RTI interviews Dr McDonald

       December 17, 2004

What led you into the rehabilitation field?

It was a serendipitous ride.  I was trained as a stroke neurologist.  I was working with Christopher  Reeve at the Christopher Reeve Paralysis Foundation (CRPF) and the work we did together swayed me to dedicate my career to spinal cord injury restoration.

How did you get into the CRPF?

I got into the CRPF as one of the junior fellows working along side Dennis Choi who was a world leader in mechanisms of cell death.  Sitting on a panel with eight of the leading scientists from around the world all talking about regeneration as if it were doable led me to get into this and it was through those early activities that I got to meet Christopher Reeve.

In 1998 I was appointed as a director of the Spinal Cord Injury Rehabilitation program at Washington University and Barnes-Jewish Hospital in St Louis. The next time I met Chris I talked to him about what he was doing at home and what his rehabilitation program was and he was really experiencing a great deal of medical complications so much so that I knew we could help him.  I knew that the work we had been doing with restorative therapies would first, forestall the progressive physical changes result from inactivity and second, reduce complications.

What is activity based restoration or Restorative Therapy as you now refer to it?

Restorative Therapy is based on the concept that the nervous system requires an optimal level of patterned activity in order to simply maintain itself as well as to maximize response of regeneration after injury.

What was the actual therapy that you were doing with Christopher Reeve?  

It was an activity based therapy that is individually tailored to the patient and changed over time to take advantage of progressive recovery.  The initial phase of it began with a Functional Electrical Stimulation (FES) ergometer with the premise that no one with a disability had time for such therapy to go down to a rehab center 3 times a week.  Therefore the therapy needs to be home based.  The FES ergometer allowed him to do the therapy 3 times a week for 1 hour, while at home.  The other things that we did with Christopher Reeve at the time were activity-based approaches for the upper extremity and torso that paralleled the approach with the leg cycling.

When did you realize that something remarkable was occurring with Christopher Reeve’s condition.

The first real breakthrough was when Chris noticed he could control the movement of his left index finger. What happened was he noticed his finger twitching and then he noted that he could control its stop and start.  This represented the beginning of an unprecedented delayed recovery.  For an individual with a worst case scenario injury (C1/C2 level, ASIA A complete), unable to breathe, and with no initial recovery over the first 5 years, this small step meant a real breakthrough.  The doors were open in terms of his recovery and restoration.  The hope instilled by this recovery motivated Chris to push forward with advancing his restorative therapies.  Then we involved other aspects of the program; aqua therapy and FES to many muscle groups and other exercises that were important for muscle groups where he regained partial control.

How did Restorative Therapy actually help Mr. Reeve?

Restorative Therapy helped Mr. Reeve across multiple domains.  The first domain was in physical integrity.  It offset many of the deteriorations of the body that accompany a lack of movement and mobility and this is true of any disorder with limited mobility whether it be ageing, diabetes, Alzheimer’s disease, Parkinson’s disease, MS or a spinal cord injury.  All these disorders are associated with a series of physical changes akin to advanced aging.  They all have the same underlying basis of inactivity due to limited mobility; therefore, limited mobility impairs the sensory activity and overall activity in the spinal cord. Physical activity is essential to offset these rapid and deleterious changes.

We were also able to restore bone density back to a normal range. He was more than 4½ standard deviations below normal which is severe osteoporosis.  The best that traditional medical care had to offer was to slow the progression using pharmacological therapies.  With Restorative Therapy we could restore bone density back to a normal range which was previously thought impossible.

We built Christopher Reeve’s muscle mass back to around 70% of normal in his legs and this is important to limit complications such as skin breakdown. The overall health benefits of this led to dramatic reductions in the normal major medical complications as well as infections.  There was a ten-fold reduction in the use of antibiotics.  Previously his poor health status made it difficult to hold a job, travel, or go on vacation with his family because he was having so many medical problems. After the Restorative Therapy he was able to travel internationally, hold a job, work at the national level and vacation with his family. 

