生物反馈电刺激仪治疗腹腔镜前列腺癌根治术后尿失禁☆

目的：应用生物反馈电刺激仪可以指导患者进行正确自主的盆底肌肉训练，观察其对腹腔镜前列腺癌根治术后控尿功能恢复的作用。 方法：选择2005-07/2007-06中山大学附属第三医院泌尿外科收治腹腔镜前列腺癌根治术后尿失禁患者41例，轻度12例，中度23例，重度6例。采用加拿大Laborie 公司生产的UROSTIM型盆腔生物反馈电刺激治疗仪电刺激联合盆底肌肉训练，生物反馈电刺激每日1次，5次为1个疗程，根据患者尿失禁程度分别治疗一两个疗程。疗效判定标准：治愈，自觉尿失禁症状消失、小便能自控，排尿正常，尿垫试验阴性；有效，自觉尿失禁次数明显减少、尿垫试验连续3次以上阴性；无效，尿失禁症状无明显改善，尿垫试验阳性。治疗结束后4周评价其治疗效果，追踪观察随访3~12个月。 结果：41例术后不同程度尿失禁患者，治愈23例(56.1%) ，有效11例(26.9%) ，无效7例(17.0%) ，总有效率为83%。轻度尿失禁患者，治愈11例，有效1例；中度尿失禁患者，治愈11例，有效8例，无效3例；重度尿失禁患者，治愈1例，有效2例，无效3例。 结论：应用生物反馈电刺激仪可促进前列腺癌根治术后患者控尿功能的恢复。     

A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis

Central neuropathic pain (CNP) occurs in many multiple sclerosis (MS) patients. The provision of adequate pain relief to these patients can very difficult. Here we report the first phase III placebo-controlled study of the efficacy of the endocannabinoid system modulator delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (USAN name, nabiximols; Sativex, GW Pharmaceuticals, Salisbury, Wiltshire, UK), to alleviate CNP. Patients who had failed to gain adequate analgesia from existing medication were treated with THC/CBD spray or placebo as an add-on treatment, in a double-blind manner, for 14 weeks to investigate the efficacy of the medication in MS-induced neuropathic pain. This parallel-group phase of the study was then followed by an 18-week randomized-withdrawal study (14-week open-label treatment period plus a double-blind 4-week randomized-withdrawal phase) to investigate time to treatment failure and show maintenance of efficacy. A total of 339 patients were randomized to phase A (167 received THC/CBD spray and 172 received placebo). Of those who completed phase A, 58 entered the randomized-withdrawal phase. The primary endpoint of responder analysis at the 30 % level at week 14 of phase A of the study was not met, with 50 % of patients on THC/CBD spray classed as responders at the 30 % level compared to 45 % of patients on placebo (p = 0.234). However, an interim analysis at week 10 showed a statistically significant treatment difference in favor of THC/CBD spray at this time point (p = 0.046). During the randomized-withdrawal phase, the primary endpoint of time to treatment failure was statistically significant in favor of THC/CBD spray, with 57 % of patients receiving placebo failing treatment versus 24 % of patients from the THC/CBD spray group (p = 0.04). The mean change from baseline in Pain Numerical Rating Scale (NRS) (p = 0.028) and sleep quality NRS (p = 0.015) scores, both secondary endpoints in phase B, were also statistically significant compared to placebo, with estimated treatment differences of ?0.79 and 0.99 points, respectively, in favor of THC/CBD spray treatment. The results of the current investigation were equivocal, with conflicting findings in the two phases of the study. While there were a large proportion of responders to THC/CBD spray treatment during the phase A double-blind period, the primary endpoint was not met due to a similarly large number of placebo responders. In contrast, there was a marked effect in phase B of the study, with an increased time to treatment failure in the THC/CBD spray group compared to placebo. These findings suggest that further studies are required to explore the full potential of THC/CBD spray in these patients.     

