Sunday, June 5, 2016

Treatment Scores Tutorial 5: Spina Bifida Surgery Treatment Score = 0

When it comes to spina bifida surgery for incontinence the Treatment Score = 0. Specifically, when it comes to the Xiao procedure for incontinence (in patients with spina bifida) the Treatment Score = 0.

What is a Treatment Score? The Treatment Score represents the “net treatment benefit for the patient.” So, for the Xiao procedure for incontinence the Treatment Score = 0, meaning the net treatment benefit for the patient = 0. We want a 100% net benefit for the patient, instead, here we have 0%.

Spina bifida is a problem of the lower spine. It is a birth defect that causes many children to be incontinent of urine and incontinent of feces. Many of those born with spina bifida will wear diapers or “pull-ups” for the rest of their lives because of incontinence.

Spina bifida means “split spine,” and is a defect in which the lower spine is not properly closed. It’s also called a “neural tube” defect. In addition to urinary incontinence and fecal incontinence, many patients suffer paralysis of the lower limbs, weakness of the legs, and other neurologic problems. Spina bifida is a terrible situation and better treatments are desperately needed for the benefit of suffering patients.

Dr. Chuan-Guo Xiao, a urologist in China, invented the procedure that now bears his name, the Xiao procedure, to treat incontinence in spina bifida patients.

The Xiao procedure is an operation where a nerve, usually from the lumbar spine, is rerouted to a nerve in the sacral spine, which is lower down in the spine. The idea is that the “good nerve” from the lumbar spine will restore innervation to the damaged nerve of the sacral spine, which will then return function to the bladder and bowels. Such a procedure is called a nerve to nerve anastomosis. “Anastomosis” means joining together.

Spina bifida patients have a problem in that the spinal cord becomes attached to the surrounding structures, becoming “tethered” to them, which interferes with the normal mobility of the spinal cord. Spina bifida patients, therefore, commonly undergo a “detethering” surgery. The Xiao procedure is added to the detethering operation as an additional procedure in an attempt to treat incontinence.

Summary:
To summarize, the exact situation I did the Treatment Score for is this:

Diagnosis: incontinence of urine, associated with spina bifida
Treatment: detethering + Xiao procedure
Main outcome measure: resolution of urinary incontinence
Follow-up time period: 3 years
Patients: children

Outcome Measure
When you review the medical literature you want to look at the outcome measure that is most important for patients. You also want to look at the “hardest” outcome measure possible. Incontinence of urine is a horrible situation so the outcome I wanted to study was resolution of urinary incontinence. It is a relatively hard outcome measure, because either you are wearing diapers or pull-ups because you are wet all the time, or you are not, because you are dry.

Studies
There have been case series reports of good results with the Xiao procedure. For example, one study reported an 85% success rate, “Of the 20 patients 17 gained satisfactory bladder control and continence within 8 to 12 months after VR [ventral root] microanastomosis.”
(Source: http://www.ncbi.nlm.nih.gov/pubmed/15879861)

Another case series of 506 patients reported that 435 of 506 = 86% of patients had “significant” improvements.
(Source: http://link.springer.com/article/10.1007%2Fs11884-012-0130-2)

Other case series studies were encouraging about the Xiao procedure including this article, “US Pilot Study of Lumbar to Sacral Nerve Rerouting to Restore Voiding and Bowel Function in Spina Bifida: 3-Year Experience” (http://www.hindawi.com/journals/au/2014/863209/), and this article, “Outcomes of lumbar to sacral nerve rerouting for spina bifida” (http://www.ncbi.nlm.nih.gov/pubmed/20639040).

Lessons about Case Series Studies
This may be a cautionary tale about the “incredible unreliability” of case series studies. Case series studies may be full of biases. How can a case series study say something works 85% of the time, and a randomized controlled study say it works 0% of the time? This scenario has happened over and over again in medical history.

Case Series Biases
There are many problems with case series studies. One is not having a “hard enough” outcome measure. Another problem is the placebo effect. It seems like in medicine the more invasive a procedure one undergoes, the more prevalent the placebo effect. For example, the patients may be highly invested in the surgery to cure incontinence and thus may report better outcomes than are actually present. Similarly, the treating physicians may be highly invested in the outcome and may be biased towards reporting good outcomes. This is why randomized controlled studies are “blind.” The physicians collecting the outcomes data are “blinded” as to whether the patients had the treatment or not.