The other big thing Restorative Therapy provided was that he had functional benefits.  We were able to restore sensation throughout his entire body which had obvious importance as he was able to localize pain and light touch; knowing when to shift his weight to avoid skin breakdown; feel the touch of a family member. 

He recovered motor abilities to about 20% of normal.  This is something remarkable.  He went from ASIA A to ASIA C; something that had previously never been recorded in any human being with a chronic severe spinal cord injury.   The previous thought was that if you hadn’t seen a recovery in the first year to two years, you would simply not see any further recovery and Chris really represented a worst case scenario – highest level of injury, worst severity, no initial recovery.  So it is possible that people can have delayed recovery, even in cases of severe and prolonged injury.

How many other people have benefited from Restorative Therapy?

Many people have benefited from Restorative Therapy. Our largest focus is in individuals with complete and incomplete spinal cord injury and that is one of the advantages of Restorative Therapy. It is applicable

to all individuals with spinal cord injury not just those who are going through their acute injury, not just those who are incomplete injury, but rather benefits can be offered to the majority of people who have injuries. We just completed a retrospective study with 30 patients in the control group and 30 patients in the Restorative Therapy group.  These individuals had more than two years of Restorative Therapy and they began therapy more than 2 years after injury.  In addition we have treated well over 100 individuals internationally where they have all gone home with an ergometer.

What steps led you to discover Restorative Therapy?

My basic science training was in developmental neuroscience and patterned neural activity is critical for all the events of development of the nervous system; for new cells to be born, for those cells to migrate to the appropriate place, for those cells to “know” what to become; for cells to set up circuitry and select that circuitry and then for that circuitry to be insulated and myelinated - something that is very important for Multiple Sclerosis.

Therefore, applying this developmental concept of activity-dependence to the same cellular processes in regeneration after an injury it is not a big leap of faith.  Certain disorders particularly spinal cord injury where activity is so dramatically reduced that these cellular processes are impaired such that if you simply restore a pattern of activity you are able to restore the body’s  ability to self repair.  It turns out, the bodies ability for self repair is much greater than we ever appreciated, it just that the conditions regulating repair require optimization.  And patterned neural activity is one of these important repair conditions.

Then there are examining outliers - individuals who had had the miracle recovery to walking. What was the pattern that was similar in all of them?  They were all dedicated to activity.  People like Patrick Rummerfield and others.  Individuals who simply should never have recovered who recovered, what did they do different?  Putting all those pieces together really led us to the activity-based approach.

Then we went to the lab in rodent models of SCI to understand the mechanisms contributing to activity-based restoration of function.  Simulating FES bicycling activity in rats with chronic spinal cord injury demonstrated that the activity restores some functions of stem cells; FES restored the birth rate of stem cells and enhanced their ability to differentiate into neural cells.  In addition, FES markedly increased regeneration of neuronal axons.

Then it comes down to providing a practical therapy.  If individuals can’t do it at home, it is never going to become a long-term practical therapy.   That is what Restorative Therapy provides; a practical, time-efficient, home-based long-term therapeutic approach to restoration after nervous system injury- really of any kind.

Why did you start Restorative Therapies, Inc (RTI) ?

I founded RTI in order to carry out a prospective study - a gold standard test to really determine in humans how applicable this treatment is.  For the first time I realized that the barriers to those studies were business and development (issues). There was no company that could make 200 FES ergometers in a half a year.  We needed to be able to send people home with these FES ergometers and then monitor them over the internet without going out and visiting each participant.  Those were the key aspects that led to the development of the new Restorative Therapy equipment.

Getting back to Christopher Reeve, what do you think will be the impact of his loss?

We need to continue to put forward his messages.  He made a very large impact in the visibility for spinal cord injury demonstrating that it is doable to repair and recover function even from a worst-case scenario injury; that we need to take risks; that we need to build businesses to provide effective therapy for those kind of challenges of the reimbursement situation that is faced with devastating neurological injuries.

