PRIMARY BLADDER NECK OBSTRUCTION: A NEW ETIOPATHOGENESIS.
Creators: name: CAMEROTA, TOMMASO CIRO
Publisher: name: Universit� degli Studi di Milano
Year: 2018

description: INTRODUCTION Urinary incontinence and bladder voiding symptoms are extremely frequent in the general population, in both sexes, independently from race and age. The onset of voiding disorders is slow in time; therefore, subjects develop adaptation mechanisms. Patients may lose their reference to normality, considering as physiological what in reality is a pathological condition [Abrams, 2013]. For reasons deeply investigated in this doctoral thesis, it is difficult to collect definitive and reliable epidemiological data on lower urinary tract symptoms and on urinary incontinence in the general population [Burkhard FE, 2016], principally in males. Urinary continence and micturition strongly depend on the integration of two different functional units of the lower urinary tract: the bladder and the urethral sphincter complex (bladder neck and rabdosphincter). Coordination within the system is guaranteed by neural control at three different levels: peripheral ganglia, spinal cord and brain [Morrison JF, 2005]. This normal physiology of the system is extensively reviewed in the thesis. A crucial step in micturition is represented by the relaxation of the urethral sphincters, which depends both on the disappearance of adrenergic and somatic excitatory inputs and on the activation of a parasympathetic reflex. This neuromuscular integrated system involves not only bladder neck and the urethral sphincters, but also the pelvic diaphragm, which is composed by a complex set of structures: the levator ani muscle, the coccygeal muscle and the surrounding connective tissue and fascias [Ayoub SF, 1979; Wallner C, 2009]. The present doctoral thesis is focused on primary bladder neck obstruction (PBNO), which is an under-investigated niche of pathology characterized by an incomplete relaxation or by an over-activity of the urethral sphincters [Nitti VW, 2005]. This urological disease is quite frequent in the young male, being identified in up to 47-54% of male patients aged 18-45 years with chronic voiding dysfunction symptoms [Kaplan SA, 1996; Nitti VW, 2002]. Unfortunately, symptoms at first presentation are vague ant too often patients are thought to be affected by chronic abacterial prostatitis, chronic pelvic pain syndrome or psychogenic voiding dysfunction. Moreover, PBNO patients in fact may be extremely disturbed by symptoms, and to date and to the best of our knowledge there are still no recognized effective treatments. In our opinion, this reflects the lack in knowledge of etiopathogenetic mechanisms. AIMS OF THE RESEARCH In the present research we intended to qualitatively and quantitatively analyse multiple variables in patients diagnosed with PBNO. The first aim of the research was to define whether a correlation between voiding dysfunction and postural or musculoskeletal aspects existed. If so, we were willing to understand if this association was only statistical/epidemiological or if a cause/effect relationship was present. The third aim was to define, if possible, the underlying etiopathogenic mechanism, in order to identify an effective treatment strategy. Finally, aim of this doctoral research was also to analyse the extent to which urological patients needed for rehabilitative medicine and dedicated rehabilitations in the field of Urology. In fact, this topic represents an innovative and challenging subject for the modern medicine, which is increasingly devoted to the patient?s needs. More efforts are needed in this field and, more in general, in functional urology, in order to provide better quality of life to our patients. MATERIALS AND METHODS From November 2013 to October 2017 all the patients presented for outpatient urological consultation to the same urologist (Tommaso Ciro Camerota) were prospectively evaluated. Among more than 6.000 outpatient evaluations and diagnostic procedures individually performed, 71 male subjects reporting chronic voiding dysfunction were diagnosed with PBNO. Patients with neurological disorders, diabetes mellitus, previous major injuries, lower limbs or back surgery were excluded from the study. All the subjects enrolled in the present research were diagnosed and personally evaluated by the researcher Tommaso Ciro Camerota. All the urologic diagnostic procedures were carried out by the same physician, and all the imaging and neurological evaluations were reviewed by the researcher. Urologic assessment was carried out according to the latest available recommendations and Guidelines on