Le syndrome douloureux chronique pelvien chez l’homme. Quelle physiopathologie? Quel traitement?

Chronic pelvic pain, in young men or elderly men, has always been a challenge to the medical profession, raising problems of assessment and management. Chronic pelvic pain has a high prevalence, which is underestimated as indicated by the following figures: 4% to 8% of patients consulting chronic pain centres, 15% of patients consulting a urologist for symptoms of chronic prostatitis with alteration of quality of life, 70,000 cases of chronic cystitis per year in the USA. The circumstances of onset are multiple: postoperative, after minor or major trauma or postinfectious, sometimes without any particular aetiology and often in a multifactorial context. The pathophysiology is therefore vague and poorly elucidated, as only about 5% of cases of chronic prostatitis have a bacterial cause. However, any form of stimulation activates pain pathways with neurogenic inflammation followed by central sensitization and modification of neuronal plasticity, and finally chronic refractory pain with organic dysfunction. This mechanism is currently proposed in numerous publications concerning postoperative chronic pelvic pain and refractory cystitis and chronic prostatitis. The pathophysiology of these types of pain is probably therefore neurogenic. In the absence of stimulation, a pudendal nerve tunnel syndrome can be suggested. The treatment of chronic pelvic pain in men can be considered in the following way: aetiological treatment whenever possible, neurogenic medical treatment (tricyclic antidepressants for continuous pain, anticonvulsants for intermittent pain, NMDA receptor antagonists in the case of failure), treatment of organic dysfunction, pudendal nerve analgesic block in the case of suspected tunnel syndrome and global treatment of patient with impaired quality of life. In conclusion, a better pathophysiological approach to these forms of chronic pelvic pain can improve these difficult patients.     

Organ cross talk modulates pelvic pain

Interstitial cystitis (IC) is a chronic bladder inflammatory disease of unknown etiology that is often regarded as a neurogenic cystitis. IC is associated with urothelial lesions, voiding dysfunction, and pain in the pelvic/perineal area, and diet can exacerbate IC symptoms. In this study, we used a murine neurogenic cystitis model to investigate the development of pelvic pain behavior. Neurogenic cystitis was induced by the injection of Bartha's strain of pseudorabies virus (PRV) into the abductor caudalis dorsalis tail base muscle of female C57BL/6J mice. Infectious PRV virions were isolated only from the spinal cord, confirming the centrally mediated nature of this neurogenic cystitis model. Pelvic pain was assessed using von Frey filament stimulation to the pelvic region, and mice infected with PRV developed progressive pelvic pain. Pelvic pain was alleviated by 2% lidocaine instillation into either the bladder or the colon but not following lidocaine instillation into the uterus. The bladders of PRV-infected mice showed markers of inflammation and increased vascular permeability compared with controls. In contrast, colon histology was normal and vascular permeability was unchanged, suggesting that development of pelvic pain was due only to bladder inflammation. Bladder-induced pelvic pain was also exacerbated by colonic administration of a subthreshold dose of capsaicin. These data indicate organ cross talk in pelvic pain and modulation of pain responses by visceral inputs distinct from the inflamed site. Furthermore, these data suggest a mechanism by which dietary modification benefits pelvic pain symptoms.     

Sacral nerve stimulation for the management of voiding dysfunction

Voiding dysfunction is common, and patients with urge incontinence, frequency/urgency syndromes, and chronic urinary retention are challenging to treat once conservative therapies (such as pharmacologic agents, pelvic floor rehabilitation, and intermittent catheterization) have been exhausted. Sacral nerve stimulation (SNS) is a new, minimally invasive, reversible therapy for the management of refractory voiding dysfunction and provides an attractive therapeutic alternative for patients with this condition. In this review, the role of SNS in the management of voiding dysfunction is examined critically, and the efficacy, risks, and benefits of this new modality are evaluated.     