We also need to carry forward his legacy in terms of the Christopher Reeve Paralysis Act and his other legislation.  We need to carry all of this forward.  That is what he would want. 

What are you working on now?

I am working on a series of activity-based therapies for the upper extremities (and) for the trunk. These other things are critical for an individual’s increased working space; being able to use the upper body and to recover function in other arenas that are very difficult for physical therapy and occupational therapy to accomplish effectively.

What is an example of that?

There are several muscle groups that are very difficult to build strength in simply because the recovery is to a point where an individual can barely move those joints.  The person can’t generate sufficient force to build muscle mass.  For example, intrinsics of the hand, flexors and the extensors of the wrist, the shoulders, the paraspinal muscles, and the pelvic muscles which are all critical for standing and for walking. 

So we can use modern FES approaches to do rapid muscle building.  We can use concentric stimulation on opposing muscles in order to rapidly build muscle mass.  All the work that we have done demonstrates that it really provides a great recovery of function, also.  In a sense we are just simply taking advantage of the recovery that has already occurred but has not manifested itself because the muscles are too weak.

We are taking the same approaches with the upper extremities that we have taken with the lower extremities in terms of increasing activity.

Stroke therapy uses constraint induced forced use; that is, constraining the good arm to force a person to use the bad arm.  Great scientific progress has been made in this area.  However, we can make this therapy more pragmatic.  Using modern FES techniques, we can get a person to use their bad arm and not inhibit the ability of their good arm.

Stroke

You started out as a stroke neurologist, how could stroke survivors benefit from Restorative Therapy?

In general, stroke along with any other neural disorder results in impaired mobility.

As soon as you are sitting in a wheelchair, your chance of recovery is very limited because you are no longer using the legs in any fashion.  Despite everyone having some regeneration they can never manifest it because the muscles have wasted away.  Analogously, if the nervous system is not being used it too begins to waste away.  Once you are in a wheelchair you are confined and you are not giving the degree of sensory stimulation and activity to the nervous system that you normally would.  In addition, stroke impairs directly control of those areas that are paralyzed in the nervous system. So we can use activity-based approaches in order to restore function.  In stroke there is a great deal of research demonstrating that patterned activity can restore function both in animals and humans so there is very good evidence already. 

What needs to be developed are practical approaches to implement that therapy. Currently it requires that an individual come into the hospital for three weeks and have this patterned mobility with the upper extremity for eight hours a day which is not necessary and it is very expensive.  We need to send people home with devices that we can monitor that can do the same thing in a more efficient, time and cost-effective way.

Have you worked with any stroke patients who have undertaken a Restorative Therapy program?

My colleague at Washington University, Alex Dromerick, has led a number of studies using constraint induced force use in stroke and we have learned a lot from his successful studies. In addition, yes, we have activity-based approaches with the upper extremity in individuals with stroke as I tested some of the early FES induced patterned movement.

What were the results?

The biggest early result is that we can use activity to control spasticity.  Spasticity or stiffness is one of the primary things that limit mobility.  Typically spasticity is treated with pharmacological agents.  It turns out that those drugs that are being used to treat spasticity actually further impair recovery of function from studies that we have just completed in animals.  We can use activity to better control spasticity and not have to use these medications that have a deleterious effect in terms of recovery of function.  One of the first things with activity we see in the upper extremity in particular the hand is reduced spasticity so individuals have a better ability to control those muscles.

You are suggesting an activity-based program would be preferable to taking baclofen to manage spasticity?

That is correct.  In general all anti-spasmodic agents, such as Baclofen, are very ineffective drugs when used orally and we all realize that as physicians.  It has a very limited benefit for a number of weeks and then the dose must be increased until most patients are on the maximum tolerable dose.  Our recent work demonstrates that baclofen impairs recovery of function and it is simply an agent that should only be implemented when everything else has been tried.

Much of your work utilizes FES and has succeeded because the individual does not have the sensation to feel the electrical current.  Many stroke survivors retain sensation and may not be able to tolerate the current.  What other options do you see for them?