non-neurogenic LUTS. Few additional imaging and procedures were carried out. Patients were comprehensively evaluated with deep investigation of general and medical history, careful characterization of the reported symptoms, accurate physical examination, urinalysis, administration of validated questionnaires (patient reported outcome measures), collection of voiding and bowel diaries (frequency-volume charts), uroflowmetry with post-void residual urine, abdominal ultrasound, outpatient flexible urethrocystoscopy, second level imaging (full spine X-ray or pelvic-perineal MRI), neurophysiological testing, pain and postural assessment, gait analysis. Not all the subjects reporting voiding dysfunction suggestive for PBNO underwent all of these diagnostic procedures. RESULTS In our study population, median age at diagnosis was 41 years (interquartile range: 33.25 - 47.75), while median symptoms duration until diagnosis was 12 months (interquartile range: 6.5 - 25.5). Almost all the subjects (97%; n.69/71) reported the presence of a physiological urinary stimulus, with no differences in perception (increased or decreased). Seventy percent of the patients (n.51/71) were afflicted by both irritative and obstructive voiding symptoms; 13% of the subjects (n.9/71) exclusively reported obstructive urinary symptoms, while 3 patients (4%) had only irritative symptoms. Voiding symptoms were not isolated in our study population; the concomitant presence of other pelvic o perineal disorders was relevant. Among all the subjects enrolled, 34% reported defecation disorders, 25% reported a variable degree of impairment in erectile function, 35% reported ejaculation disorders, while pain was present in 76% of the subjects. 62% of the entire study population correctly filled and delivered bladder diaries, which showed an increased voiding frequency per 24 hours (mostly during daytime hours), a preserved total voided volume per 24 hours, and a significant reduction of the volume emptied per single void (median 172.5, interquartile range 141.3 ? 287.8). Uroflowmetry showed reduced mean peak flow rate (12.89 � 4.58 mL/s), reduced mean average flow rate (6.22 � 2.98 mL/s), and pathological mean post-void residual urine (72.72 � 53.32 mL); mean voided volume was 304.2 mL. Twenty-eight percent (n. 20/71) patients presented intermittent (complete or incomplete) stream 69% (n. 49/71) subjects had plateau flow, while 82% (n. 58/71) of the study population had urinary straining. The great majority of patients presented a combination of more than one of these flow characteristics. At urethrocystoscopy, all the 71 PBNO patients presented small non-obstructive prostate, tight external urethral sphincter, and contracted bladder neck; none had cicatricial urethral strictures, benign prostatic obstruction, transitional cell carcinoma of the bladder or vesical stones. Forty-nine percent (n. 35/71) of the study population underwent full spine X-ray on a single image. None of the patients showed a physiologic appearance. When compared to normalcy, the major pathological findings were lumbar hyperlordosis, horizontalization of the sacrum and increase of the sacral slope, hooked coccyx, anterior tilt of the pelvis, lower limb length discrepancy, variable degrees of scoliosis, obturator foramina asymmetry, partial or complete congenital sacralization of L5 vertebrae, mild anterolisthesis of L5 on S1, radiographic L5-S1 disk height reduction; cervical spine rectification. MRI of the pelvis and of the perineum (axial, coronal, and sagittal 1.5T or 3T, depending on the scanner) was obtained in 31% (n. 22/71) of the patients enrolled in this research. Hypertonicity or hypertrophy of pelvic floor muscles were identified in all the 22 subjects. Moreover, various and heterogeneous anomalies (skeletal or muscular) were identified, as for example: external urethral muscle thickening, hooked coccyx or its anterior angulation, sacroiliac joint sclerosis or sacroiliitis, posterior disc protrusion al L3-L4-L5-S1, sacrotuberous ligament thickening, piriformis muscle contraction or hypertrophy, pelvic upslip or rotation, femoroacetabolar impingement, levator ani muscle thickening, sacralization or hemisacralization of L5, sclerosis or erosion at the pubic symphysis, etc. Neurophysiological testing was carried out in 23 subjects. Among these, 87% presented a variable degree (from mild to moderate) of sacral and/or pudendal neuropathy, which could be either unilateral or bilateral. Pain was found to be present in a relevant percentage of subjects enrolled in this research (76%). A deep clinical evaluation was carried out by dedicated physicians. Characteristics, entity