**3. Proposed mechanism of mixed urinary incontinence**

There are several theories of DO in MUI. The most commonly proposed mechanism attributes MUI primarily to triggering of an involuntary bladder contraction. (Serels et al., 2000) Detrusor overactivity is, however, often not identified in many patients undergoing analysis for OAB wet symptoms. As previously noted, the underlying source of mixed incontinence may be detrusor overactivity associated with SUI which may represent a reflex stimulated by urine entering the proximal urethra during stress events. (Dmochowski & Staskin, 2005) This supposition has been shown to correlate with certain urodynamic factors including diminished urethral functional length in patients with urethral instability. Urethral instability instigates a bladder contraction response (detrusor overactivity), which is a normal physiological event. Webster et al. reported on a series of 73 patients with cystometrically diagnosed detrusor overactivity in combination with SUI. (Webster et al., 1984) A third of these patients had a period of electromyographic silence immediately preceding an unstable detrusor contraction. They concluded that the unstable contraction may have been induced by a urethral event and, therefore, was not a primary bladder abnormality.

There is a possibility that mixed symptoms may be due to a more severe form of stress component rather than two separate mechanisms for urge and stress incontinence(Bump et al., 2003); or that DO is caused by a weak urethral sphincter mechanism, resulting in funnelling of the proximal urethra. Major et al. identified that patients with detrusor overactivity had thinner urethral longitudinal smooth muscle layers and lower MUCP. (Major et al., 2002) McLennan et al. demonstrated that the functional urethral length was significantly shorter in patients with urethral instability. (McLennan et al., 2001) This shortened functional length may allow urine to enter the urethra, as there is less of a barrier, resulting in a weak urethral sphincter mechanism, which leads to funneling of the proximal urethra. When intra-abdominal pressure is increased, urine enters the proximal urethra, producing sensory stimulation and resulting in a reflex bladder contraction. (Fulford et al., 1999) This "urethrogenic" theory has also been supported by observations that patients with detrusor overactivity have significantly lower MUCP on urethral pressure profilometry, as well as lower angle of deflection measured by Q-tip cotton swab test. (Awad & McGinnis, 1983; Kim et al., 2010) The authors compared urodynamic characteristics, as well as physical examination findings in a retrospective study of 241 patients who were diagnosed with urinary incontinence. We found that patients with mixed incontinence showed lower Q-tip angle (28.6° vs. 42.1°) and lower MUCP (44.1cmH2O vs. 54.7cmH2O), in addition to higher symptom severity and lower bladder capacity. (Kim et al., 2010)

There are several possible explanations why UUI may improve after MUS surgery. One particular explanation is that MUS prevents urine from entering into the upper posterior urethra with increases in intra-abdominal pressure thereby avoiding reflex urgency. (Koonings et al., 1988; Minassian et al., 2008) Another possible explanation is that MUS may stabilize urethral overactivity, both statically and dynamically. (Kim et al., 2010) The current MUS are generally designed to be applied in a tension free manner at the urethra, theoretically providing a kinking axis, rather than a pressure aided coaptation of the urethra. Such mechanisms underscore the beneficial effects that MUS may provide to the urgency symptom per se, rather than an incidental improvement through relief of stress symptoms.

There are several theories of DO in MUI. The most commonly proposed mechanism attributes MUI primarily to triggering of an involuntary bladder contraction. (Serels et al., 2000) Detrusor overactivity is, however, often not identified in many patients undergoing analysis for OAB wet symptoms. As previously noted, the underlying source of mixed incontinence may be detrusor overactivity associated with SUI which may represent a reflex stimulated by urine entering the proximal urethra during stress events. (Dmochowski & Staskin, 2005) This supposition has been shown to correlate with certain urodynamic factors including diminished urethral functional length in patients with urethral instability. Urethral instability instigates a bladder contraction response (detrusor overactivity), which is a normal physiological event. Webster et al. reported on a series of 73 patients with cystometrically diagnosed detrusor overactivity in combination with SUI. (Webster et al., 1984) A third of these patients had a period of electromyographic silence immediately preceding an unstable detrusor contraction. They concluded that the unstable contraction may have been induced by a urethral event and, therefore, was not a primary bladder