There is a certain subset of individuals who have either recovered enough sensation or retained sensation such that they cannot be stimulated with the existing FES systems that are out there.  This is true of all disorders of the nervous system.

Modern technology can overcome that.  We know the physiology of pain fibers versus muscle fibers and other sensory fibers.  It will be possible to change the waveform of the pattern of stimulation to make it more tolerable. 

Will RTI be looking at developing this in a practical fashion?

RTI is a prime candidate to be able to do this kind of work.

Getting back to stroke survivors with sensation, what can they do now?

Individuals with sensation often have some preserved motor function.  They would benefit from a motor assisted system that takes advantage of this and lets them build the muscles over which they do have control.

RTI has a motorized cycle ergometer without FES – the RT100 - that is especially designed to do this.  It allows these individuals to benefit from the same concepts of patterned neural activity that we have been discussing.  The cycle allows an individual with sensation to do passive and active therapy.   In fact all of our cycles provide both therapies.

What do you mean by passive and active therapy?

Passive therapy is when a machine or a physical therapist’s manipulations move the body.  Active therapy is when an individual’s muscles power the cycle, for example, either through their own volition or with the assistance of FES.  In passive therapy your muscles are not applying much force.  Building muscle mass is more difficult without force.  You build a heck of a lot more through active therapy and FES, because large forces are generated.

Multiple Sclerosis

How do you think people with MS could benefit from Restorative Therapy?

In general, for MS the most common lesion that causes the major disability is in the spinal cord, so you can view MS similarly to a spinal cord injury. Demyelination of the spinal cord is what causes the most severe problems.  Now many individuals in addition have lesions in the head that are asymptomatic meaning they don’t show symptoms.   But again MS causes impaired mobility and sensation and that in turn reduces patterned neural activity in the nervous system.  If we restore that activity, we can stimulate those activity dependent processes such as myelination. 

MS is one particular disease that has the most hope for restoration because it is primarily a disease of demyelination of the insulation, but the circuits, the neurons, are still there; so it is a much simpler repair strategy.

Can restorative therapy cause remyelination of damaged nerves in MS ?

Currently there is not a great deal offered in restorative type therapies for chronic injuries which account for the majority of disabilities in the U.S.  Injury prevention has been the primary focus for individuals with MS.  The benefits of exercise alone are sufficient to warrant Restorative Therapy in terms of maintaining physical integrity to offset medical complications. 

We believe that we can restore function through regeneration for individuals with MS, similar to that we have shown for SCI rats, because research has shown that remyelination is a highly activity-dependent process.  Recently, research from multiple groups has shown that stem cells present in the nervous system can be stimulated to remyelinate areas that have been demyelinated.  The thinking used to be that remyelination was not possible, but research now demonstrates that it is doable and that this process requires optimizing to facilitate recovery.

Once again your work has utilized FES which has an electrical current.   Many people with MS retain sensation and may not be able to tolerate the current.  What other options do you see for them in terms of Restorative Therapy?

One option is that RTI develop approaches to overcome those issues of stimulating the pain fibers by changing the waveform (in the FES system).  A second option is motorized cycling and motorized movement.  Very rapid cycling causes the muscles spindles and the muscle cells to fire and that produces patterned activity in the nervous system so passive and active motorized movement would be effective.  The RT100 motorized cycle is designed to achieve this.

Once again, people with MS also take baclofen to manage spasticity.  What is your view on this?   Is it similar to your view on stroke and the use of baclofen?

MS is a combination of stroke and spinal cord injury with the exception that largely it only affects the cells that do the insulation and the circuits remain intact.  We know that baclofen can dramatically impair remyelination by inhibiting activity in rodent studies.  The majority of people with MS take baclofen and it is not always necessary as an activity based approach therapy can control spasticity. 

Remyelination is a central issue in MS.  Does the management of spasticity outweigh the possibility of remyelination and that is why baclofen is used?