Interstitial cystitis-epidemiology, diagnostic criteria, clinical markers

Knowledge of the epidemiology of interstitial cystitis (IC), the burden of the disease in the population, and the identification of possible risk factors remains largely fragmentary. The most reliable information comes from the few population-based studies that have appeared in the literature over the past 25 years, but two major issues urgently need to be addressed by appropriate epidemiologic studies: although studies find that only 10% of IC occurs in men, the hallmark symptoms of chronic prostatitis-pelvic pain, voiding dysfunction, and pain associated with sexual activity-overlap with those in men who carry the IC diagnosis. In addition, it is not known whether children suffer from the condition. The definition of IC is grounded in the symptomatology of pelvic pain and urinary frequency of a chronic nature and unexplained by any known urologic or other system pathology, but undue reliance on cystoscopic criteria has undoubtedly led to significant underdiagnosis. Efforts to identify clinical markers for diagnosis of IC are continuing and may lead the way to ascertaining the etiology and pathophysiology of IC.     

Sacral anterior root stimulation and cryotechnique: A new option for selective urethral sphincter block and reversible deafferentation in the future?

A possible application of cryotechnique might be a selective block of nerve fiber activity during sacral anterior root stimulation to achieve selective block of urethral sphincter and reversible deafferentation. In 13 foxhounds, electrical stimulation of sacral anterior roots S2 was performed while the accompanying spinal nerves were simultaneously cooled down from +25 degrees C in a stepwise fashion until a block of urethral sphincter activity was observed. The effects of cold block on the urethral sphincter and bladder were monitored by urodynamic investigation. In 2 additional dogs sacral posterior roots S2 were cooled down to +3 degrees C while accompanying anterior and posterior roots were stimulated distal to the cryothermode. Compound action potentials (APs) were registered proximal to the cryothermode before, during and after cooling and recovery time of cold blocked nerves was evaluated. Complete cold block of the urethral sphincter during spinal nerve cooling was achieved in all cases. Block temperature averaged +12 degrees C. Detrusor pressure was a mean 5,2 cm water. Recovery time was on average 5 min. The cold block was always reversible. In both dogs of the second series the compound action potentials disappeared nearly completely at +3 degrees C. Three min after the end of the cooling period the appearance of the compound action potentials was back to normal. In this study, cryotechnique proved to be effective for selective and reversible block of nerve fibers during sacral anterior root stimulation. In functional electrical stimulation this technique may lead to an improvement of quality of life in para- or tetraplegic patients resulting in optimization of voiding, standing, walking and grasping and does so without the necessity of surgical dorsal root rhizotomy.     

Ca(2+)/calmodulin-dependent protein kinase II is associated with pelvic pain of neurogenic cystitis

Interstitial cystitis/painful bladder syndrome is a chronic bladder inflammatory disease of unknown etiology that is often regarded as a neurogenic cystitis. Interstitial cystitis is associated with urothelial lesions, voiding dysfunction, and pain in the pelvic/perineal area. In this study, we used a murine neurogenic cystitis model to identify genes participating in the development of pelvic pain. Neurogenic cystitis was induced by the injection of Bartha's strain of pseudorabies virus (PRV) into the abductor caudalis dorsalis (tail base) muscle of female C57BL/6J mice. Mice infected with PRV developed progressive pelvic pain. The sacral spinal cord was harvested on postinfection days (PID) 2 and 4, and gene expression was analyzed by microarrays and confirmed by quantitative RT-PCR. On PID 2, the overall expression profile was similar to that of uninfected sacral spinal cord; by PID 4, there were substantial differences in expression of multiple functional classes of genes, especially inflammation. Analysis of pain-signaling pathways at the dorsal horn suggested that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) contributes to neurogenic cystitis pelvic pain. Consistent with this, CaMKIIδ expression exhibited a mast cell-dependent increase in the sacral spinal cord at the mRNA level, and phospho-CaMKII immunoreactivity in the dorsal horn was increased on postinfection day (PID) 4 during PRV infection. Finally, intrathecal injection of the CaMKII inhibitor KN-93 attenuated the PRV pain response. These data suggest that CaMKII plays a functional role in pelvic pain due to neurogenic cystitis.     