盆底生物反馈电刺激治疗缺血性脑卒中尿失禁患者的临床观察

目的观察盆底生物反馈电刺激对缺血性脑卒中尿失禁患者的治疗效果。方法将80例缺血性脑卒中临床症状表现为尿失禁的患者,随机分为治疗组及对照组。治疗组予以标准护理干预联合盆底生物反馈电刺激治疗,对照组仅予以标准护理干预,并分别于治疗前、治疗4周后,行床旁B超测定膀胱残余尿量、并对泌尿症状困扰及国际下尿路症状进行评分。结果两组患者经治疗后症状均有好转,但与对照组相比,治疗组膀胱残余尿量减少、泌尿症状困扰评分及国际下尿路症状评分改善明显,且有统计学意义(P0.05)。结论盆底生物反馈电刺激能改善缺血性脑卒中患者尿失禁症状,并提高患者的生活质量。     

THC/CBD oromucosal spray in patients with multiple sclerosis overactive bladder: a pilot prospective study

Lower urinary tract dysfunctions (LUTDs) are commonly reported in multiple sclerosis (MS) patients and are mainly related to neurogenic overactive bladder (OAB). The aim of this observational study was to assess the effect of a tetrahydrocannabinol-cannabidiol (THC/CBD) oromucosal spray on resistant OAB by means of clinical and instrumental tools. Twenty-one MS patients were screened, and 15 cases have been evaluated. They underwent a specific clinical assessment (overactive bladder symptom score, OABSS) and a urodynamic assessment evaluating the maximal cystometric capacity (CCmax), bladder compliance (Qmax), maximum detrusor pressure (Pdet max), detrusor pressure at the first desire (Pdet first), bladder volume at the first desire (BVFD), leakage volume (LV), and post-void residual volume (PVR), before and after 4 weeks of THC/CBD administration. A complete neurological evaluation, including the assessment of their spasticity using the Modified Ashworth Scale (MAS) and the spasticity 0–10 numerical rating scale (NRS), was performed at the same times. Mobility was evaluated through the 25-ft walking-time test (T25-WT). The THC/CBD treatment successfully reduced the OAB symptoms (p = 0.001). Regarding the urodynamic findings after the end of treatment, PVR was significantly reduced (p = 0.016). Regarding the urodynamic findings after the end of treatment, PVR was significantly reduced (p = 0.016), while BVFD and CCmax were increased although the difference was not statistically significant. THC/CBD oromucosal spray has shown to be effective in improving overactive bladder symptoms in MS patients demonstrating a favorable impact on detrusor overactivity.     

Sativex® as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind,placebo-controlled randomised clinical trial

Purpose/aim: To evaluate the efficacy of tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex^®) as add-on therapy to optimised standard antispasticity treatment in patients with moderate to severe multiple sclerosis (MS) spasticity.

Methods: Sativex^® as add-on therapy vs. further optimised first-line ANTispastics (SAVANT) was a two-phase trial. In Phase A, eligible patients received add-on THC:CBD spray for 4 weeks to identify initial responders [≥20% improvement from baseline in spasticity 0–10 numerical rating scale (NRS) score]. Following washout, eligible initial responders were randomised to receive THC:CBD spray or placebo for 12 weeks (double-blinded, Phase B). Optimisation of underlying antispasticity medications was permitted in both groups across all study periods.

Results: Of 191 patients who entered Phase A, 106 were randomised in Phase B to receive add-on THC:CBD spray (n?=?53) or placebo (n?=?53). The proportion of clinically relevant responders after 12 weeks (≥30% NRS improvement; primary efficacy endpoint) was significantly greater with THC:CBD spray than placebo (77.4 vs. 32.1%; p?<?0.0001). Compared with placebo, THC:CBD spray also significantly improved key secondary endpoints: changes in mean spasticity NRS (p?<?0.0001), mean pain NRS (p?=?0.0013), and mean modified Ashworth’s scale (p?=?0.0007) scores from Phase B baseline to week 12. Adverse events, when present, were mild/moderate and without new safety concerns.

Conclusions: Add-on THC:CBD oromucosal spray provided better and clinically relevant improvement of resistant MS spasticity compared with adjusting first-line antispasticity medication alone.     

Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients

The objective was to determine whether a cannabis-based medicinal extract (CBME) benefits a range of symptoms due to multiple sclerosis (MS). A parallel group, double-blind, randomized, placebo-controlled study was undertaken in three centres, recruiting 160 outpatients with MS experiencing significant problems from at least one of the following: spasticity, spasms, bladder problems, tremor or pain. The interventions were oromucosal sprays of matched placebo, or whole plant CBME containing equal amounts of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) at a dose of 2.5-120 mg of each daily, in divided doses. The primary outcome measure was a Visual Analogue Scale (VAS) score for each patient's most troublesome symptom. Additional measures included VAS scores of other symptoms, and measures of disability, cognition, mood, sleep and fatigue. Following CBME the primary symptom score reduced from mean (SE) 74.36 (11.1) to 48.89 (22.0) following CBME and from 74.31 (12.5) to 54.79 (26.3) following placebo [ns]. Spasticity VAS scores were significantly reduced by CBME (Sativex) in comparison with placebo (P =0.001). There were no significant adverse effects on cognition or mood and intoxication was generally mild.     

Vesicourethral dysfunction in multiple sclerosis. Initial assessment based on lower urinary tract symptoms and their pathophysiology

The most common lower urinary tract symptoms (LUTS) in multiple sclerosis (MS) are irritative, obstructive or mixed (association of irritative and obstructive LUTS). Generally irritative LUTS are typical in patients with cortical, brainstem or mild spinal cord lesions; obstructive symptoms are frequent in patients with spinal cord lesions (below the pontine micturition centre) or at the level of the sacral micturition centre. Irritative LUTS are often associated with detrusor overactivity, whereas obstructive LUTS are associated with detrusor sphincter dyssynergia or detrusor areflexia/hypocontractility. Proper management of these LUTS often could be planned without specialised assessment, in accordance with the algorithms proposed by International Consultation on Incontinence.     

Muscle elastography: a new imaging technique for multiple sclerosis spasticity measurement

Multiple sclerosis (MS) spasticity is currently evaluated on the basis of neurological examinations such as Ashworth Scale (AS) and 0–10 NRS. Severity of spasticity is difficult to quantify. We investigated the use of real time elastography (RTHE) ultrasounds for evaluating objectively the muscle fibers status in MS spasticity patients and their changes after a new antispasticity treatment. Two studies were performed. In study A, 110 MS patients underwent a neurological evaluation based on the AS and RTHE. The RTHE images were scored with the new 1-5 muscle fibers rigidity imaging scale, here called MEMSs (Muscle Elastography Multiple Sclerosis Score). The correlation between AS and MEMSs was found to be statistically significant. In study B, 55 MS patients treated with THC:CBD oromucosal spray for their resistant spasticity were followed prospectively. MS spasticity was evaluated by the 0–10 NRS scale at baseline and after 4 weeks of treatment. MEMSs’ figures were obtained at both timepoints. Responders to THC:CBD oromucosal spray (pre-defined as an improvement ≥20% in their 0–10 NRS spasticity score vs. baseline) were 65% of sample. These patients had a mean 0-10 NRS reduction of 1.87 and a MEMSs reduction of 1.97 (P values <0.0001). The remaining 35% of patients, classified as clinically non-responders, showed still a significant mean reduction in MEMSs (0.8, P = 0.002). Our overall results showed that RTHE, operativized throughout MEMSs, could be an objective gold standard to evaluate MS muscle spasticity as well as the effectiveness of antispasticity therapy.     

