PLoS Med 13 6 : e This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All relevant data are within the paper and its Supporting Information files.
The study funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report, and in the decision to submit the article for publication.
The researchers were independent from funders. Competing interests: We have read the journal's policy, and the authors of this manuscript have the following competing interests: EFA has received a speaker honorarium from Astellas, Coloplast, Glaxo Smith Kline, and Lilly.
EFA is also a consultant for Allergan and has participated in Astellas trials. All other authors have declared that no competing interests exist. Traumatic spinal cord injury SCI affects each year 15—53 new individuals per million in Western countries and often results in severe lifelong disability and considerable burden on the health care system [ 1 — 4 ]. It follows that early diagnosis and treatment of neurogenic bladder dysfunction is essential to prevent irreversible deterioration of urinary tract function and potential life-threatening complications [ 8 , 9 ].
However, little is known about bladder function in the acute phase of SCI, and the urological assessments are often postponed to a chronic stage, i. Neurourological management aims to preserve or improve upper urinary tract function, control UTIs, and maintain a low-pressure bladder that is both continent and capable of emptying completely [ 8 , 9 , 11 ].
The recommended assessment according to the European Association of Urology EAU Guidelines on Neuro-Urology [ 8 ] includes history taking, physical examination, bladder diary, urinalysis and urine culture, blood chemistry, uroflowmetry, ultrasonography postvoid residual and upper urinary tract morphology , videourodynamic investigation assessment of detrusor and bladder outlet function, compliance, and vesicoureterorenal reflux , urethrocystoscopy, and bladder washing cytology [ 8 , 9 ]. Recovery of bladder function represents an absolute priority for individuals affected by SCI, and it is often considered to be more important than recovery of walking or reduction of chronic pain [ 5 ].
Early definition of bladder function prognosis is essential to counsel patients, to set rehabilitative goals, and to orient a patient-tailored intervention [ 12 , 13 ]. Moreover, prediction of bladder function might improve the stratification of patients for future clinical trials [ 14 ]. However, a reliable urological prognosis is actually impossible, since appropriate predictive factors have not been identified and no predictive algorithm is available. We hypothesized that bladder function after traumatic SCI is predictable, similarly to other clinical outcomes such as locomotion [ 15 ] and upper limb function [ 16 ].
Therefore, we employed a large dataset of patients with SCI from a European prospective observational multicentre study to develop two prediction models for urinary continence and complete bladder emptying 1 y after traumatic SCI.
At a later stage, we performed an external validation of our models in an independent clinical dataset. Started in July , EMSCI is a prospective longitudinal cohort study conforming to the standards established by the Declaration of Helsinki and approved by the local ethics committees of all participating centres.
Before entering the study, patients were thoroughly informed about the study procedures and provided written informed consent. Data for neurological and functional assessments were prospectively collected per protocol within the first 15 d very acute , between 16—40 d acute I , and 3 mo acute II , 6 mo acute III , and 12 mo chronic after SCI Fig 1. All patients entered a rehabilitation program that included bladder and bowel management.
In brief, based on urodynamic investigation, the appropriate therapeutic strategy in order to preserve both upper and lower urinary tract function was determined. In patients with detrusor overactivity, the concept was to convert the overactive detrusor into a normo- or underactive detrusor using antimuscarinics or intradetrusor onabotulinumtoxinA injections in a refractory situation. ISNCSCI assessments were performed by trained physicians with certified experience in SCI examination and classification, after a specific centralized training program [ 22 ].
The SCIM is a validated tool specifically designed for the assessment of functional capacity of patients affected by SCI and investigates the ability to perform SCI-relevant tasks of daily life activity, clustered into three subscales: the self-care domain with a score range of 0—20 , including feeding, bathing, dressing, and grooming; respiration and sphincter management score range 0—40 , including respiration, bladder, and bowel management and use of toilet; and mobility score range 0—40 , including mobility in bed, transfers, mobility indoors and outdoors, and stair management.
The total SCIM score ranges between 0 and , with higher scores reflecting higher levels of independence. SCIM version II and III show minor differences in item organization and scoring but have the same maximum scores within the three subscales and concerning total score calculation. The version used in the initial assessment of each patient was employed for further follow-up evaluations. SCIM assessments were performed by health professionals specially trained and experienced in the use of this tool.
All predictive variables have been recorded within the first 40 d from injury Fig 1. The primary outcome was urinary continence assessed by bladder diary and complete bladder emptying i. Patients were dichotomized on the basis of bladder function 1 y after SCI into a urinary continence and complete bladder emptying when rated with the maximum item 6 score i. Based on an earlier publication derived from the same database, which included patients from July until June [ 15 ], we anticipated a substantial number of missing data in the outcome.