Urinary Bladder Distention Evoked Visceromotor Responses as a Model for Bladder Pain in Mice

Approximately 3-8 million people in the United States suffer from interstitial cystitis/bladder pain syndrome (IC/BPS), a debilitating condition characterized by increased urgency and frequency of urination, as well as nocturia and general pelvic pain, especially upon bladder filling or voiding. Despite years of research, the cause of IC/BPS remains elusive and treatment strategies are unable to provide complete relief to patients. In order to study nervous system contributions to the condition, many animal models have been developed to mimic the pain and symptoms associated with IC/BPS. One such murine model is urinary bladder distension (UBD). In this model, compressed air of a specific pressure is delivered to the bladder of a lightly anesthetized animal over a set period of time. Throughout the procedure, wires in the superior oblique abdominal muscles record electrical activity from the muscle. This activity is known as the visceromotor response (VMR) and is a reliable and reproducible measure of nociception. Here, we describe the steps necessary to perform this technique in mice including surgical manipulations, physiological recording, and data analysis. With the use of this model, the coordination between primary sensory neurons, spinal cord secondary afferents, and higher central nervous system areas involved in bladder pain can be unraveled. This basic science knowledge can then be clinically translated to treat patients suffering from IC/BPS.     

慢性非细菌性前列腺炎／慢性骨盆疼痛综合征患者的尿动力学检查

目的：探讨尿动力学检查在了解慢性非细菌性前列腺炎／慢性骨盆疼痛综合征 （Chronic abacterial prostatitis/chronic pelvic pain syndrome, CPPS） 患者中下尿路症状（LUTS）产生原因的作用。方法：对36例难治胜慢性前列腺炎／盆腔疼痛综合征患者行尿流动力学压力-流率测定,同步测定膀胱压、逼尿肌压、同步肌电图测定,了解其症状产生的原因。结果：36例患者中,尿动力学证实膀胱出口梗阻14例（39％）;逼尿肌过度活动者8例,其中有7例与BOO同时存在;假性逼尿肌尿道外括约肌协同失调6例（16．7％）;逼尿肌收缩力低下者5例（13．9％）。结论：对难治性CPPS患者进行尿动力学检查有助于对此类患者LUTS产生的原因进行鉴别。从而可以采取有针对性的治疗。     

Deafferentation of the urinary bladder and implantation of a sacral anterior root stimulator (SARS) for treatment of the neurogenic bladder in paraplegic patients.

Since 25 years electrical stimulation has become an established and widely acknowledged therapy option. Today, FES is widely employed, e.g. for cardiostimulation, diaphragm stimulation, kinetotherapy, for treatment of tremor in Parkinson patients, and finally for bladder stimulation in patients with bladder voiding dysfunctions. Brindley was the first researcher who succeeded in stimulating the spinal nerves via implanted electrodes in an animal model. In the years 1978/79 Brindley implanted five paraplegic patients with so-called sacral anterior root stimulators; all of them were able to void under stimulation. This method of sacral anterior root stimulation (SARS) proved an alternative to frequent one-way catheterisation for patients with severe voiding dysfunctions, without achieving complete continence, however. The following study is to provide an overview over the latest insights in the context of implanting sacral anterior root stimulators; it discusses the preconditions required for such interventions and presents criteria to decide in which cases there is a contraindication for sacral deafferentation of the posterior roots. Moreover, it contrasts advantages and disadvantages of the intradural and extradural implantation methods and presents the currently available long-term follow-up results with SDAF and SARS for treatment of bladder voiding dysfunctions.     

Mast cell-derived histamine mediates cystitis pain

Background

Mast cells trigger inflammation that is associated with local pain, but the mechanisms mediating pain are unclear. Interstitial cystitis (IC) is a bladder disease that causes debilitating pelvic pain of unknown origin and without consistent inflammation, but IC symptoms correlate with elevated bladder lamina propria mast cell counts. We hypothesized that mast cells mediate pelvic pain directly and examined pain behavior using a murine model that recapitulates key aspects of IC.