Sacral Nerve Stimulation for Treatment of Intractable Pain Associated with Cauda Equina Syndrome

Sacral nerve stimulation (SNS) is an effective treatment for bladder and bowel dysfunction, and also has a role in the treatment of chronic pelvic pain. We report two cases of intractable pain associated with cauda equina syndrome (CES) that were treated successfully by SNS. The first patient suffered from intractable pelvic pain with urinary incontinence and fecal incontinence after surgery for a herniated lumbar disc. The second patient underwent surgery for treatment of a burst fracture and developed intractable pelvic area pain, right leg pain, excessive urinary frequency, urinary incontinence, voiding difficulty and constipation one year after surgery. A SNS trial was performed on both patients. Both patients'' pain was significantly improved and urinary symptoms were much relieved. Neuromodulation of the sacral nerves is an effective treatment for idiopathic urinary frequency, urgency, and urge incontinence. Sacral neuromodulation has also been used to control various forms of pelvic pain. Although the mechanism of action of neuromodulation remains unexplained, numerous clinical success reports suggest that it is a therapy with efficacy and durability. From the results of our research, we believe that SNS can be a safe and effective option for the treatment of intractable pelvic pain with incomplete CES.     

Placebo Effects in a Multiple Sclerosis Spasticity Enriched Clinical Trial with the Oromucosal Cannabinoid Spray (THC/CBD): Dimension and Possible Causes

Regulatory authorities admit clinical studies with an initial enrichment phase to select patients that respond to treatment before randomization (Enriched Design Studies; EDSs). The trial period aims to prevent long‐term drug exposure risks in patients with limited chances of improvement while optimizing costs. In EDSs for symptom control therapies providing early improvements and without a wash‐out period, it is difficult to show further improvements and thus large therapeutic gains versus placebo. Moreover, in trials with cannabinoids, the therapeutic gains can be further biased in the postenrichment randomized phase because of carryover and other effects. The aims of the present review article are to examine the placebo effects in the enrichment and postenrichment phases of an EDS with Δ⁹‐tetrahydrocannabinol and cannabidiol (THC/CBD) oromucosal spray in patients with multiple sclerosis (MS) spasticity and to discuss the possible causes of maintained efficacy after randomization in the placebo‐allocated patients. The overall mean therapeutic gain of THC/CBD spray over placebo in resistant MS spasticity after 16 weeks can be estimated as a ~1.27‐point improvement on the spasticity 0–10 Numerical Rating Scale (NRS; ~?20.1% of the baseline NRS score). We conclude that careful interpretation of the results of EDSs is required, especially when cannabinoid‐based medications are being investigated.     

Lower urinary tract symptoms and bladder control in advanced Parkinson's disease: effects of deep brain stimulation in the subthalamic nucleus.

Deep brain stimulation in the subthalamic nucleus (STN) leads to significant improvement in motor function in patients with advanced Parkinson's disease (PD). In this prospective study including 16 patients with PD, we investigated (1) lower urinary tract symptoms (LUTS) by questionnaires International Prostate Symptom Score (IPSS, symptoms only) and Danish Prostate Symptom Score (DanPSS, symptoms and bother of symptoms) and (2) bladder control (assessed by urodynamics) before and after implantation of electrodes in the STN. PD symptoms (Unified Parkinson's Disease Rating Scale score) improved significantly (P < 0.0001), and symptoms of overactive bladder (IPSS) decreased along with the troublesome symptoms of overactive bladder (DanPSS; P < 0.01 for both). Urodynamic parameters before and after implantation of electrodes in the STN, evaluated with and without the stimulation on, did not change significantly.     

Effects of inhibitory rTMS on bladder function in Parkinson's disease patients

Patients affected by Parkinson's disease (PD) may present with lower urinary tract (LUT) dysfunction characterized by involuntary detrusor overactivity. We evaluated possible impact of a 2‐week course of low frequency 1 Hz repetitive transcranial magnetic stimulation (rTMS) on LUT behavior in eight advanced PD patients complaining of urinary disturbances. We tested the effects of rTMS measuring urodynamic examination and the International Prostate Symptoms Score (IPSS) questionnaire, used for evaluation of subjective LUTS. rTMS was able to improve temporarily LUT behavior in PD patients, increasing bladder capacity and the first sensation of filling phase. Moreover, a reduction of IPSS score was noticed, due to an improvement on filling phase symptoms. The beneficial effects assessed with the IPSS lasted for up to 2 weeks after the end of the stimulation. rTMS seems to be an effective, noninvasive alternative treatment for PD patients with urinary disturbances. © 2009 Movement Disorder Society     

