Archive for the ‘CareCure Posts’ Category

FAQ #4: What Can I Do Now to Be Ready for the Cure?

January 13, 2009

FAQ #4.  What Can I Do Now to Be Ready for the Cure?
By Wise Young, Ph.D., M.D., Rutgers University
W. M. Keck Center for Collaborative Neuroscience
604 Allison Road, Piscataway, NJ 08854-8082
Posted 11 January 2009, last updated 13 January 2009

The fourth most frequently asked question, usually asked after the questions if a cure is possible, when it will be available, and whether it would be applicable to chronic spinal cord injury, is what people can do to prepare for the cure.  Obviously, the first priority should be to take care of the body, to prevent muscle and bone atrophy, and other changes that prevent recovery of function.

Muscles undergo atrophy when they are not used.  Such atrophy is reversible.  Spasticity naturally prevents atrophy and therefore should not be over suppressed with drugs.  Standing will prevent atrophy of extensor anti-gravity muscles and will exercise balancing reflexes.  Stimulating muscles for certain functions, such as walking and standing, can rebuild muscles.

Bones also undergo atrophy when not used.  Until recently, no therapy had been shown to be effective for reversing bone loss after spinal cord injury. Recent studies suggest that the bisphosphonate alendronate restores bone mineral density but it is not clear that it increases bone strength and reduces fracture risk.   So, it seems reasonable to do both, i.e. weight bearing and alendronate.

It is also common sense to avoid irreversible surgery.  For example, tendon transfers, the Mitrofanoff procedure and bladder augmentation, colostomy, and sphincterotomy can significantly improve quality of life but may not be readily reversible.  People should recognize that the surgery may not be reversible.

What about locomotor training? Many studies suggest that weight-supported treadmill training can restore unassisted ambulation, even after severe incomplete spinal cord injury.  However, recent studies suggest that toverground walking may achieve similar results in people with incomplete spinal cord injuries.

Finally, what should we do about the brain?  Over half of the brain is devoted to input from and output to the spinal cord.  Non-use of neurons may cause atrophy or new connections in brain and spinal cord.  These connections are responsible for recovery, spasticity, spasms, and neuropathic pain.  Exercise, training, electrical stimulation, and pharmacological therapies can affect neural reorganization and function.

In the following sections, I will discuss some practical approaches to reversing atrophy of muscle and bone, some surgical therapies to avoid, the effects of locomotor training and spinal cord stimulation, the role of CNS reorganization, and the importance of education.  The goal is to provide a framework for how people can best prepare their bodies and central nervous system for recovery after spinal cord injury.

Reversing Muscle Atrophy

Immobilization causes muscle atrophy.  An immobilized leg will show measurable loss of muscle and bone calcium.  Spinal cord injury causes  muscle and bone losses in body parts innervated by spinal cord below the injury.  Muscle atrophy was recognized in the earliest descriptions of spinal cord injury [1].  Atrophy is most marked in patients with flaccid paraplegia resulting from lower thoracic or lumbar spinal cord injury [2].  Studies in rats revealed significant changes in muscles at 3, 7 and 30 days after spinal cord injury, similar to changes seen after denervation [3].  Scelsi, et al. [4] biopsied muscle from 22 paraplegic patients and found similar muscle degeneration.

Spasticity [5, 6] naturally prevents muscle atrophy.  In fact, I wonder if spasticity had not evolved as a mechanism to prevent atrophy.  In 1988, Robinson, et al. [7] showed that patients with greater spasticity had greater stimulated muscle responses and strength in their legs. While extensor spasms may interfere with transfers and flexor spasms at night may interfere with sleep [8], these activities are a form of free exercise and spasticity should not be completely suppressed with drugs.  High doses of anti-spasticity drugs, such baclofen given orally [9] or intrathecally, will reduce spasticity [10] and convert it to flaccidity [11].

Standing prevents atrophy of leg muscles. Standing is a reflex and balancing involves multiple reflexes [12].  When a person stands, pressure on the soles of the feet activates extensor muscles.  Of many approaches to rebuilding muscles [13], standing is the least costly and has extensively documented health benefits, including relief of skin pressure [14], reduction of constipation [15], improved bladder function, and better ability to straighten legs [16, 17]. Consumer pressure [18] for standing devices have led to availability of several standing wheelchairs [19] and many other standing devices.  People should utilize such devices to stand several hours every day if possible.

Functional electrical stimulation (FES) can reverse muscle atrophy.  Many devices are available, including those designed to build muscles for standing and walking [20-27], new walking orthoses [28, 29] and neuroprostheses [30-32], and treadmills for gait training [33].   FES of innervated will reverse atrophy [34].  Lower extremity functional electrical stimulation (FES) for pedaling a bicycle against variable resistance not only increases muscle endurance, speed, and strength but also increases aerobic metabolism and endurance [35, 36].  Upper limb FES can restore upper limb muscles[37, 38].  FES can also be used to assist gait [39] and will suppress spasticity as well to reduce the amount of anti-spasticity drugs [40].

High intensity stimulation is required to reverse atrophy of denervated muscles [41].  Surface FES stimulates nerves that enter and they activate the deeper musculature.  In denervated muscle, FES cannot stimulate nerves to activate deeper muscles and hence are ineffective.  Very high currents are required to penetrate into and activate deeper muscles.  However, care must be taken to use large electrode so that the currents are spread out over a large area of skin [42-47].  Such stimulation can restore even denervated muscles.

Reversing Osteoporosis

Bone loss occurs after spinal cord injury [48].  The most significant bone losses occur in the lower extremities [49, 50].  Biering-Sorenson, et al. [51] studied 6 men and 2 women with “complete” SCI for up to 53 months, comparing upper and lower extremity bone, finding that certain areas showed rapid loss but other, including the spine and femoral shaft continued to decline slowly as long as 4 years after injury.  Frotzler, et al. [52] used quantitative CT to measure bone loss and found that bone loss reached a plateau in 15 months.  The bone loss did not seem to be due to testicular hormonal levels [53].

Mechanical loading and FES-induced muscle activity reduces but does not prevent bone loss. Dudley-Javorski, et al. [54] reported their experience with one patient who performed nearly 8,000 electrically stimulated soleus muscle contractions per month in one leg, resulting in significant increases in soleus muscle torque and fatigue index of the stimulated side compared to the unstimulated control side.  Bone mass density (BMD) of the untrained leg declined by 14% during the first year but fell only 7% in the trained leg.  Shields, et al. [55] had earlier shown that FES significantly improved BMD in one leg compared to the other untrained leg.  Others [56] found no effect of FES on BMD.

The bisphosphonate alendronate [57] prevents bone loss in patients with acute spinal cord injury [58].  In 31 age- and gender-matched patients randomized to the drug or placebo, treated patients had an average of 5.3% whole body BMD and 17.6% difference in hip BMD, confirming an earlier Brazilian study [59] reporting that the drug increased bone calcium.  Sniger & Garshick [60] had reported that alendronate increases bone density in people with chronic spinal cord injury.  As early as 1999, Lyles [61] and Harris, et al. [62] were already recommending alendronate for vertebral compression fractures in older women.  Alendronate prevents the hypercalciuria after spinal cord injury [63].

Bone loss increases risk of lower extremity fractures [64] and hip instability is common in patients after spinal cord injury [65].  Increasing BMD alone may not increase strength and may make bone more brittle. Dionyssoiotis, et al. [66] studied tibial strength in 50 patients with acute and chronic spinal cord injury, comparing those that had T4-7 levels and those with T8-12 levels.  Bone strength declined significantly over time in the lower thoracic and not the upper thoracic injuries.  The authors suggested that neurogenic factors may be involved in bone loss.  Maimoun, et al. [67, 68] had concluded that neurological factors were more important than mechanical or hormonal factors.

In summary, bone loss is a serious unsolved problem in spinal cord injury.  Mechanical loading and FES-induced muscle activity will reduce but does not completely prevent bone loss in acute spinal cord injury.  The bisphophonate alendronate prevents bone loss in acute spinal cord injury and may even restore bone mineral density in chronic spinal cord injury but may not normalize bone strength.  However, a combination of mechanical loading, FES-induced muscle activity, and alendronate may be necessary to restore bone mineral density and bone strength in people with spinal cord injury.

Reversible Surgery

Surgical therapies are frequently done to improve function and to increase independence in people with spinal cord injury. These include tendon transfers for the hand, the Mitrofanoff procedure and bladder augmentation to facilitate bladder care, colostomy and sphincterotomy to reduce the time required for take care of the bowel and bladder. I will discuss some of these procedures from the viewpoint of their reversibility.   If the procedure will provide significant function, independence, or better quality of life now, people should make the decision in favor of what they need today and not wait for tomorrow.  However, they need to understand if the surgery is not easily reversible.

Tendon surgery.  Tendon transfers take part of a tendon from a muscle and transfer the power of that muscle to another that is weak.  It is useful for restoring tenodesis or ability to use fingers to oppose the thumb to pick things up and to feed oneself.  It can be used to restore the triceps, which locks the elbow and allows a person independence to transfer on their own.  Although tendon transfers are reversible in theory, I know of few occasions in which reversals were done.

Mitrofanoff procedure.  Originally developed for children with spina bifida and other conditions that compromise bladder function, this procedure uses the appendix as a conduit to the bladder through the umbilicus, allowing people to catheterize themselves through their belly button. For quadriplegic women, it is a boon because it allows them to catheterize themselves without having to take their clothes off and lying down.  The surgeon may sew a piece of intestine to the bladder wall, so that the bladder can no longer contract, allowing people to reduce anti-cholinergic drugs for bladder spasticity.  The procedure itself should be reversible since it does not interfere with the bladder sphincter at all.

Colostomy.  A colostomy is a procedure where the colon is connected to an opening in the abdominal wall, allowing feces to come out into a bag.  It is a blessing for many people who spend hours every morning doing their bowel routines and for people with fecal incontinence.  Depending on how the procedure is carried out, it can be either temporary or permanent.  Many people have had temporary colostomies that have been reversed.

Sphincterotomy.  Many men with paralyzed bladder opt for a sphincterotomy, i.e. cutting the bladder sphincter so that the urine drains through a condom catheter to a bag.  The surgery is simple and it saves work required for intermittent catheterization.  However, the sphincterotomies are probably difficult to reverse and seldom done in practice.

Of these procedures, the colostomy and Mitrofanoff should be reversible if the surgeon takes care to minimize tissue removal.  Tendon surgeries should also be reversible.  Sphincterotomies may be less reversible although they should be reparable in theory.  If the surgeon knows that there is wish for reversal of procedure, they can take precautions to preserve tissues that may be required for reversal of the procedure.  This is something that should be discussed with the surgeon.

Locomotor Training

Scientists have long known that it was possible to train animals with transected spinal cords to walk [69-71], that noradrenergic and serotonergic agonists facilitate walking [72, 73], and the mammalian lumbar spinal cord is capable of great plasticity [74] and even learning [75, 76], providing a rational basis for locomotor training in people with spinal cord injury [73].  Training cats with transected spinal cords for 30 minutes per day and 5 days a week improves their stepping ability [75, 77].  Muir & Steeves [78] showed that phasic cutaneous input facilitates locomotor recovery after incomplete spinal cord injuries in chick.  De Leon, et al. [79] showed that the animals maintained walking functions after training ended.  Kim, et al. [79] found that serotonin agonists enhanced locomotor recovery in rats that received neural transplants [80]. Although treadmill training did not affect locomotor recovery in rats after spinal contusion injury [81] and enriched environment alone facilitated walking recovery[82], many scientists speculated that treadmill training would improve locomotor function after spinal cord injury.

Treadmill training improves walking in humans after spinal cord injury.  Wernig & Muller [83] first reported in 1992 that treadmill training restored walking in people with chronic spinal cord injury. By 1995, Wernig, et al. [84] had trained 89 people, 44 of whom had chronic incomplete spinal cord injury.  The 44 subjects with chronic spinal cord injury trained for 3-20 weeks at 0.5 to 18 years after injury and 33 were unable to walk or stand unassisted before training.  By the end of training, 25 of the 33 (75%) initially wheelchair bound subjects could walk independently, 7 improved but still needed help, and one did not improve.  Only 6 of the 44 people could do staircase walking before the therapy but 34 were able to do so after training.  In 1998, Wernig, et al. [85] reported that 31 of 35 subjects maintained their locomotor improvement, 3 showed further improvement, and one lost function.

Dietz, et al. [75] similarly found in 1995 that treadmill training with body weight support modulated electromyographic activity in leg muscles, similar to healthy subjects, except that activity in the gastrocnemius (the main antigravity muscle during gait) was significantly lower.  Dobkin, et al. [86] studied the effects of weight-supported locomotor training on complete and incomplete subjects with spinal cord injury[86] and showed the sensory input associated with rhythmic locomotion can enhance the output of lumbosacral neural circuits and contribute to stepping activity.  Behrman & Harkema [87] showed that treadmill training improved ability of people to perform stepping and the training either achieved or improved overground walking.

Based on the above studies, the U.S. National Institutes of Health commissioned a multicenter study to assess treadmill locomotor training.  Dobkins, et al. [88] compared weight-supported treadmill and over-ground walking training after acute incomplete spinal cord injury.  In 146 subjects recruited at 6 regional centers within 8 weeks after injury, all had FIM-locomotor scores of <4 and were randomized to treadmill or overground training. At 6 months, both groups showed substantial improvement:  35% of ASIA B, 92% of ASIA C, and all of ASIA D subjects walked independently. There was no difference between the two treatments.

Spinal Cord Stimulation

Many scientists speculated that humans have a central pattern generator (CPG) for locomotion in the human spinal cord [89-91] and proposed the use of spinal cord stimulation to activate locomotion [92].  Hadi, et al. [93] showed that destruction of interneurons neurons in the L2  spinal cord produced lasting loss of walking ability in rats, suggesting that this is where the mammalian CPG may be located.  Ribotta, et al. [80] showed that transplantation of loecus coreulus cells to provide serotonergic innervation of L1-L2 spinal cord segment restored well-defined locomotor patterns in rats.  The serotonin agonist 8-OH-DPAT induces locomotor movements in low thoracic transected mice [94].  Yakovenko, et al [95] showed that intraspinal stimulation of spinal cords of transected rats significantly increased locomotor scores.

Dimitrijevic, et al. [96, 97] reported evidence of a spinal central pattern generator and showed that stimulation of this center improved gait in people after spinal cord injury.  The center can be readily stimulated with epidural electrodes placed over the L2 spinal cord [98, 99].  The stimulation initiates extension of lower limb [100] and can produce stepping-like movements [101] in subjects with complete spinal cord injury.  In both complete and incomplete spinal cord injury, reorganization of the spinal cord circuitry provides alternative mechanisms of locomotor and motor control [102, 103].  In 2007, Mianssian, et al. [104] found that human lumbar cord circuitry can be activated by extrinsic tonic input to generate locomotor-like activity.  Early application both FES and CPG stimulation may be helpful in preventing disuse atrophy of both muscle and neurons.

CPG stimulation helps locomotor training.  Barriere, et al. [105] pointed out the important role of the central pattern generator in the recovery of voluntary locomotion. Herman, et al. [106-108] has shown that epidural stimulation of the T10/T12 central pattern generator in humans facilitates walking recovery in people with chronic spinal cord injury, improving walking speed and endurance while reducing the sense of effort by the subject.  In particular, Carhart, et al. [107] described a patient with chronic incomplete tetraplegia in whom partial weight-bearing therapy alone was insufficient to achieve functional ambulation.  However, application of the T10/T12 stimulation not only produced further improvements in treadmill walking but facilitated transfer of these gains to overground walking.  The participant initially reported a reduction in the sense of effort for overground walking from 8/10 to 3/10 (Borg scale) and was able to double his walking speed to 0.35 m/sec and distance to 325 m.

Spinal cord stimulation facilitates walking not by directly activating neurons that control walking but by lowering the threshold to activate walking and to recruit additional muscles that may not be under voluntary control.  The stimulation not only increases the efficiency and speed of walking but reduces both perceived and actual effort required for walking, including metabolic energy utilization during walking [106].  Recent studies suggest that the electrodes don’t even have to be placed epidurally but can activate the spinal cord when placed on skin overlying the lumbar cord [104, 109]. Note that rhythmic auditory stimulation likewise has strong entrainment effects on gait cadence, velocity, and stride length in patients with incomplete spinal cord injury [110].

Plasticity

Over half of the brain is devoted to processing sensory and motor signals coming from or going to the spinal cord.  What happens to the parts of the brain that are longer receiving and no longer having a place to send commands to?  Early studies by Goldberger, et al. [111-114] had shown that local neurons sprout to fill in synaptic sites vacated by injured axons.  Depending on the source of the sprouting axons, the neuron may become suppressed or hyperexcitable.

Jain, et al. [115] found new brainstem connections in adult monkeys after dorsal column transection, where face afferents from the trigeminal would grow into the cuneate nucleus, expanding the face region into the hand region of the somatosensory cortex. Kaas, et al. [116] reported that damage to sensory afferents in the spinal dorsal columns render the corresponding parts of the primary somatosensory inactive to tactile stimulation and initiate maladaptive neuronal circuitry, including hyperalgesia [117].  If some dorsal column afferents are present, they will activate larger portions of the somatosensory cortex.

The corticospinal tract (that directly connects the cortex to spinal cord) reorganizes after spinal cord injury. Diffusion tensor imaging show progressive degeneration and sprouting of spared fibers in the corticospinal tract [118].  Corticospinal evoked potentials revealed enhanced pathways targeting muscles rostral (above) to the spinal injury [119] and stimulating remaining pathways produces exaggerated motor responses.  Hayes, et al. [120] used magnetic transcranial stimulation to reinforce reflexes in patients after spinal cord injury.

The spinal cord proximal to the injury site also reorganizes.  Functional MRI studies of rats after midthoracic spinal cord injuries show that small sensory stimuli that would not normally activate spinal cord also activate neurons in the dorsal horn of spinal cord below the injury site [121]. People show exaggerated startle responses in muscles proximal to the injury site [122].  Hand motor evoked potentials in people with chronic complete thoracic spinal have longer central conduction times [123].