Methods and Findings

Infection of mice with pseudorabies virus (PRV) induces a neurogenic cystitis associated with lamina propria mast cell accumulation dependent upon tumor necrosis factor alpha (TNF), TNF-mediated bladder barrier dysfunction, and pelvic pain behavior, but the molecular basis for pelvic pain is unknown. In this study, both PRV-induced pelvic pain and bladder pathophysiology were abrogated in mast cell-deficient mice but were restored by reconstitution with wild type bone marrow. Pelvic pain developed normally in TNF- and TNF receptor-deficient mice, while bladder pathophysiology was abrogated. Conversely, genetic or pharmacologic disruption of histamine receptor H1R or H2R attenuated pelvic pain without altering pathophysiology.

Conclusions

These data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and TNF, respectively. Therefore, pain is independent of pathology and inflammation, and histamine receptors represent direct therapeutic targets for pain in IC and other chronic pain conditions.     

会阴部皮肤和盆腔内脏的伤害感受性信息在猫骶髓后连合核神经元的汇聚

在戊巴比妥钠麻醉的猫上,用玻璃微电极细胞外记录的方法,观察了躯体和内脏的伤害性刺激对骶髓后连合核神经元活动的影响。结果表明,所有接受盆神经内Ａδ纤维传入的神经元皆为特异性伤害感受或广动力范围神经元－它们可被包括会阴部皮肤的躯体感受野的机械性及强电刺激诱发。上述结果提示,Ａδ纤维可能在盆腔内脏的伤害感受性传递中起重要作用。     

Asymptomatic Bacteriuria Escherichia coli Are Live Biotherapeutics for UTI

Urinary tract infections (UTI) account for approximately 8 million clinic visits annually with symptoms that include acute pelvic pain, dysuria, and irritative voiding. Empiric UTI management with antimicrobials is complicated by increasing antimicrobial resistance among uropathogens, but live biotherapeutics products (LBPs), such as asymptomatic bacteriuria (ASB) strains of E. coli, offer the potential to circumvent antimicrobial resistance. Here we evaluated ASB E. coli as LBPs, relative to ciprofloxacin, for efficacy against infection and visceral pain in a murine UTI model. Visceral pain was quantified as tactile allodynia of the pelvic region in response to mechanical stimulation with von Frey filaments. Whereas ciprofloxacin promoted clearance of uropathogenic E. coli (UPEC), it did not reduce pelvic tactile allodynia, a measure of visceral pain. In contrast, ASB E. coli administered intravesically or intravaginally provided comparable reduction of allodynia similar to intravesical lidocaine. Moreover, ASB E. coli were similarly effective against UTI allodynia induced by Proteus mirabilis, Enterococccus faecalis and Klebsiella pneumoniae. Therefore, ASB E. coli have anti-infective activity comparable to the current standard of care yet also provide superior analgesia. These studies suggest that ASB E. coli represent novel LBPs for UTI symptoms.     

Is There a Role for alpha-Blockers for the Treatment of Voiding Dysfunction Unrelated to Benign Prostatic Hyperplasia?

alpha-Adrenoreceptor antagonists have become the primary medical treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). It was presumed that the primary mechanism by which alpha-blockers reduced lower urinary tract symptoms (LUTS) was by relaxation of smooth muscle in the prostate through a sympathetic response. Reduction of outlet resistance leads to changes in bladder function, thus improving both storage and voiding symptoms. However, it was observed that many patients with BPH-associated LUTS had significant improvement in storage symptoms without subjective or objective improvement in voiding. Storage symptoms associated with detrusor overactivity (frequency, urgency, and urge incontinence) are typically thought of as being parasympathetically mediated, and therefore anticholinergic medications have been the mainstay of pharmacological treatment, but recent work has suggested that several nonparasympathetic-mediated mechanisms may cause detrusor overactivity. Because alpha receptors appear to play a role in lower urinary tract function at multiple sites and levels, alpha-blockers could be used to treat voiding dysfunction not related to BPH. In addition, these nonprostate effects should be gender-independent, making the use of alpha-blockers plausible in women with specific types of voiding dysfunction.     