骶神经刺激治疗神经源性膀胱的疗效观察

目的 观察骶神经刺激(SNS)治疗神经源性膀胱的疗效.方法 使用SNS治疗94例神经源性膀胱患者,观察SNS治疗前和治疗1周后的尿失禁症状简易评分(ICI-Q-SF评分)、排尿日记(包括尿失禁次数、尿垫试验、排尿次数、夜尿次数、排尿量等)和尿动力学检查指标(包括膀胱容量、逼尿肌压、最大尿流率、平均尿流率、膀胱颈压、最大尿道压、功能性尿道长度和残余尿量等),并对所得数据进行统计学分析.结果 治疗前ICI-Q-SF评分为(17.2±1.8)分,治疗后为(8.3±1.6)分,差异有统计学意义(P<0.05).与治疗前比较,尿失禁次数、排尿次数和夜尿次数显著减少(P<0.05),尿垫显著减轻(P<0.05),排尿量显著增加(P<0.05);膀胱容量、最大尿流率和平均尿流率显著增加(P<0.05),残余尿量显著减少(P<0.05),而逼尿肌压、膀胱颈压、最大尿道压和功能性尿道长度等无显著性改变(P＞0.05).本组总有效率为75.5%,无一例并发症发生.结论 SNS治疗神经源性膀胱的效果确切,症状改善明显,并发症少且发生率低,是值得临床推广的治疗方法.     

Multiple sclerosis and coexisting intradural extramedullary spinal cord tumour: a case report

We report the coexistence of multiple sclerosis (MS) and an intradural extramedullary spinal cord tumour in a 46-year-old woman with a 2-year history of MS. The patient presented with right hemitrunk and lower extremity paraesthesias, urinary incontinence, and intermittent lower right back and abdominal pain, which did not respond to pulse steroid therapy. A spinal magnetic resonance imaging (MRI) study revealed an intradural extramedullary spinal cord tumour in the lower thoracic spine, later diagnosed as schwannoma. We call attention to this rare association of MS and a spinal cord tumour, and emphasize the need for scrutiny of new and uncommon symptoms during the follow-up of MS patients. Received: 2 April 2002 / Accepted in revised form: 28 May 2002 Correspondence to V. Etus     

Cannabinoids for Treatment of MS Symptoms: State of the Evidence

Purpose of Review

Cannabis and cannabinoids have been used medically and recreationally for thousands of years and recently there has been a growing body of research in this area. With increased access now that medical marijuana is available in many jurisdictions, patients and providers want to know more about the evidence for benefits and risks of cannabinoid use. This paper provides an overview of the available cannabinoid-based formulations, a summary of the highest quality evidence for the use of cannabinoids for treating spasticity and pain associated with multiple sclerosis (MS), and a discussion of possible dosing regimens based on information from these studies.

Recent Findings

Two recent high-quality systematic reviews concluded that the only strong evidence for medical marijuana in neurological disorders was for reducing the symptoms of patient-reported spasticity and central pain in MS and that the only complementary and alternative medicine (CAM) intervention in MS with strong supportive evidence was cannabinoids. Based on this review, they concluded that nabiximols (Sativex oral spray), oral cannabis extract (OCE), and synthetic tetrahydrocannabinol (THC) are probably effective at reducing patient-reported symptoms of spasticity in people with MS, but OCE and synthetic THC were not found to be effective for reducing physician-administered measures of spasticity. In addition, nabiximols, OCE, and synthetic THC are probably effective at reducing MS-related pain. Cannabinoids were generally well-tolerated. However, cannabis use has been associated with an increased risk of psychosis and schizophrenia in at-risk individuals, there is growing evidence that cannabis can increase the risk for cardiovascular diseases, including myocardial infarction (MI), hypertension, heart failure, and stroke, and a recently recognized adverse effect of cannabis is cannabinoid hyperemesis syndrome.

