Urogenital dysfunction in male patients with Charcot-Marie-Tooth: a systematic review

Aims Purposes of this study were to describe lower urinary tract symptoms (LUTS) and related urodynamic patterns in patients with hereditary spastic paraplegia (HSP), and to characterize LUTS management and associated uronephrological complications. Methods We retrospectively reviewed medical files of HSP patients, consecutively followed in our Physical and Rehabilitation Medicine Department between 1999 and 2016. Clinical, urodynamic, and radiological data were collected and analyzed. Different treatments which have been prescribed and uronephrological complications were also recorded. Patients with other neurological or urological diseases were excluded. Results Thirty-three patients with HSP were included. Mean duration of follow-up was 8.1 ± 5 years, mean age 62 ± 14 years, and 70% were men. The most frequent LUTS was urgency and voiding dysfunction (both 69.7%). Incontinence and retention with a significant postvoid residue above 100 mL accounted for 66.7% and 57.6% of initial symptoms respectively. Neurogenic detrusor overactivity was diagnosed in 80.7% of patients. Two-thirds of our cohort were treated with anticholinergics and 9.1% required intradetrusor botulinum-toxin injections. Only 27.3% of patients performed clean intermittent self-catheterization. Febrile urinary tract infections (21.2%), urolithiasis (15,1%), hydronephrosis (6%), and chronic renal failure (9.1%) were found. Conclusion Given their high prevalence and the risk of uronephrological complications, LUTS should be systematically assessed in HSP patients. The systematic screening of urological dysfunction in this population would improve its management, decrease the incidence of uronephrological complications, and increase the quality of life

Development and assessment of herpes simplex virus type 1 (HSV-1) amplicon vectors with sensory neuron-selective promoters

Background: Neurogenic detrusor overactivity (NDO) is a severe pathological condition characterized by involuntary detrusor contractions leading to urine leakage. This condition is frequent after spinal cord injury (SCI). Gene therapy for NDO requires the development of vectors that express therapeutic transgenes driven by sensory neuron-specific promoters. The aim of this study was to develop and assess tools for the characterization of sensory neuron-specific promoters in dorsal root ganglia (DRG) neurons after transduction with herpes simplex virus type 1 (HSV-1)-based amplicon defective vectors. Methods: The HSV-1 vector genome encoded two independent transcription cassettes: one expressed firefly luciferase (FLuc) driven by different promoters’ candidates (rTRPV1, rASIC3, rCGRP, or hCGRP), and the other expressed a reporter gene driven by an invariable promoter. The strength and selectivity of promoters was assessed in organotypic cultures of explanted adult DRG, or sympathetic and parasympathetic ganglia from control and SCI rats. Results: The rCGRP promoter induced selective expression in the DRG of normal rats. The rTRPV-1 promoter, which did not display selective activity in control rats, induced selective expression in DRG explanted from SCI rats. Conclusions: This study provides a methodology to assess sensory neuron-specific promoters, opening new perspectives for future gene therapy for ND

Construction et validation d'un vecteur herpétique (HSV-1) permettant une expression prolongée et sélective de transgènes au sein des neurones afférents de la vessie pour la prise en charge de l'hyperactivité détrusorienne neurogène. : Une approche translationnelle