The spinal cord below the injury site also changes.  Except for loss of motoneurons [124] and second lesions in the lower spinal cord [125, 126], circuits in spinal cord below the injury site often show increased recurrent inhibition after injury [127].   Konya, et al. [128] found proliferation of endogenous neural stem cells, increased immunoreactivity of serotonin and synaptophysin, and faster neurite growth/sprouting after anastomoses of functional nerves with distal nerves.  Peripheral nerve injury induces more reorganization of spinal circuits below the injury site [129].

The brain and spinal cord above and below the injury site are plastic and reorganize after injury, often in response to a variety of inputs.  Exercise and other activities in the brain and spinal cord are likely to affect both brain and spinal cord after injury, including spasticity and neuropathic pain. Much of the recovery of locomotor and other functions occur solely because of this reorganization and not regeneration [130].

Education

Many studies indicate that one of the best predictor of quality of life after spinal cord injury is education level.  According to Smith, et al. [131], higher levels of education were associated with lower odds of FMD (frequent mental distress), FDS (frequent depressive symptoms), and poor or fair health in U.S. veterans with spinal cord injury. More education in the United States is associated with greater Internet use and higher quality of life [132].  In Canada, individuals with more formal education had better quality of life [133].  Likewise, education predicts quality of life quotients in Europe [134-136].  But there are other reasons for education.

Understanding of the mechanisms and treatments of spinal cord injury is essential for informed decisions concerning therapies.  In the coming years, many therapies are likely to be claimed beneficial for spinal cord injury.  Not all the therapies will be appropriate for everybody.  People must become expert on spinal cord injury and treatments.  You will not only help yourself but also become a better advocate for the cure by understanding what is needed.  There is a lot of learn and the earlier that you start, the better it will be.

Learning the normal anatomy and physiology of the spinal cord is the first step.  It would be useful for people to know the dermatomes and segmental representation of the muscle, how signals are conducted in the spinal cord, and how different sensations are represented in spinal cord tracts.  In addition to helping people evaluate their own recovery, it will allow them to understand their doctors and communicate.

Understanding the pathophysiology of spinal cord injury is the second step.  For example, it would be helpful for people to understand the mechanisms of spasticity and neuropathic pain, what causes syringomyelia, and autonomic dysreflexia.  Most people have little idea of why spinal cord injury causes all these problems.

Knowing what must be accomplished to restore function is the third step.  For example, it is important to understand regeneration.  A common misconception is that spinal nerve fibers or axons are like wires and that all one has to do is to reconnect the wires.  Axons are living parts of neurons.  When axons are injured, the part that has been separated from the cell dies.  Regeneration means regrowing axons back to their original connection.

Keeping up with the latest advances regarding therapies for spinal cord injury is important because our understanding of treatments is moving so quickly.  Stem cells are only the latest wave and it is important to know what they can and cannot do.  The cells alone are unlikely to facilitate regeneration and replace neurons.  They need to be applied in combination with growth factors, growth inhibitor blockers, and other treatments, as well as repetitive exercise to reverse learned non-use.

Education is the best guarantor of the cure.  If you don’t know the normal anatomy and physiology, don’t understand the pathophysiology and what must be done to restore function, and are not up on the latest information concerning therapies, you depend on the knowledge and understanding of others.  You don’t have to know and understand it all but the more you know, the more likely you will make the best decision.

Summary and Conclusions

What should a person do now to be ready for the cure?  First, people should prevent and reverse atrophy of muscle and bone.  Second, they should avoid surgical procedures that are irreversible.  Third, locomotor training can restore ambulation, particularly after incomplete injuries.  Fourth spinal cord stimulation may help locomotor training.  Fifth, the brain and spinal cord reorganizes after injury.  Finally education is important, not only because academic achievement improves quality of life after spinal cord injury but people also need to understand their injury and the therapies to make informed decisions.

Spasticity prevents muscle atrophy.  It is free exercise and people should avoid taking so much anti-spasticity drugs that their muscles are flaccid.  Standing exercises reflexes responsible for weight bearing and balance.  Electrical stimulation (FES) can reverse atrophy.  Normally, surface stimulation depends on muscle innervation to activate deeper muscles.  Higher intensity stimulation is required to activate deeper muscles and reverse atrophy of denervated muscles.

Osteoporosis or bone loss occurs after spinal cord injury.  Bone loss occurs primarily in parts of the body that are paralyzed.  Reinstatement of mechanical stress on bone, i.e. standing, is often not sufficient to rebuild bone.  Recent clinical trials suggest that the bisphosphonate alendronate prevents bone calcium loss but it is unclear that this drug restores bone strength.  Mechanical loading and FES-induced muscle activity probably should be combined with mechanical stress to rebuild bone.

Certain surgical procedures improve quality of life.  For example, tendon transfer can restore hand or arm function while tendon lengthening can reduce need for anti-spasticity medication.  The Mitrofanoff procedure allows people to catheterize themselves through their belly button.  Combined with augmentation, it reduces need for drugs to prevent bladder spasms.  A colostomy or sphincterotomy may reduce time and effort needed for bowel and bladder routines.  However, people should understand that these procedures are not easily reversible and they should discuss this with their surgeons.

Locomotor training can be beneficial, even in people with severe incomplete injuries who have not walked for many years after spinal cord injury.  A recent clinical trial showed that treadmill and overground training have similar benefits, restoring unassisted ambulation in over 90% of people during the first year after incomplete spinal cord injury.  Walking is programmed into the spinal cord and few spinal axons are required to initiate walking.  Spinal cord stimulation can reduce effort, speeds up, and increases efficiency of walking.

The brain and spinal cord undergoes extensive reorganization after spinal cord injury.  Spasticity, spasms, and neuropathic pain are a result of reorganization.  Exercise and training may reduce or alter spasticity and neuropathic pain.  Finally, education is important not only because formal educational achievement is one of the best predictor of quality of life after spinal cord injury but people need to learn as much as possible about their condition and the treatments that may help them.

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FAQ #3: Will the Cure Be for Chronic Spinal Cord Injury?

January 3, 2009

FAQ #3: Will the Cure Be for Chronic Spinal Cord Injury?
By Wise Young, Ph.D., M.D., Rutgers University
W. M Keck Center for Collaborative Neuroscience
604 Allison Road, Piscataway, NJ 08854-8082

Will a cure work for chronic spinal cord injury?  Many people are anxious that all the treatments that they hear about seem to be aimed at acute spinal cord injury.  When they look at their bodies, they ask how any therapy can restore a body that has been paralyzed and senseless for years, in some cases decades.  How will therapy restore muscle and bone?   Not surprisingly, many people with chronic spinal cord injury think that the cure is for the newly injured and not for those with chronic spinal cord injury.

I believe there will be effective restorative therapies for chronic spinal cord injury for the following reasons. First, much animal and human data indicate that regeneration of relatively few axons can restore function such as walking, bladder function, and sexual function. This is because the spinal cord contains much of the circuitry necessary to execute and control these functions. Only 10% of the axons in the spinal cord are necessary and sufficient to restore locomotor and other functions.  Second, axons continue to try to regrow for many years after injury. Treatments that provide a path for growth, that negate factors that inhibit growth, and that provide long-term stimulation of axonal growth can restore function.  Third, many people recover function years after injury.  These observations give me hope that there will be therapies that will restore function in chronic spinal cord injury.

Most of my reasons for hope do not stem from animal studies of spinal cord injury but from many years of observing people with spinal cord injury.  People can and do recover after injury, often years afterwards.  I have seen people recover when their spinal cords have been decompressed or an arteriovenous malformation has been obliterated, often after years of paralysis and sensory loss.  Sometimes the recovery is rapid, suggesting that connections were present but suppressed.  Other times, the recovery occurs over weeks, suggestive of remyelination.  The recovery may take years, suggestive of regeneration.

Before discussing these reasons for hope, I want to first deal with several misapprehensions that many people seem have about their spinal cord injury.  Over the years, many people have expressed surprise when I have told them that the spinal cord below the injury site is alive and kicking.  They think that the spinal cord below the injury site is “dead”.  Another common belief is that it is not possible to restore atrophic muscle and bone that have become flaccid and osteoporotic.  Finally, there is a general notion that the spinal cord is far too complex for it to be reparable with a dash of cells, a squirt of growth factors, and a sprinkle of growth inhibitor blockers.   These concerns are understandable.

Common Misapprehensions about Spinal Cord Injury

Many people are anxious that the therapies will not work for chronic spinal cord injury. Some believe that the spinal cord below the injury site is “dead” and cannot be revived.  Other think that chronic spinal cord injury is associated with many changes of the body that cannot be reversed, including atrophy of muscle and bone.  Finally, most people are concerned that the spinal cord is too complex to be repaired by transplanting some cells, splashing on some growth factors, blocking a few axonal growth inhibitors, and exercising.  Let me address these concerns first.

Isn’t the spinal cord dead below the injury site?  Christopher Reeve asked me once why his legs move whenever his respirator filled his lungs with air.  Aren’t they supposed to be paralyzed?  I answered that Penelope is there waiting for Odysseus to come home, referring of course to the Greek myth where Penelope is Odysseus’ wife waiting for him to come home from a long journey.  Many suitors are knocking on her door.  Like the neurons in the spinal cord below the injury site, she is impatient for her husband’s return.  Spasticity and spasms are proof that the spinal cord is alive and kicking. People who have flaccid paralysis below the injury site may have had some damage to the spinal cord below the injury site.  However, this does not necessarily mean that the spinal cord is “dead”.  It does mean that there is insufficient excitability to cause spasticity and spasms.

Can we reverse nerve, muscle and bone atrophy?  It takes time and a lot of work but activity can and will reverse the bone and muscle loss.  For example, recent studies suggest that even completely denervated muscles can be restored with intense electrical stimulation.  Astronauts who stay for prolonged periods of time in microgravity lose bone just like people in spinal cord injury but bone will return as the person spends time weight bearing in normal gravity.  Finally, the central nervous system is like muscle and bone in that it also undergoes atrophy when it is not active.  Called “learned non-use”, the central nervous system “forgets” its function.  Much evidence suggests that learned “non-use” could be reversed by intensive repetitive exercise.

Isn’t the spinal cord is too complex to repair and restore?  How can we hope to restore millions of connections between the brain and spinal cord?  It turns out that the spinal cord is not only much simpler but is much capable and plastic than we had ever imagined.  Your brain doesn’t control muscles directly when you walk.  The brain simply turns on the walking program that resides in the spinal cord and then modulates it to go faster slower, to turn, to slow down, to turn, etc.  The central pattern generator (CPG) resides in the L2 spinal cord and controls walking.  One does not need many axons to initiate and control walking.  That is why both humans and animals can walk with only 10% of the nerve fibers in their spinal cord.

In summary, the spinal cord below the injury site is alive and often kicking.  Flaccidity simply means insufficient excitability.  Although it takes time and a lot of work, atrophy of nerves, muscles, and bone can be reversed.  The spinal cord can learn and possess programs for movements, including walking.  It doesn’t take a lot to turn the programs on and control them.  That is why people with 10% of their spinal cord can walk.

The Ten Percent Rule

Less than ten percent of the spinal cord is necessary and sufficient to support complex functions such as walking.  We know from animal studies that rats and cats can walk with less than 10% of the spinal tracts crossing an injury site [1].  This is true for humans as well.  In the 1980’s, I use to do evoked potential monitoring [2, 3] for Fred Epstein, a neurosurgeon who operated on spinal cord tumors of kids.  He would often cut open the spinal cord and remove the tumor, leaving behind spinal cord that is thin that it is almost transparent.  On the Upper East Side of New York, there used to be bagel store where some Chinese guy would cut lox that is so thin that you could almost see through it.  That was what the spinal cord of these kids looked like and yet they would walk out of the hospital.

How do people walk with so little spinal cord?  The brain doesn’t directly control the muscles used for walking.  The spinal cord does [4].  All the movements for walking a programmed into the spinal cord [5].  To start walking, the brain sends a message to the spinal cord to tell it to walk [6].  A center in the L2 spinal cord called the central pattern generator (CPG) initiates and coordinates the muscles responsible for walking [7, 8].  The CPG is of course why chickens can continue to run around after their heads have been cut off [9].  It is also the reason why we can sleepwalk at nights.  You don’t need much of your brain to walk.  In fact, it is possible to stimulate the lower spinal cord at L2 and activate walking and the CPG is under sensory control [10].

Herman, et al. [11-13] reported in 1999 that subthreshold stimulus (not strong enough to activate walking by itself) made it easier for people with spinal cord injury to initiate and control walking.  This is of interest for locomotor training.  Herman describes a person who is just a household walker after years of overground locomotor training, normally taking over 160 seconds to walk ten meters.  However, when the L2 stimulator was turned out, at a level that does not activate walking, the person is able to walk 10 meters in less than half the time.  The walking recruited more muscles and the gait was more efficient.  After several months of training with the stimulator, the person is now able to walk more than a km at normal speeds.  Energy studies indicate that the walking pattern is much more efficient when the stimulator has been turned on.

Humans evolved tremendous redundancy of the spinal cord because of spinal cord injury because regeneration takes too long.  At one mm a day, regeneration may take a year or more to restore function.  No animal can survive his long without being able to escape, hunt, and procreate.  Therefore, animals (and humans) have evolved redundant spinal cords.  Such redundancy provides a major survival advantage because spinal cord injury is relatively common.  For example, although there are over a million cases of cervical whiplash every year in the United States, less than 10,000 result in spinal cord injury requiring hospitalization.  By having a redundant spinal cord, humans could survive even after 90% of their spinal cord has been damaged.  This is why a football player can keep playing after having gotten a “stinger” and people with incomplete spinal cord injury, ever severe ones destroying 90% of the spinal cord, will recover walking.

Axons Keep Trying to Grow

The first thing that I was taught in neuroscience as a graduate student was that the central nervous system cannot regenerate.  But, if you look at the injured spinal cord, this is not true.  Axons in the spinal cord not only can and do grow but continue to try growing throughout adult life.  This may sound like heresy but science is really about overturning dogmas and the dogma that the spinal cord cannot regenerate has been toppled many times over the past 20 years.  The spinal cord not only can grow and does so routinely but it continues to try to grow many years after spinal cord injury.  Let me explain.

After an injury, the spinal axons that have been damaged “die-back” a short distance and then start regrowing towards the injury site.  In most cases, they stop at the edge of the injury site, although some axons apparently will invade into the injury site itself.  In the first detailed and systematic study of axon regrowth in contused spinal cords [14], we found axonal growth into the injury site of over 70% of contused rat spinal cords at 6 weeks after injury.  Most of the axons did not grow out of the injury site but they have clearly grown up to and into the spinal cord.   Many axons, however, stop at the injury and appear to be waiting.

Ramon y Cajal [15] first described these waiting axons.   They have enlarged bulbous endings that he called “sterile terminal bulbs”.  He thought that these were just axons that had been damaged and could not grow.  The problem is that you can find these at 2 week, 2 years, and even 20 years after injury.  My friend Richard Bunge [16] once showed me a slide of a human spinal cord 20 years after injury.  The spinal cord was from a woman who had died 20 years after injury.  At the injury edge, thousands of axons with their bulbous endings were present, as if they were waiting.  This amazed me. Were these axons just sitting there for 20 years?  That seemed highly unlikely.

The answer to this question did not come to me until I saw a talk once by Jerry Silver.  He was trying to get axons to grow in culture dishes.  To mimic the inhibitory growth environment of the spinal cord, he and his students had coated a cell culture with laminin (which supports axonal growth) and put a drop of solution containing chondroitin-6-sulfate-proteogylan or CSPG (which stops axonal growth).  As the drop of CSPG solution dried, it left a concentration gradient of CSPG that was lowest at the center of the drop zone and highest at the drop edge.  Jerry then placed a dorsal root ganglion in the center of the drop zone and took videos of the dorsal root ganglion axons growing.

When an axon grows, it forms a growth cone at the tip.  In its fast growth mode, the growth cone is like a spearhead.  However, as axons grow in a progressively growth inhibitory environment, the growth cones tend to spread out.  They eventually stop and become bulbous terminals.  In his useful insight way, Jerry called these “frustrated” growth cones.  When viewed in on video, one can see that axons start growing, becoming frustrated, and then falling back, repeatedly trying over and over again.  The fact that these terminal bulbs are present in spinal cord 20 years after injury tells me that there is continued regrowth in the spinal cord, probably for the entire life of the individual.  Even if it did not, there are probably ways to kickstart the growth again.

Give Them a Path and They will Take it All the Way

In the 1980’s, Sam David and Alberto Aguayo [17, 18] literally stood the non-regeneration dogma on its head when they hypothesized that spinal axons can grow but that there are growth inhibitors in the spinal cord that stops growth.  To test the hypothesis, they excised a peripheral nerve, one end into the cervical spinal cord and the other end into the lumbar spinal cord of a rat.  Spinal axons grew into the nerve inserted into the spinal cord (on both sides) and all the way to the other end.  However, they would not re-enter the spinal cord on the other side.

In 1999, I heard Thomas Carlstedt [19] of the Royal National Orthopedic Hospital at Stanmore speak about his work inserting avulsed brachial plexus nerves back into the spinal cord.  Brachial plexus injuries cause avulsion of the spinal root from the cord.  He would expose the spinal cord and insert the avulsed nerve back into the spinal cord.  Several months later, all the patients recovered some movement in their paralyzed arm.  In fact, some of these patients had “breathing arms” because their arms would move as they breathed, suggesting that the axons that normally activate breathing have entered into the peripheral nerve to the arms.  To me, this is proof that if you give spinal axons a path to grow, they will take it and go all the way.

Giorgio Brunelli, et al. [20] used peripheral nerves to bridge from the spinal cord above the injury site to muscles below the injury site.  He started by using a branch of the ulnar nerve that innervates the little finger side of the hand and moving the nerve to the sciatic nerve of the leg, to innervate the leg muscles.  He has done this to a number of people but moved from this procedure to doing a nerve bridge from above the spinal cord to muscles below the injury site [21]. Brunelli et al. [22, 23] have shown that glutamatergic spinal axons from the spinal cord innervate muscle.

Shaochen Zhang [24] has done thousands of peripheral nerve grafts above the injury site to muscles below the injury site, not only from arms to the legs but from neck to arms, from upper arm and shoulder nerves to the hand, and from intercostal nerves to the bladder and legs.  Xiao, et al. [25-30] has been diverting the L2 or L3 ventral root to reinnervate the pudendal nerve (S2), which innervates the bladder.  This procedure restores bladder function in close to 80% of patients.  Scratching the dermatome for L2 can initiate micturition (bladder voiding).  Many patients were able to produce a 3-foot stream of urine.  The procedure seems to work in spinal cord injury and spina bifida.

