Spinal cord injury (SCI) remains a devastating condition with an incidence of 40 new cases per million people throughout the world each year, affecting mainly young people (1). Several patterns of urological dysfunctions are described following SCI, depending on the level of the injury, as described by Madersbacher. All these patterns could induce urinary complications (urinary infection, lithiasis and renal failure) and will significantly decrease patients’ quality of life. The main goal of neurogenic detrusor overactivity (NDO) management following SCI is to achieve regular bladder emptying without stasis, avoiding high intra-detrusor pressure and maintaining continence, in order to improve patients’ quality of life and to prevent renal failure. Current NDO management is well standardized (2). First line treatment combines oral antimuscarinics with intermittent bladder catheterization 5-6 times a day. The second-line treatment is injections of Onabotulinum toxin A injection (BTX-A) into the detrusor with a clinical, urodynamic and quality of life improvement well demonstrated (2). The third therapeutic line consists in bladder surgery including augmentation cystoplasty with or without cutaneous continent urinary diversion, or non-continent surgical urinary diversion or sphincterotomy. Alternatively, the Finetech-Brindley stimulator could be implanted for micturition in SCI patients. 
However, to the best of our knowledge no study ever described the therapeutic journey of these patients. As a result, the aim of this study was to describe the therapeutic escalation in SCI patients presenting with neurogenic lower urinary tract symptoms (NLUTS).

We conducted a bicentric retrospective review of medical files of SCI patients followed in two departments of Physical Medicine and Rehabilitation between January 2000 and January 2018. 

Patients
SCI patients above 18 with a level of injury below Th4 were eligible. Patients who were assessed with clinical examination and urodynamics during the first six months following SCI were included. We excluded from analysis patients with other documented neurological disorders and patients who were not able to perform clean intermittent self-catheterization. Based on these medical records anthropometric and clinical data were extracted: sex, age, level of injury (NLI assessment). Urodynamic parameters were also recorded. The urodynamic assessments were performed following ICS recommendations. Cystometry was performed in the first year of follow-up and after each therapeutic change. If no therapeutic adjustment was conducted, an annual cystometry follow-up was performed. 
 Finally, we reviewed all therapeutic lines for each patient, from anticholinergics to bladder surgery or Brindley procedure.  
In both centers, therapeutic escalation was based on the same rationale. The failure of a therapeutic was characterized either on clinical aspects (urine leakage or patient’s willing) or urodynamic parameters (detrusor pressure >40cmH2O or low bladder compliance < 20 ml/cmH2O). Two consecutive assessments were necessary to consider failure of a therapeutic line. 
Stress urinary incontinence surgeries including placement of periurethral balloons ACT or Pro ACT, artificial sphincter, peri-cervical or mid uretra tape were also noticed.

Primary outcome was the description of the natural journey of neurogenic bladder in this population, from the awakening of detrusor activity to the last therapeutic line. 
 
Ethic
Our database was approved by the French Data Protection Authority (Commission Nationale Informatique et Libertés – CNIL) under the agreement number 2209010-V0, in accordance with the French Legislation for retrospective studies

Statistics
Survival curves of therapeutic introduction and failures of treatment were calculated with a 95%-confidence interval using the Kaplan-Meier method. Onset time-laps of therapeutic introductions were calculated from the lesion to introduction of a treatment or until the end of the study (10 year follow-up).  Onset time-laps of therapeutic failures were calculated from the therapeutic introduction to the next line of treatment or the end of follow-up (10 year follow-up).  Patients lost to follow-up or missing data were considered as censured data. Correlations between variables were performed calculating Spearman coefficient. A p-value <0.05 was considered significant. Statistical analysis was performed using GraphPad Prism v5, San Diego, CA 92108, USA.

One hundred and five patients were included in this study. Eighty percent were male, with a mean age of 32,8(+/-12,9) years old. Seventy-five-point two percent presented a complete paraplegia, 9,5% were AIS B; 5,7% AIS C; 8,6% AIS D and 1% AIS E. Forty seven percent presented NLI between Th3 and Th8 and 52% between Th9 and L5. NLI was not defined for one patient. Following urodynamic assessment two patterns of patients were described: (i) either patients with NDO (70 patients, 6 months post SCI) with or without impaired sphincter activity (ISA) (defined by a stress incontinence and low uretral closure pressure <30cmH2O) or (ii) patients with neurogenic detrusor underactivity (NDU) associated to ISA (15 patients, 6 months post SCI). During the first year of follow-up, two cystometry assessment were performed with an appearance of NDO in 39 and 70 patients before and after the 6th month respectively. Twenty-three patients were already treated by anticholinergics before the first cystometry. 

Following the first cystometry, antimuscarinics were introduced in patients presenting NDO and or incontinence. The median time of treatment introduction was 1 year with 70,5% (IC95%[63,7–76,2]) of patients treated.  Intradetrusor injection of BTX-A was introduced with a median time of 7 years with 55,4% (IC95%[43,8–65,5]) of patients treated. Bladder surgeries including cystoplasty augmentation or sphincterotomy were performed in 9 and 2 patients respectively after a failure of first and second therapeutics lines (Figure 1).

 A modest correlation was found between cystoplasty augmentation and compliance < 20ml/cmH2O (r = 0,41 p < 0,001). 
Five patients were finally managed with Brindley procedure. Seven patients underwent a stress incontinence surgery, either with TVT/TOT or proACT/ACT balloons and 1 with urethral closure because of a failure of previous therapeutics, associated to a bladder augmentation and a continent urinary diversion.

Failure of antimuscarinic treatment alone appeared 5 years post introduction with 44,5% (IC95%[30,5–57,5]) of patients still treated. Failure of BTX-A appeared after 4 years of treatment with 43,7% (IC95%[27-59,1]) of patients still treated (Figure 2).

This is the first study describing the neurogenic bladder journey of SCI patients. As expected, most of patients presented NDO within the first year of follow-up, for whom antimuscarinic drugs were introduced. We report a failure of this first line after 5 years of follow up, reason why intradetrusor injection of BTX-A was proposed and introduced after 7 years of follow up. The median year of failure for BTX-A was 4 years. This result is lower than those observed in recent published studies (3). It could be the result of an inclusion bias considering only paraplegic patients with a significant number of lumbar NLI associated to 12% of bladder compliance < 20ml/cmH2O.

This is the first study describing the neurogenic bladder journey of SCI patients, demonstrating the mid-term efficacy of the two first therapeutic lines of NDO management. As a result, an improvement of non-surgical therapeutics is needed, either with an improvement of actual therapeutics lasting; or with emergence of new long-lasting therapeutics. These therapeutics improvement could significantly change the paradigm of management of these patients.

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Nambiar A, Lucas M. Chapter 4: Guidelines for the diagnosis and treatment of overactive bladder (OAB) and neurogenic detrusor overactivity (NDO). Neurourol Urodyn. 2014;33 Suppl 3:S21-25.
Baron M, Peyronnet B, Aublé A, Hascoet J, Castel-Lacanal E, Miget G, et al. Long-Term Discontinuation of Botulinum Toxin A Intradetrusor Injections for Neurogenic Detrusor Overactivity: A Multicenter Study. J Urol. 8 janv 2019