There is a possibility that mixed symptoms may be due to a more severe form of stress component rather than two separate mechanisms for urge and stress incontinence(Bump et al., 2003); or that DO is caused by a weak urethral sphincter mechanism, resulting in funnelling of the proximal urethra. Major et al. identified that patients with detrusor overactivity had thinner urethral longitudinal smooth muscle layers and lower MUCP. (Major et al., 2002) McLennan et al. demonstrated that the functional urethral length was significantly shorter in patients with urethral instability. (McLennan et al., 2001) This shortened functional length may allow urine to enter the urethra, as there is less of a barrier, resulting in a weak urethral sphincter mechanism, which leads to funneling of the proximal urethra. When intra-abdominal pressure is increased, urine enters the proximal urethra, producing sensory stimulation and resulting in a reflex bladder contraction. (Fulford et al., 1999) This "urethrogenic" theory has also been supported by observations that patients with detrusor overactivity have significantly lower MUCP on urethral pressure profilometry, as well as lower angle of deflection measured by Q-tip cotton swab test. (Awad & McGinnis, 1983; Kim et al., 2010) The authors compared urodynamic characteristics, as well as physical examination findings in a retrospective study of 241 patients who were diagnosed with urinary incontinence. We found that patients with mixed incontinence showed lower Q-tip angle (28.6° vs. 42.1°) and lower MUCP (44.1cmH2O vs. 54.7cmH2O), in addition to higher

There are several possible explanations why UUI may improve after MUS surgery. One particular explanation is that MUS prevents urine from entering into the upper posterior urethra with increases in intra-abdominal pressure thereby avoiding reflex urgency. (Koonings et al., 1988; Minassian et al., 2008) Another possible explanation is that MUS may stabilize urethral overactivity, both statically and dynamically. (Kim et al., 2010) The current MUS are generally designed to be applied in a tension free manner at the urethra, theoretically providing a kinking axis, rather than a pressure aided coaptation of the urethra. Such mechanisms underscore the beneficial effects that MUS may provide to the urgency symptom per se, rather than an incidental improvement through relief of stress

**3. Proposed mechanism of mixed urinary incontinence** 

symptom severity and lower bladder capacity. (Kim et al., 2010)

abnormality.

symptoms.

The presenting symptoms of patients may be a guide to the approach to MUI. In those cases where either the stress or urge symptoms predominate, the most bothersome symptom should be approached first to potentially lessen the impact of the secondary symptom. Older surgical literature implies that patients with significant stress symptoms preoperatively, even if detrusor over activity is present, have a greater likelihood of success than those patients with a significant preoperative urge. The use of history (inclusive of symptomatic appraisal) associated with physical examination demonstrating (or not) stress incontinence may be very helpful in assessing the relative contributions of stress and urgency symptoms as well as the other potential insensate urinary loss that some patients experience.(Dmochowski & Staskin, 2005) Once the patient's initial response to the primary intervention is determined, further therapies can be recommended for persistent symptoms or for secondary symptoms, should those symptoms remain problematic. For instance, patients with mixed symptoms with a strong urge component and definable but less severe stress component could undergo therapy specially defined to ameliorate the urgency symptoms including anticholinergic use followed by neuromodulation (and/or botulinum toxin) and a secondary intervention for the bladder outlet, should persistent stress symptoms remain bothersome. Similarly, patients with predominant stress symptoms could undergo intervention for SUI with secondary interventions for UUI depending upon the results of the primary intervention and persistence of bothersome urinary symptoms. Therefore, the approach to MUI should be based on symptomatic segregation, with therapy promulgated on the basis of the most bothersome symptom and secondary interventions reserved for either persistence of the primary symptom or bother arising from the less prominent initial symptom. In those individuals with relatively equal bother, or who are unable to segregate their symptoms, the initial guideline to therapy may become apparent only after beginning more intensive evaluation (such as urodynamic studies). Alternatively, conservative or minimally invasive intervention may be initiated to establish response, followed by more intensive intervention for nonresponse. Ideally, patients should be informed about which symptoms may persist or become problematic post-intervention.