To me, the finding that spinal axons will grow into peripheral nerves and connect cells at the end is proof that they can regenerate and that all you have to do is give them a path and they will take it all the way.  They will make synapses with the cells that they find at the end, including muscles.  But, even more amazing was the finding somatic motor nerves from the lumbar cord will reinnervate and make the bladder function again.  This is amazing because micturition (the act of urination) is a complex act that involves bladder contraction and relaxation of the bladder sphincter and ability to stop when the bladder is empty.  For a somatic nerve to mediate this complex response is amazing.

Recovery is Possible in Chronic Spinal Cord Injury

Recovery is the rule and not the exception after spinal cord injury.  Since most people have incomplete spinal cord injury, a majority of people recover substantial function.  Even those with so-called “complete” spinal cord injuries usually recover 1 or more segments.  This may come as a surprise to most people who are used to being told that people do not recover after spinal cord injury. Spontaneous recovery from spinal cord injury provide several insights into the mechanisms [31].  First, recovery is often slow and may take years. Second, repetitive training facilitates and accelerates the recovery.  Third, absence of function does not necessarily mean that the structures are absent. These will be discussed in turn below.

Most people continue to recover some function years after the original injury.  For example, Christopher Reeve, who was certified by many doctors to have a so-called “complete” spinal cord injury and did not receive any experimental regenerative therapy, begin recovering sensory about 2 years after injury, to the point that he had light touch sensation over 75% of his body [32-35].  His anal area was so sensitive that they had to use lidocaine cream during bowel procedures.  At 6 years, his wife Dana noticed that Christopher could move his left index finger.  It turns out that he has quite good control on his left index finger.  Christopher also found that he could move his legs slightly.  The time frame and nature of this recovery is consistent with the possibility of spontaneous regeneration after spinal cord injury [36].

Repetitive training can restore function even in people who have not functioned for years after injury. When a particular function has not been used for a long period of time, atrophy is not limited to bone and muscle.  It appears also to occur in the central nervous system.  Called “learned non-use”, this remarkable phenomena can be mimicked by denervating an animal’s arm by cutting the dorsal root, and then allowing the subject to stop using the arm.  After several months, the arm become effectively paralyzed.  However, intensive and repetitive exercise can restore function, even many years after injury [37].  Constraint-induced movement therapy [38] is now used to treat multiple sclerosis [39], stroke [40], and many other conditions [41].   Locomotor training is a formed of forced-use exercise [42-45] that can and has been used to restore locomotor function in people, often many years after their spinal cord injury.

Finally, neurologists have long assumed that absence of function means loss of the structure mediating the function.  However, central nervous system function can be suppressed for years without loss of structure.  For example, treating an arteriovenous malformation (AVM) or decompressing the spinal cord can result in rapid recovery of function.  I use to monitor evoked potentials of patients undergoing surgical or radiological procedures [3, 46-48].  One of the patients was a paraplegic athlete with thoracic spinal cord AVM. Although paralyzed for nearly 7 years, he recovered rapidly after the embolization and walked out of the hospital after embolization. Such rapid functional recovery could not have been due to regeneration or remyelination.  It was due to removing a cause that had suppressed function for many years.

Summary and Conclusions

Many people are concerned that the cure for spinal cord injury will apply to newly injured people and not to people with chronic spinal cord injury.  While these concerns are legitimate, it is important to dispose several common misapprehensions. First, the spinal cord is not “dead” below the injury site.  Injury disconnects the lower spinal cord from the brain and upper spinal cord. Spasticity and spasms is proof that the lower spinal cord is alive and kicking.  Second, neural, muscle, and bone atrophy can be reversed even after years of loss.  Finally, the spinal cord contains programs for complex functions such as walking.  Those should be preserved and the goal is to reconnect enough axons to initiate and modulate these programs.

About 10% of spinal cord tracts is necessary and sufficient to support complex functions, including walking.  Humans, for example, can walk even after damage to 90% of the spinal cord because the brain does not directly control walking.  All the movements for walking, for example, are programmed in the spinal cord.  The brain sends a message to the central pattern generator (CPG) in the spinal cord, telling it to walk. The CPG is located in the L2 lumbar cord and can be stimulated to initiate or facilitate walking of people after spinal cord injury.  Humans evolved redundancy of the spinal cord because regeneration is too slow to help an animal to survive after spinal cord injury.

Axons continue to try to grow after injury.  At the injury site, they die back a short distance and grow back to the lesion edge.  In contusion injuries, some axons grow into the injury site but many stop at the lesion edge.  Ramon y Cajal described axons at the injury site with terminal bulbs.  These axons with bulbous endings were present in human spinal cords even 20 years after injury.  These terminal bulbs are “frustrated” axons that are still trying to grow at the injury site, due to growth inhibitors that collect in the extracellular matrix surrounding the injury site.

If you give axons a path to grow, they will take it and grow all the way.   David & Aguayo first showed this in the 1980’s by inserting peripheral nerves into the spinal cord and showing that many axons from the spinal cord would grow into the nerve and continue all the way to the other end.  Thomas Carlstedt used this method to treat patients with avulsed brachial plexus, showing that axons from the spinal cord not only grew in the nerve by innervated muscle.  Giorgio Brunelli likewise showed that the axons that grew into the peripheral nerves were spinal axons rather than motoneurons and that they form glutamatergic synapses.  Finally, Zhang and Xiao in China diverted nerves from various parts of the spinal cord to innervate and control organs that they normally do not.

Recovery is possible in chronic spinal cord injury.  A majority of people recover substantially after spinal cord injury, particularly those with incomplete spinal cord injuries.  Even people with so-called “complete” spinal cord injuries continue to recover some function, often years after injury. Christopher Reeve is an example.  Likewise, intensive repetitive training can reverse learned non-use, including restoration of locomotion in people who have not walked for many years after spinal cord injury.  Finally, certain conditions in the spinal cord can suppress function for years and removal of the causes can result in rapid restoration of function, within days.

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FAQ #2: When will the Cure be Available for Spinal Cord Injury?

January 1, 2009

FAQ #2: When will the Cure be Available for Spinal Cord Injury?
Wise Young, Ph.D., M.D., Rutgers University
W. M. Keck Center for Collaborative Neuroscience
604 Allison Rd, Piscataway, NJ 08854-8082
First posted 23 December 2008, final version 3 January 2009

Introduction

When will a cure for spinal cord injury be available?  This is the second most frequently asked question, usually asked right after the first most frequently asked question, “Will there be a cure for spinal cord injury?” While I don’t have a crystal ball for the future, some therapies are already beginning to restore function in people with spinal cord injury with spinal cord injury, several regenerative therapies have begun clinical trials, and the first combination therapies will soon go into clinical trial.  If we work hard, the resources are available, and we are lucky, we should expect the first restorative therapies within 5 years and perhaps the first curative combination therapies within a decade.

First generation therapies for spinal cord injury are already restoring some function to some people with spinal cord injury.  Methylprednisolone (MP) was the first therapy to show any beneficial effects when given after spinal cord injury.  MP improves motor and sensory recovery by about 20% compared to control.  A second therapy is Fampridine (4-aminopyridine), which is restoring function to some people with demyelination. The third therapy is locomotor training for people with “incomplete” spinal cord injuries.

Second generation therapies are now or will soon be in clinical trial.  These include cell transplants (olfactory ensheathing glia, Schwann cells, bone marrow stem cells, neural stem cells, oligodendroglial progenitor cells, embryonic stem cells), nogo and nogo receptor blockers, chondroitinase, growth factors, lithium, and many others. These therapies are likely to stimulate modest regeneration in the spinal cord and restore more function to more people.

Third generation therapies will be combination therapies that will bring substantially more function to most people, fulfilling the definition of what many people may call “cures” for spinal cord injury.  The optimal combination will probably differ depending on the individual.  The combination therapies should include not only therapies that regenerate spinal axons but also remyelination and neuronal replacement, including motoneurons.

What can we learn from these experiences?  I will describe below eight examples of therapies for spinal cord injury, i.e. methyprednisolone, locomotor training, fampridine, cethrin, nogo antibody, and human embryonic stem cells, bone marrow stem cells, and combination therapy with cord blood mononuclear cells and lithium.  I chose these treatments because each have undergone or are going through clinical trial.  I will describe the development of each of the therapies to date, the lessons from this experience, and the probability of the first restorative therapies and combination therapies.

Methylprednisolone (MP)

MP was the first therapy shown to be effective for acute spinal cord injury.  In the 1970’s, neurosurgeons were using high doses of the anti-inflammatory glucocorticoid drug methylprednisolone (MP) to treat arachnoiditis [1] and head injury [2].  Some clinicians wondered if MP would be effective for acute spinal cord injury [3, 4].  In 1979, ten spinal cord injury centers joined to do the first double blind randomized clinical trial of high-dose and low-dose MP for acute spinal cord injury.

The first National Acute Spinal Cord Injury Study (NASCIS 1) randomized 300 patients to 1000 mg/day or 100 mg/day of intravenous MP for 10 days starting within 24 hours after injury. The trial found no significant difference between the two doses of MP [5].  However, in 1982, animal studies showed that much higher doses (30 mg/kg) were required to inhibit lipid peroxidation [6] and that very early treatment was necessary for to reduce extracellular calcium entry into cells and to prevent post-traumatic ischemia [7].  The opiate receptor blocker naloxone was beneficial in animal models [8, 9] and a phase 2 trial [10].

The second National Acute Spinal Cord Injury Study (NASCIS 2) therefore randomized 487 patients to placebo, high-dose MP (30 mg/kg bolus followed by 5.4 mg/kg/hour over 24 hours), and naloxone (5.4 mg/kg + 3.0 mg/kg/hour over 24 hours).  Starting in 1985, the trial proposed to segregate patients by the median treatment time, which was 8 hours, assess the effects of treatment timing.  NASCIS 2 [11] showed that high-dose MP improved motor and sensory recovery compared to placebo when treatment started within 8 hours but not when started later than 8 hours [12].  Naloxone had intermediate effects between MP and placebo.  MP was not associated with significant morbidity or mortality. From 1991-1993, <50% of people with acute spinal cord injury in Colorado received MP [13] and physicians tended to give the drug to more severely injured patients.

The third National Acute Spinal Cord Injury Study (NASCIS 3) randomized 499 patients with acute spinal cord injury and treated all within 8 hours with a 30 mg/kg MP bolus, followed by 5.4 mg/kg/hour for 24 hours (MP24), MP given for 48 hours (MP48), or tirilazad mesylate (TM) 2.5 mg bolus given every 6 hours for 48 hours (TM48).  The median treatment time was 3 hours.  All three treatment groups had similar outcomes when started within 3 hours but MP48 was better than either MP24 or TM48 when given more than 3 hours after injury [14, 15].  The treatments were not associated with significant mortality or morbidity except for an increase in severe pneumonia after MP48.

The NASCIS group recommended MP24 when it could be started within 3 hours, MP48 between 3-8 hours, and no MP if it could not be started within 8 hours after injury. Several randomized trials [16-19] have confirmed beneficial effects and safety of MP use in human acute spinal cord injury and related conditions [20, 21].  However, one small randomized trial [22] and several retrospective studies [23-27] suggested MP may be ineffective. One study suggested that MP Retrospective studies are biased because clinicians tend to give MP to more severely injured patients.  Nevertheless, criticisms of NASCIS mounted [28-36].  Today, MP is an option and not a standard treatment of acute spinal cord injury in the United States.

Locomotor Training

Most doctors believe that recovery of walking is unlikely after spinal cord injury and thus few encourage their patients to walk after injury.  In 1992, Wernig & Muller [37] reported that intensive treadmill training restored unassisted walking to 8 patients, starting at 5-20 months after spinal cord injury.  By 1995, Wernig et al. [38] had studied 89 patients (44 chronic, 45 acute) with spinal cord injury.  Of 44 chronic patients trained for 3-20 weeks, 33 were initially wheelchair-bound and could not stand or walk.  After training, 25 (76%) of the 33 wheelchair-bound patients achieved unassisted walking.  Of 11 patients who were walking before training, all had better speed and endurance.  In a 1998 followup [39], at 6-72 months after training, 31 of 35 chronic patients who recovered unassisted walking maintained, three improved, and one stopped walking.  Of 41 initially acute spinal cord injuries, 15 improved and one stopped walking.

In 1998, the National Institutes of Health (NIH) commissioned a multicenter study to compare weight-supported treadmill and overground walking training in spinal cord injury.  The Spinal Cord Injury Locomotor Trial or SCILT [40] showed that <10% of patients with ASIA B, 92% of those with ASIA C, and 100% of ASIA D recovered walking at >0.8 meter/second and over 260 meters in 6 minutes.  An ASIA (American Spinal Injury Association) B classification refers to an injury that preserves only sensation below the injury site, including anal sensation.  ASIA C indicate injuries that preserve anal sensation or sphincter function and motor function below the injury site but less than half of ten key muscles have strength grades exceeding 3 of 5 (0=paralyzed, 1=slight, 2=definite, 3=anti-gravity, 4=against resistance, 5=normal).  ASIA D indicates injuries with 5 or more key muscles with strength grades of 3 or more.  SCILT indicated no difference between training with weight-supported treadmill and overground walking.

Although intensive training can restore locomotion in animals after even severe spinal cord injuries [41-45], the finding that >90% of people with incomplete spinal cord injury can recover unassisted walking even without treadmill training nonetheless took many clinicians by surprise.  Despite initial resistance, this finding is transforming rehabilitation of spinal cord injury.  Motor incomplete patients can walk.  Many investigators are now examining the effects of treadmill training patients with ASIA A (complete) or B (sensory incomplete).  Others are assessing other training approaches, in combination with functional electrical stimulation [46], serotonin receptor agonists [47], and other methods of increasing motor control [48].

In summary, early studies in the 1990’s reported that weight-supported treadmill training could restore unassisted locomotion to people with chronic spinal cord injury.  In 1998, the NIH funded SCILT to study weight-supported treadmill training of patients with incomplete spinal cord injuries.  The study surprisingly showed that >90% of motor incomplete patients recovered unassisted locomotion, whether they were trained by treadmill or overground walking, suggesting that most people who have preserved motor function after injury can recover locomotion if they worked on it.  Many investigators are examining various adjuncts to locomotor training.

Fampridine (4-AP)

Trauma, ischemia, and inflammation demyelinate the spinal cord. 4-aminopyridine (4-AP or fampridine) blocks potassium channels on demyelinated axons, improves conduction, and increases neurotransmitter release [49].  In 1981, Bostock, et al. [50] reported that 4-AP improves conduction in demyelinated axons and Zangger, et al. [51] showed that it also facilitates L-DOPA induced spinal locomotor rhythms in spinal-injured animals.  In 1986, Eliasson, et al. [52] showed that 4-AP restores conduction in heat-injured nerve and spinal roots in animals.  In 1987, Bowe, et al. [53] confirmed that 4-AP improves conduction in demyelinated axons and Blight & Gruner [54] found that 4-AP improved vestibulospinal free fall responses in spinal-injured cats.  In 1989, Blight et al. studied the effects of 4-AP in dogs [55] and proposed clinical trials of 4-AP in spinal cord injury.

In 1993, Hansebout, et al. [56] did the a double-blind, crossover trial of 4-AP in eight patients, finding the drug improved motor and sensory function.  Hayes, et al. [57] confirmed the 4-AP effects on function [58] and motor evoked potentials [59] in patients with spinal cord injury.  In 1997, Segal & Brunnemann [60] found that 4-AP improves pulmonary function in quadriplegic humans with chronic spinal cord injury [60].  In 1997, Acorda Therapeutics licensed the use patent for 4-AP treatment of spinal cord injury. In 1998, Potter, et al. [61] did a randomized crossover trial of a sustained release 4-AP (Fampridine SR) made by Elan.  In 1999, Acorda partnered with Elan to develop Fampridine SR, including preclinical studies [62, 63], studies to assess pharmacokinetics of intravenous [64], intrathecal [65], oral [66] 4AP in humans and animals [67].

In 2001, van der Bruggen, et al. [68] found that 4-AP (0.5 mg/kg) did not improve neurological function of 20 patients with chronic incomplete spinal cord injury.  However, 4-AP improved motor evoked potentials patients with chronic spinal cord injury [69] and Grijalva, et al. [70] randomized 27 patients to 4-AP or placebo, and found that 30 mg/day 4AP for 12 weeks improved neurological function in 69% compared to 46% on placebo. In 2004, Deforge, et al. [71] found no difference between 4-AP (40 mg/day) or placebo in 15 people who were walking after spinal cord injury.

From 2005 to 2007, after a phase 2 [72], more pharmacokinetics [73, 74] and safety trials [75], Acorda did two large randomized placebo-controlled phase 3 trials involving over 800 patients with chronic spinal cord injury to assess Fampridine SR effects on spasticity.  Both trials [not yet published] showed no significant difference between Fampridine SR and placebo.  However, Acorda also did two phase 3 clinical trials that showed that Fampridine SR significantly improves walking performance in multiple sclerosis (MS).

In summary, over a decade of clinical trials yielded promising and conflicting results concerning 4-AP effects on chronic spinal cord injury.  The trials surprisingly revealed that people with spinal cord injury are susceptible to placebo.  Over 40% of patients responded to placebo and perhaps half of the patients responded to 4-AP.  Until better outcome measures can be found, it may be better to choose a condition that is more responsive to 4-AP and go back later to demonstrate efficacy for spinal cord injury.

Nogo-A Antibody

In 1990, Schwab, et al. stunned the world with his study showing that IN-1, an antibody against an as-yet-unidentified myelin component [76], stimulates regeneration of rat corticospinal tract [77].  The first demonstration of a treatment that regenerates the spinal cord, the work convinced many neuroscientists that Aguayo and David [78-80] were right in their proposal that there is something about central myelin that stops axonal growth.  Unfortunately, the IN-1 antibody was promiscuous and bound to many proteins.  It took ten years before Schwab and his colleagues were able to isolate and clone the gene for the protein, now named Nogo [81-86].  With the purified protein finally available, Novartis licensed the patent for Nogo antibody treatment of spinal cord injury and embarked on an intensive program to develop the first regenerative therapy for spinal cord injury.

