Thread: ChinaSCINet Update

  1. #1551
    If a person has not walked for many years, has spasticity, spasms, and orthopedic issues on top of muscle and central nervous system atrophy, it seems common sense that the intensive locomotor training must be done before the person will recover walking. The question that we don't have an answer for is how intensive, how often, and how long that therapy should be (or must be) to restore locomotor function?

    In Kunming, they believe patients should train as much as 6 hours a day. The 6 hour figure is not as arbitrary as it sounds. In the 1990's Edward Taub and his colleagues showed that 6 hours of daily constraint-induced exercise are necessary to reverse "learned non-use" of hemiplegic patients after stroke. During overground walking, the spinal cord is engaging in rhythmic activity that activate and strengthen the central pattern generator programs.

    Patients who cannot stand are classified as being at Kunming Locomotor Score (KLS) I. Most patients can stand when somebody or a standing frame is holding their knees straight (KLS II). If they have spasticity, many can stand without manual knee support (KLS III). Using a rolling stand, the patient take steps with both legs with only a person in the back with ropes to pull on the knees from behind to prevent buckling (KLS IV). Eventually, the patient walks without ropes (KLS V). They progress to walking with a 4-point walker (KLS VI), crutches (KLS VII), cane (KLS VIII), unstable walking with no device (KLS IX), and normal overground walking without device (KLS X).

    The transition from KLS III to KLS IV is the most difficult. It is my impression that most people with chronic spinal cord injury cannot achieve that transition unless the patient is incomplete but this impression must be documented in randomized and double-blind clinical trials. Of course, the patient must be highly motivated and practice daily to get to KLS IV. Once they get to that level, they can start walking 6 hours a day.

    In the United States and Europe, many rehabilitation centers have embraced the concept of using weight-supported treadmill locomotor training. Such training, especially with older weight support systems, must be limited to an hour a day not just due to the expense of having multiple therapists work on the patient (e.g. one therapist per leg, one to control the hips, and one to supervise and run the computer) but because the weight-support harnesses put pressure on skin and can easily lead to pressure sores.

    In Kunming, they believe that the treadmill training with weight-support, bracing of the knees and ankles, and functional electrical stimulation of muscles teach bad walking habits. That is why they use a rolling walker, do not use knee bracing (only the ropes pulled from the back of the knees to lock the knees in stance phase), and use a flexible elastic band looped in a figure 8 mobius strip around the ankles to keep the foot from dragging on the ground and interfering with walking. They don't use electrical stimulation.

    I have posted the pictures of the various stages of the Kunming Locomotor Scoring (KLS) system before but here it is again. AND, let me emphasize that these are not data pictures. These are illustrations of the various stages of walking recovery that are indicated by the KLS scores. The last time I posted these pictures, many people jumped to the conclusion that these represent the walking of patients in the trial.

    Wise.



    Quote Originally Posted by tritro2085 View Post
    Dr. Young

    I posted this idea before,


    I'm not a neurologist or neurophysiologist, maybe the CPG kicking in first is a good thing, most infants and toddlers I knew/know are able to crawl, walk, or squat up & down before being able to successfully manipulate their legs. They're like machines all they know is GO. We've all heard learn to walk before you run right? Well maybe since a form of a connection has been made, "Running" using CPG first is the way to activate (Muscle & Nerve memory) and strengthened the group of muscles, while "walking" is gaining control of voluntary movement so manipulation can be achieved. They learn to walk and run long before they, stomp, jump, or tap their feet. Just an idea.

    do you think it may have any merit?
    Last edited by Wise Young; 01-23-2013 at 07:01 AM.

  2. #1552
    Quote Originally Posted by Wise Young View Post
    ay2012,

    Please, why should it be odd? When I went to Kunming in 2004, I found an army hospital walking hundreds of spinal-injured patients in the most intense locomotor training that I have ever seen. When I questioned them about the procedure, they showed me their techniques, explained their philosophy, and told me that they push the patients to walk to tolerance. I coined the term 6:6:6 to describe the intensity and duration of the training but of course not everybody reaches that 6 hours a day, 6 days a week, for 6 months. Much depends on the motivation of the individual patient.