Cinquante à 80% des patients atteints d'une lésion médullaire traumatique (LM) présente des d'épisodes d'incontinence urinaire liés à une hyperactivité détrusorienne neurogène (HDN). L’HDN est caractérisée par des contractions non inhibées du détrusor pendant la phase de remplissage vésical, qui conduit à une augmentation des pressions détrusoriennes, particulièrement lorsque l’HDN est associée à une dyssynergie vésico-sphinctérienne. L'objectif principal de la prise en charge de l’HDN est d'obtenir une vidange vésicale régulière, complète et à basse pression, ainsi que de maintenir la continence urinaire, afin d'améliorer la qualité de vie des patients et de prévenir les complications uro-néphrologiques dont l’insuffisance rénale. La prise en charge actuelle repose sur une pharmacothérapie agissant principalement au niveau de la branche efférente, motrice, du réflexe mictionnel, permettant ainsi un remplissage vésical à basse pression. Le traitement de première intention repose sur des antimuscariniques oraux, le plus souvent associés à la réalisation d’autosondages pluriquotidiens. En cas d’échec de cette thérapeutique, l’injection intradétrusorienne de toxine botulique A est proposée. Cependant, malgré leur efficacité, ces traitements induisent des effets secondaires et souffrent d’un échappement thérapeutique, conduisant à un traitement chirurgical de troisième ligne. La technique de Brindley, qui consiste en une désafférentation des racines postérieures sacrées innervant la vessie associée à une stimulation électrique, à la demande, des racines antérieures est une alternative prometteuse, mais reste peu proposée en raison de la complexité de la procédure chirurgicale requise. L'HDN résulte de l'émergence d'un réflexe spinal anormal médié par une plasticité des afférences vésicales de type-C dans les suites de la LM. Le projet de mon équipe est de réaliser une déafférentation vésicale par thérapie génique afin d'abolir le réflexe de miction spinale altérée. Dans un second temps, la miction sera déclenchée par une stimulation électrique à la demande, des neurones efférents de la vessie. Mon travail de thèse consistait à développer les outils nécessaires à une telle désafférentation moléculaire. En conséquence, j'ai construit des vecteurs défectifs HSV-1 délivrant comme transgène thérapeutique la chaine légère d’un toxine botulique (BoNT-LC), sous le contrôle du promoteur du gène codant pour la protéine liée au gène de la calcitonine (hCGRP), permettant une expression sélective au sein des neurones sensoriels. La cassette de transcription a été insérée dans le locus LAT du génome HSV-1, la seule région du génome du virus qui reste active sur le plan transcriptionnel pendant une infection latente. Ces vecteurs ont été évalués (i) in vitro, sur des lignées cellulaires d'origine neurale et sur des cultures primaires de neurones sensoriels embryonnaires et adultes de rats, ainsi que sur des cultures primaires de neurones sensoriels et sympathiques humains adultes, (ii) ex vivo, sur des cultures organotypiques de ganglions sensoriels, sympathiques et parasympathiques de rats adultes, et (iii) in vivo, post inoculation au niveau du coussinet plantaire de rats adultes. Nos résultats indiquent que (i) les vecteurs expriment des BoNT-LC fonctionnelles, clivant ainsi les protéines SNARE post infection de cultures primaires de neurones sensoriels de rats et d’être humain, et inhibant la libération du neuromédiateur CGRP dans les neurones sensoriels de rat, (ii) la sélectivité d’expression de ces vecteurs dans des neurones sensoriels humains, par rapport aux neurones sympathiques humains, et (iii) une expression transgénique prolongée in-vivo au sein de ganglions sensoriels (DRG), au moins pour trois mois, après injection. Par conséquent, ces vecteurs semblent présenter les trois principales spécifications requises pour le développement d’une future stratégie de thérapie génique visant à traiter l’HDN.Fifty to 80% of patients with traumatic spinal cord injury (SCI) undergo urinary incontinence episodes, mostly related to neurogenic detrusor overactivity (NDO). NDO is characterized by uninhibited detrusor contractions during the bladder-filling phase which could lead to a significant increase in bladder pressures, especially when associated to sphincter-destrusor-dyssynergia, leading to uro-nephrological complications. The main goal of NDO management following SCI is to achieve regular and complete bladder emptying, avoiding high intra-detrusor pressure and maintaining continence, in order to improve patients’ quality of life and to prevent renal failure. The current management is well characterized and relies on pharmacotherapy acting primarily at the level of efferent motor micturition reflex branch, thus allowing bladder filling at low pressure. First line treatment relies on oral antimuscarinics, often associated to clean intermittent bladder self-catheterization. When patients are refractory to antimuscarinics, injection of botulinum toxin A into the detrusor is proposed. However, despite their efficacy, these treatments fail to persist in the long term, leading to a third-line surgical treatment, which consists in cystoplasty augmentation or sacral neuromodulation. The Brindley technique, which consist in a sacral deafferentation of bladder posterior roots associated to an electrical stimulation, on demand, of anterior roots is a promising alternative, but remains seldom performed because of the complex surgical procedure required. NDO results from the emergence, secondary to neuronal plasticity following SCI, of an abnormal micturition reflex mediated by bladder afferent C-fibers, conveying aberrant sensory information to the spinal cord. The aim of the team where I developed my work is to silence these bladder afferent C-fibers in order to abolish the impaired spinal micturition reflex after SCI. In a second time, micturition would be fired, on demand, by electric stimulation of the bladder efferent neurons. My work consisted in developing the tools and methods required for such molecular deafferentation. Accordingly, I constructed replication-incompetent HSV-1 vectors conceived to deliver a therapeutic transcription cassette, consisting in the light chains of botulinum toxin (BoNT-LC) driven by the human version of the promoter of the gene encoding calcitonin gene-related protein (hCGRP), to achieve sensory neuron-selective transgenic expression. The transcription cassette was inserted into the LAT locus of the HSV-1 genome, the only region of the virus genome that remains transcriptionally active during latent infection. These vectors have been assessed (i) in vitro, on cell lines of neural origin and on primary cultures of rat embryonic and adult sensory neurons, and on primary cultures of adult human sensory and sympathetic neurons, (ii) ex vivo, on organotypic cultures of sensory, sympathetic and parasympathetic ganglia from adult rats, and (iii) in vivo, in sensory ganglia following infection at the hind footpad of adult rats.Our results indicate that (i) the vectors express functional BoNT-LC, thereby cleaving proteins of the SNARE complex in rat and human sensory neurons and inhibiting release of the neuromediator CGRP in rat sensory neurons, (ii) the transcription cassette delivered by the vectors display highly selectively expression towards human sensory neurons, as compared to human sympathetic neurons, and (iii) the vectors induced long-term transgenic expression in sensory (DRG) ganglia (at least for three months) following footpad injection. Therefore, the vectors seem to accomplish the three main specifications required for a future gene therapy strategy, allowing to restore urinary continence and micturition without catheterization and without any major surgery. This approach will represent a major breakthrough in the management of NDO in SCI patients with complete and incomplete lesion