Many investigators tried different approaches to using the discovery of myelin-based growth inhibitory proteins to regenerate the spinal cord injury.  For example, Huang, et al. [87] reported that vaccinating mice with spinal cord may have induced antibodies that stimulated spinal cord regeneration, an approach that was later validated when the nogo protein itself was available to determine whether the vaccination induced the antibodies against nogo [88, 89].  If vaccination will induce antibodies that can stimulate spinal cord regeneration, this would be a very powerful approach indeed.

Novartis developed specific nogo-A antibodies that improve behavioral outcome and corticospinal plasticity in rats after experimental stroke [90], stimulated corticospinal regeneration in marmosets [91], increased plasticity in many different preparations [92-94].  After demonstrating that the antibodies penetrated into the spinal cord when infused intrathecally [95] and showing that the anti-Nogo-A antibody stimulated sprouting of corticospinal axons in macaque monkeys [96] and the treatment restores serotonin projections in rats after spinal cord injury [97], the Nogo-A antibody was taken to clinical trial in patients with chronic spinal cord injury.

The Novartis phase 1 trial of Nogo-A-antibody (ATI355) was recently completed.  The phase 1 trial (ClinicalTrials.gov identifier NCT00406016) was an open-label multicenter study to assess feasibility, safety, and tolerability of continuous infusing five doses of ATI355 intrathecally into patients starting 4-14 days after injury.  Paraplegic and ASIA A tetraplegic patients were included.  Tetraplegic patients who require artificial respiration could receive treatment as late as 60 days after injury, as soon as they were weaned off the respirator.  Patient with complete anatomical transection or obstruction of the spinal canal, multiple spinal cord lesions, cauda equina injury, brachial or lumbar plexus injury, significant head injury and systemic disease were excluded.  A phase 2 trial has started, indicating that the phase 1 trial has shown safety and feasibility.

In summary, the development of the Nogo antibody has taken nearly 2 decades since the initial discovery that that something in myelin inhibits spinal axonal regeneration.  The treatment has been validated in many laboratory studies and completed phase 1, indicating feasibility and safety.  Upcoming phase 2 trials will optimize the therapy and outcome measures, to be followed by pivotal phase 3 studies to show efficacy.

Cethrin

In 2001, Strittmatter et al. [98-107] described the receptor for Nogo.  The receptor, like many others that stop axonal growth and cellular migration, inhibits axonal growth by activating the intracellular messenger rho with rho kinase [108].  The Strittmatter laboratory identified a 66-amino acid fragment of Nogo that blocks the Nogo receptor [109-112] and other Nogo receptor blockers [113-124].  They even showed that MP and Nogo-66 have a synergistic effect on regeneration [125].  Working with Biogen, they subsequently found that the soluble Nogo receptor protein itself tightly bind molecules that inhibit axonal growth [123] and improves recovery after spinal cord contusion [126].

In the meantime, after studies of rho activation patterns in the spinal cord [127], Lisa McKerracher proposed [128] a new approach to target rho to stimulate repair and regeneration after spinal cord injury.  She used the bacterial toxin C3 to inhibit rho, modifying it so that it entered cells.  She formed the company Bioaxone to develop the drug.  The resulting cell-permeable recombinant protein BA-210 prevented secondary damage and promoted function recovery in spinal cord injury [129].  BA-210 or Cethrin subsequently went to phase 1 clinical trial [130, 131].  Bioaxone was recently bought be Alseres Pharmaceuticals (formerly Boston Life Sciences).

The Cethrin trial (ClinicalTrials.gov identifier NCT00500812) was a Phase I/IIa dose-ranging study to evaluate the safety, tolerability, and pharmacokinetics of BA-210 and the neurological status of patients following administration of a single extradural application of Cethrin during surgery for acute thoracic and cervical Spinal Cord Injury.  All the patients were ASIA A (complete).  Carried out from February 2005 to October 2008, the final data collection of the trial will be in June 2009.   The trial compared 0.3, 1, 6, and 9 mg of BA-210 applied to the dura surface of the injured spinal cord, during surgery that exposed the spinal cord for decompression.

Presentations of the Cethrin phase 1 trial results suggest possible beneficial effects of Cethrin in recovery after spinal cord injury [132].  Of 37 patients entered into the trial, they found no serious adverse side effects.  All the patients were ASIA A on admission.  The six-month patient data indicated that 28% of the patients (10 of 36) improved by one or more ASIA grades as compared to reported literature results of 6.7% [133].  Five of the patients improved to ASIA C and two improved to ASIA D.  One patient died form acute respiratory distress syndrome.

A phase 2 trial will start soon to evaluate the safety and efficacy of Cethrin in adult subjects with acute cervical spinal cord injury [134].   The trial is a randomized, double blind, placebo controlled study that will use mean ASIA motor score change as the primary outcome measure.  Six experimental groups will be compared:  placebo, 1 mg, 3 mg, 6 mg, 12 mg, and 18 mg Cethrin.  All the treatments will be applied epidurally during surgery exposing the spinal cord for decompressive or other purposes during the first several weeks after spinal cord injury.

Olfactory Ensheathing Glia (OEG)

The olfactory nerve is the only part in the central nervous system that continuously regenerates in adult mammals.  Its regenerative ability has been attributed to olfactory ensheathing glial (OEG) cells that are born in the nasal mucosa and migrate to the olfactory bulb.  Doucette [135] suggested that OEG cells would facilitate regeneration in other parts of the central nervous system, including the spinal cord.  In 1996, Smale, et al. [136] used OEG cells to repair transected fornix in the rat.  In 1997, Li, et al. [137] used OEG cells to repair adult rat corticospinal tract.  In 1998, Ramon-Cueto, et al. [138] reported that OEG transplants promoted regeneration in transected rat spinal cords.

In 2000, Barnett, et al. [139, 140] reported that human OEG cells can remyelinate axons.  Imaizumi, et al. [141, 142] used pig OEG cells to promote regeneration and remyelination in the spinal cord.  Ramon-Cueto, et al. [143, 144] reported functional regeneration in rats after spinal cord transection.  Many investigators enthused about the promise of OEG cells to bridge the gap in spinal cord injury [145-151].  One company (Alexion) grew OEG from genetically modified pigs as a substitute for human cells.

In 2001, Lu, et al. [152] reported that transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats.  Shortly thereafter, in Portugal, Lima, et al. [153] began transplanting nasal mucosa into patients with chronic spinal cord injury and reported recovery of motor scores, as well as light touch and pinprick scores.  In total he transplanted nasal mucosa to over 160 patients with chronic spinal cord injury.  Several places, including Osaka University Medical School [154], want to continue the study.

In Brisbane, MacKay-Sim, et al. [155] successfully cultivated olfactory ensheathing cells from the nasal mucosa of 3 patients with chronic spinal cord injury and transplanted the cells into their spinal cords,  Compared with 3 patients matched for injury severity and other characteristics, the transplanted patients showed no adverse effects of the transplants. However, they also did not show any significant functional change or neuropathic pain at 3 years after the transplant.

In the largest published series to date, Huang, et al. [156] transplanted OEG isolated from olfactory bulbs of aborted fetuses into 171 patients with chronic spinal cord injury.  The patients showed significant increases in sensory scores but only modest improvements in motor function.  Dobkin, et al. [157] criticized the study, claiming that there were unreported complications and five patients did not show improvements.  Huang has denied these criticisms and published further studies suggesting that OEG transplants are safe and efficacious [158, 159].  He has transplanted OEG into over 1200 patients to date.

In summary, the discovery that OEG cells facilitate regeneration in animal spinal cords excited clinicians. Carlos Lima in Portugal transplanted autologous nasal mucosa into over 160 patients with chronic spinal cord injury with modest results.  McKay-Sim in Brisbane cultured nasal mucosa OEG cells and transplanted them into 3 patients who had no significant beneficial effects after 3 year.  Huang Beijing transplanted fetal OEG cells into more than 700 patients and find that they consistently restore significant sensory.

Human Embryonic Stem (HES) Cells

The 1977 disovery by Thomson, et al. [160] that pluripotent human embryonic stem (HES) cells can be isolated and cultivated indefinitely transformed stem cell research. The first study reporting efficacy of embryonic stem cells for spinal cord injury appeared in 1999 [172].  While several other cell transplants have reported to be beneficial for spinal cord injury, i.e. marrow stromal cells [162], fetal neural stem cells [163], and other cells [164-171], people thought that the only way to get cells for transplantation was to collect them from fetuses, blood, or bone marrow. HES cells can produce many cell types for transplants, including neural stem cells, which in turn can produce neurons, astrocytes, microglia, and oligodendroglia [161].

Geron helped fund the early work leading to the first successful cultivation of HES cells.  Working with Keirstead at UC Irvine [173-177], Geron has concentrated their attention on treating spinal cord injury with oligodendroglial progenitor cells derived from human embryonic stem cells [178-180].  However, after many announcements of clinical trials since 2005 [181], the first phase 1 trial of HES cells has not yet been approved by the FDA.

Many people assumed that the delays are due to opposition by the Bush Administration to clinical trials of HES cells in the United States, including a May 2008 hold by the FDA [182].  Some scientists are concerned that the first clinical trial of HES must be very carefully designed.  As Evan Snyder of the Burnham Institute pointed out, “The last thing we need is another Jesse Gelsinger, referring to the 18-year-old man who died during a gene therapy trial at the University of Pennsylvania in 1999.  After Gelsinger’s death, the FDA closed down many gene-therapy trials for several years.  Because it is the first time that human embryonic stem cells are being transplanted into human, the trial will be under a microscope and any adverse effect will be emphasized [183].

In statements to the public [184], Geron CEO Thomas Okarma has suggested that the company plans to study 40 people with acute spinal cord injury.  The trial will focus on patients who are “complete” (ASIA A) and within the first two weeks after injury.  It is not clear whether and how much immunosuppression will be used.  Geron scientists have reported that oligodendroglial cells differentiated from HES cells are not targets of innate and adaptive human effectors cells and are resistant to lysis by Neu5Gc antibodies [179]. However, Keirstead has suggeted that long-term immunosuppression may be necessary.

In summary, human embryonic stem cells have been the object of much hope and controversy.  Due to their pluripotency, many regard the cells to be a promising source of cells for transplantation.  Geron is one of the first companies to fund research leading to the first successful cultivation of human embryonic stem cells a decade ago.  The cells have not yet reached clinical trial stage. Geron chose to focus on spinal cord injury in their first clinical trials.  However, since 2005, despite repeated announcements, the first phase 1 trials have not yet been approved by the FDA.  The trial will likely study 40 patients with subacute spinal cord injury with oligodendroglial cells differentiated from a human embryonic stem cell line.  A major question is immune rejection of the cells and whether immunosuppression will be used.

Combination Therapies

Combination therapies achieve greater axonal growth than individual therapies [185].  To regenerate the spinal cord, therapies must address the following obstacles to regeneration.

  • Bridging the injury site.  The spinal cord injury site does not support regenerating axons for several reasons.  The injury site is disorganized, filled with inflammatory cells, lacks cellular adhesion molecules to guide axonal growth, and may contain factors the inhibit axonal growth.  Many laboratories are consequently transplanting cells or placing biomaterials to provide a bridge for axonal growth across the injury site.
  • Sustained source of growth factors.  Axons grow slowly, less than a mm a day.  They must grow long distances, as much as a meter, to reach their original targets.  To do so, there must be a sustained source of growth factors. Several neurotrophins, including NGF, NT-3, and GDNF are critical growth factors.  One way is to infuse the factors but a better way may be to stimulate either endogenous or transplanted cells to secrete growth factors.
  • Blocking growth inhibitors. Several factors block axonal growth in the spinal cord.  The best defined is the myelin-based factor Nogo.  Other include extracellular glycoproteins such as CSPG.  The former can be blocked by anti-Nogo-A antibodies, Nogo receptor blockers, rho inhibitors, and even soluble nogo receptor protein.  The latter can be digested by enzymes, including chondroitinase.

Individual therapies are being tested in clinical trials. To test combination therapies, we must have clinical trial networks that can test therapies rigorously and efficiently.  We have set up a clinical trial network to test spinal cord injury therapies in China.  Called the China Spinal Cord Injury Network (ChinaSCINet), this network currently has 25 centers in Mainland China, Hong Kong, and Taiwan, capable of randomizing many thousands of subjects per year.

ChinaSCINet is carrying out the first clinical trials of combination therapies of spinal cord injury, i.e. umbilical cord blood mononuclear cells (UCBMC) and lithium.  Many laboratories have reported beneficial effects of UCBMC on spinal cord injury [165-168, 170, 171, 186-188].  In 2004, Yick, et al. [189] reported that lithium stimulates regeneration in rat spinal cord. Subsequently, Su, et al. [190] found that lithium stimulates proliferation of neural stem cells in the spinal cord and Dill, et al. [191] showed that lithium promotes axon regeneration and recovery in rat spinal cord injury.

Lithium stimulates UCBMC cells to secrete NGF, NT-3, and GNDF and we therefore propose to carry out studies of lithium and UCBMC cells individually, in combination, and then with axonal growth inhibitor blockers such as anti-nogo-A antibody, nogo receptor protein, cethrin, and chondroitinase. UCBMC and lithium are attractive first therapies for clinical trial since both have been extensively used in humans for many years.  If UCBMC are effective, many cord blood banks are available to supply the cells.  Lithium is very low cost and can be taken orally.

Lessons Learned

What lessons have we learned from the above therapies for spinal cord injury?   Three lessons are clear:

  • Slow and Tortuous Process. Few therapies go through the development gauntlet without major hitches. The average time for therapy development exceeded a decade for all therapies described above. For example, development of MP required 13 years (1977 to 1990) from first preclinical discovery to NASCIS 2.  Weight-supported treadmill locomotor training required 14 years (1991-2005).  Fampridine (1987-now) and  Nogo-A antibody (1990-now) both are likely to take over 20 years to develop. The development of Cethrin began in 2003 and may complete clinical trials before 2013. OEG (1997-now) and embryonic stem cells (1997-now) both have taken over a decade already.
  • Rigorous proof-of-concept of treatment efficacy is required for companies, government, or foundations to invest millions of dollars into development of a therapy. In the case of companies, intellectual property protection is also necessary.  A large part of the development time for most of the therapies resulted from a prolonged period of research to establish proof-of-concept.  In certain cases, e.g. MP and locomotor training, the clinical trials and proof-of-concept research in animals proceeded in parallel.  However, both fampridine and nogo antibody therapies went through 10 years of extensive preclinical studies before the drugs was licensed.
  • Clinical Trials are Inherently Risky. A single mistake in clinical trial design can set a program by five or more years.  It is important to have systematic preclinical data before starting clinical trials.  For example, NASCIS 1 compared a ten-day course of 1000 mg/day and 100 mg/day without sufficient animal to indicate the optimal dose or timing of therapy, wasting over 5 years.  A wrong choice of outcome measures, such as the choice of spasticity as the primary outcome of the Fampridine trials added over five years to the development of fampridine for spinal cord injury.  Neither OEG nor HES cells have undergone any controlled clinical trials.

The development times for spinal cord injury therapies may have been particularly long because all of the therapies are the first in their class.  For example, MP was the first neuroprotective drug, weight-supported locomotor training the first major restorative rehabilitation treatment, fampridine was the first conduction enhancing drug, nogo antibody and cethrin are the first regenerative therapies, and OEG and HES transplants are both first of their class. Trailblazing is inherently time-consuming.

Clinical trial networks should reduce treatment development times because much time and expense of clinical trials must be spent on recruiting and train clinical trial centers. Having clinical trial networks that are ready and able to test therapies will not only improve the quality of clinical trials but should speed up and defray costs significantly. This will encourage companies to invest in spinal cord injury therapies.

Probability

How soon can we expect curative therapies of spinal cord injury?  To date, most spinal cord injury therapies have taken 10-20 years to complete clinical trials.  Establishment of clinical trial networks  and increased interest of pharmaceutical companies in spinal cord injury therapies may shorten the development time.  However, until significant new funding becomes available for spinal cord injury clinical trials, the rate of progress in developing therapies is unlikely to change significantly.

Fortunately, we are not starting from scratch and several promising therapies are already in the clinical trial pipeline.  Six of the 8 therapies described above are in or soon will be in clinical trials.  If each therapy has a 50% chance of success, we would have to be rather unlucky for all the trials will fail. In the case of 6 trials, the probability of all six trials failing is 1 in 64.  Clearly, it behooves us to have as many clinical trials going in parallel as possible.  The reason is that if one trial is successful, everybody wins.

The likelihood that a given clinical trial will be successful of course depends on the therapy and the amount of data supporting that particular therapy and clinical trial design.  If one rushes into a clinical trial without much preclinical data, one has a much greater risk of failure.  Since we have limited clinical trial funds and facilities, it would also increase the likelihood of successful clinical trials by focusing on those therapies that have the most supporting data.

The first successful clinical trial that restores function to people with subacute or chronic spinal cord injury will increase enthusiasm and funding for more clinical trials.  If any of the six therapies listed above, or dozens of therapies that are awaiting clinical trials, were to succeed, I believe that companies will begin investing in spinal cord injury therapies.   The first therapy is always the most difficult to get funded and moving.  Many of the therapies would also be the first of their classes, i.e. the first regenerative therapy, the first cell transplant therapy, the first remyelinative therapy.

Two types of clinical trial failures are harmful to the spinal cord injury community, the investigators, and the sponsors.  The first and worst are false negative trials, i.e. a trial that falsely indicates that treatment is ineffective, are particularly deleterious. Such trials may be underpowered, i.e. a trial that does not have enough subjects to establish significance.  It may also happen if the wrong outcome measure is chosen.  The second are inconclusive trials.  Inconclusive trials may result from poor followup and high drop out rates.

Finally, it is important to note that clinical trials that show that a treatment is ineffective are not “failures”.  Showing that a therapy does not work is just as important as showing that a therapy works.  It stops the waste of further time and resources on that particular therapy.  Thus, for example, many people believe that umbilical cord blood cells are beneficial for spinal cord injury.  In fact, several overseas clinics are offering and charging for umbilical cord blood treatment of spinal cord injury as if they have already been proven to be effective.  A rigorously conducted clinical trial that shows it is ineffective will stop wasteful practices.