Case Series Studies with Soft Outcome Measures
As noted, the outcome measure for one of the case series studies was rather soft. Here is a quote of the outcome measure used: “17 gained satisfactory bladder control and continence within 8 to 12 months after VR [ventral root] microanastomosis.” Technically, that is an 85% success rate for 17 of the 20 patients studied. However, what is “satisfactory bladder control?” Who is it satisfactory for? Is it satisfactory in the opinion of the physicians? Or satisfactory in the opinion of the patients? Why wasn’t a hard outcome measure used?
(Source: http://www.ncbi.nlm.nih.gov/pubmed/15879861)

Lessons about Randomized Controlled Trials
The purpose of randomized controlled trials is to remove all biases and produce as much certainty as possible. Randomized controlled trials are the heart of science-based medicine and evidence-based medicine. Randomized controlled trials have been recognized as the epitome of clinical evidence since 1948, when the first randomized controlled trial was published in the British Medical Journal about treating tuberculosis with streptomycin. The hero behind that RCT was Sir Austin Bradford Hill.

The Randomized Controlled Trial on the Xiao Procedure
Physicians and researchers got together and performed a randomized controlled trial on the Xiao procedure, which was published in 2016, after several case series studies had been done, and after the procedure had been presented at medical conferences. The group were concerned with the following:

“… high success rates (70% – 85%) were reported…”
“… many of these studies did not use blinded observers…”
“…did not have control groups…”
“…limited follow-up durations.”
“…lack of…detailed follow up.”

(Source: http://www.ncbi.nlm.nih.gov/pubmed/27137626)

The group studied the Xiao procedure in children with a median age of 9 years, that ranged in age from a 1-year-old to an 18-year-old; 13 of the patients were boys, and 7 of the patients were girls. The authors stated in their paper that: “All patients were incontinent of urine, all wore pull-ups or diapers, and none were able to void voluntarily or on command.”

The results were bad. Urinary incontinence did not resolve in any of the patients who underwent the Xiao procedure. The study says, “…all patients required diapers or Pull-Ups throughout the three year period.”

Why Another Randomized Controlled Trial Needs to Be Done
No medical study is ever perfect and the randomized controlled trial by Gerald F. Tuite, M.D., et al. is no exception. The most glaring problem for me was that the issue of fecal incontinence was not reported. I did not find it reported in the randomized controlled study itself, or in the attached appendix. If more of the treated patients regained continence of feces compared to the control group that would be a very important outcome, a beneficial outcome. We are left to assume that since urinary incontinence did not improve that fecal incontinence probably did not improve either.

Dr.  Xiao’s Letter-to-the-Editor
Dr. Xiao wrote a letter to the editor addressing the “Tuite study,” the randomized controlled trial of 20 patients, regarding the Xiao procedure in spina bifida. The letter can be found here:
http://www.jurology.com/article/S0022-5347(15)04294-9/abstract
Dr. Xiao believes "...that there must be something fundamentally wrong in the trial."

There are concerns about whether the patients operated on in the “Tuite study” are similar to the patients that Dr. Xiao typically operates on. For example, all the patients in the “Tuite study” had previously underwent surgeries. In addition, apparently all of the patients in the “Tuite study” had previously had anticholinergic medications and clean intermittent catheterizations as routine treatments. In theory, these things might have prevented nerve regeneration from working. Previous surgeries may have done damage, and anticholinergic medications are thought to make the bladder “floppy.”

For example, one anticholinergic medication commonly used in spina bifida patients is Ditropan (oxybutynin). It reduces bladder spasms in patients with overactive bladders and treats frequent or urgent urination.

Importantly, the “Tuite study” says: “Based on Xiao’s 2012 guidelines, it is clear that the typical patient selected for the procedure by Xiao differs from the type of patients with spinal dysraphism [defective closure of the neural tube] we would typically consider for the procedure in our clinical practice in the US.”

Other issues with the “Tuite study” include these statements from the study which make it sound like the authors might not have known how to replicate the Xiao surgery:

“… The EMG and intraoperative nerve root selection protocol remained ambiguous to us.”
“… Only half of our patients who underwent the Xiao procedure had intact muscle strength at the donor root level before surgery….”

“We routinely sectioned the entire sacral root selected, both the dorsal and ventral roots, because there was no way to reliably differentiate the ventral and dorsal sacral rootlets without electrical stimulation data.”

“Even though Xiao et al. and Peters et al. have reported better results than we obtained, neither group has provided detailed information concerning nerve root selection in their previous publications, making it impossible to know if the lack of efficacy in our patients could be explained by surgical variation.”

There are other differences between the patients that Dr. Xiao operates on and the patients in the “Tuite study.” There are differences in age, the number of previous operations, and although not clear, there are probably differences in the signs and symptoms the patients exhibit. Only a more detailed analysis would tell us for sure.