Validation transculturelle de la version française du questionnaire SIGAM Mobility Scale

Objectif : L incidence de l amputation de membres inférieurs reste importante en France, avec une nécessité d évaluation sur le plan fonctionnel de ces patients afin de prendre au mieux en charge leurs déficiences. Des échelles existent mais ne permettent qu une analyse restreinte, ou restent trop complexes en pratique clinique quotidienne. Le but de ce travail est de réaliser une validation transculturelle de la SIGAM-mobility Scale, auto-questionnaire de 21 questions à choix fermés, de passation rapide, évaluant de nombreuses dimensions fonctionnelles, et facilement analysable par un algorithme spécifique. Cette échelle est recommandée par la société anglaise de médecine physique et réadaptation en raison de ses propriétés psychométriques. Méthode : Phase 1. Traduction : réalisée par des français, bilingues, dont 1 traducteur n appartenant pas au milieu médical. Après consensus sur les discordances obtenu par un panel d experts, une rétro-traduction a été réalisée par un anglophone n appartenant pas au milieu médical. Enfin cette rétro-traduction a été analysée par l auteur du questionnaire original. Cette phase de traduction s est achevée par un pré-test en auto-questionnaire sur 5 patients. Phase 2 : Validation des propriétés psychométriques en hétéro-questionnaire, par interrogatoire téléphonique. Etude menée chez des patients amputés de membres inférieurs à la phase d appareillage définitif. La validité de critère a été évaluée en comparaison à la Hougthon Scale, la validité de construit par analyse des corrélations entre le questionnaire et des dimensions convergentes et divergentes, la cohérence interne par le coefficient alpha de Cronbach et la reproductibilité test-retest à l aide du coefficient kappa de Cohen. Résultats : 49 patients ont été évalués. Bonnes propriétés psychométriques en hétéro-questionnaire en langue française avec une validité de critère excellente (r=0,89), une cohérence interne correcte (alpha de cronbach > 0,7) et une excellente reproductibilité (coefficient Kappa à 0,868). La validation de construit est également correcte. Conclusion : La version française du questionnaire SIGAM/VF a de bonnes propriétés psychométriques en hétéro-questionnaire pouvant permettre son utilisation en pratique clinique. Il permet une analyse de nombreuses dimensions, avec une bonne rapidité de passation. D autres études sont en cours permettant de valider ce questionnaire en auto-questionnaire.DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