Alpha-blockers for the treatment of prostatitis-like syndromes

Prostatitis is a common medical diagnosis. The etiology of this symptomatic syndrome can be an acute or chronic bacterial infection, a noninfectious initiator (the most common cause), or iatrogenic heat or radiation; the syndrome may coexist with benign prostatic hyperplasia. Alpha-blockers have a role in the treatment of the prostatitis syndromes. In Category I, acute bacterial prostatitis, alpha-blockers have been shown to possibly ameliorate obstructive and irritative voiding symptoms. In Category II, chronic bacterial prostatitis, alpha-blockers seem to reduce the risk of clinical and bacteriological recurrence. In Category III, chronic pelvic pain syndrome, alpha-blockers improve symptoms and quality of life. Alpha-blockers also seem to ameliorate the symptoms and reduce the risk of acute urinary retention in patients who suffer from either heat- or radiation-induced prostatic inflammation. Alpha-blockers improve lower urinary tract symptoms, including pain, in patients who are diagnosed with both prostatitis and benign prostatic hyperplasia. Evidence has proven there is definitely a role for alpha-blockers in the management of the prostatitis syndromes.     

Vesical Dysfunction Due to Prolapsed Disc

Neural disturbance of micturition may occur as a result of a prolapsed intervertebral disc. Single nerve root lesions are unlikely to cause bladder dysfunction; a massive central protrusion producing total blockage of the vertebral canal or multiple disc lesions are more likely to cause disturbance of voiding. High lesions are more prone to cause severe bladder dysfunction. Vesical dysfunction may sometimes be present without the typical back and leg pain.Provided a gynaecological cause is excluded, any young or middle-aged woman developing incontinence and retention with a sterile urine must be fully investigated to exclude a disc lesion. Once the disc has been removed, bladder function will improve, but in some cases recovery will be slow. Rarely some patients have permanent bladder dysfunction following a disc operation.     

Electrostimulation: a future treatment option for patients with neurogenic urodynamic disorders?

This paper provides an overview of electrical stimulation of the nervous system as a treatment option for urodynamic dysfunction and of some of the recent results in this field. The set-up used in our studies for improved bladder filling in spinal cord injured patients by conditional stimulation of the dorsal penile/clitoral nerve is a highly efficient way to limit neurogenic detrusor overactivity and increase bladder capacity. Ongoing studies suggest that recording of bladder nerve activity is stable over time and may be a technique for chronic monitoring of bladder activity. Bladder emptying exploiting an anodal blocking technique permits bladder emptying without simultaneous urethral-perineal contraction, thus enabling a physiological voiding pattern in one continuous sequence. In patients with supraspinal lesions, deep brain electrical stimulation is established only as treatment for a subgroup of patients suffering from Parkinson's disease. Yet, with improved electrode designs and increased clinical experience and experimental results, probably other groups of patients may be candidates for deep brain stimulation. In our study in pigs there was a trend towards increased bladder capacity and compliance in response to stimulation, which is encouraging as several neurological diseases are accompanied by overactive bladder with reduced capacity.     

Umbilical cord-derived mesenchymal stem cells alleviated inflammation and inhibited apoptosis in interstitial cystitis via AKT/mTOR signaling pathway