Summary and Conclusions

Many people frequently ask how long it will take for a cure of spinal cord injury to be available.  In the last two decades, about a dozen therapies have gone to clinical trial.  To illustrate the course of therapy development, I described 8 therapies that have been through or are going into clinical trials for spinal cord injury.

  1. High-dose methylprednisolone (MP) is the first spinal cord injury treatment to be tested in a placebo-controlled randomized clinical trial.
  2. Weight-supported locomotor training is the first rehabilitation therapy that has been shown to restore function after spinal cord injury.
  3. Fampridine (4AP) is the first therapy that improves conduction in demyelinated axons but has not yet been shown to be effective in spinal cord injury.
  4. Nogo antibody is the first therapy shown to regenerate the spinal cord of rats and is currently in phase 2 clinical trials.
  5. Cethrin is a membrane-permeable recombinant bacterial toxin C3 that blocks rho, improves recovery in animals and humans, and is in phase 2 clinical trial.
  6. Olfactory ensheathing glia (OEG)  have been transplanted to >1200 patients with chronic spinal cord injury but has not yet been tested in a controlled trial.
  7. Human embryonic stem (HES) cells have been announced for clinical trial by Geron since 2005 and is still awaiting approval by the U.S. FDA.
  8. Combination therapies.  The China Spinal Cord Injury Network is now testing umbilical cord blood mononuclear cells and lithium alone and in combination.

The history of spinal cord injury therapy development teaches us three important lessons.  First, therapy development is slow and tortuous, with each therapy taking 10 or more years. Second, rigorous proof of concept is required before companies, government, or foundations will invest millions into developing a therapy. Finally, clinical trials are inherently risky.  A single mistake in trial design may set a program back by many years.

Development of curative therapies for spinal cord injury will require large clinical trial networks to test combination therapies systematically.  To regrow large numbers of axons across the injury site, therapies need to bridge the injury site with cells that support growing axons, provide a long-term source of growth factors, and block growth inhibitors in the spinal cord, as well as replace cells. We know that each of these is possible.

The China Spinal Cord Injury Network is beginning clinical trials of the first combination therapy: umbilical cord blood mononuclear cells and lithium.  Several groups had reported that cord blood cells are beneficial in animal models of spinal cord injury. Lithium enhances regeneration in the spinal cord, stimulates proliferation of cord blood cells and neural stem cells, and increases the production of neurotrophic factors.  If this combination is effective, we will add growth inhibitor blockers.

So, how long will it take?  Fortunately, we are not starting from scratch.  Six of the eight therapies described above are already in or will soon be in clinical trials.  Other therapies are achieving proof-of-concept and should reach clinical trial soon.  Even if each of these trials has only a 50% chance of success, the odds ratio that at least one will succeed in the next few years is high.  The time needed to develop curative combination therapies depends on funding and availability of clinical trial network.

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FAQ #1: Will There Be A Cure For Spinal Cord Injury?

December 22, 2008

FAQ #1:  Will There Be A Cure for Spinal Cord Injury?
By Wise Young PhD MD, Rutgers University,
W. M. Keck Center for Collaborative Neuroscience
604 Allison Rd, Piscataway, NJ 08854-8082
First posted 22 December 2008

Will there be a cure for spinal cord injury?  This is the most frequently asked and often first question asked by people and families after spinal cord injury.  I answer yes to this question for the following reasons.

  • People and animals often recover substantially after “incomplete” spinal cord injury.  Animals can walk with only 5-10% of their axons [1].  A large majority (>90%) of people with even slight initial preservation of function at the lowest level of their spinal cord, i.e. anal sensation and sphincter control, recover ability to walk [2].  Examination of their spinal cords may indicate that they have only 10% of their spinal cord tracts remaining at the injury site.  The spinal cord is capable of tremendous plasticity.  Thus, depending on what the person has, regenerating and remyelinating even a small proportion of the axons in the spinal cord may be sufficient to restore substantial function to people with spinal cord injury.
  • The spinal cord can regenerate.  For over a century, scientists have reported that spinal cords of some animals and even mammals can regenerate under certain circumstances.  For example, lamprey [3], tadpoles [4], goldfish [5], and many other animals are able to regenerate their spinal cords.  For a long time, people thought that this was because these animals are evolutionarily primitive and that mammalian axons cannot regrow.  However, Aguayo, et al. [6-8] found that spinal axons can regrow in peripheral nerve but certain factors in the spinal cord inhibit growth [9].
  • Many therapies regenerate the spinal cords.  Over 100 individual therapies have been reported to stimulate axonal regeneration in the spinal cord. Please note that the following is by no means an exhaustive list of curative therapies of spinal cord injury.  I only cite representative recent publications supporting each therapy.  The point is that *many* therapies have been reported to regenerate the spinal cord.
    • Nogo and Nogo receptor blockers.  Nogo is a myelin-based protein that activates axonal receptors that act through rho and rho kinase to stop axonal growth.  Many ways of blocking Nogo or its receptors have been shown to increase regeneration:
      • Binding of Nogo with antibodies [10, 11] or soluble Nogo receptor protein [12]  stimulate regeneration.  The former is currently in clinical trial by Novartis.  The latter is being developed for clinical trial by Biogen.
      • Blocking Nogo receptor with a 66-amino acid fragment of Nogo [13].  The fragment apparently binds the nogo receptor and prevents further activation.
      • Blocking Lingo co-receptor also stimulates regeneration [14, 15].  .  Lingo is a co-receptor of the Nogo receptor.  This is being developed by Biogen.
      • Blocking rho kinase and rho (“rhok and rho”).  Rho kinase blockers stimulate regeneration in the spinal cord.  A modified version of a bacterial toxin that blocks rho, named Cethrin, has been reported to stimulate regeneration and functional recover in animals and in clinical trials  [23-27]
    • Chondroitinase.  The extracellular space contains glycoproteins that inhibit axonal growth.  These include chondroitin-6-sulfate proteoglycans (CSPG), which impedes axonal guidance and growth [28, 29].  Chondroitinase ABC is a bacterial enzyme that break down CSPG [30], allows regeneration [31, 32], and improves locomotor recovery [33].
    • Cyclic nucleotides.  Cyclic nucleotides convert neuronal growth cone responses from repulsion to attraction [34].  An increase in intracellular cAMP in axons will stimulate axons to grow and ignore growth inhibitors such as Nogo and CSPG [35, 36].   In zebrafish, where regeneration can occur but not of all neurons, cAMP application is helpful [37].  Several treatments are available to increase cAMP levels in neurons.  One is rolipram, a phosphodiesterase 4 (PDE4) inhibitor localized to the central nervous system.  Dibutyryl cAMP will enter the cells and directly increase cAMP.  The combination of Schwann cell transplant, rolipram, and dibutyryl-cAMP strongly stimulate regeneration [38, 39].
    • Combination Neurotrophins.  Several neurotrophins are known to stimulate regeneration in the spinal cord, even in the presence of growth inhibitors.  These include nerve growth factor (NGF), neurotrophin-3 (NT3), and glial-derived neurotrophic factor (GDNF).  Much evidence point to the importance of NT-3 [40-42] in combination with other factors [43-46].  BDNF may have undesirable effects [47].  A sustained source of these neurotrophins, however, is required for long-distance regeneration.   Fibroblast growth factor (FGF-2) [48] and FGF-1 [49] apparently improved regeneration.  This may be through stimulation of endogenous neural stem cells in the spinal cord [50].
    • Cellular Adhesion Molecules.  A number of cell adhesion molecules play a major role in axonal regeneration [51].  The most interesting one is L1, a member of the IgG superfamily of cell adhesion molecules, that bind to L1 expressed by other growing axons and stimulate the axons to grow in bundles, a process called fasciculation.  Increasing L1 expressing in the spinal cord stimulates regeneration [52].  Elimination of L1 reduces sensor fiber sprouting in mice [53] perhaps through manipulation of semaphorins [54].  Another regenerative CAM is N-CAM [55] but increasing CHL1 cellular adhesion may inhibit recovery [56].
    • Cell Transplants.  Many cell transplants have been reported to improve recovery after spinal cord injury
      • Olfactory Ensheathing Glia.  These cells are born in the nasal mucosa and migrate in the olfactory nerve to the olfactory bulb, facilitating growth and connection of olfactory axons.  The olfactory nerve is the only nerve in the body that continuously regenerates throughout adult life and its ability to do so is believe to be due to the presence of OEG cells.  These cells also express L1 and neurotrophins. Astrocytes do not respond to exposure to olfactory ensheathing glia with GFAP or CSPG secretion.  Transplantation of these cells improves recovery after spinal cord injury [57-69] and ventral root repair [70, 71], although one group suggests that Schwann cells may be better in a direct comparison [72, 73].
      • Umbilical cord blood mononuclear cells.  Several groups have reported the umbilical cord blood mononuclear cells, particularly CD34+ cells, stimulate regeneration and improve recovery in animals after spinal cord injury [74-79].  The mechanisms of action were not clear.   Human umbilical cord blood-derived CD34+ cells may attenuate spinal cord injury by stimulating vascular endothelial and other neurotrophic factors [80] and downregulated FAS [81]. Cord blood cells may even myelinated axons [82].  We recently found that cord blood mononuclear cells secrete neurotrophins and that lithium strongly boosts neurotrophin production by these cells.   One study suggest that myeloid cells are essential for peripheral nerve regeneration [83].  Cord blood cells are already being used for multiple neurological applications [84].
      • Mesenchymal stem cells.  These are pluripotent stem cells that can be isolated from bone marrow and other tissues.  Several groups have now reported that these cells are beneficial in spinal cord injury [85-87].   These cells may act through similar mechanisms as umbilical cord blood mononuclear cells production of neurotrophins and provision of a hospitable environment for axonal growth.  Mesenchymal cells can be isolated from human umbilical cord and have been reported to have beneficial effects in animal spinal cord injury models [88, 89] and stroke [90].  Carvalho, et al. [91], however, found that CD45+/CD34+ mesenchymal stem cells do not improve neurological recovery in Wistar rats after spinal cord contusion.
      • Astrocytes.  Several studies [92, 93] suggest that certain types of astrocytes facilitate regeneration in the spinal cord.  As opposed to astrocytes that react to injury and surround the injury site, these astrocytes provide a conducive pathway for axonal growth in the spinal cord [94]. Neural stem cells produce these astrocytes and this may account for beneficial effects of neural stem cell transplants into injured spinal cords.  Glial precursor cells likewise may be beneficial [95].
      • Neural stem cells.  These can be obtained from embryonic stem cells, aborted fetuses, or even autologous from the hippocampus or subventricular zones [96].  Many groups have suggested that these cells alone [97, 98], after differentiation [99] or genetic manipulation [100] or in combination with other cells such as olfactory ensheathing glia [101] or Schwann cells [41, 42] are beneficial for spinal cord injury.  One of the main questions that has not yet been answered is how will the transplanted cells interact with neural stem cells that may already be present in the spinal cord [102].
      • Oligodendroglial progenitor cells.  Many groups have transplanted oligodendroglial progenitor cells (O2A) to the spinal cord and have found significant improvement of function [103].  Whether this is due to the remyelination observed or regeneration of axons is not clear.  Keirstead, et al. [93-95] are planning to go to clinical trial with oligodendroglial progenitor cells derived from human embryonic stem cells with Geron.
    • Purine nucleotides.  Several purine nucleotides have been reported to stimulate regeneration of the spinal cord.  These include cGMP and adenosine [34] and the modified guanosine analog AIT-082 [104, 105].  The mechanism is not well understood but may be related to increased cAMP levels and other mechanisms described above.  Several groups have reported the beneficial effects of inosine on regeneration of the spinal cord [106].
    • Ephrins.  The ephrins are guidance molecules that play a role in telling axons whether they have grown into the right places in the central nervous system [107].  Injury upregulated certain ephrins and blockade of these ephrins stimulates regeneration in mammalian spinal cords [107-111].   In particular, EphA4 blocking peptide enhances corticospinal tract regeneration [112].  EphA4-deficient mice regenerate axons and show less astrocytic gliosis [113].
    • Biomaterials.  Many different biomaterials have been reported to support regeneration in spinal cord injury.  For example, self-assembling peptides form a scaffold that can be used to bridge injured rat spinal cords [114, 115] and inhibit glial scar formation and promote axonal elongation [116].  Many types of hydrogels [117-120], other gels [121], poly-lactic-coglycolic acid [122-124], poly-lactic acid [125-127], and other synthetic materials [128] have been tried.  Natural materials such chitosan [129], agarose [130, 131], and alginate [132] have been used.  Plasma, fibrin glue, laminin, and collagen are popular [133-138].  Many types of configurations have been used with and without embedded biological factors [139] or drugs [140].  Many invetigators seeded biomaterials with Schwann cells [141, 142], neural stem cells [143], bone marrow stromal cells [144].
    • Therapeutic vaccines.  Many investigators have vaccinated animals with various putative substances in the hopes of stimulating them to produce antibodies against axonal growth inhibitors, such as Nogo.  For example, Huang, et al. [145] immunized rats with their own spinal cords and found that this stimulated extensive regeneration of large numbers of corticospinal axons.  Vaccination with p472 (a peptide derived from Nogo A [146] and Nogo-66 [10] promotes axonal regeneration and motor recovery after spinal cord injury. DNA vaccination efficiently induces antibodies to Nogo-A without exacerbating experimental autoimmune encephalomyelitis [147, 148] and can stimulate retinal ganglion cell regeneration [149].  DNA vaccines of other known inhibitors, such a MAG and OMGP have been tried as well [150, 151].
    • Electrical Stimulation.  Many early studies suggest that electrical currents stimulate regeneration [152-160].  Electrical stimulation is often used to enhance regeneration and reinnervation by peripheral nerves [161, 162].  A recent clinical trial of oscillating currents [163] suggests improved function in humans [164].
    • Other Therapies.  Many other therapies have been reported to be beneficial for regeneration:
      • Artemin.  This factor promotes re-entry of multiple classes of sensory fiber into the spinal cord and re-establishment of synaptic function and behavior improvements [165].  Incidentally, olfactory ensheathing glia express artemin [166].
      • Erythropoietin.  This hematopoietic hormone is a potent inducer of immune system [167], is neuroprotective [168], reduces oxidative stress [169], enhances regeneration in the spinal cord [170], and has been reported to improve recovery after spinal cord injury[171].
      • Bone Morphogenetic Protein (BMP) inhibitors.  BMP’s are potent inhibitors of axons regeneration [107].  BMP-2/4 are elevated in oligodendroglial cells.  Intrathecal administration of Noggin, a soluble BMP antagonist, results in enhanced locomotor recovery and significant regrowth of the corticospinal tract after spinal cord contusion [172].  BMP, however, is used to treat glial-restricted precursor cells to create astrocytes that support axonal regeneration [93].
      • Methylprednisolone (MP).  While MP has long been regarded to be an inhibitor of axonal growth, if it is applied for too long, it apparently reduces CSPG expression by astrocytes and enhances axonal growth in injured spinal cord as a result [173].
      • Polysialic acid.  Induced expression of these molecules increased the number of axons growing into the lesion cavity by 20-fold [174].
      • Granulocyte colony-stimulating factor (G-CSF).  Pan, et al. [175] reported that G-CSF inhibits programmed cell death and stimulates neuronal progenitor differentiation, that the combination of G-CSF and neural stem cell transplants enhances regeneration in transected rat spinal cords.
  • Neuronal replacement therapies.  Injuries to the spinal cord, particularly to the cervical and lumbosacral enlargement, damage neurons.  When motoneurons are damaged, the muscles they innervate may undergo atrophy.  Most muscles are innervated by many motoneurons and therefore will survive even after severe injuries.  However, cauda equina and peripheral nerve injuries will eliminate all or most of the motor innervations of a muscle and cause the muscle to undergo atrophy.  Likewise, injuries to the conus may cause severe damage to sacral motor centers controlling bowel, bladder, and sexual functions.  In such situations, motoneuronal replacement may be required.  If you had asked me a decade ago whether neuronal replacement therapies were possible, I would have said that it was unlikely.  However, the discovery of stem cells has changed this situation considerably.
    • Neural stem cell transplants.  Scientists who receive their education more than a decade ago were taught that we were born with the neurons that we die with.  In other words, no new neurons are supposed to be created after birth.  This situation changed when many groups discovered that the brain and spinal cord contain neural stem cells that continue to make many thousands of neurons every day.  Therefore, replacement of neurons by endogenous neural stem cells is not only possible but also likely.
    • Embryonic stem cells.  Kerr, et al. [176, 177] has shown that neural stem cells derived from embryonic stem cells are able to replace motoneurons in the spinal cord of animals that have had viral induced motoneuronal death.  When the cell transplants were combined with some of regenerative therapies described above, the neurons not only received input from descending tracts but grew their axons out of ventral roots to re-innervate muscle.   However, some researchers have found that embryonic stem cells do not replace neurons [178].
    • Stimulation of endogenous stem cells.  Lithium drug has long been used to treat manic depression.  Recent studies suggest that this drug may be acting through stimulation of endogenous neural stem cells [179], stimulates spinal cord regeneration [180, 181], supports retinal ganglion survival and axon regeneration [182], and may even reduce neuropathic pain [183].  A recent study [184, 185] suggests that this drug remarkably stops progression of amyotrophic lateral sclerosis.  Although the mechanisms are not well understood, one possible mechanism is through stimulation of endogenous neural stem cells in the spinal cord.
  • Many therapies stimulate remyelination of spinal axons.  Trauma damages not only axons and neurons but also oligodendroglia responsible for myelinating axons in the spinal cord.  Remyelination decreases with age [186].  In addition, oligodendroglia undergo apoptosis in the spinal cord when exposed to pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha).  Furthermore, regenerating axons are naked and need to be myelinated in order to function optimally.  Fortunately, many therapies remyelinate the spinal cord.
    • Oligodendroglial progenitors.  These are cells that make oligodendroglia and can be derived from embryonic stem cells or neural stem cells.  Many investigators have shown that these cells will remyelinate the spinal cord [187]. Geron is planning a clinical trial to assess the effects of pre-differentiated oligodendroglia progenitor cells derived from human embryonic stem cells [188].
    • Schwann cells.  These are of course the cells that myelinate peripheral axons.  Schwann cells sometimes invade into the spinal cord injury site and, when they do invade, will remyelinate most of the spinal axons.   Transplanted Schwann cells were the first transplanted cells to remyelinate axons of the central nervous system [189].  The Schwann cells can also be genetically modified to express molecules that facilitate myelination [55].   However, they have been reported to be non-contributory to regeneration [190].
    • Olfactory ensheathing glia.  In addition to facilitating regeneration [191], OEG cells not only stimulate myelination [192, 193] but themselves can myelinate axons [194, 195] like Schwann cells. These cells can be obtained from adult olfactory bulb and nasal mucosa [196] and fetal olfactory bulb.  The first would be autografts and the latter would be heterografts.
    • Mesenchymal stem cells.  These have been reported to stimulate remyelination in rats [197].  Likewise, bone marrow cells have been reported to stimulate remyelination of the spinal cord [85, 198-201].
    • Myelination antibodies.  Several IgM antibodies have been reported to stimulate remyelination in the spinal cord.  The mechanism is not well understood but these antibodies appear to working as signalling antibodies that stimulate remyelination to occur in the spinal cord [202-204].
  • Combination therapies are necessary for significant regeneration.  It has become clear that combination therapies are necessary for the cure of spinal cord injury.  No single therapy can address all the obstacles to regeneration and neuronal replacement in the spinal cord.  In order for rivers of axons to cross the spinal cord injury site, therapies will need to address at least three obstacles:
    • Bridge the injury site.  Shortly after injury, the injury site is often filled with inflammatory cells and is bereft of cellular adhesion molecules that may help guide and facilitate axonal growth.  In chronic spinal cord injury, the injury site is often walled off by astrocytes that may consider the injury site to be “outside” of the central nervous system.  The extracellular matrix may be filled with CSPG.  To get around this, it is often useful to transplant cells that can “bridge” the gap and allow axons to growth through the injury site.  Many cells can serve this purpose, including astrocytes, olfactory ensheathing glia, umbilical cord blood mononuclear cells, mesenchymal stem cells, and others.
    • Sustained source of growth factors.  Axonal regeneration is very slow, probably no faster than a millimeter per day.  Therefore, a source of sustained growth factor is necessary for long-distance and long-term growth.  These include cells that secrete neurotrophins and a means of stimulating them to do so for long periods.  We recently discovered that lithium stimulates umbilical cord blood mononuclear cells to secrete three of the most important neurotrophins and therefore have proposed a clinical trial to test the effects of combination umbilical cord blood mononuclear cell transplants and lithium.
    • Block growth inhibitors.  At least two known proteins are known to inhibit axonal growth in the spinal cord.  The first is Nogo and several therapies are known to block Nogo, including antibodies against Nogo, Nogo receptor blockers, and blockers of rho [26] or rho kinase that mediate the effects of Nogo.  The second is CSPG and chondroitinase is known to break down CSPG and allow regeneration.  An alternative is a molecule called decorin, which inhibits CSPG production and may allow axonal growth to occur in chronic spinal cord injury [205, 206].