and time of onset of pain were extremely variable among our study population (12.64�10.87 months, mean�SD). Pain was reported to be distributed in different areas: lumbar muscles and vertebrae, sacroiliac joint, hip, coccyx, pubic bones, pelvic muscles, iliohypogastric, ilioinguinal, genitofemoral and pudendal nerves. A significant amount of patients presented a myofascial pain syndrome or articular pain, while neuropathic pain was found in only 5% of the studied patients. Gait analysis was carried out on 7 patients diagnosed with PBNO. A different degree of discordancy from normal controls was found to be present in 6/7 subjects enrolled. This non-invasive procedure allowed to identify the pelvis level as the variable more different from controls, followed by variables at the ankle level. Post-treatment clinical outcome was collected in 25% of the study population (n. 18/71). No traditional urological treatments (e.g. alpha-lytic drugs, bladder neck incision, etc) were proposed to any of the enrolled patients. Interestingly, when PBNO subjects were comprehensively treated (rehabilitation, myorelaxants, pain therapy, plantar in case of lower limbs dysmetria, etc.) an immediate and significant improvement was noticed in post-treatment bladder diaries and uroflowmetries collected. DISCUSSION According to the available literature [Kaplan, 1994; Nitti, 2002; Camerota, 2016], the results provided in this doctoral research confirm that PBNO is characterized by a significant clinical heterogeneity. Voiding symptoms (e.g.: hesitancy, decreased force of stream, intermittent stream, incomplete emptying), storage symptoms (e.g.: frequency, urgency), or a combination of the both may be reported by patients at first presentation. Frequency was the most common symptom in our study population (69%), coherently with previously published papers which showed a variable incidence from 74% to 79% [Yang SS, 2002; Grafstein NH, 2005; Glassberg KI, 2010]. Other common complaints were straining (65%), urgency (54%), feeling of incomplete voiding (58%) and intermittent stream (41%); nycturia and urinary incontinence were occasionally present. The collected bladder diaries showed multiple low-volume voids during daytime, few to none voids during night-time, and normal voided volumes at first micturition after awakening. As previously shown in females [Weiss JM, 2001; Peters KM, 2006, Butrick CW, 2009c], hypertonicity of pelvic floor muscles may be confused and interpreted as a normal stimulus to void. In this scenario, when subjects lie down ? fact that usually occurs at night ? intrapelvic pressure reduces, pelvic floor relaxes, and the false urinary stimulus disappears. Consequently, the bladder has the time and the physical space to fill up, and patients urinate when a proper voiding stimulus is generated at an adequate bladder volume. In our study population, pain represented a relevant component of the initial clinical presentation in our cohort of patients (76%); more than one pain trigger was present in the same PBNO patient. Therefore, an accurate pain assessment is suggested in a second-level specialist pain centre. In fact, similarly to traumas, muscular hypertonicity represents an inflammatory trigger which induces local release of prostaglandins, histamine, serotonin and bradykinins [Butrick CW, 2009b]. This mediators act as sensitizers on muscle nociceptors; the result is the development of mechanical allodynia and hyperalgesia, also known as peripheral sensitization. It is also known that, in the presence of a prolonged noxious stimulus, neuroplastic changes occur in the central nervous system. These are characterized by the amplification of entity and/or area of the initial pain impulse, or by the generation of independent (spontaneous) pain impulses. This phenomenon is also known as central sensitization. Moreover, pelvic hypertonicity may result in myofascial pain syndrome [Butrick CW, 2009b]. In patients reporting LUTS, a deep investigation of general and urological history is mandatory as it should support the proper identification of the possible causes of reported disorder [Novara G, 2006; Irani J, 2003; McVary KT, 2011; Bosch J, 2013]. Moreover, a careful characterization of the reported symptoms is strongly suggested. In fact, patients tend to focus only on a predominant symptom and have no complete perception of the complexity of the micturition discomfort or of other associated disorders (bowel or penile sensitivity alteration, pelvic or perineal pain or dysesthesia). Frequently patients realize their whole symptomatology during the urological evaluation; in this occasion, they