    The program not only differs from patient to patient, depends on the level and severity of injury, but relies on motivation and progress shown by the patient. All patients reach plateau phases in their training and get discouraged when they do not progress. So, the doctors and nursing staff are constantly thinking of what they can do to motivate and help the patient to move to the next level. They sometimes do untethering surgery and have tried many other therapies over the years. It is an organic, passionate, and caring program that is hard to describe, much less document systematically.

    Followup of the patients is limited to a small minority of patients, usually the best responders. In our upcoming trial, we want to monitor the amount of walking by the patients, using a pedometer and daily diaries. We want to make sure that we get 6-week, 3-month, 6-months, and 12-month followup of the patients. In fact, once they leave, it is very hard to convince a patient to come back for followup. Travel is expensive and very difficult. Family members must accompany the person. In China, family members are in short supply because there are few or no siblings in families.

    We are very concerned that some patients are losing whatever progress they have made when they go home and sit for 6 months without doing any walking. You also cannot begin to imagine the poverty of many of our patients. Some don't have enough to eat. Many do not have access to medical services. It takes our nurse/doctor teams days to travel to remote villages, often many hours by airplane, train, car, and walking. So, we are going to try to keep the patients in the hospital for as long as possible after the treatment.

    I have been going to Kunming several times a year since 2006. I have brought scores of doctors to see the program. When I formed SCINetUSA, the investigators spent many hours discussing what kind of rehabilitation program would be feasible in the United States. The consensus was that an inpatient 6:6:6 walking program would not be possible and would be impossibly expensive. However, a 3:3:3 (3 hours a day, 3 days a week outpatient program for 3 months) program should be doable. Due to funding limitations, we may have to end up with doing only 6 weeks of outpatient rehabilitation in the U.S. trial. Even so, the cost will probably be over $100,000 per patient for the surgery and rehabilitation.

    Wise.
    Thanks again for the detailed follow up Dr. Young. I don't doubt all of the difficulties you mentioned, by odd I just meant that I assumed the documentation and in depth explanation would need to occur before a paper was published (it was, after all, part of the treatment received) or before the method was exported to a US centres.

  3. #1553
    Dr. Young,

    Thank you for posting this information as well!

    Are there any collaboration efforts to merge this treatment with the NRN therapy system in the future for USASCINET trials? I would assume that the easiest way to bring this type of therapy to the US, as they have a somewhat similar program set up with trained personnel, standards, systematic measurement, and infrastructure. Even a modified NRN program may be easier to implement.

    I noticed in the model that it appears that to be a KLS II one has to be able to hold their hips forward. Is this correct? Do patients lower than a IV score or III still do a 6 hour standing routine? What else do they do to get to there, especially from stage I to II if hips are required? To be eligible for this trial, does one must be able to stand with assistance and control their hips forward? To me that would seem to be a large hurdle and milestone difference at that stage of recovery.

    Also, in response to a post a while ago you suggested that acute patients recovered more successfully than chronic patients with the 6:6:6 program. Are there any theories as to why acute's recover faster and better, such as; greater general health, temporary spinal cord shock, neurons that haven't been destroyed yet, greater brain power (as it seems the motor cortex shrinks in SCI populations), less of a formed scar barrier, or anything else? Perhaps the greater blood flow from acute swelling promotes more nerve regeneration than we think, compared to relatively low blood flow with scar tissue, even though the swelling pressure is also destroying nerons? I find this interesting, as some of the cellular and chemical trials suggest to be more effective on chronic models than acute.

    Thank You!
    Last edited by Skipow; 01-23-2013 at 12:12 PM. Reason: Clarity

  4. #1554
    Skipow,

    Good questions. I am not sure that many clinicians in the United States believe that such an intensive locomotor training program is necessary or sufficient to promote recovery of walking after therapy. To tell you the truth, I was quite skeptical when I first saw this program. I don't think that it restores walking to people with ASIA A chronic spinal cord injury without some kind of therapy. As I pointed out, I have brought doctors, therapists, and others to observe the program and the techniques they use. Lots of U.S. doctors, when they first see the program, are actually quite critical of the walking. They say that the people are not placing their feet correctly, that overground walking does not allow control of the speed of the walking that treadmills provide, and that the posture of the patients is wrong, etc.