One legitimate question that might be asked is why we don’t have a cure for spinal cord injury already, given all these treatments that regenerate and remyelinate the spinal cords of animals?  Scientists design their experiments to show the possibilities of therapies, choosing models and outcome measures that maximally reflect the benefits of the therapies.  In the clinical situation, different obstacles to regeneration and recovery may be present, such as learned non-use, atrophy, spasticity, and pain.  Of course, animals aren’t being told by their doctors that they won’t walk.  They keep trying.  Animal models of spinal cord differ from the human situation in one important respect.  The distances that axons have to regrow in a rat are much shorter than those in the human.  Finally, few of these therapies have been tried in clinical trials.  When they have been applied, it is often in situations that mitigated against showing the therapeutic efficacy, e.g. using cells that are not immune-matched for transplantation, not addressing all the obstacles to regeneration, not including rehabilitation in the clinical trial protocol, and not providing credible documentation of patient recovery.

In summary, there are many reasons to be optimistic that there will be not just one but many “cures” for spinal cord injury.  I defined a cure as a treatment that would make it so that an observer who did not know you wouldn’t be able to tell that you have spinal cord injury.  I believe that there will be a cure because much data indicate that the spinal cord can regenerate and many therapies restore function in animal studies.  One or more of these will be shown to be successful in people in the coming years, hopefully sooner rather than later.  At the present, we don’t have the clinical trial infrastructure to test all the therapies that have shown promise in animal models.  It is likely that some combination of the therapies will provide cures.  However, we must be aware that the translation of findings from animal studies to human clinical trials will not necessarily be smooth and there will be bumps along the way.

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Ten Frequently Asked Questions Concerning Cure of Spinal Cord Injury

December 21, 2008

Ten Frequently Asked Questions Concerning Cure of Spinal Cord Injury
By Wise Young, Ph.D., M.D., Rutgers University
W. M. Keck Center for Collaborative Neuroscience
Revised 20 December 2008 from 21 July 2004

Many questions recur repeatedly on CareCure every few days.  On 21 July 2004, I posted a summary of answers to the ten most frequently asked questions on CareCure (Link) .  That thread received over 450 responses and over 80,000 page-views. Here, I update some of responses to the questions and will expand each of the answers with sequential articles to follow.

1. Will there be a cure for spinal cord injury?

The answer to this question depends on one’s definition of a cure. If a “cure” requires complete eradication of spinal cord injury, I think that it would unlikely in my lifetime.  If a cure means complete restoration of all functions to pre-injury levels for all people with spinal cord injury, I think that this would also be unlikely.  Not only are we unlikely to be able to reverse aging but we may not be able to reverse all changes in the body due to spinal cord injury.  On the other hand, I believe that there will be therapies that will restore sufficient function to a person with severe spinal cord injury so that a casual third-party observer would not be able to tell that the person had spinal cord injury.  This is a reasonably practical definition of a cure for me and I think that will happen.

2. When will a cure be available?

First generation therapies are already restoring function to people with spinal cord injury, including weight-supported treadmill ambulation training, decompression and untethering of a spinal cord, and Fampridine.  Preliminary data suggest that olfactory ensheathing glia transplants may restore some sensory function but only modest motor function, perhaps because the cells are not HLA-matched and are immune-rejected after a few weeks.  Second generation therapies are in or soon-to-be started clinical trial, including umbilical cord blood mononuclear cells, Schwann cells, and embryonic stem cells.  Several therapies such as Nogo receptor blockers and Nogo antibodies, glial-derived neurotrophic factor, cethrin, and other treatments are already in or are close to clinical trial.  Finally, third generation therapies include combination cell transplants, growth factors, and growth inhibitor blockers.  These should be in clinical trial in the next few years. The timing of clinical trials depends on availability of funding for clinical trials. With sufficient funding, I think that one or more of these clinical trials will yield the first therapies that restore function in chronic spinal cord injury.

3. Will a cure work for chronic spinal cord injury?

I believe there will be effective restorative therapies for chronic spinal cord injury for the following reasons. First, much animal and human data indicate that regeneration of relatively few axons can restore function such as walking, bladder function, and sexual function. This is because the spinal cord contains much of the circuitry necessary to execute and control these functions. Only 10% of the axons in the spinal cord are necessary and sufficient to restore locomotor and other functions.  Second, axons continue to try to regrow for many years after injury. Treatments that provide a path for growth, that negate factors that inhibit growth, and that provide long-term stimulation of axonal growth can restore function.  Third, many people recover function years after injury.  These observations give me hope that there will be therapies that facilitate functional recovery in chronic spinal cord injury.

4. What can I do now to be ready for the cure?

People with spinal cord injury should work hard to take care of their body and to prevent muscle and bone atrophy that may prevent recovery of function. This includes disciplined exercise to maintain their muscle and bone.  They must take care of their skin, bladder, and bowels. People should avoid procedures that cause irreversible loss of peripheral nerve and other functions. On the other hand, it is important to weigh the benefits of procedures such as tendon transfers, which can provide greater functionality and independence for people with weak hands. Likewise, certain procedures such as Mitrofanoff and bladder augmentation to reduce bladder spasticity may provide greater independence but may not be easily reversible.  Finally, many studies have shown that people with the highest levels of education after injury are more likely to have better quality of life and health. It is important that people do not neglect their brain, the most important part of their body.

5. What can I do about spasticity, spasms, and neuropathic pain?

Many people suffer from spasticity (increased tone), spasms (spontaneous movements), and neuropathic pain (in areas below the injury site where there sensory loss). Neurons that have lost their inputs tend to become hyperexcitable. Spasticity is the most common manifestation of spinal motoneurons that have been disconnected from the brain. Several treatments reduce spasticity. The most commonly used anti-spasticity drug is baclofen (a drug that stimulates GABA-B receptors in the spinal cord). Oral doses (80-120 mg/day) of baclofen reduce spasticity.  However, for some people such doses are not enough or have too many side effects.  For these people, it may be useful to combine lower doses of baclofen with clonidine or tizanidine, which activate alpha-adrenergic receptors. While anti-spasticity drugs reduce spasticity, they also weaken muscles and may cause flaccidity and muscle atrophy. So, people should titrate the dose of anti-spasticity drugs so that they retain some muscle tone.  Unless they are taken in doses high enough to cause flaccidity, anti-spasticity drugs usually do not prevent spasms.  However, gabapentin (Neurontin) and other anti-epileptic drugs may reduce both spasms and neuropathic pain.  Neuropathic pain results from increased excitability of sensory neurons that have been disconnected and may manifest in “burning”, “freezing”, or “pressure” pain.  People accommodate to gabapentin and high doses of as much as 4000 mg/day may be necessary for pain relief.  In some people, low doses (20 mg/day) of the tricyclic anti-depressant drug amitriptyline (Elavil) may provide relief from neuropathic pain.  Intrathecal delivery of baclofen or morphine may be necessary.

6. How can I exercise and will it do any good?

Exercise is difficult for paralyzed people and specialized equipment may be necessary.  First, most people should stand for an hour or two every day.  This can be done with standing frames.  A device called a Glider 6000 allows both standing and leg movements.  Second, functional electrical stimulation (FES) can be used to activate muscles.  Arms and legs can be stimulated to pedal exercise devices.  Third, standing, walking, and swimming in a pool allows people to exercise in an environment where the water supports their weight. Fourth, weight-supported treadmill ambulation training improves walking recovery. Finally, people should think about setting aside a month or two every year where they would essentially engage in full-time training. During the rest of the year, they need to maintain the gains that they have achieved by spending an hour or so per day on exercising. Although there have been few formal studies of the subject, many people with spinal cord injury have reported significant increases in the girth of their legs when they use FES regularly.

7. What is osteoporosis, its mechanisms and consequences, and ways to reverse it?

Osteoporosis is bone loss.  It occurs after spinal cord injury, particularly in the pelvis and leg bones below the injury site. The mechanism is not well understood but appears to be related to loss of gravitational and other mechanical stresses on the bone. In acute spinal cord injury, bone begins to decalcify within days after spinal cord injury, with significant increases in urine calcium (hypercalciuria) within 10 days. The pattern of bone loss is 2-4 times greater than those associated with prolonged bed rest without spinal cord injury. Increased dietary calcium intake may slow down but does not prevent the bone loss.  Parathyroid hormone level is usually low in the first year but may increase above normal after the first year. Substantial (25-43%) decreases in bone mineral densities occur in the leg bones within a year and may exceed 50% loss by 10 years.  People with spasticity have less bone loss than those who are flaccid. Osteoporosis is associated with greater fracture rates. The Model Spinal Cord Injury System, for example, reported a 14% incidence of fracture by 5 years after injury, 28% and 39% by 10 and 15 years, usually in the most demineralized bone. People with complete spinal cord injury and paraplegia have ten times greater fracture rates than incomplete injury or tetraplegia. Weight bearing and bicycling with functional electrical stimulation may prevent osteoporosis. Bisphosphonates (Pamidronate) and parathyroid hormone (Teriparatide) can reduce osteoporosis and fracture rates in people with chronic spinal cord injury.  Much research is underway to find effective therapies of osteoporosis.

8.  What is autonomic dysreflexia, its mechanisms and consequences, and treatments?

Autonomic dysreflexia (AD) refers to increased activity of the sympathetic nervous system, associated with profuse sweating, rash, elevated blood pressure, and vasodilation above the injury level.  AD usually causes a headache due to vasodilation of brain blood vessels. Heart rate falls and vision may be blurred. Nasal congestion may be present. Between 40-90% of people with spinal cord injury suffer from AD.  It is more severe in people with spinal cord injury above T6. AD can be triggered by many potential causes, including bladder distension, urinary tract infection, and manipulation of the bowel and bladder system, pain or irritation, menstruation, labor and delivery, sexual intercourse, temperature changes, constrictive clothing, sunburns, and insect bites. When AD occurs, doctors usually catheterize the bladder to ensure adequate urinary drainage, check for fecal impaction manually using lidocaine jelly as a lubricant, and eliminate all other potential causes of irritation to the body. Treatment includes use of the calcium channel blocker Nifedipine (Procardia 10 mg capsule) to reduce blood pressure or adrenergic alpha-receptor blocking agent phenoxybenzamine (10 mg twice a day), mecamylamine (Inversine 2.5 mg orally), and Diazoxide (Hyperstat 1-3 mg/kg).  Doctors in emergency room may not know how to handle AD crises in people with spinal cord injury and it may be useful for patients to carry a card that give treatment instructions.

9. What is syringomyelia, its mechanisms and consequences, and treatments?

Syringomyelia refers to the development a spinal cord cyst that results from enlargement of the central canal. The central canal is typically tiny and not visible on magnetic resonance images (MRI) of the spinal cord. As many as 15% of people develop a syringomyelic cyst in their spinal cords and 5% may show symptoms of pain and loss of function associated with cyst enlargement, as early as one month and as late as 45 years after injury. Pain is the most commonly reported symptom associated with syringomyelia. Other symptoms include increased weakness, loss of sensation, greater spasticity, and increased sweating. The symptoms may be aggravated by postural changes and Valsalva maneuver (that increase pressure in the chest).  It may also be associated with changes in bladder reflexes, autonomic dysreflexia, painless joint deformity or swelling, increased spasticity, dissociation of sensation and temperature, respiratory impairment. Syringomyelic cysts can be observed with MRI scans. It is usually associated with scarring of meninges or arachnoid membranes of the spinal cord, observable with CT-scan with myelography. Surgical intervention is recommended when there is progressive neurological loss. Traditionally, syringomyelia has been treated with shunting of the cyst by placement of a catheter between the cyst and the subarachnoid space or pleural cavity. But shunting alone is frequently associated with shunt blockade within a year. More recent studies suggest that meticulous removal of adhesions with duroplasty (repairing the dura by grafting membrane) to re-establish subarachnoid cerebrospinal fluid flow is more effective and may eliminate the cyst in 80% of cases.

10.  How does spinal cord injury affect sexual function and what can be done to improve such function?

Most people with spinal cord injury above the T10 will continue to have reflex erections associated with stimulation. Some people may have prolonged erections called priapism. A majority can have ejaculation although increased stimulation including vibration may be required. In many people, ejaculation may be retrograde, i.e. the ejaculate goes into the bladder rather comes out, because the external sphincter may be open. Retrograde ejaculation should not be harmful or cause urinary tract infections. A serious associated complication of sexual intercourse in both men and women is the occurrence of autonomic dysreflexia (AD) with orgasm, with associated headaches and other symptoms of AD. These can be treated with drugs to lower blood pressure (see answer to AD above). In addition, sexual intercourse may be associated with increased spasticity and spasms. People with injuries below T10 may have damage to the spinal cord centers responsible for erection and ejaculation. Many techniques are available to increase erection, including drugs such as Sildenafil (Viagra), vacuum pumps, cock rings, and penile prostheses. Several studies have reported that women with “complete” spinal cord injury can achieve orgasms, possibly through neural pathways outside of the spinal cord.

Spinal Cord Injury Levels and Classification

December 19, 2008

Spinal Cord Injury Levels and Classification
Wise Young, Ph.D., M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, 604 Allison Rd., Piscataway, NJ 08854-8082

Revised on 20 December 2008 from an article posted on 24 June 2003

People with spinal cord injury are often told that they have an injury at a given spinal cord level, that they are “complete” or “incomplete”, that they have a bony fracture at one or more spinal vertebral levels, and that they are classified as A, B, C, D, or E according to the American Spinal Injury Association (ASIA) Classification. What is the meaning of the different spinal cord injury levels, the definition of complete and incomplete injury, and the different classification of spinal cord injury?  In this article, I will try to explain the currently accepted definitions of spinal cord injury levels and classification.

Vertebral vs. Cord Segmental Levels

The spinal cord is situated within the spine. The spine consists of a series of vertebral segments. The spinal cord itself has “neurological” segmental levels that are defined by spinal roots that enter and exit the spinal column between vertebral segments. As shown figure 1, the spinal cord segmental levels do not necessarily correspond to the bony segments. The vertebral levels are indicated on the left side while the cord segmental levels are listed for the cervical (red), thoracic (blue), lumbar (green), and sacral (gray) cord.

The spine has 7 cervical (neck), 12 thoracic (chest), 5 lumbar (back), and 5 sacral (tail) vertebra.  The spinal cord is shorter than the spinal canal, usually ending just below the L1 vertebral body.   The C1 spinal roots exit the spinal column above the C1 vertebral body.  There is no C8 vertebral body and so the C8 roots exit between C7 and T1.  The T1 roots exit between T1 and T2 and the L5 roots exit between L1 and S1 vertebrae.

The first and second cervical vertebra hold and pivot the head. The C1 vertebrae, upon which the head is perched, is called Atlas after the Greek god who holds the earth. The back of the head is the occiput. The junction between the occiput and atlas is thus the atlanto-occiput junction.  The C2 vertebra, upon which Atlas pivots, is called Axis, The junction between C1 and C2 vertebra is the atlanto-axis junction. The cervical cord innervates the diaphragm (C3), the deltoids (C4), biceps (C4-5), wrist extensors (C6), triceps (C7), wrist extensors (C8), and hand muscles (C8-T1).

The twelve thoracic vertebrae have  associated ribs. The spinal roots form the intercostal (between the ribs) nerves that run on the bottom side of the ribs and connect to the intercostal muscles and associated dermatomes.  About 5% of people have a vestigial 13th rib.  The spinal cord ends just below L1.  The conus is the tip of the spinal cord.  Below the conus, the spinal roots of L2 to S5 form the cauda equina.  Injuries to the lower thoracic spinal cords generally damage the lumbar enlargement.  Injuries to the lumbosacral spine invariably reults in damage to the lumbosacral enlargement.

spinalcord01
Figure 1. Spinal cord and vertebral levels.