We therefore used a weighting approach to correct for missing data. In this method, complete cases are weighted by the inverse probability of being a complete case [ 23 ]. The most relevant factors associated with missing outcome data were centre, year of inclusion, and age. All available covariates were used. Based on the Akaike information criterion and using a stepwise forward procedure, we selected the potential predictors.
No interactions were considered. At each step, the area under the receiver operating characteristics curve aROC was calculated. Statistical analyses S2 Text were performed using the R statistics package R version 2. To evaluate the predictive power of our models in an independent clinical dataset, we retrospectively collected data of patients affected by traumatic SCI, which were referred to the Spinal Cord Rehabilitation Unit of Santa Lucia Foundation, Rome, Italy S3 Data. For the validation of our models, we considered all patients with traumatic SCI evaluated within 40 d of the injury, fulfilling the inclusion and exclusion criteria of EMSCI from January to January The physicians who performed the selection of patients and data collection were blinded to the prediction model characteristics.
Of those, the outcome measure 1 y after injury was available in 1, patients, but the initial ISNCSCI assessment was missing in 81 patients, leaving the data of 1, patients for the prediction analysis. The clinical characteristics at inclusion for patients considered for the model derivation and for those missing 1-y follow-up are reported in Table 1. There were significant differences between the two groups regarding age, percentage of paraplegics, percentage of patients with complete lesions AIS A , and SCIM total score. The aROC of the final model was 0. The complete function along with an example is shown in S4 Data.
The simplified model red line relies on LEMS only. When applying the model in sensitivity analyses after excluding the 55 patients with very acute measurements only and the patients with urinary continence and complete bladder emptying at inclusion, the aROCs were 0. As the aROC of a model with the best predictor, i. The aROC was 0. When applying the model after excluding the 55 patients with very acute measurements and the patients with urinary continence and complete bladder emptying at inclusion, the aROCs were 0.
The relationship of LEMS values at the time of inclusion and corresponding estimated probabilities for urinary continence and complete bladder emptying is shown in Fig 3 and Table 2. Data of patients with traumatic SCI were collected. The outcome measure 1 y after injury was available for patients, who were considered for external validation.
At the time of inclusion, there were differences between the validation and lost at 1-y follow-up groups regarding age, neurological level, severity of neurological deficit, LEMS, urinary continence and complete bladder emptying, and SCIM total score. The validation versus derivation cohort was significantly different: patients of the validation cohort were younger, more often men, and paraplegics. In addition, they were more severely affected, i. External validation of the full and simplified model confirmed excellent predictive power: 0.
In the present study, we derived two reliable prediction models with excellent performance to estimate the probability of urinary continence and complete bladder emptying 1 y after traumatic SCI. Also, the simplified model retains an excellent predictive performance and is easier and faster to apply in daily clinical practice.
It exclusively relies on LEMS, which is part of routine neurological assessment of patients with SCI, and introduces a very simple, rapid, noninvasive, and inexpensive tool to predict urinary continence and complete bladder emptying 1 y after injury without the need of any specific equipment. Thank you for visiting nature. You are using a browser version with limited support for CSS.
All subjects achieved volitional urination. We conclude that neuromodulation of spinal micturition circuitry by TMSCS may be used to ameliorate bladder function. Spinal cord injury SCI leads to long-term disabilities with significant social and economic consequences. After SCI, bladder dysfunction is common and improved bladder function consistently ranks as the top quality of life priority in individuals with SCI 1 , 2.
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Patients with a neurogenic bladder following SCI often catheterize themselves to empty the bladder, and urinary tract infections and obstructive uropathies are common 3 , 4 , 5. Direct muscle stimulation 6 , stimulation of peripheral nerves 7 , or rhizotomy 8 to restore bladder function all have limitations. Most of these interventions fail to restore the complex, orchestrated sequence of muscle contraction and relaxation that normal, voluntary micturition requires 9. Recently, epidural spinal cord stimulation SCS was used to enhance motor function in individuals with chronic SCI 10 , 11 , It is our hypothesis that spinal networks have the capacity to execute a range of complicated movements requiring detailed coordination among motor pools within the spine with minimal or even no input from the brain 12 , and electrical or magnetic stimulation of the spine restores or permits coordinated activation of these spinal circuits.