Interstitial cystitis (IC) is a bladder syndrome characterized by pelvic pain and urinary frequency without infection or other identifiable pathology. There are no effective treatments to cure IC. This study investigated the effects of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) injection on IC rat model. Furthermore, we used a coculture system to find the possible molecular mechanism on the human uroepithelial cells (SV-HUC-1), which was the cell model of IC. A rat model of IC was established via systemic injection with cyclophosphamide (CYP) and a cell model of IC was induced by being exposed to tumor necrosis factor (TNF)-α (10 ng/ml). After one week, UC-MSCs injection significantly ameliorated the bladder voiding function in IC rat model. And the Histo- and immunohistochemical analyses showed that UC-MSCs can repair impaired bladder, reduce mast cell infiltration and inhibit apoptosis of urothelium. ELISA results showed that UC-MSCs can decrease IL-1β, IL-6 and TNF-α in bladder. In the coculture system, UC-MSCs can promote proliferation of impaired SV-HUC-1 cells, and inhibit apoptosis. However, while knocked down EGF secreted by UC-MSCs with siRNA, the effects would be weaken. Western blot showed that UC-MSCs increase protein expression levels of p-AKT and p-mTOR in SV-HUC-1 cells, and decrease the levels of cleaved caspase-3. Taken together, we provide evidence that UC-MSCs therapy can successfully alleviate IC in a preclinical animal Model and cell model by alleviating inflammation, promoting proliferation and inhibiting apoptosis. In addition, we demonstrate that the AKT/mTOR signaling pathway was activated.     

Complementary and alternative therapies as treatment approaches for interstitial cystitis

The management of interstitial cystitis (IC) is predominantly the reduction of the symptoms of frequency, urgency, and pain. Multimodal treatment approaches for IC are helpful in customizing therapy for individual patients. Complementary and alternative therapies are a quintessential addition to the therapeutic armamentarium and frequently include dietary modification, nutraceuticals, bladder training, neuromodulation, stress reduction, and sex therapy. Dietary modification involves elimination of bladder irritants, fluid regulation, and a bowel regimen. Nutraceuticals studied for the treatment of IC include calcium glycerophosphate, L-arginine, mucopolysaccharides, bioflavinoids, and Chinese herbs. Bladder training is effective after pain reduction. The neuromodulation of high-tone pelvic-floor muscle dysfunction is achieved with physical therapy and acupuncture. Stress reduction and sex therapy are best administered by a qualified stress manager and sex therapist. Multimodal, nonconventional management may add efficacy to the treatment of IC.     

老年男性脑卒中患者排尿功能障碍的尿动力学评估

目的:存在阻塞性尿路疾患的老年男性在发生脑血管意外后,是否可通过早期症状或排尿症状类型(梗阻性还是刺激性)来预判排尿功能障碍的病因。方法:选择57例脑卒中后主诉排尿障碍的老年男性患者,所有患者均有继发于良性前列腺增生(BPH)的膀胱出口梗阻(BOO)症状。采集病史并行体检,57位患者均实行尿动力学检查,检查结果行A-G图分析并分类为:有梗阻,无梗阻及可疑梗阻。结果:患者平均年龄70岁(54-87),按排尿障碍的主诉类型分组(纯刺激症状42%,纯梗阻症状34%,两者混合24%),其中51例(89%)在脑卒中发生后即出现排尿症状,47(82%)例患者出现逼尿肌反射亢进(DH),在三组患者中无显著统计学差异。压力流率分析显示,36(63%)位患者有出口梗阻,无梗阻14(24%)例,可疑梗阻7(13%)例。在3组患者中亦无显著统计学差异。结论:所有老年男性患者呈现的症状不能预测膀胱出口梗阻或逼尿肌反射亢进的尿动力学结果。中风发生后排尿功能障碍症状的发生率明显升高,表明由脑血管意外引起的排尿功能障碍合并前期具有膀胱出口梗阻疾病时,可能会使后者的症状恶化,反之亦然。     

Medical and minimally invasive treatment of urinary incontinence

Newer agents and procedures give urologists more options in treating patients who have urinary incontinence related to such etiologies as an ineffective sphincter, detrusor hypersensitivity, obstruction, or a combination of these. Abolition of the involuntary contractions characteristic of detrusor instability can be accomplished pharmacologically or surgically. First-line anticholinergic agents are tolterodine and oxybutynin XL, given orally. Alternatively, intravesical administration provides a high concentration of drug, such as capsaicin or resiniferatoxin, at the detrusor muscle level. However, this commits the patient to intermittent self-catheterization. Surgery is reserved for those who have failed prolonged trials of conservative therapies. For patients with intractable urge incontinence, urologists have the new technique of sacral nerve stimulation.