also may discover correlations with daily activity or other dysfunction. Moreover, an accurate physical examination was performed on all patients by the same urologist (Tommaso Ciro Camerota). The examination focused on abdominal, flank, pelvic and suprapubic evidences, in order to rule out conditions which may interfere with normal bladder voiding (e.g.: bladder overdistension/urinary retention, urethral meatal stenosis, urethral discharge, phimosis, etc.). Digital rectal examination was performed only in case of long-term presence of symptoms (more than two years), reported fever (to exclude prostatitis), age over 40 years-old, or in case benign prostatic enlargement were suspected. A deep neurological evaluation was performed by a pain management specialist, in order to rule out neurological diseases. Frequency-volume charts were pathologic in all the patients, with a substantial increased voiding frequency per 24 hours with low-volume voided per individual void. Uroflowmetric measurements were performed accordingly with 2016 International Continence Society Good Urodynamic Practices and Terms [Rosier PFWM, 2017]. PVR measurement was always obtained by transabdominal ultrasound; we preferred this method to bladder scan or catheterization respectively because of its reliability/reproducibility and because of its non-invasiveness. In the present research, frequently observed pathological patterns at pre-treatment uroflowmetry were reduced voided volume and morphology of the curve characterized by the presence of a plateau flow and/or stream intermittency. Due to the increased urinary frequency and/or to the increased perception of bladder fullness, these patients usually present a reduction of voided volume per each bladder emptying. But when considering the sum of voided volume and post-void residual urine, the full bladder filling volume before uroflowmetry usually appears to be more than adequate (being quite always more than 150 mL). Therefore, the collected uroflowmetries are considered reliable. Invasive procedures are justified if uroflowmetry shows pathological results in patients with bothersome symptomatology [Nitti VW, 2002]. In PBNO patients urethrocystoscopy allows to exclude cicatricial urethral strictures, benign prostatic obstruction, transitional cell carcinoma of the bladder or vesical stones. In all the patients enrolled in this doctoral research, not only the internal urinary sphincter (bladder neck) but also the external urethral sphincter (rabdosphincter) was found to be contracted endoscopically. Neurophysiological testing showed the presence of a variable degree (from mild to moderate) of sacral and/or pudendal neuropathy, which could be either unilateral or bilateral. None of the 23 patients studied had a clear nerve injury, but only a malfunctioning along pelvic nerves path. These evidences are consistent with previously published observations in women with pelvic floor disorders [Walters MD, 2014]. Three subjects showed normal results. Motor unit potential of irregular and polyphasic shape were observed, in the absence of signs of neuropathy. This is an indirect sign of rearrangements of motor unit fibres, which is typical of slowly progressing processes [Zalewska E, 1998]. Full spine X-ray provided interesting data in our study population. All the PBNO patients studied (n. 35/71, 49%) with this imaging showed discordance from normalcy. Obturator foramina asymmetry reflects pelvic torsion, which was subsequently confirmed at gait analysis. Cervical spine rectification, increased sacral slope, reduction of thoracic kyphosis and other changes in spino-pelvic parameters are known compensatory mechanisms to lumbar lordosis modifications [During J, 1985; Jackson RP, 2000; Roussouly P, 2005; Vaz G, 2002]. In few patients we also found a partial or complete congenital sacralization/hemisacralization of L5. A significant variability was observed in our study population. All the subjects studied with MRI presented various degree of discordances from normalcy. Some of these pathological aspects were recurrent, but unfortunately a unique common pattern was not identified. Nevertheless, we were able to categorize abnormalities into four groups: 1. hypertrophy or hypertonicity of pelvic floor muscles, which were present ? with different degrees ? in all the 22 subjects; 2. tendon inflammation; 3. joints (e.g. sacroiliac or pubic symphysis) inflammation or sclerosis; 4. skeletal abnormalities as for example anterolisthesis, hooked coccyx, posterolateral disc protrusion at lumbar spine or femoroacetabolar impingement. Recurvatum coccyx was found to be present in 15 of the 22 