We hypothesize that a similar mechanism of SCS to the restoration of reaching and grasping function may be at play with respect to bladder function whereby co-contraction of agonist-antagonist muscles is abolished and voluntary motor control of micturition may be restored Epidural electrical stimulation can activate micturition in rodents 14 , but epidural stimulation is invasive and costly. We were able to demonstrate recently that transcutaneous electrical stimulation of the spine can activate descending motor pathways non-invasively in paraplegic individuals, but such stimulation can be painful, and the spread of electrical current may activate other susceptible structures with adverse or painful consequences Magnetic stimulation can also be used to modulate neural circuits, and with figure-eight coils, the energy can be targeted to some extent.
Moreover, transcutaneous magnetic stimulation is non-invasive and painless. Transcranial magnetic stimulation TMS has been used to modulate neuronal function in a variety of settings from migraine treatment 16 to depression 17 to restoration of motor function after ischemic stroke In the current study, we used transcutaneous magnetic spinal cord stimulation TMSCS to stimulate the lumbar spine to try to improve bladder function in five patients with SCI who were unable to urinate voluntarily.
We hypothesized that neuromodulation of the spine using TMSCS would allow these patients to achieve voluntary micturition and reduce or eliminate the need for bladder self-catheterization. Subjects underwent 3 study phases Fig. The average duration of SCI was 8. None of the subjects had been able to void voluntarily since the time of injury as shown in at least three prior urodynamic studies in each subject.
Overview of the study. There were three phases of the study: assessment, treatment and follow-up. The time frame for each is shown in the flow chart. A synopsis of the formal neuroradiology report was reviewed and included here for reference. A Prominent metallic artifact from fusion hardware in the superior to mid thoracic spine significantly obscures evaluation at these levels.
The small segment in which the cord can be visualized at T4-T5 demonstrates prominent cord myelomalacia. Stable compression deformity of T5 without retropulsion. Scattered discogenic changes are seen in the thoracic spine from T8 through T12 without significant foraminal or canal stenosis.
The book Functional Bladder Reconstruction Following Spinal Cord Injury via Neural Approaches introduces how to solve this problem using multi-disciplinary . Spinal cord injury (SCI), either traumatic or non-traumatic, is a devastating disorder focused on functional bladder reconstruction through neural approaches.
The cord is unremarkable at these levels. B Metallic artifact from instrumentation hardware in upper thoracic spine makes the evaluation of the spinal cord difficult at high thoracic spine levels. On axial images, significant myelomalacia is noted at T level. Below T5, the spinal cord appears to have normal caliber. No significant canal or foraminal stenosis. C Severe spinal cord myelomalacia at C5-C6. No evidence of spinal cord edema. Grossly stable anterior and posterior fusion from C4 to C6. Left vertebral artery occlusion, possibly related to chronic traumatic dissection.
D Status post anterior fusion from C5 to C7 and posterior fusion. Metallic distortion artefact is noted through the fused C5 to C7 levels and significant myelomalacia or cord edema is noted at these levels. Visualized upper thoracic spinal cord appears to be in normal caliber with no compression. Spinal cord edema and swelling spans from C4-T1. In contrast, high frequency stimulation either increased the BCR amplitude or had no significant effect. The average BCR latency was Examples of evoked EMG activity from a single subject in selected muscles are shown in C.
The left L perineum, left vastus lateralis, right R vastus lateralis and left quadriceps femoris muscles were recorded. The arrows in panel A represent the peak and the nadir of the BCR. During the assessment phase, the urethral P urethra and detrusor pressures P detrusor obtained during urodynamic testing during attempted volitional micturition were significantly different during high and low frequency TMSCS Fig. Not surprisingly, increasing detrusor contraction and bladder pressure while simultaneously decreasing urethral pressure allowed voluntary micturition Fig.
The first video images in each sequence show the pre-voiding bladder capacity, which increased after TMSCS.
The second images show the initiation of volitional voiding and opening the bladder neck white arrows , and the final images show the post-void residuals. In panel B, examples of urine flow red line ; urethral pressure black line and detrusor pressure blue line are shown before upper graph and after the week TCSMS treatment lower graph. Note that detrusor pressure remained below urethral pressure before TMSCS, and no urine flow was generated; whereas detrusor pressure exceeded urethral pressure and urine flow was generated after 16 weeks of TMSCS.
All five subjects achieved at least some volitional urination following 16 weeks of bladder rehabilitation with TMSCS Fig. No subject achieved volitional urination until at least 4 weekly TMSCS treatments had been given, and the capacity to urinate voluntarily was restored in all 5 subjects on average 5. The capacity to urinate voluntarily was maintained throughout the week treatment period. The top panel shows the timing of recovery and loss of voluntary control of micturition and the volume of urine produced each day as a function of time.