Safety and Effectiveness of Repeated Botulinum Toxin A Intracavernosal Injections in Men with Erectile Dysfunction Unresponsive to Approved Pharmacological Treatments: Real-World Observational Data

Intracavernosal injections of botulinum toxin A (BTX/A ic) may be effective for difficult-to-treat erectile dysfunction (ED). This is a retrospective case series study of the effectiveness of repeated off-label BTX/A ic (onabotulinumtoxinA 100U, incobotulinumtoxinA 100U or abobotulinumtoxinA 500U) in men with ED and insufficient response to phosphodiesterase type 5 inhibitors (PDE5-Is) or prostaglandinE1 intracavernosal injections (PGE1 ICIs), defined as an International Index of Erectile Function-Erectile Function domain score (IIEF-EF) ic was defined as the achievement of the minimally clinically important difference in IIEF-EF adjusted to the severity of ED on treatment at baseline. Out of 216 men treated with BTX/A ic and PDE5-Is or PGE1-ICIs, 92 (42.6%) requested at least a second injection. The median time since the preceding injection was 8.7 months. In total, 85, 44 and 23 men received, respectively, two, three and four BTX/A ic. The overall response rate was 77.5%: 85.7% in men with mild ED, 79% for moderate ED and 64.3% for severe ED on treatment. The response increased with repeated injections: 67.5%, 87.5% and 94.7%, respectively, after the second, third and fourth injections. Post-injection changes in IIEF-EF were similar across injections. The time from injection to request for a further injection varied little. Four men reported penile pain at the time of injection (1.5% of all injections), and one experienced a burn at the penile crus. Repeated BTX/A injections combined with PDE5-Is or PGE1-ICIs produced an effective and durable response, with acceptable safety

Safety and Efficacy of Intracavernosal Injections of AbobotulinumtoxinA (Dysport^®) as Add on Therapy to Phosphosdiesterase Type 5 Inhibitors or Prostaglandin E1 for Erectile Dysfunction—Case Studies

Erectile dysfunction (ED) is a highly prevalent condition with a variety of possible risk factors and/or etiologies. Despite significant advances regarding ED pharmacological management, there are still insufficient responders to existing pharmacological treatments e.g., approximately 30% of patients are insufficient responders to phosphodiesterase type 5 inhibitors (PDE5-Is). It has been recently proposed that botulinum toxin A intracavernosally (IC) delivered could be effective in these patients. Data from a retrospective uncontrolled single center study of 47 ED patients, consecutively recruited, insufficient responders to existing pharmacological treatments e.g., PDE5-Is or IC PGE1 injections treated with IC abobotulinumtoxinA 250 or 500 U as free combination with their existing treatment have been analyzed. Response rate, according to the International Index of Erectile Function-Erectile Function domain score, 6 weeks following IC abobotulinumtoxinA in combination with prior pharmacological treatment, was 54%. Two patients have reported mild penile pain on injection or during the 3 days following injection. Therapeutic efficacy did not seem to be influenced by the etiologies and/or risk factors for ED. Conversely, the less severe ED, the higher the response rate. Preliminary evidence for the therapeutical potential with acceptable safety of IC abobotulinumtoxinA as add-on therapy for ED not sufficiently responsive to standard therapy should be confirmed in randomized clinical trials