Summary

The medical use of cannabinoids remains controversial. While cannabinoids have been studied for a variety of neurologic disorders, there is strongest evidence to indicate benefits in treatment of spasticity and neuropathic pain in multiple sclerosis. Although the best dose for an individual remains uncertain, most participants in the studies discussed in this paper used between 20 and 40 mg of THC a day in divided doses. Adverse events in studies were generally more common in the groups using cannabinoid products but serious adverse events were rare and cannabis products were generally well-tolerated. Cannabis use does appear to be associated with increased risk of certain adverse events, including psychosis, cardiovascular diseases, and cannabinoid hyperemesis syndrome.

     

The place of the botulinum toxin in the management of multiple sclerosis

Multiple sclerosis (MS) is the most common disabling chronic disease of the central nervous system among young adults. These patients suffer from variety of symptoms that have a profound affect on their working ability, activities of daily living and general quality of life. Treatment of these symptoms is important in order to relief them and improve daily function and quality of life. Many of these symptoms are often resistant to treatment. Botulinum toxin A (BTX) is mainly used for spasticity and bladder dysfunction in MS. It is an effective treatment option for spasticity of the thigh adductor, pes equinus, striatal toe or adductor of the shoulder joint. BTX injections are effective in reducing incontinence episodes and urinary urgency, daytime frequency and nocturia, as well as sustained improvements in quality of life of MS patients with detrusor overreactivity. In addition, BTX is potentially effective in treating pain, trigeminal neuralgia, tremor, neuro-ophthalmologic complications, facial myokymia, gastroparesis, sialorrhea, and hyperhidrosis, however no studies have confirmed its efficacy in MS patients.     

Increased free light chains in the urine from patients with multiple sclerosis

We quantitated free kappa (kappa) and lambda light (L) chains in coded urine specimens from subjects with clinically definite multiple sclerosis (MS) (N = 56), other neurologic diseases (OND) (N = 30), and age-matched normal controls (N = 28). Urine from MS patients showed statistically significant increases in free L chains compared with the other groups, although there was overlap between MS patients and OND patients. The ratio of kappa/creatinine was significantly greater in the relapsing-remitting MS group than in patients with clinically stable MS, OND, and normal controls. Elevated free L chains were usually independent of urinary albumin and beta 2-microglobulin levels. Serial studies showed that urinary free kappa/creatinine ratios were elevated during periods of clinical worsening in seven of eight MS patients and subsequently decreased during clinical recovery. The measurement of free L chains in urine obtained at intervals from MS patients may be useful as a marker to monitor disease activity.     

Electrophysiology of motor pathways for sphincter control in multiple sclerosis.

The central and peripheral motor pathways serving striated sphincter muscle function were studied using cortical and lumbar transcutaneous electrical stimulation, pudendal nerve stimulation and sphincter electromyography in 23 patients with multiple sclerosis (MS), and sphincter disturbance, including incontinence of urine or faeces, urinary voiding dysfunction, or constipation. The central motor conduction time was significantly increased in the MS group compared to controls (p less than 0.05). Damage to both the upper and lower motor neuron pathways can contribute to sphincter disturbance in MS. The latter may be due to coexisting pathology or to involvement of the conus medullaris by MS.     

Bladder dysfunction in mice with experimental autoimmune encephalomyelitis

The vast majority of patients with multiple sclerosis (MS) develop bladder control problems including urgency to urinate, urinary incontinence, frequency of urination, and retention of urine. Over 60% of MS patients show detrusor-sphincter dyssynergia, an abnormality characterized by obstruction of urinary outflow as a result of discoordinated contraction of the urethral sphincter muscle and the bladder detrusor muscle. In the current study we examined bladder function in female SWXJ mice with different defined levels of neurological impairment following induction of experimental autoimmune encephalomyelitis (EAE), an animal model of central nervous system inflammation widely used in MS research. We found that EAE mice develop profound bladder dysfunction characterized by significantly increased micturition frequencies and significantly decreased urine output per micturition. Moreover, we found that the severity of bladder abnormalities in EAE mice was directly related to the severity of clinical EAE and neurologic disability. Our study is the first to show and characterize micturition abnormalities in EAE mice thereby providing a most useful model system for understanding and treating neurogenic bladder.