All five subjects recovered the capacity to urinate voluntarily, and about 2—3 weeks after the termination of TMSCS, the capacity to urinate voluntarily declined rapidly back to the baseline unable to void voluntarily. Daily self-catheterization decreased from 6. This variation did not appear to be the result of differences in their AIS. The average time that volitional micturition was maintained after the sham stimulation began was 3. Follow-up diary entries confirmed that the ability to void voluntarily rapidly decayed in all subjects after the cessation of effective TMSCS, and no subject maintained the capacity for voluntary micturition five weeks after the last effective stimulation.
Voluntary micturition requires complex, orchestrated neuromuscular control of the urinary bladder by sensory, motor and autonomic systems. During voluntary micturition, sympathetic inhibition of bladder contraction is withdrawn, parasympathetic activation of the detrusor contraction emerges to increase vesicular pressure, and contraction of the urethral sphincter is inhibited to allow urine to flow out of the bladder. This control is achieved through fronto-pontine-spinal cord projections to parasympathetic ganglia in the abdomen and to sympathetic and somatic neurons in the caudal spine.
In individuals with SCI, coordination among parasympathetic, sympathetic and somatic nerve activities is lost: bladder pressure is elevated, but the bladder cannot be completely emptied because contraction of the external sphincter is not inhibited. Patients with SCI must perform multiple bladder self-catheterizations each day to evacuate urine and to prevent kidney injury due to high pressure; which increase the risk and frequency of infection and traumatic injury to the urethra. Any decrease in catheterization frequency, which was achieved in all study subjects, represents a potential decrease in complications associated with catheterization.
Isolated regions of lumbosacral spinal cord contain circuits that are capable of carrying out complex motor activities 20 , Furthermore, spinal cord injury in most motor complete, AIS A and B SCI subjects is not anatomically complete, and many spinal circuits remain intact, especially those below the level of the spinal cord injury In both animal and human subjects with chronic paralysis from SCI, motor movements have improved after invasive, epidural, electrical stimulation 10 , 11 , In this study, we hypothesized that the spinal micturition circuit remains intact in subjects with SCI, and since this circuit is semiautonomous, we should be able to enhance activation of patterned muscle activities controlled by these circuits and activate or modulate them using TMSCS over the thoracolumbar spine.
The mechanism of action appears to be similar to the use of stimulation to improve upper extremity function in which the threshold of motor circuit activation is diminished to enable volitional, coordinated agonist-antagonist muscle activity Other attempts to restore urination in SCI patients by stimulating multiple peripheral nerves, specifically the pudendal, pelvic, hypogastric and tibial nerves 23 , 24 , 25 , did not consistently improve bladder function.
Furthermore, sacral nerve modulation requires electrode implantation, which is invasive and risky 26 , In addition, TMSCS provides more consistent and effective bladder emptying than existing epidural stimulation of selected peripheral nerves 6 , 7 , 8. We believe that TMSCS allowed volitional activation of a coordinated pattern of parasympathetic withdrawal and sympathetic activation and somatic muscle inhibition as demonstrated in urodynamic studies.
While the precise mechanism of TMSCS remains unknown, the coordinated activity of detrusor and sphincter muscles suggests that TMSCS works by activating or enhancing activation of central pattern generating circuits within the lumbosacral spinal cord and does not rely solely on activation of motor neurons or peripheral nerves. The different stimulation frequencies elicited different bladder behaviors as if different central pattern generators CPGs or different aspects of a micturition CPG were activated. These divergent responses suggest that TMSCS may be applicable to a broader range of conditions such as hyperactive bladder, which may benefit from higher frequency stimulation.
We selected patients with detrusor-sphincter dyssynergia specifically because this is the group of SCI patients most recalcitrant to treatment. A regular schedule of self-catheterization prevents ureteral reflux and the development of obstructive uropathy and chronic renal failure, but frequent catheterization has risks of its own: infection, creation of false passages, urethral stricture 28 , 29 , a reduced quality of life, and a loss of independence.
Improving quality of life is our ultimate goal using TMSCS, but this cannot be achieved if the risk of ureteral reflux and chronic renal failure increases. Therefore, any benefits of TMSCS, such as a more physiological voiding sequence with low storage pressures and increased bladder capacity and a better coordination of increased detrusor compliance and reduced external sphincter pressures that enable unobstructed voiding in a low pressure system, will be beneficial in the long term only if ureteral reflux is not increased.
Video urodynamics performed at the initiation and termination of our study demonstrated no evidence of reflux. While this was a proof of concept, pilot study with patients followed for 16 weeks, additional studies are needed in an expanded cohort with extended follow-up to ensure that stable bladder and renal function are maintained when TMSCS is used to increase voluntary micturition and reduce the frequency of self-catheterization. Write a customer review.
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