subjects who underwent MRI (68%), consistently with the results we obtained from full spine X-ray performed in another group of 35 patients with PBNO. This morphologic modification suggests the presence of a chronic condition, which had time to shape the coccyx. Another frequent observation was the evidence of an anococcygeal raphe thickening. This condition was usually associated with a reduction in the rectal angle due to anococcygeus muscles hypertonicity. When looking at the results of the performed evaluations, one of the main findings of this doctoral research is that patients with voiding dysfunction may present a variable degree of abnormal kinematic gait patterns. In particular, we recorded gait cycles of seven self-selected subjects already diagnosed with PBNO, and we were able to quantitatively detect deviations at the ankle and pelvis level with respect to normal subjects. Four patients differed from controls in more than a third of the variables, two patients presented a mild discordance, while only one patient (P3) was almost comparable to normal subjects. Postural defects were not subjectively perceived by any of the seven participants in the gait study. In fact, all patients were completely asymptomatic from a musculoskeletal point of view. A comprehensive approach was used to treat PBNO patients enrolled in this doctoral research. These treatments provided good results. When analysing PBNO patients before and after treatment, our outcome measures were: improvement in uroflowmetric parameters (peak flow rate, average flow rate, PVR, and morphology of the curve), reduction or disappearance of pain (if present at first consultation), improvement in bladder diaries or in patient?s perceived discomfort. An increase in voided volume and a normalization of the curve shape was observed in all the uroflowmetries collected after rehabilitative treatments (25%, n. 18/71). Urethrocystoscopy was not repeated due to its invasiveness; moreover, we believe that it would not have added any further useful information. The relationship between urinary continence and posture was previously proposed and evaluated in a female population [Sahinkanat T, 2011]. In addition, affections in the musculoskeletal system were previously proposed as influencing elements in other pelvic dysfunctions such as chronic pelvic pain in male patients [Segura JW, 1979; Salvati EP, 1987; Hetrick DC, 2003] or anal incontinence in both male and female patients [Altomare DF, 2001]. In females, variations in the contractility of pelvic floor muscles and in the generation of intra-pelvic pressure may occur in case of maladjustment of the lumbo-pelvic area [O?Sullivan PB, 2002; Hungerford B, 2004; B� K, 2005]. To the best of our knowledge, no previous scientific study proved a correlation between postural defects/modifications and bladder voiding disorders in the male population (e.g.: urgency, frequency, intermittency, etc.). We previously hypothesised the existence of a possible correlation between altered biomechanics of the pelvis and urethral sphincters activity in male patients reporting voiding dysfunction in the absence of neurological or orthopaedic signs [Camerota TC, 2016]. The results of this doctoral research show that gait variables at ankle and pelvis level were vastly discordant from normalcy, while gait variables at knee and trunk level were little-to-no interested. In our hypothesis, a modification in the normal static posture of the pelvis (for example, in the case of anteversion, retroversion or torsion) invariably determines a variation in the contractile state of the pelvic floor muscles. This support system behaves like a hammock between two trees: a movement in the structural part induces an adjustment on the elastic side. In the case of PBNO, we propose that the urethral sphincters hypertonicity might depend from a hypercontraction of the entire pelvic floor, due to an adaptation sustained by a modified static of the pelvis. Moreover, when magnetic resonance imaging was performed in a group of consecutive subjects enrolled in this doctoral research, it was frequently observed a hypertonicity of muscular structures of the perineal plane and/or a variation in the angle of inclination of the coccyx. An increased activity of the pelvic floor muscles may determine a modification of the coccygeal curvature; in our patients, this modification was evident both at MRI and at traditional X-ray imaging. Moreover, when we evaluated the full spine X-ray in two projections of the seven participants to gait analysis, we observed various discordant aspects from normality (e.g.: slight pelvic upslip, moderate sacral