The role of surgery in the treatment of mixed incontinence had been historically considered highly controversial due to a high failure rate, from symptomatic or asymptomatic DO. (Stanton et al., 1978) More recently, several studies have concluded that an effective pubovaginal sling can cure stress incontinence and may also have benefit for urge symptoms. Langer et al. reported the results of a study of 30 women with mixed incontinence who underwent Burch colposuspension. (Langer, 1988) The proportion of patients with symptoms of DO decreased significantly from 73.3% before to 33.3%after surgery. In all, 50% of patients had marked improvement in clinical symptoms of DO. Normal cystometric findings were present postoperatively in 60% of patients, and only 40% had evidence of DO on postoperative urodynamic assessments. Ulmsten et al. evaluated the effect of TVT in 80 women suffering from MUI. (Ulmsten et al., 1996) They demonstrated that at a mean of 4 years, both SUI and UUI were cured in 85% of patients, significantly improved in 4%, and unchanged or worse in 11%. They concluded that TVT could be used to treat women patients with MUI. This study excluded patients with significant detrusor overactivity; therefore, the population was somewhat selected. Anger and Rodriguez reported that surgical intervention for patients with mixed incontinence resulted in

Preoperative Factors as Predictors of Outcome

the lower overall success rates of around 55%.

recent MUS procedures. (Langer, 1988)

**5. Preoperative risk factors for mixed urinary incontinence** 

of Midurethral Sling in Women with Mixed Urinary Incontinence 213

as clear as the majority of studies did not include urodynamically proven MUI. MUI implies a component of detrusor dysfunction that may be motor or sensory and is associated with superimposed urethral sphincteric underactivity. Rates of incontinence improvement in pharmacologic studies are approximately 70% although a substantive percentage of these patients are improved, not cured. Potential pharmacologic approaches to the treatment of mixed incontinence include antimuscarinic agents, estrogen replacement therapy (for postmenopausal women), and dopamine, serotonin, and norepinephrine reuptake inhibitors. (Khullar et al., 2010) Electrical stimulation is another conservative measure that could potentially be used for the treatment of MUI. (Sand, 1996) Surgery should be considered after failed medical management, proper work up, and careful counselling about

Though various factors have been described in the literature to predict the persistence of urge components following incontinence procedures, no single predictor has presented consistent value between studies. Earlier studies, investigating Burch colposuspension, suggested precedence in patient symptom history were indicative of symptom predominance within a mixed profile of incontinence, and consequently better outcomes for patients with precedent stress symtoms. Scotti et al. investigated 82 women who underwent Burch colposuspension. (Scotti et al., 1998) They found that patients with a history of stress symptoms preceding the onset of urge symptoms showed higher cure rates compared to antecedent urge patients (78.6% vs 22.2%, p<0.001). Langer et al. also showed similar results, also with Burch colposuspension. However, these results have not been reproduced in

Urodynamic studies would appear to have predictive benefit for some patients with mixed symptoms in elucidating the gravity of urethral dysfunction (stress component) and any associated detrusor dysfunction. (Lin et al., 2004) Certain aspects of detrusor dysfunction, such as high-pressure detrusor overactivity, have been suggested to be indicative of outcome, though investigators varied in their use of its reference value. The authors retrospectively reviewed 279 patients with MUI who underwent MUS with at least 2 years of follow up. (Kim et al., 2008) Patients were divided into patient with a predominance of bother symptoms and a predominance of DO, where DO patients were further divided into patients with high pressure DO and low pressure DO with a reference level of 15cmH2O of maximum detrusor pressure at which involuntary contraction occurs during filling cystometry. We found that patients with high pressure DO showed improvement of urge symptoms in 70% compared to 91.4% for patient with low pressure DO (p=0.03). These factors also seemed to affect resolution of stress components as patients with high pressure DO showed lower resolution rates than low pressure DO patients (90% vs. 96.6%, p=0.04). In a retrospective study of 51 patients, Panayi et al. found that higher opening detrusor pressure, lower volume at DO during cystometry and higher detrusor pressure were predictive of persistent DO. (Panayi et al., 2009) Schrepferman et al. evaluated 84 women undergoing a pubovaginal sling surgery for MUI. (Schrepferman et al., 2000) Of those patients, 69 had urgency symptoms. Urgency was related to defined motor urge (as established on urodynamic testing) in 41 women. Twenty-eight patients experienced sensory urgency (urge symptoms with/ without urodynamic findings). Complete resolution