This is the Future of Treatment Transparency
The graphic below demonstrates what we believe will be the future of treatment transparency. To understand a medical treatment, you need to understand the gross benefit of the treatment. The main statistic, in this case “incontinence of urine resolved” represents the gross benefit of the treatment and it stands at 0%.

Then on the scale to the right are the event rates of the side benefits and side effects. The calculation that needs to be made to get the Treatment Score, or the net treatment benefit, is the Main Statistic – side effects + side benefits.



The problem is that all of these statistics are on different scales. You can think of it like this: the main statistic is in dollars, and all the secondary statistics are in different currencies. Every secondary statistic has to be converted into dollars. Right now, there are apparently very few physicians in the entire world that understand that this needs to be done and how to do it.

Side Effects
There are some possible side benefits that show up on the right next to the green scale. However, each of these side of benefits are actually less than 1% certain. In the future we will display these numbers differently to show that.

Why the Treatment Score May Be Negative
For the purpose of demonstrating Treatment Scores, it is enough to know that the Treatment Score for the Xiao procedure equals zero. However, it may actually be negative.

There are definitely negative side effects to the Xiao procedure. 100% of the patients will be at bed rest for three days after the operation. 100% of the patients will have their operation time increased. In fact, when the Xiao procedure is added on top of the detethering operation, on average it adds 85 minutes to the overall surgery time.

Pudendal nerve damage
90% of the patients had pudendal nerve damage on the side of the surgery according to one study which documented the phenomenon.
(Source: http://www.ncbi.nlm.nih.gov/pubmed/25158270
It makes sense that there would be nerve damage during the Xiao procedure because they are harvesting a good nerve root to try to repair a bad nerve root.

Side Effects: Wound Infections
Why did 50% of the Xiao procedure patients have wound infections that required oral antibiotics? The authors of the Tuite, et al. randomized controlled trial speculate that the additional 90 minutes of operating time to do the Xiao procedure put the patients at risk of increased infection.

Quality Adjusted Life Years
One source says that urinary incontinence like losing 3.5 months per year due to quality-of-life issues. (Source: http://www.hindawi.com/journals/jger/2015/703425/)

Another source says that having a stroke is like losing 8.7 quality adjusted life years.
(http://stroke.ahajournals.org/content/41/4/739.full)

Remember, that a stroke was a side effect in the patients who underwent the Xiao procedure. Other serious side effects were erectile dysfunction, footdrop, pudendal nerve dysfunction, spinal fluid leakage, and wound infection. Because of these things, it would be easy to give the Xiao procedure of Treatment Score of negative 10%. My problem with giving a negative score at this time for the Xiao procedure is the data on fecal incontinence is not complete enough.

Most Important Outcome
The most important outcome from the Tuite, et al. randomized controlled trial is this: “No patient in either group was continent of urine before surgery or at any time during follow-up. All patients wore diapers or pull-ups before and at all points in the three-year follow-up.”

What Might Have Gone Wrong
What are some other things that might have gone wrong with the case series studies that seem to show that the Xiao procedure worked? Why do some physicians believe it works? Here are two ideas:

These children may simply grow out of being incontinent over time. The surgeons doing the Xiao procedure may think it worked when it was simply due to the normal growth of the children and normal growth of their neurologic system.

The detethering operation may be responsible any good outcomes, and the Xiao procedure actually adds no benefit on top of the detethering.

What Needs to be Done Now
Right now the Treatment Score for the Xiao procedure = 0, or is actually negative, based on the best available studies. However, there are enough issues with the one and only randomized controlled trial, that another randomized controlled trial should be done. Ideally, it should be done by Dr. Chuan-Guo Xiao in China on Chinese patients. It should be a double blinded study with all the outcome measures followed up by a group that are independent of Dr. Chuan-Guo Xiao.

If Dr. Xiao did such a study, and the results of the study were good, it would vindicate the Xiao procedure and would be a great lesson about doing medical research.

However, it takes a lot of time and resources to do a randomized controlled trial, especially one that involves independent researchers. It would be great if it were to happen, but I am not sure that it ever will.

