodies in Botulinum Neurotoxin Type A DOI: http://dx.doi.org/10.5772/intechopen.102896*

#### **Figure 1.**

*Kaplan-Meier survival curve to remain AB-negative in patients with cervical dystonia being treated with BoNT/A. With increasing duration of treatment beyond 10 years, the probability to remain AB-negative declines rapidly down to values around 50%.*

that there is a nonlinear decline of the probability to remain MHDA-negative with the duration of treatment, especially in the higher dose groups.

In summary, induction of NABs occurs frequently and inevitably progresses with the duration of treatment as long as complex protein-containing BoNT/A preparations are used. The induction of NABs is probably significantly lower in complex protein-free BoNT/A preparations [5, 15] (see Section 3 below).