incontinence resolution rates ranging from 20 to 70%. (Anger & Rodriguez, 2004) They concluded that those patients with predominant symptoms should have the primary symptoms initially managed. They further concluded that persistent symptomatology may not require secondary therapy and intervention for symptomatic persistence should be based on patient bother. In the study by Segal et al. (Segal et al., 2004), the improvement rate of the irritative subscales in the Urinary Distress Inventory for patients with MUI was 87.8%.

On the other hand, several studies have presented that these results were only transient. Several studies report good cure rates of stress component (85–97%) and lower (30–85%) and declining cure rates of urge incontinence over time following MUS in MUI. Holmgren et al. presented initial good cure rates of TVT, with up to 60% at 4 years, for MUI which did not persist after 4 years, decreasing to 30% cure rate from 4 to 8 years. (Holmgren et al., 2005) There seems to be no significant difference in the overall subjective and UUI cure between tapes used by retropubic (TVT) or transobturator routes. Colombo et al. (Colombo et al., 1996) assessed women who underwent Burch colposuspension. These investigators retrospectively compared findings from 44 women with mixed incontinence and matched controls with USI. At the 2-year follow-up point, the cure rate for stress incontinence was significantly lower in the group with mixed incontinence than in the group with stress incontinence alone (75% vs. 95%, P 0.02). One study reported that the overall cure rate was lower in women with MUI (55%) as compared with women with SUI only (81%) at 5-year follow-up after surgery. (Ankardal et al., 2006) They found type of incontinence was the only independent variable found to influence surgical outcome. In another study, when cure rate was defined as stress and urge indices of two or less (episode of incontinence one to four times a month or less), the observed subjective cure was 60% at 7 months and 53.8% at 38 months. But on the other hand, when cure was defined as complete dryness, the subjective cure rate dropped to 35.9% at 7 months and 28.4% after 38 months. (Kulseng Hanssen et al., 2007)

Another pitfall in the interpretation of these data is the discrepancy between subjective and objective determination of treatment success. Karram and Bhatia reported results in 52 women, 27 of whom underwent surgery (i.e., modified Burch colposuspension procedures). (Karram & Bhatia, 1989) Cure, defined as complete subjective relief of incontinence plus objective evidence of the disappearance of both stress incontinence and DO on repeat urodynamic testing, was achieved in 59% of the patients who underwent the surgery. Another 22% of surgically treated patients had improvement, defined as complete subjective relief of symptoms with objective evidence of the persistence of incontinence at the time of testing, or adequate relief of symptoms, such that the patient did not desire any further therapy. Of the 25 patients treated medically, 32% achieved cure and 28% were markedly improved. In another study that assessed TVT in women with either USI or mixed incontinence, the objective cure rate (89.3%) was similar for both types of incontinence, but the subjective cure rate was 66%, a significant difference (P 0.05), for objective versus subjective evaluations. (Jeffry et al., 2001) The lower subjective value was attributed to patients with de novo urge symptoms.