Long Term Effectiveness and Safety of Intracavernosal Botulinum Toxin A as an Add-on Therapy to Phosphosdiesterase Type 5 Inhibitors or Prostaglandin E1 Injections for Erectile Dysfunction

International audienceBackground: Some evidence suggests that intracavernosal botulinum toxin A (BTX-A IC) injections administered in addition to phosphodiesterase type 5 inhibitors (PDE5-Is) or prostaglandin E1 intracavernosal injections (PGE1 ICI) could effectively treat erectile dysfunction (ED) in non–responders, or insufficient responders to these pharmacologic treatments. Aim: To determine the long-term effectiveness and safety of combined treatment involving a single injection of BTX-A IC as an add on therapy to PDE5-Is or PGE1-ICI for the treatment of ED of different etiologies. Methods: A retrospective, uncontrolled, single center study was conducted. Data from 123 consecutive patients with ED who were insufficient responders to PDE5-Is or PGE1-ICI and who received onabotulinumtoxinA 100 U, abobotulinumtoxinA 250 U or 500 U IC as an add on to their current pharmacologic treatment were analyzed. All analyses were exploratory. Qualitative data were compared using the Fisher's exact test. Univariate and multivariate analysis were performed using logistic regression with Odds Ratios (OR). Only variables with P < .05 in the univariate analysis were selected for multivariate analysis. Results: The minimally clinically important difference (relative to baseline severity of ED) in the International Index of Erectile Function-Erectile function domain (IIEF-EF) score was achieved in 50% of patients at 34 (27–42) days and in 41% at 5.9 (3.9 – 8.1) months following BTX-A IC in combination with PDE5-Is or PGE1 ICI. The severity of ED influenced response to BTX-A IC according to the multivariate analysis (OR = 0.3, IC(95%]) = (0.16 – 0.56). Neither being post prostatectomy nor the type of BTX-A affected the response. Effectiveness tended to decrease more over time with abobotulinumtoxinA 250 U than 500 U. The only side-effects were mild penile pain on injection (n = 1) and mild penile pain for 3 days following injection (n = 1); no systemic effects were reported. Clinical implications: BTX-A IC (all types) administered as an add on to registered pharmacologic treatments improved erectile function for at least 6 months in 41% of patients with ED of varying etiologies, and was safe. Strengths & Limitations: A relatively large cohort of patients with ED was included, with a long follow-up period, however the study was retrospective, and uncontrolled. Conclusion: This study provides preliminary evidence that BTX-A IC administered as an add-on therapy for ED that is insufficiently responsive to standard therapy is effective for at least 6 months, and is safe. Randomized clinical trials are now needed to fully confirm these results. Giuliano F, Joussain C, Denys P, Long Term Effectiveness and Safety of Intracavernosal Botulinum Toxin A as an Add-on Therapy to Phosphosdiesterase Type 5 Inhibitors or Prostaglandin E1 Injections for Erectile Dysfunction. J Sex Med 2022;19:83–89

Effectiveness and Safety of Intracavernosal IncobotulinumtoxinA (Xeomin® ) 100 U as an Add-on Therapy to Standard Pharmacological Treatment for Difficult-to-Treat Erectile Dysfunction: A Case Series