Sources and URLs:
Source of the Randomized Controlled Trial:
Tuite GF, Polsky EG, Homsy Y, Reilly MA, Carey CM, Parrish Winesett S, Rodriguez LF, Storrs BB, Gaskill SJ, Tetreault LL, Martinez DG,Amankwah EK. “Lack of efficacy of an intradural somatic-to-autonomic nerve anastomosis (Xiao procedure) for bladder control in children with myelomeningocele and lipomyelomeningocele: results of a prospective, randomized, double-blind study.” J Neurosurg Pediatr. 2016 May 3:1-14.
http://www.ncbi.nlm.nih.gov/pubmed/27137626
DOI: 10.3171/2015.10.PEDS15271

Additional Sources:
Xiao CG1, Du MX, Li B, Liu Z, Chen M, Chen ZH, Cheng P, Xue XN, Shapiro E, Lepor H. "An artificial somatic-autonomic reflex pathway procedure for bladder control in children with spina bifida." J Urol. 2005 Jun;173(6):2112-6.
http://www.ncbi.nlm.nih.gov/pubmed/15879861

“Response: Some lessons learned from negative results of a randomized controlled trial for bladder reinnervation with the Xiao procedure.” Tuite GF, Polsky EG, Homsy Y, Reilly MA, Carey CM, Parrish Winesett S, Rodriguez LF, Storrs BB, Gaskill SJ, Tetreault LL, Martinez DG, Amankwah EK. J Neurosurg Pediatr. 2016 May 3:1-2.
http://www.ncbi.nlm.nih.gov/pubmed/27137925

[An electrophysiological study on the artificial somato-autonomic pathway for inducing voiding]. Liu Z, Liu CJ, Hu XW, Du MX, Xiao CG. Zhonghua Yi Xue Za Zhi. 2005 May 25;85(19):1315-8.
http://www.ncbi.nlm.nih.gov/pubmed/16029629

“Electrophysiological monitoring and identification of neural roots during somatic-autonomic reflex pathway procedure for neurogenic bladder.” Dai CF1, Xiao CG. Chin J Traumatol. 2005 Apr;8(2):74-6.
http://www.ncbi.nlm.nih.gov/pubmed/15769303

“An artificial somatic-central nervous system-autonomic reflex pathway for controllable micturition after spinal cord injury: preliminary results in 15 patients.” Xiao CG1, Du MX, Dai C, Li B, Nitti VW, de Groat WC. J Urol. 2003 Oct;170(4 Pt 1):1237-41.
http://www.ncbi.nlm.nih.gov/pubmed/14501733

"Skin-CNS-bladder" reflex pathway for micturition after spinal cord injury and its underlying mechanisms. Xiao CG1, de Groat WC, Godec CJ, Dai C, Xiao Q. J Urol. 1999 Sep;162(3 Pt 1):936-42. http://www.ncbi.nlm.nih.gov/pubmed/10458412

“Xiao Procedure for Neurogenic Bladder in Spinal Cord Injury and Spina Bifida.” Neurogenic Bladder (F Daneshgari, Section Editor). Chuan-Guo Xiao. Current Bladder Dysfunction Reports. June 2012, Volume 7, Issue 2, pp 83-87. First online: 01 April 2012.
http://link.springer.com/article/10.1007%2Fs11884-012-0130-2

“US Pilot Study of Lumbar to Sacral Nerve Rerouting to Restore Voiding and Bowel Function in Spina Bifida: 3-Year Experience.” Kenneth M. Peters, Holly Gilmer, Kevin Feber, Benjamin J. Girdler, William Nantau, Gary Trock, Kim A. Killinger, and Judith A. Boura1. Advances in Urology. Volume 2014 (2014). Article ID 863209, 7 pages.
http://www.hindawi.com/journals/au/2014/863209/

“Outcomes of lumbar to sacral nerve rerouting for spina bifida.” Peters KM, Girdler B, Turzewski C, Trock G, Feber K, Nantau W, Bush B, Gonzalez J, Kass E, de Benito J, Diokno A. J Urol. 2010 Aug;184(2):702-7. doi: 10.1016/j.juro.2010.03.058. Epub 2010 Jun 19.
http://www.ncbi.nlm.nih.gov/pubmed/20639040

“The artificial somato-autonomic reflex arch does not improve lower urinary tract function in patients with spinal cord lesions.” Rasmussen MM, Rawashdeh YF, Clemmensen D, Tankisi H, Fuglsang-Frederiksen A, Krogh K, Christensen P. J Urol. 2015 Feb;193(2):598-604.
http://www.ncbi.nlm.nih.gov/pubmed/25158270

“Double-blinded randomized controlled trial of the Xiao procedure in children.”
http://www.eurekalert.org/pub_releases/2016-05/jonp-drc042716.php

“Double-blinded randomized controlled trial of the Xiao procedure in children.”
www.sciencedaily.com/releases/2016/05/160503072231.htm

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