Appropriate case selection is of utmost importance in order to get good results after surgery. Cure rate of MUI is better in a group of women with predominant SUI symptoms in comparison to a group with predominant UUI symptoms. (Kulseng Hanssen et al., 2007) The effect of detrusor overactivity on urodyamics associated with MUI on outcomes is not

incontinence resolution rates ranging from 20 to 70%. (Anger & Rodriguez, 2004) They concluded that those patients with predominant symptoms should have the primary symptoms initially managed. They further concluded that persistent symptomatology may not require secondary therapy and intervention for symptomatic persistence should be based on patient bother. In the study by Segal et al. (Segal et al., 2004), the improvement rate of the irritative subscales in the Urinary Distress Inventory for patients with MUI was 87.8%. On the other hand, several studies have presented that these results were only transient. Several studies report good cure rates of stress component (85–97%) and lower (30–85%) and declining cure rates of urge incontinence over time following MUS in MUI. Holmgren et al. presented initial good cure rates of TVT, with up to 60% at 4 years, for MUI which did not persist after 4 years, decreasing to 30% cure rate from 4 to 8 years. (Holmgren et al., 2005) There seems to be no significant difference in the overall subjective and UUI cure between tapes used by retropubic (TVT) or transobturator routes. Colombo et al. (Colombo et al., 1996) assessed women who underwent Burch colposuspension. These investigators retrospectively compared findings from 44 women with mixed incontinence and matched controls with USI. At the 2-year follow-up point, the cure rate for stress incontinence was significantly lower in the group with mixed incontinence than in the group with stress incontinence alone (75% vs. 95%, P 0.02). One study reported that the overall cure rate was lower in women with MUI (55%) as compared with women with SUI only (81%) at 5-year follow-up after surgery. (Ankardal et al., 2006) They found type of incontinence was the only independent variable found to influence surgical outcome. In another study, when cure rate was defined as stress and urge indices of two or less (episode of incontinence one to four times a month or less), the observed subjective cure was 60% at 7 months and 53.8% at 38 months. But on the other hand, when cure was defined as complete dryness, the subjective cure rate dropped to 35.9% at 7 months and 28.4% after 38 months. (Kulseng

Another pitfall in the interpretation of these data is the discrepancy between subjective and objective determination of treatment success. Karram and Bhatia reported results in 52 women, 27 of whom underwent surgery (i.e., modified Burch colposuspension procedures). (Karram & Bhatia, 1989) Cure, defined as complete subjective relief of incontinence plus objective evidence of the disappearance of both stress incontinence and DO on repeat urodynamic testing, was achieved in 59% of the patients who underwent the surgery. Another 22% of surgically treated patients had improvement, defined as complete subjective relief of symptoms with objective evidence of the persistence of incontinence at the time of testing, or adequate relief of symptoms, such that the patient did not desire any further therapy. Of the 25 patients treated medically, 32% achieved cure and 28% were markedly improved. In another study that assessed TVT in women with either USI or mixed incontinence, the objective cure rate (89.3%) was similar for both types of incontinence, but the subjective cure rate was 66%, a significant difference (P 0.05), for objective versus subjective evaluations. (Jeffry et al., 2001) The lower subjective value was attributed to

Appropriate case selection is of utmost importance in order to get good results after surgery. Cure rate of MUI is better in a group of women with predominant SUI symptoms in comparison to a group with predominant UUI symptoms. (Kulseng Hanssen et al., 2007) The effect of detrusor overactivity on urodyamics associated with MUI on outcomes is not

Hanssen et al., 2007)

patients with de novo urge symptoms.

as clear as the majority of studies did not include urodynamically proven MUI. MUI implies a component of detrusor dysfunction that may be motor or sensory and is associated with superimposed urethral sphincteric underactivity. Rates of incontinence improvement in pharmacologic studies are approximately 70% although a substantive percentage of these patients are improved, not cured. Potential pharmacologic approaches to the treatment of mixed incontinence include antimuscarinic agents, estrogen replacement therapy (for postmenopausal women), and dopamine, serotonin, and norepinephrine reuptake inhibitors. (Khullar et al., 2010) Electrical stimulation is another conservative measure that could potentially be used for the treatment of MUI. (Sand, 1996) Surgery should be considered after failed medical management, proper work up, and careful counselling about the lower overall success rates of around 55%.