In summary, spinal vertebral and spinal cord segmental levels are not necessarily the same. In the upper spinal cord, the first two cervical cord segments roughly match the first two cervical vertebral levels. However, the C3 through C8 segments of the spinal cords are situated between C3 through C7 bony vertebral levels. Likewise, in the thoracic spinal cord, the first two thoracic cord segments roughly match first two thoracic vertebral levels. However, T3 through T12 cord segments are situated between T3 to T8. The lumbar cord segments are situated at the T9 through T11 levels while the sacral segments are situated from T12 to L1. The tip of the spinal cord or conus is situated at L2 vertebral level. Below L2, there is only spinal roots, called the cauda equina.

Motor and Sensory Examination

Each spinal cord segment innervates a patch of skin, called a dermatome.  That dermatome is tested for light touch (proprioceptive) and pinprick (pain) sensation at a particular defined point.  The muscles innervated by a spinal cord segment is called a myotome but this is seldom used because multiple segments innervate each muscle and there is substantial overlap of myotomes.  Figure 2 is taken from the ASIA classification manual, obtainable from the ASIA web site. Each dermatome has a specific point recommended for testing and shown in the figure.  The muscle groups specificed in the ASIA classifications are a gross oversimplication. Almost every muscle receives innervation from two or more segments.

The C2 dermatome covers the occiput and the top half of the neck while C3 covers the lower neck down to the clavicle.  The C4 dermatome is located below the clavicle.  The dermatomes for the arms are not straightforward.  The C5 to T2 dermatomes progress from proximal to distal on the lateral side of the arm (C5 lateral upper arm, C6 radial hand, and C7 middle finger) and then from distal to proximal on the medial side of the arm (C8 ulnar hand, T1 medial forearm, T2 medial upper arm).  The T3 dermatome is back on the chest, above the nipples.  The nipples are situated in the middle of T4.  The umbilicus in the middle of T10.  T12 is above the hip girdle while L1 covers the hip girdle and groin.  L2 and L3 cover the front  of the thighs while L4 and L5 cover the medial and lateral aspects of the lower leg.  S1 covers the heel and middle back of the leg.  S2 covers the back of the thighs.  S3 covers the medial sides of the buttocks and S4/5 covers the perineal region.

Figure 2. Sensory and motor segmentation of the spinal cord. These are the dermatomes and muscles recommended by the American Spinal Injury Association.

Ten muscle groups represent the motor functions of the spinal cord. The ASIA motor score does not include abdomenal muscles (i.e. T10-11) and has only one muscle per segment.   Thus, even though the segment innervates other muscles, the motor score uses elbow flexors (biceps) for C5, the wrist extensors for C6, the elbow extensors (triceps) for C7, the finger flexors for C8, and the little finger abductors for T1.  The hip flexors (psoas) represent L2, knee extensors (quadriceps) are L3, ankle dorsiflexors (anterior tibialis) are L4, the long toe extensors (hallucis longus) are L5, and the ankle plantar flexors (gastrocnemius) are S1.

The anal examination is an essential part of the ASIA examination.  If a person can perceive light touch or pinprick around the anus or can achieve voluntary anal contraction, regardless of any other finding, that person is by definition an incomplete injury.  Strictly speaking, deep rectal sensation does not count.  However, it may be a good sign.  Unless the anal examination is done, the ASIA classification cannot be made.

In summary, the spinal cord segments serve specific motor and sensory regions of the body. The sensory regions are called dermatomes.  The distribution of these dermatomes are relatively straightforward except on the limbs. In the arms, the cervical dermatomes C5 to T1 are arrayed from proximal (C5) to distal (C6-8) on the radial side of the arm and from distal to proximal on the medial side of the arm medial (T1). In the legs, the L1 to L5 dermatomes cover the front of the leg from proximal to distal while the sacral dermatomes cover the back of the leg from distal to proximal.

Spinal Cord Injury Levels

Differences between neurological and rehabilitation definitions of spinal cord injury levels. Doctors often use different definitions for spinal cord injury levels.  Given the same neurological examination and findings, neurologists, physiatrists, and surgeons may not assign the same level.  Neurologists define spinal cord injury level as the first spinal segmental level that shows abnormal neurological loss whereas physiatrists define the neurological level as the lowest contiguous “intact” segment.  Thus, for example, if a person has loss of bicep function, a neurologist would say that the motor level of the injury is C5 while a physiatrit would say the motor level is C4.  Many surgeons refer to the bony level of injury as the level of injury.   Since the spinal cord is foreshortened, e.g. the C6 cord is located at C5 vertebral level, the vertebral level usually is lower than the neurological level but the two may coincide as the spinal cord recovers a level.

  • EXAMPLE.  The most common cervical spinal injuries involve C4 or C5.  Let’s consider a person who has had a burst fracture of the C5 vertebral body.  The C5 vertebral injury may have injured the underlying C4 spinal cord, the C5 spinal roots that exit the spinal canal between the C4 and C5 vertebra, and possibly the C6 spinal roots that leave spinal canal between the C5 and C6 vertebra.  Such an injury should cause a loss of sensations in C5 dermatome and weak biceps (C5) due to injury to the C5 cord and roots. Due to edema (swelling) of the spinal cord, the deltoids (C4) may be initially weak but may recover over time.  Function below C5 should be compromised as well, due to the spinal cord injury.  Based on the above, a neurosurgeon or neurologist would assign a C5 level.  However, a physiatrist would assign a C4 neurological level because C4 is the lowest “intact” segment.

Lower thoracic vertebral and cord levels. The spinal vertebral and cord segmental levels become increasingly discrepant further down the spinal column.  This is particularly true in the lower thoracic spine.  For example, a T12 vertebral injury may result in a L2 neurological level.  An L1 injury may damage only the conus and sacral segments.  An L2 vertebral injury may not damage spinal cord at all and just cause a cauda equina injury.

  • EXAMPLE. The most common thoracic spinal cord injury involves T11 and T12 vertebral.  Since the spinal segments of L1 to L4 are situated the spinal canal of the T11 and T12 vertebra, a patient with a T12 vertebral injury may lose motor and sensory function  in L2 through L4 dermatomes which include the front of the leg down to the mid-shin level.  Such a patient may lose hip flexors, knee extensors, and even ankle dorsiflexion. Sacral functions such as anal sensation and sphincter control may be lost.   Because of injury to the lumbar enlargement gray matter, many patients with T11 or T12 injuries will have flaccid paralysis due to motoneuronal damage.  A with a T12 verteral injury may recover some L2 function, including hip flexors.

Conus and Cauda Equina Injury. Injuries to the spinal column at L1 or lower will damage the tip of the spinal cord, called the conus, or the cauda equina, a “horse’s tail” of spinal roots that descend in the L1-S5 spinal canal to exit at the appropriate spinal vertebral levels.  The spinal roots for L2 through S5 are present in the cauda equina.  Strictly speaking, the spinal roots are peripheral to the central nervous system.  However, both motor and sensory recovery is usually very limited after cauda equina injuries because injury to the conus or cauda equina may damage motoneurons and sensoy fibers in the spinal roots cannot re-enter the spinal cord.

  • EXAMPLE.  Cauda equina injury is the most common consequence of lumbosacral vertebral injuries.  The motor fibers in the spinal roots come from motoneurons situated in the spinal cord.  Injury to motor axons close to the motoneurons may result in loss of some motoneurons.  Sensory fibers in the spinal root come from dorsal root sensory ganglion that are situated just outside the spinal canal.  These neurons send an axon out the peripheral nerve and an axon to the spinal cord.  The axons will not be able to regenerate across the central nervous system and peripheral nervous system (CNS:PNS) barrier.   Fibroblasts can form adhesive scars within the roots that may cause pain, contribute to further injury, and prevent regeneration.

Complete versus Incomplete Injury

Most clinicians describe spinal cord injuries as “complete” or “incomplete”. Traditionally, “complete” means having no voluntary motor or conscious sensory function below the injury site. However, this definition is often difficult to apply. The following three example illustrate the weaknesses and ambiguity of the traditional definition of complete and incomplete spinal cord injury.

  • Zone of partial preservation. Some people have some function for several segments below the injury site but below which no motor and sensory function was present. This is in fact rather common. Many people have zones of partial preservation. Is such a person “complete” or “incomplete”, and at what level?
  • Difference in levels on each side. A person may have partial preservation of function on one side but not the other or at a different level. For example, if a person has a C4 level on one side and a T1 level on the other side, is the person complete and at what level?
  • Recovery of function. A person may initially have no function below the injury level but recovers substantial motor or sensory function below the injury site. Was that person a “complete” spinal cord injury and became “complete”? This is not a trivial question because if one has a clinical trial that stipulates “complete” spinal cord injuries, a time must be stipulated for when the status was determined.

The ASIA committee recommended a change in the definition of “complete” spinal cord injury based on presence or absence of anal sensation and voluntary sphincter contraction.  Most clinicians would regard a person as complete if the person has any level below which no motor or sensory function is present. The ASIA Committee took this criterion to its logical limit, i.e. if the person has any spinal level below which there is no neurological function, that person is classified as a “complete” injury. This translates into a straightforward definition of “complete” spinal cord injury:  a person is a “complete” if they do not have motor and sensory function in the anal and perineal region representing the lowest sacral cord (S4-S5).

The decision to make the absence and presence of function at S4-5 the definition for “complete” injury not only resolved the problem of the zone of partial preservation but lateral preservation of function but it also resolved the issue of functional recovery.   As it turns out, very few patients who have loss of S4/5 function recovered such function spontaneously. As shown in figure 3 below, while this simplifies the criterion for assessing whether an injury is “complete”, the ASIA classification committee decided that both motor and sensory levels should be expressed on each side separately, as well as the zone of partial preservation.

Figure 3. Neurological level, completeness, and zone of partial preservation

The absence of motor and sensory function below the injury site does not necessarily mean that no axons are crossing the injury site.  Many clinicians equate a “complete” spinal cord injury with lack of axons crossing the injury site. Much animal and clinical data suggest that as many as 5-10% of animals or persons with initially no sensory or voluntary function below the injury site will recover some function.  If a person is incomplete, recent studies suggest that nearly 90% will be recover independent locomotion again with intensive practice and exercise.  The goal of regenerative and remyelinative treatment is to make a person more “incomplete”.

Classification of Spinal Cord Injury

Clinicians have long used a clinical scale to grade severity of neurological loss. First devised at Stokes Manville before World War II and popularized by Frankel in the 1970’s, the original scoring approach segregated patients into five categories, i.e. no function (A), sensory only (B), some sensory and motor preservation (C), useful motor function (D), and normal (E).  The ASIA Impairment Scale (AIS) follows the Frankel scale but differs from the older scale in several important respects.  First, AIS A is defined as no motor or sensory function in the sacral segments S4-S5.  Second, AIS B requires preserved sacral S4-S5 sensation.  Third, AIS C now has a quantitative criterion: half of the muscles below the injury level has a motor score of 3/5 or less.  Since a score of 3 indicates anti-gravity, this means that half of the muscles are not capable of lifting more than their own weight.

These changes significantly improved reliability and consistency of the classification.  The AIS A classification circumvented previous ambiguities concerning “complete” injuries and took the definition of complete spinal cord injury to its logical conclusion, i.e. an injury that causes loss of all voluntary motor and conscious pin and touch sensation below some spinal cord segmental level.  Likewise, it made ASIA B classification more consistent by requiring anal sensation.  On the other hand, the classificiation now depends on a single clinical finding, the presence of anal sensation or voluntary anal sphincter contraction.  The scale cannot be applied if that examination has not been not done or extenuating circumstances such as surgery, peripheral nerve injury, or other conditions compromised anal sensation or function.

The original Frankel scale asked clinicians to evaluate the usefulness of lower limb function. This not only introduced a subjective element to the scale but ignored arm and hand function in patients with cervical spinal cord injury. To get around this problem, the ASIA committee stipulated that a patient would be an AIS C if more than half of the muscles evaluated had a grade of less than 3/5.  If not, the person was assigned to AIS D.  AIS E is presumably “normal” in the sense that motor and sensory scores should be normal.  However, such a person may have spasticity or spasms, coordination or balance problems, or sporadic weakness.  The person also may have bladder problems.  The ASIA classification system does not document any of these problems.

ASIA Impairment Scale (AIS) A indicates no motor or sensory function in the S4-S5 sacral segments.  It is equivalent to a “complete” spinal cord injury.AIS B is a sensory incomplete, including the sacral segments S4-S5.AIS C is a motor incomplete but more than half of the key muscles have a muscle grade or less than 3.AIS D is a motor incomplete where more than half of the key muscles have grades of 3 or greater.

AIS E is when the motor and sensory scores are “normal”.  Note that such a person would be categorized as an ASIA E.

ASIA recognized five incomplete syndromes.  The central cord syndrome is associated with greater loss of upper limb function than the lower limbs. The Brown-Sequard syndrome reflects greater injury to one side of the spinal cord.  The anterior cord syndrome affects primarily anterior spinal tracts, including vestibulospinal tract. Conus medullaris and cauda equina syndromes signify damage to conus or spinal roots.

Figure 4. ASIA Impairment Scale and Clinical Syndromes.

Conclusions

Much confusion surrounds the terminology associated with spinal cord injury levels, severity, and classification. The American Spinal Injury Association tried to sort some of these issues and standardize the language that is used to describe spinal cord injury. The ASIA Spinal Cord Injury Classification approach has now been adopted by almost every major organization associated with spinal cord injury. This has resulted in more consistent terminology being used to describe the findings in spinal cord injury around the world.

© Wise Young

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Devic’s Syndrome: Close to a Cure?

December 18, 2008

Devic’s Syndrome:  Close to a Cure?
by Wise Young, PhD MD
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, Piscataway, New Jersey 08854-8082
18 December 2008

Devic’s syndrome was first described in 1870 by Sir Thomas Allbutt (what a name to have had as a kid!) who pointed out an association between myelitis and optic nerve disorder.  In 1894, Eugene Devic and his student Fernand Gault described 16 patients who had lost vision in one or both eyes and developed spastic weakness, sensory loss, and incontinence.  For many years, Devic’s syndrome was just one of several variants of multiple sclerosis that presented with relapsing optic neuritis followed by spastic weakness and sensory loss.  The other name of the condition was neuromyelitis optica (NMO).

A major breakthrough came in 2004 when a specific marker NMO-IgG was found for the disorder [1].  IgG stands for immunoglobulin (a kind of antibody).   NMO-IgG is a autoantibody (an antibody against a protein in one’s own body) and turned out to target aquaporin-4 (a protein that is responsible for water channels in cells).  The identification of NMO-IgG as a marker for Devic’s syndrome allows the disease to be distinguished from other autoimmune diseases, i.e. myasthenia gravis [2], systemic lupus erythematosus [3], necrotizing myelopathy [4], paraneoplastic myelopathy [5].  More important, it has allowed the creation of animal models and the study of the mechanisms of the disease [6].

Aquaporin-4 is a water channel that plays an important role in the blood brain barrier and astrocytic function.  Devic’s disease is now classified as an “autoimmune channelopathy” disease [7].  With that recognition, the treatment of the disease has become more rational.  While intravenous high-dose glucocorticoids is recommended for acute relapses of the condition, clinicians are using rescue plasmapheresis for severe, progressive, and steroid-resistant cases.  In between attacks, immunosuppression with azathioprine or mycophenolate mofetil is recommended for mild conditions and rituximab for those with more recent severe attacks [8].

Much progress has been made in immunoablative therapies.  In Hong Kong, Mok, et al. [9] recently described the use of immunoablative cyclophosphamide to treat refractory lupus-related neuromyeltis optica.  This approach uses a chemotherapeutic agent (cyclophosphamide) to kill a significant part of the immune system, in the hopes that it will eliminate those cells in the immune system that are producing the particular antibodies.  When the immune system reconstitutes itself from the remaining cells, the auto-antibodies are sometimes eliminated.

An alternative approach may be immunoablation followed by umbilical cord blood transplants.  This approach will replace the immune system with normal hematopoeitic cells from cord blood.  This would allow more intensive immunoablation and increase the probability of ablating the auto-immune cells.  If autologous cord blood is available, this would be the least risky.  Haller, et al. [10] used autologous umbilical cord blood infusions to treat type 1 diabetes, another autoimmune diseases.  However, heterologous cord blood can also be used.

Use of cord blood or bone marrow transplants have now been successfully to treat many patient with autoimmune diseases.  According to Burt, et al. [11], 26 reports from 1997-2007 indicated that 854 patients treated with immune-ablation and transplantation had less than 1% treatment related mortality (2/220 patients for nonmyeloablative, 3/197 for dose-reduced myeloablative, and 13% for intensive myeloablative regimens).  While no randomized trials have been performed, all the trials indicate potent disease-remitting effects.

In summary, for sufferers of Devic’s syndrome, effective treatments are becoming available.  The identification of a specific marker NMO-IgG has not only eased the diagnosis of the condition but also provide a rational approach to therapy of the condition.  Not only are there therapies that can reduce the impact of relapsing attacks and prevent attacks but a cure may be possible by myeloablation and hematopoietic cell replacement.  For a long time, myeloablation had an unacceptable mortality of >10%.  However, with reduced-dose myeloablative regimens, the mortality is now approaching 1%, less than the mortality of the diseases themselves.  Of course, eliminating the autoimmune disease does not necessarily restore function that has been lost, but regenerative therapies are being worked on.