horizontalization, or scoliosis). These characteristics are coherent with previously published evidences. In fact, it is known that poor posture contributes to pelvic floor muscle shortening or tensing. Based on the evidences produced with the present doctoral research, we propose the following pathogenic mechanisms as underlying causes for PBNO: - at a static evaluation, a horizontalization of the sacrum linked to an anteversion of the pelvis causes a flexion of the coccyx; - when a dynamic approach is applied, postural imbalances identified at gait analysis determine an anomalous activation of the pelvic floor muscles, with consequent perineal plane hypertonicity; - from a morphological and functional point of view, this is accompanied by a shortening of pelvic floor muscles length. All these mechanisms may lead to urinary sphincters hypercontraction and to the development of urinary voiding symptoms in male patients with no significant morphological alterations. Moreover, a diffuse hypertonia of the pelvic floor may lead to a further modification of the coccygeal curvature, which consequently appears dysmorphic at X-ray and at magnetic resonance imaging. In this setting, PBNO may be a possible presentation of the so called ?overactive pelvic floor muscles? condition. CONCLUSIONS The relationship between musculoskeletal affections and pelvic dysfunctions (such as chronic pelvic pain, or anal incontinence) have been previously described [Hetrick DC, 2003; Salvati EP, 1987; Segura JW, 1979; Altomare DF, 2001], mainly in the female population. The most innovative aspect of our research is the application of this hypothesis to a new study population. To the best of our knowledge, in the male population, the association between postural impairments and voiding symptoms has never been investigated with the approach we are proposing in this doctoral thesis. In our research we proved that ? when examining male patients with chronic voiding symptoms (with or without associated pelvic pain) suspected for PBNO ? comprehensive urologic, neurologic and pain assessment evaluations with deep pelvic floor muscle examination are required. This is crucial for the clear comprehension of patients? discomfort (for example, to rule out other possible interference factors), for the definition of the optimal diagnostic workflow, and for the identification of the best therapeutic approach. The observations provided in this doctoral thesis are coherent with our initial hypothesis [Camerota TC, 2016] and preliminary data [Zago M, 2017], and may be summarized as follows: - a variable combination of irritative and obstructive voiding symptoms are reported at the first clinical evaluation; - pathologic flow characteristics were always present at uroflowmetry, with recurrent patterns (e.g.: plateau and stream intermittency); - internal and external urethral sphincters hypercontraction (urethral functional stricture) was always found at a flexible outpatient urethrocystoscopy; - myofascial pain syndrome was frequently diagnosed at pelvic pain assessment; - hooked coccyx, lumbar hyperlordosis, short leg syndrome, and different degrees of modifications in spino-pelvic parameters (e.g.: pelvic tilt) were identified at full spine X-ray; - external urethral sphincter thickening, pelvic floor muscles hypertonicity, hooked coccyx, sacroiliac joint sclerosis, and different degrees of modifications in spino-pelvic parameters (e.g.: pelvic tilt) were shown at MRI; - different degrees of pudendal or sacral neuropathy were found at neurophysiological testing, while sustained contractions and/or poor post-contraction relaxations were found at EMG; - non-subjectively perceived postural defects were identified in all the subjects who underwent gait analysis. In a general framework, our data confirm that static and dynamic pelvic balances are associated with pelvic floor muscles hypertonicity which is in the end responsible for voiding symptoms. In our cohort of patients, voiding dysfunction and pain appear to derive from a common pathogenetic mechanism: muscular hypertonicity is both a trigger for pain and an obstacle to normal urine flow. Moreover, the evidence of both sacroiliac joint suffering and modifications in coccygeal appearance at imaging confirm the presence of an important hypertonic contraction of the pelvic floor muscles in patients diagnosed with PBNO. This hypertonicity is strictly associated with postural imbalances, as shown by kinematics. Gait analysis is a useful tool to quantitatively measure kinematic variables of human movement. In our research, this methodology showed a significant deviation from normalcy in PBNO