International audienceRegistered pharmacological treatments are insufficiently effective for erectile dysfunction (ED) in around 30% of affected men. Intracavernosal injection (ICI) of ona-and abobotulinumtox-inA can reduce ED in insufficient responders. We aimed to assess the safety and effectiveness of incobotulinumtoxinA ICI as an add-on therapy to phosphodiesterase-type 5 inhibitors (PDE5-Is) or prostaglandinE1 ICIs (PGE1 ICIs) to treat ED that did not respond sufficiently to this treatment alone. We retrospectively analyzed data from 66 men with difficult to treat ED treated with single or repeated incobotulinumtoxinA 100U ICI as an add-on therapy. Response rate (increase in International Index of Erectile Function-Erectile Function domain score ≥ the minimum clinically important difference) was 52% (median (1st–3rd quartile) 43.5 (34–71) days post-incobotulinumtoxinA ICI). ED etiology (except spinal cord injury) and severity did not influence effectiveness. Only a clinically significant response to the 1st injection predicted a request for a 2nd injection (OR = 5.6, 95%, CI 1.6–19.4). Three men reported mild penile pain during the injection. These results provide preliminary evidence for the effectiveness and safety of incobotulinumtoxinA ICI as an add-on therapy to treat ED that is insufficiently responsive to standard care and provides support for the multicenter randomized clinical trial NCT05196308

Editorial Comment: Long-term outcomes and risks factors for failure of intradetrusor onabotulinumtoxin A injections for the treatment of refractory neurogenic detrusor overactivity

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Intracavernosal OnabotulinumtoxinA Exerts a Synergistic Pro-Erectile Effect When Combined With Sildenafil in Spontaneously Hypertensive Rats

International audienceBackground: Botulinum toxin A (BTX-A) has a variety of uses in medicine. Some evidence suggests that intracavernosal (ic) BTX-A injection administered in addition to phosphodiesterase type 5 inhibitors (PDE5-Is) could effectively treat erectile dysfunction (ED) in insufficient responders to PDE5-Is. Aim: To provide experimental pharmacological evidence for the use of onabotulinumtoxinA ic alone or in combination with PDE5-Is for difficult-to-treat ED. We thus compared the effects of BTX-A ic alone and BTX-A ic combined with PDE5-I iv, and a placebo treatment ic or iv. Methods: Erectile function was evaluated following cavernous nerve electrical stimulation (6 V, 1-millisecond pulse, 45-second duration) at different frequencies (0, 2, 3, 4, 5, 7.5, and 10 Hz) in 4 groups (n = 8 / group) of anesthetized, spontaneously hypertensive rats, a robust animal model of ED of vascular origin. Rats were treated by onabotulinumtoxinA 10U or saline ic 1 week prior to erectile function testing and sildenafil (0.3 mg/kg) or saline iv 4 minutes prior to testing. Frequency-response curves were compared with a 2 way ANOVA. Outcomes: Both onabotulinumtoxinA ic, and sildenafil iv significantly improved erectile responses in spontaneously hypertensive rats, however the effect was greatly amplified when the treatments were combined. Results: Intracavernosal pressure and/or mean arterial pressure ratios were significantly increased by sildenafil and onabotulinumtoxinA ic versus the control condition. OnabotulinumtoxinA 10U ic combined with sildenafil iv significantly potentiated erectile responses. Area under the curve and/or mean arterial pressure ratio increased by 19% with sildenafil iv, by 15% with onabotulinumtoxinA ic and by 58% with the combined treatment following cavernous nerve electrical stimulation at 6V, 1 ms, 10 Hz: these stimulation parameters elicited the maximal erectile response. Clinical Translation: These data provide a pharmacological rationale for the combined administration of onabotulinumtoxinA ic and sildenafil iv since the effects of both treatments were potentiated when their administration was combined. Strengths & Limitations: First evidence of a synergistic pro-erectile effect of BTX-A combined with PDE5-I, however the mechanism behind the pro-erectile effect of BTX-A ic remains hypothetical. Conclusions: These results support further studies into the mechanisms behind the pro-erectile effect of BTX-A ic, as well as multicenter randomized control trials to evaluate the safety and efficacy of BTX-A ic combined with sildenafil for difficult-to-treat ED. Giuliano F., Joussain C., Denys P., et al. Intracavernosal OnabotulinumtoxinA Exerts a Synergistic Pro-Erectile Effect When Combined With Sildenafil in Spontaneously Hypertensive Rats. J Sex Med 2022;19:899–906