    At the same time, Zhu Hui has been skeptical of the treadmill training programs in the United States. She thinks that weight-supported treadmill walking, particularly on highly automated machines, not only are not effective but teach bad habits by controlling too much of the patient's posture and movements. She believes that the the patient must have more degrees of freedom and be forced to correct his or her posture during walking. The length of time that harness-based weight-supported treadmill programs is also insufficient. Finally, the economics of the treadmill training programs is not suitable to China or our trial. For example, if each hour of a Locomat or other treadmill training costs $1000... A 1:3:3 program, i.e. 1 hour a day, 3 days a week for 3 month will cost $36,000. This is in addition to other therapies that we will want to do.

    I am sure that Zhu Hui would welcome any collaboration but most American investigators are quite vested in their devices and treadmill training approach. Perhaps the best time to initiate collaboration efforts would be when we have shown that the Kunming overground locomotor training program makes a significant difference in a prospectively randomized clinical trial. That is one of the reasons why we are planning to randomize half of the patients in the ChinaSCINet Phase III trial (CN103) to train in Kunming, versus half who will do outpatient 3:3:3 programs in their home institutions.

    Regarding the pre-walking routine, the answer is variable and depends on the patient and trainers. The patients do stand for a while but they are also being pushed to do stepping. So, as soon as a patient gets to KLS III, they are pushing patient to start stepping, to get to KLS IV. This is a physically laborious task, because a person must crouch at the leg level to push each foot forward during stepping. Neither the trainer nor the patients can do this for 6 hours a day. They do bouts of 2-3 minutes for 30 minutes, stop and rest, and then go again for 30 minutes. Usually, at the end of each 30 minutes, the patient is panting with effort and the person moving the leg is panting as well. Note that patients really can't keep this effort going if they don't get to the KLS IV stage.

    Regarding the effects of the training on acute and chronic spinal cord injury, the only patients that we have acute data on are the 30 patients that received 3-month intensive training after intradural decompression after ASIA A injury. About half of them recovered to KLS IV or higher by 3 months. This is probably because the intradural decompression converted some of them to become incomplete. You can see this occurring after the surgery because a majority of the patients get back some sensory and motor scores along with improvements in their walking scores.

    This is a very different situation from our current trial where we believe that we are regenerating the spinal cords. The patients don't recover motor and sensory scores. Instead, they improve their locomotor scores without improving their motor and sensory scores. It also takes them longer to reach KLS IV stage. I think that this is because regeneration takes a long time and we are not seeing regenerating fibers appear on the DTI/MRI scans until 6 months. Note that there may have been fibers earlier but we did not see them any earlier or in all the patients.

    Wise.




    Quote Originally Posted by Skipow View Post
    Dr. Young,

    Thank you for posting this information as well!

    Are there any collaboration efforts to merge this treatment with the NRN therapy system in the future for USASCINET trials? I would assume that the easiest way to bring this type of therapy to the US, as they have a somewhat similar program set up with trained personnel, standards, systematic measurement, and infrastructure. Even a modified NRN program may be easier to implement.

    I noticed in the model that it appears that to be a KLS II one has to be able to hold their hips forward. Is this correct? Do patients lower than a IV score or III still do a 6 hour standing routine? What else do they do to get to there, especially from stage I to II if hips are required? To be eligible for this trial, does one must be able to stand with assistance and control their hips forward? To me that would seem to be a large hurdle and milestone difference at that stage of recovery.

    Also, in response to a post a while ago you suggested that acute patients recovered more successfully than chronic patients with the 6:6:6 program. Are there any theories as to why acute's recover faster and better, such as; greater general health, temporary spinal cord shock, neurons that haven't been destroyed yet, greater brain power (as it seems the motor cortex shrinks in SCI populations), less of a formed scar barrier, or anything else? Perhaps the greater blood flow from acute swelling promotes more nerve regeneration than we think, compared to relatively low blood flow with scar tissue, even though the swelling pressure is also destroying nerons? I find this interesting, as some of the cellular and chemical trials suggest to be more effective on chronic models than acute.

    Thank You!

  5. #1555
    All quiet on the eastern front
    Just wondering, in what ways will you be able to forward without the final data collection (one year)? You've said the IND will only rely on six minth data but how about the manuscript for a paper? Just trying to glean when we might be treated to the next update on the results... Sorry, but it's tough knowing the info is there.