No.  Baclofen has largely been used because we never appreciated that it could possibly do any harm.  Remember, no one thought that regeneration was possible and no one linked the two things together.  It wasn’t thought that any harm could be done from baclofen because regeneration wasn’t thought of as doable; no one was expected to recover function. The point is that we need to exhaust the other possibilities to control spasticity before we start implementing medication to maintain control.  In that list of approaches to be exhausted are activity-based approaches.   Again, the physical integrity benefits from these approaches are reason enough to participate.

Have you worked with MS patients in Restorative Therapy?

Sure, we have worked with both MS patients as well as individuals who have a subtype of MS, called transverse myelitis (TM), which is basically MS confined to the spinal cord.

What are their stories?

Their stories are similar.  They tend to have a lot of spasticity. So one of the first things we see with Restorative Therapy is a reduction of spasticity which can occur over the first week of activity-based therapy.   More often they are able to reduce their oral baclofen doses or anti-spasmodic agents.  Then they can have the same physical integrity benefits that we have seen with individuals with spinal cord injuries - we can reverse the loss of muscle mass back into the normal range; we can offset the complications that occur as well as the infections.

Wrap up

Recovery of function and the possibility of regeneration are key themes in your work.  These are brave new words to some clinicians as well as patients.

Yes.  People didn’t think these regeneration was possible, but we and many other scientists are demonstrating that regeneration can be accomplished. There needs to be a shift in the theory, practice, and treatment of chronic neurological illness.  There is an opportunity for recovery of function and a better quality of life for many years after the injury.  The old medical system largely dealt with acute problems as well as acute rehabilitation and therapies were terminated after this acute treatment phase.  This needs to change, a transition to a long-term therapy based approach that is designed to have multiple benefits. 

Simply recovering function is not sufficient.  Insurance companies won’t fund that.  They need to fund things that are cost-effective; they are interested in saving money while providing important improvements in their clients' condition.  The honor is on us to demonstrate that a particular therapy can actually save money.  I believe that Restorative Therapies can do exactly that.  They do that by reducing medical complications, maintaining physical integrity, keeping individuals out of the hospital  allowing them to work; and, simultaneously allowing them to have functional recovery through regeneration.

I think it is pretty easy to see that if there is a long-term therapy that is going to be provided, the only way it is going to be cost-effective is if it is delivered in the home.  It is doable. We can accomplish it.  We can monitor it from home using modern tele-medicine approaches and control those systems. 

What is an example of this?

For example, RTI has produced a cycle with FES that is being used in clinical trials.  This cycle has inbuilt internet connectivity.  This allows a clinician to monitor the performance and progress of an individual no matter where they are.  But the need remains to operate within the constraints of the reimbursement system to help our patients. The answer is that we need to move to home-based therapy approaches.

One purpose of these clinical studies is to demonstrate the cost-effectiveness of these approaches; that is the critical piece.  The honor is on us to demonstrate to the reimbursement groups that the therapy is cost-effective.  In these studies were are going to quantify the therapeutic efficacy of Restorative Therapy and also get a better idea of how we can maximize recovery.  Based on our early work in single cases and our large retrospective study, we believe that we can dramatically reduce complications and normalize someone’s physical integrity which is going to be critical. 

So no matter what, when a cure is found, if everything is wasted away and there is nothing left, you have a big problem.  Even if you can restore the nervous system, the problems of severe muscle wasting and accumulation of medical complications may be such that those individuals will never recover function. 

Individuals need to meet the scientists half way.  They need to meet the cure half way. They need to maintain their own body’s physical integrity. 

Dr. McDonald, you have a lot of energy, tremendous commitment and plans for the future, what other messages would you like to impart?

I think the most important message is that there is hope; there are things that can be done now and we should never give up.  We need to try everything that we can do safely. Therapy such as Restorative Therapy will always work because the physical integrity benefits alone are reason enough to do it.

We can’t predict how much functional recovery anyone will have, if any, but it does not matter.  If you don’t try, you won’t get any functional recovery; that’s a certainty.