patients, with alterations mainly at the pelvis and ankle levels. Unfortunately, it was not possible to identify a clear correlation between the severity of urological reported symptomatology and the altered gait pattern per each patient (as quantified by the gait score), maybe due to the reduced sample size. In addition, it was not possible to find a unique morphologic pattern at imaging. Gait analysis is a reliable and reproducible functional test, it is both non-invasive and inexpensive. Unfortunately, gait evaluations are time-consuming and cannot be used on a routine basis due to equipment availability. Moreover, data analysis requires highly-specialized competences (e.g.: biomedical engineering). Furthermore, gait analysis is not currently recognized as a diagnostic procedure in Urology, and there is no reimbursement from the National Health System. Considering its positive characteristics, we propose gait analysis as a potential innovative tool for longitudinal study and for monitoring clinical response to treatment in PBNO. To the best of our knowledge, this research is the first to investigate and to prove a correlation among voiding dysfunction and postural/kinematic patterns in males. Pelvic floor hypertonicity is easy to be diagnosed and treated. In our opinion, the actual major limitation in the everyday clinical practice is represented by the fact that this condition is not looked for in males, and thus remains misunderstood. With our research we provide evidences proving that PBNO and pelvic floor muscles hypertonicity are strictly linked. Performing unconventional imaging in patients with dysfunctional voiding may be crucial to get an accurate diagnosis, thus leading to optimal clinical and therapeutic management. Therefore, multimodal comprehensive therapeutic plans are essential to properly treat patients diagnosed with PBNO. Pelvic floor rehabilitation is a crucial component of this approach. Patients should first of all understand the normal function of their pelvic floor; relaxation exercises and physical manipulations represent a second step. We strongly believe that this doctoral research may open up new possible horizons in the field of Urology. In fact, voiding symptoms and urological diseases were traditionally considered to be mostly surgical. Our recent innovative experience sustains the hypothesis that ? if properly identified and diagnosed ? there is a group of urological patients who may benefit from alternative treatments. Moreover, it is still well known that comprehensive treatments are more effective when the underlying mechanisms of a disease are properly understood. Therefore, results provided with our research appear to be relevant as they reveal an important need for rehabilitative medicine. Unfortunately, to date there is still insufficient knowledge of the real need for rehabilitation in Urology. In our opinion, the proper identification and characterization of these new needs represents the most ambitious challenge for innovative urologic services. Future researches are needed to verify after treatment results in the entire study population. Long-term follow-up (maintenance of clinical benefits over time) is also required. Cost/effect ratio needs to be thoroughly investigated. Moreover, additional research in the field of gait analysis applied to functional urological patients should be done. Further researches are also needed to better assess the cause/effect sequence between pelvic floor muscles hypertonicity and skeletal disorders (e.g.: hooked coccyx, sacroiliac joint dysfunction). Finally, the following limitations can be identified in this doctoral research: 1. PBNO is a heterogeneous disease, therefore it?s possible that ? due to the selection criteria adopted ? we are comparing subjects belonging to different clinical groups; 2. our follow-up (maximum four years) is not sufficient to affirm that PBNO does not represent the first clinical manifestation of an evolutive major neurological disorder; 3. the absence of a clear direct correlation between the severity of urological reported symptomatology and the altered gait pattern per each patient may be strongly influenced by the sample size of our study population; 4. some important morphometric characteristics may be missed while interpreting results, due to the lack of body mass index; 5. post-treatment urological and clinical improvements were proved in the group of PBNO patients whose data were available (25% of the entire study population); therefore, statistical results may change as we receive the missing data. REFERENCES Abrams P et al. 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