  6. #1556
    Dr. Young, I just watched the open house stream and I've got a few questions:
    1) you showed a video of one of the patients walking, at 12 months, with the walking cart and an individual locking the knees behind them with a rope. For those who didn't see it, I'd just like to say this looked like legitimate stepping. It did NOT look like, as I think someone predicted before, simply "dragging dead legs". But just so no one is confused: this was a video of someone in the Kunming chronic trial (I.e. not receiving decompression surgery in the subacute phase), correct?
    2) my stream broke up for a significant portion of the Q&A but it seems that it was stated that there are still no motor or sensory improvements... Is this in reference to the six month follow up data or is that still being analyzed?
    3) earlier on in the talk you suggested that you will reduce the number of patients for the Phase III trial because the results had been even more robust than you had expected and fewer patients will be required to statistically show the potential benefit of the therapy. Keeping in mind 2), what is more robust? Has the walking shown even greater and later improvements? Have later stages in the KLS been achieved?
    As always, thanks again Dr. Young. Your heartfelt words at the start of the talk show once again you get it, you understand the urgency, and you're working hard for us...I hope it bears fruit and the sooner the better.

  7. #1557
    ay, can you post a link to what you watched please?

  8. #1558

  9. #1559
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    Dr Young you said "I think that this is because regeneration takes a long time and we are not seeing regenerating fibers appear on the DTI/MRI scans until 6 months." this may be a dumb question but if your not seeing growth until 6 months then why arnt you just waiting until the 6 month mark before you start the walking therapy? Wouldnt that save alot of money to take away that 6 months of therapy if its not helping any?

  10. #1560
    Quote Originally Posted by ay2012 View Post
    Dr. Young, I just watched the open house stream and I've got a few questions:
    1) you showed a video of one of the patients walking, at 12 months, with the walking cart and an individual locking the knees behind them with a rope. For those who didn't see it, I'd just like to say this looked like legitimate stepping. It did NOT look like, as I think someone predicted before, simply "dragging dead legs". But just so no one is confused: this was a video of someone in the Kunming chronic trial (I.e. not receiving decompression surgery in the subacute phase), correct?
    2) my stream broke up for a significant portion of the Q&A but it seems that it was stated that there are still no motor or sensory improvements... Is this in reference to the six month follow up data or is that still being analyzed?
    3) earlier on in the talk you suggested that you will reduce the number of patients for the Phase III trial because the results had been even more robust than you had expected and fewer patients will be required to statistically show the potential benefit of the therapy. Keeping in mind 2), what is more robust? Has the walking shown even greater and later improvements? Have later stages in the KLS been achieved?
    As always, thanks again Dr. Young. Your heartfelt words at the start of the talk show once again you get it, you understand the urgency, and you're working hard for us...I hope it bears fruit and the sooner the better.
    The video I showed was an individual at 12 months after receiving UCBMC cell transplant. The person was about 4 years after injury when he received the transplant. This person did not have big changes in motor or sensory scores. Yes, one subject has achieved a KLS score of VI but most have been KLS IV. A majority of the transplanted chronic subjects have achieved KLS scores of IV. Unfortunately, several lost function when they went home and sat in a chair for 6 months without walking.

    In my observations of chronic ASIA A patients who have had no untethering surgery and no cell transplant, few (probably <10%) recover to KLS IV. The question that we posed to the Kunming group was how many subjects who had untethering alone showed improved walking. They have seen patients get to KLS IV after untethering surgery. They told us that they have untethered and trained 300 subjects. They are collecting that data for us now.

    From preliminary power analyses (what one does to estimate the number of patients necessary to show statistically significant effects), we think that 15 subjects per treatment group will show statistically significant effect if half or more subjects recover to KLS IV after untethering surgery and transplantation, compared to only a quarter of subjects who receive untethering surgery alone. If so, this means that we can reduce the number of subjects in China to 120 as opposed to our original 400. With four treatment groups with 30 each, we can randomize half of the subjects in each group to locomotor training at Kunming. They have agreed to do this.

    Wise.
    Last edited by Wise Young; 02-02-2013 at 10:58 AM.

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