References

  1. Wingerchuk DM and Weinshenker BG (2005).  Neuromyelitis Optica.  Curr Treat Options Neurol.  7: 173-182.  Link
  2. Furukawa Y, Yoshikawa H, Yachie A and Yamada M (2006).  Neuromyelitis optica associated with myasthenia gravis: characteristic phenotype in Japanese population.  Eur J Neurol.  13: 655-8. Link
  3. Jacobi C, Stingele K, Kretz R, Hartmann M, Storch-Hagenlocher B, Breitbart A and Wildemann B (2006).  Neuromyelitis optica (Devic’s syndrome) as first manifestation of systemic lupus erythematosus.  Lupus.  15: 107-9.  Link
  4. Okai AF, Muppidi S, Bagla R and Leist TP (2006).  Progressive necrotizing myelopathy: part of the spectrum of neuromyelitis optica?  Neurol Res 28: 354-9.  Link
  5. Jacob A, Matiello M, Wingerchuk DM, Lucchinetti CF, Pittock SJ and Weinshenker BG (2007).  Neuromyelitis optica: changing concepts.  J Neuroimmunol 187: 126-38.  Link
  6. Mueller S, Dubal DB and Josephson SA (2008).  A case of paraneoplastic myelopathy associated with the neuromyelitis optica antibody.  Nat Clin Pract Neurol 4: 284-8.  Link
  7. Lalive PH, Perrin L and Chofflon M (2007).  [Neuromyelitis optica/Devic’s syndrome: new perspectives].  Rev Med Suisse 3: 950-5.  Link
  8. Wingerchuk DM and Weinshenker BG (2008).  Neuromyelitis optica.  Curr Treat Options Neurol 10: 55-66. Link
  9. Mok CC, To CH, Mak A and Poon WL (2008).  Immunoablative cyclophosphamide for refractory lupus-related neuromyelitis optica.  J Rheumatol 35: 172-4.  Link
  10. Haller MJ, Viener HL, Wasserfall C, Brusko T, Atkinson MA and Schatz DA (2008).  Autologous umbilical cord blood infusion for type 1 diabetes.  Exp Hematol 36: 710-5.  Link
  11. Burt RK, Loh Y, Pearce W, Beohar N, Barr WG, Craig R, Wen Y, Rapp JA and Kessler J (2008). Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases. Jama 299: 925-36. Link

Recommended Reading

Devic’s disease – Wikipedia, the free encyclopedia

Holiday Hopes for Spinal Cord Injury

December 17, 2008

Holiday Hopes for Spinal Cord Injury
by Wise Young PhD MD
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, Piscataway, NJ 08854-8082
17 December 2008

I write to wish everybody Happy Holidays and to explain why I have so much hope for 2009:

  1. A Renaissance of Stem Cell Research. For nearly 8 years, the Bush Administration has suppressed not only embryonic stem cell (ESC) research but all stem cell research.  Last year, for example, NIH funded only $600 million of stem cell research, i.e. $300 million for animal stem cells, $260 million for human adult stem cells, and $40 million for human ESC.  The total NIH budget was about $30 billion i 2007.  So, even though stem cells are widely acknowledged by scientists to be the most important biomedical advance of the decade, the NIH spent only 2% of its budget on all of stem cell research, only 1% on human stem cells, and less than 0.2% on human ESC research.  The Obama Administration will lift these restrictions and strongly encourage stem cell research.  I hope for a renaissance of stem cell research in 2009.
  2. The Christopher and Dana Reeve Paralysis Act.  In 2003, Christopher Reeve proposed legislation to encourage research to reverse paralysis.  Now called the Christopher and Dana Reeve Paralysis Act (CDRPA), this bill will fund NIH and other governmental agencies to accelerate development of therapies to reverse paralysis.  In 2005 and each year after Christopher Reeve’s untimely death, members of the spinal cord injury community lobbied in Washington DC for the bill.  In 2006, the House and Senate resurrected the bill.  In October 2007, the House of Representatives passed the bill by a large majority and sent the bill to the Senate.  However, Senator Tom Coburn of Oklahoma singlehandedly stopped the bill and prevented it from coming to a vote.  With a larger Democratic majority in the Senate, CRDPA should pass in 2009.  I sincerely hope that it will bring much needed funding for paralysis research and clinical trials for spinal cord injury.
  3. Promising SCI Therapies.  Many therapies improve neurological recovery in animal SCI models.
    • Nogo receptor protein. Biogen recently made a soluble Nogo receptor protein that will bind to all molecules that activate the Nogo receptor.  Animal eperiments suggest that this protein stimulates regeneration after spinal cordinjury. They are thinking of starting clinical trials in China.  I hope so.
    • Chondroitinase. The extracellular matrix of injured spinal cords accumulate a substance called chondroitin-6-sulfate proteoglycan (CSPG) and blocks regeneration.  Chondroitinase is a bacterial enzyme that breaks down CSPG and allows regeneration of axons.  Many laboratories since 2001 have confirmed that chondrotinase facilitates regeneration in the spinal cord of rats.  Acorda Therapeutics licensed this treatment and is developing it.  I hope that it goes into clinical trial.
    • Decorin. This is an extracellular protein that Stephen Davies found to enhance regeneration in the spinal cord.  He is now doing experiments in chronic spinal cord injury.  Decorin is a natural substance that normally “decorates” collagen but is not usually found in the injured spinal cord.  Thus is an interesting and important therapeutic approach to regenerating the spinal cord.  I hope that the experiments in chronic spinal cord injury show positive results.
    • Mesenchymal Stem Cells. These are stem cells present in many tissues, including bone marrow, fat, skin, blood, and gut.  Many laboratories have reported that these mesenchymal stem cells are beneficial in animal models of spinal cord injury, including stimulation of remyelination.  Because these cells would be isolated from the same individuals, they should be immune-compatible.  Many groups are beginning to study such cells for stroke in clinical trial.
    • Induced Pluripotent Stem Cells. Until recently, there were only two source of immune-compatible stem cells for transplantation: umbilical cord blood and bone marrow mesenchymal stem cells.  Now, for the first time, by expressing four genes, scientists can convert skin and other cells to pluripotent stem cells.  Many groups are working feverishly on safe methods to convert these cells without using viruses and with less risk of producing tumors.  I am looking forward to reports of beneficial effects of IPS cell transplants in spinal cord injury.
  4. Clinical trials.  Several therapies are already in or should soon be in clinical trial.
    • Nogo antibody.* Nogo is a myelin protein that blocks regeneration. Novartis is now testing Nogo antibodies in patients with chronic spinal cord injury in Europe.  This antibody has shown promise in animal studies. I hope that this trial shows positive results.
    • Cethrin.*  Bioaxone completed a phase 2 clinical trial showing that Cethrin improves neurologic recovery in patients with spinal cord injury.  Cethrin is a modified bacterial toxin that blocks rho, the intracellular messenger for the Nogo receptor.  Alceres recently bought Bioaxone and will start more trials with Cethrin.  I hope that they are successful in raising funds for the trial.
    • Lithium.  In 2004, Yick, et al. at Hong Kong University reported that lithium and chondroitinase stimulate regeneration and improve neurological recovery after spinal cord injury.  Recent studies indicate that lithium stimulates stem cells to proliferate and produce neurotrophins, including nerve growth factor (NGF), neurotrophin-3 (NT-3), and glia-derived neurotrophic factor (GDNF).  A recent clinical trials suggests that lithium may be beneficial for amyotrophic lateral sclerosis.  ChinaSCINet completed a phase 1 trial showing that lithium can be safely given to people with chronic spinal cord injury and is now doing a phase 2 study comparing a 6-week course of lithium with placebo.  I hope that this trial shows positive results.
    • Umbilical cord blood mononuclear cells (UCBMC). Several independent laboratories have reported beneficial effects of UCBMC on animal SCI models.  Several clinics have been using the cells.  The China Spinal Cord Injury Network is applying for permission to carry out the first clinical trial of this treatment in chronic spinal cord injury.
    • Embryonic stem cells (ESC). Hans Keirstead at UC Irvine has reported that human ESC-derived oligodendroglial precursor cells improve regeneration and locomotor recovery in rats.  Regeneron has applied for permission to test these cells in patients with subacute spinal cord injury.  The trial is likely to be approved in 2009 and will be the first clinical trial of human ESC.
    • Schwann cell transplants. Much animal data suggest beneficial effects of Schwann cell transplants in spinal cord injury, particularly in combination with drugs that increase cAMP levels in the spinal cord.  After being discussed for many years, the first clinical trials of Schwann cell transplants for spinal cord injury may start in the United States.  Several groups in China have transplanted fetal and adult Schwann cells to people with subacute and chronic spinal cord injury.  The Miami Project is planning clinical trials to assess autografts of Schwann cells.  I hope that these trials start in 2009.
  5. Clinical Trial Networks.  Clinical trial networks are being established for spinal cord injury around the world.
    • The China Spinal Cord Injury Network (ChinaSCINet).  This is a network of 24 major spinal cord injury centers in mainland China, Hong Kong, and Taiwan.  This is the network that I have spent four years building in China.  We completed an observation trial of over 500 subjects, a phase 1 study to assess safety and feasibility of giving a 6-week course of lithium to people with chronic SCI, and started a phase 2 trial to compare lithium versus placebo treatment of chronic SCI.  We have applied for a phase 2 to assess increasing doses of umbilical cord blood mononuclear cell (UCBM) transplants and a phase 3 trial to assess UCBM cells with and without lithium.
    • A U.S. Spinal Cord Injury Network. We are planning and raising money for this network to do parallel clinical trials of cord blood mononuclear cell transplants and lithium transplants in chronic spinal cord injury.  Several centers have signed up for this study in New Jersey, Philadelophia, New York, and Austin (TX).  During 2009, we will be training and fundraising.  We hope to start trials in 2010.
    • North American Spinal Cord Injury Network. Funded in part by Reeve Foundation, this network has already started an observational trial.  It is planning trials of acute spinal cord injury therapies in conjunction with other networks.
    • Rehabilitation Networks. In France, a network of 148 rehabilitation units that treat SCI have begun to work together.  In the United States, the Spinal Cord Injury Locomotor Trial (SCILT) evaluated walking outcomes.

In summary, there is much reason for hope for spinal cord injury research.  The year 2009 should be a renaissance of stem cell research. Hopefully, Congress will pass the Christopher and Dana Reeve Paralysis Act, which many of us have lobbied for, to provide much needed funding for paralysis research and clinical trials.  Many promising therapies have been shown to improve recovery in animals and are ready for clinical trials.  Several clinical trial networks have been or are being formed to test these therapies.  I believe that much of this hard work will come to fruition in 2009.  Merry Christmas and Happy New Year!

Wise.

Please post responses:  Holiday Hopes for Spinal Cord Injury on CareCure.

Treatment of Neuropathic Pain Disorder: A Review of Recent Studies

December 15, 2008

Neuropathic Pain:  A Review of Recent Publications
by Wise Young, PhD MD
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, 604 Allison Rd, Piscataway, NJ 08852-8082
15 December 2008

Neuropathic pain or pain that originates from the central nervous system, as opposed to pain that arise from noxious sensory input, afflicts millions of people after injuries to the nervous system.  Here is a review of recent studies of neuropathic pain and its treatment in human in 2008.

Neuropathic Pain in Germany. Berger, et al. [1] studied 275,685 adults with painful neuropathic disorder (PND) in Germany.  These patients are more likely (47% versus 20% of age- and sex-matched controls) to have co-morbidities, such as circulatory disorders, depression, and anxiety.  They are also more likely to have received pain medications (57% vs. 13% of controls).  They expressed the concern that these patients are not being optimally treated.  It is quite impressive to me that these authors were able to find a database of over 275,000 patients with PND.  Given that Germany has a population of 82 million, this suggests an incidence of >3354 case/million.

Pregabalin Treatment of PND.  In a separate study, Berger, et al. [2] looked for Pregabalin use in patient with PND that were 18 or older between 2004 and 2006.  They found 1400 patients in UK that started pregabalin therapy.  Most had received at 3 or more drugs before starting pregabalin.  After starting the drug, they averaged 4 prescriptions, totaling 93 therapy days.  The patients took fewer other pain drugs once they started pregabalin, including tricyclic antidepressants (16% versus 37% before), opioids (55% versus 64% before), and anti-epileptic drugs other than pregabalin (16% vs. 36% before).  Pregabalin seems to be associated with reduced concomitant use of other pain drugs.

Painful Diabetic Neuropathy.  O’Connor, et al. [3] compared the costs for four drug therapies (desipramine 100 mg/day, gabapentin 2400 mg/day, pregabalin 300 mg/day, and duloxetine 60 mg/day) for pain diabetic neuropathy.  They used a controversial method called quality adjusted life year (QALY) to measure the cost-effectiveness of the treatment.  Desipramine and duloxetine were both more effective and less expensive than gabapentin and pregabalin.  As I understand the study results, based on clinical trial data of efficacy and the cot of the drug, desipramine had the best effect with the least cost.  Desipramine is a tricyclic antidepressant drug.  Jones, et al. [4] found the chronic administration of desipramine significantly attenuated mechanical allodynia in rats with selective spinal nerve ligation.  Desipramine treated rats showed significantly greater activation of multiple brain sites than sham-operated and saline control rats.

Memantine profoundly reduced pain.  Hackworth, et al. [5] gave memantine to two patients iwth severe phantom limb pain.  Memantine is the first of a novel calss of anti-Alzheimer drugs that blocks NMDA glutamate receptors.  It is a old drug, having been patented in 1968 by Eli Lilly.  Both patients were refractory to high dose opioids and adjunctive pain medications and were receiving large doses of oral methadone, intravenous hydromorphone, tricyclic anti-depressants, anti-inflammatory and anti-epileptic drugs.  Both patients had profound relief from their pain without any apparent side effects from the drug. Yamamoto, et al. [6] and others have shown that NMDA receptors contribute to neuropathic pain and ketamine (a long used NMDA receptor blocker) has been used to treat cancer pain.

Effect of tricyclic antidepressants on neutrophils.  Tricyclic anti-depressants (TCA) are amongst the most commonly used medications for depression and neuropathic pain.  Ploppa, et al. [7] studied the effects of amitriptyline, nortriptyline, and fluoxetine on neutrophils (the white blood cells that are responsible for killing bacteria in blood).  At concentrations of 0.10 mM , none of the the compounds had any effect on neutrophil phagocytosis.  However, at 1 mM concentration, all three compounds were highly toxic to neutrophils.  Amitriptyline didn’t kill the cells but stopped their function while nortriptyline and fluoxetine caused “marked disruption of neutrophils”.  This particular side effect of TCA is a hard limiting factor on the dose of these drugs.

Effect of amitriptyline on stomach emptying.  In healthy volunteers, Bouras, et al. [8] showed that 25 mg of amitriptyline slowed down gastric emptying at 2 and 4 hours without affect gastric volumes or satiation volume.  It reduced nausea scores at 30 minutes after a high calorie liquid load.  These findings suggest a basis for the long-term use of TCA drugs to treat chronic somatic and gastrointestinal pain disorders, including refractory dyspepsia.  Given that people with spinal cord injury have slower gastric emptying anyway, this suggests that perhaps the best time to take amitriptyline may be several hours after a meal.

A case for opioid therapy of neuropathic pain.  Allen [9] made a plea for rationale multiple drug therapy of neuropathic pain, pointing out that opioids will never replace tricyclic antidepressants and anti-epileptic drugs as the first line therapy for neuropathic pain but that opioids are now full established as effective second- and third-line therapies.  In 2006, Dobecki, et al. [9] pointed out that neuropathic pain is a very common condition, affecting nearly 1.5% of the U.S. population.  The US FDA has approved five medications for neuropathic pain, including gabapentin, pregabalin, duloxetine, 5% lidocaine patch, and carbamazepine.  Other agents with proven efficacy in multiple randomized placebo-controlled trials include opioids, tricyclic antidepressants, venlafaxine, and tramadol.  All the these agents have been recommended as first-line therapies for neuropathic pain.  So, the field has moved in the last few years, from a budding recognition that some drugs may work for neuropathic pain to formal acknowledgment that they are first-line therapies.

In summary, neuropathic pain is a very common and unsolved problem.  In Germany, one study alone identified over a quarter million people who have neuropathic and suggested that this population is not being adequately cared for.  A study of Pregabalin treatment suggest that it is often given after patients have tried other treatments but it significantly reduced the concomitant use of other pain medications.  A comparison of desipramine 100 mg/day, gabapentin 2400 mg/day, pregabalin 300 mg/day, and duloxetine suggested that the tricyclic antidepressant desipramine had the best effective and was the least costly.  One study reported that memantine, an NMDA receptor blocker, remarkably reduced severe phantom limb pain in two patients who had become refractory to all other drugs.  Several studies provided some insight into why tricyclic antidepressant drugs are toxic and how amitriptyline may slow gastric emptying.  Finally, the field of central pain management is beginning to understand and accept the use of opioid therapies for neuropathic pain.

References

  1. Berger A, Toelle T, Sadosky A, Dukes E, Edelsberg J and Oster G (2008).  Clinical and Economic Characteristics of Patients with Painful Neuropathic Disorders in Germany.  Pain Pract.   Policy Analysis Inc. (PAI), Brookline, Massachusetts, U.S.A. blacksquare, square, filled Abstract: Using a large database with information from general practitioners (GP) throughout Germany, we identified all adults (age >/=18 years) with encounters for painful neuropathic disorders (PNDs) between August 1, 2005 and July 31, 2006 (PND patients). We also constituted an age- and sex-matched comparison group, consisting of randomly selected patients without any GP encounters for PNDs during the same period. Selected characteristics were then compared between PND patients and those in the comparison group over the 1-year study period. The study sample consisted of 275,685 PND patients and a similar number in the matched comparison group; mean age was 53.7 years, and 57% were women. PND patients were more likely than matched comparators to have encounters for various comorbidities, including circulatory system disorders (47% vs. 20%, respectively), depression (9% vs. 2%), and anxiety (4% vs. 1%) (all P < 0.01). They also were more likely to have received pain-related medications (57% vs. 13% for comparison group; P < 0.01)-most commonly, nonsteroidal anti-inflammatory drugs, benzodiazepines, and opioids, and less often, tricyclic antidepressants and anti-epileptics. PND patients averaged 7.3 more GP visits during the year (mean [95% CI] = 9.9 [9.9, 9.9] vs. 2.6 [2.6, 2.7] for comparison group); they also had significantly more specialist referrals and physician-excused absences from work (all P < 0.01). Patients with PNDs under the care of GPs in Germany have comparatively more comorbidities and higher levels of use of healthcare services. The pain-related medications that these patients receive raise concerns that PNDs may not be optimally treated in these settings. blacksquare, square, filled.
  2. Berger A, Sadosky A, Dukes E, Edelsberg J and Oster G (2008).  Use of Pregabalin in Patients with Painful Neuropathic Disorders under the Care of General Practitioners in the U.K.  Pain Pract.   Policy Analysis Inc. (PAI), Brookline, Massachusetts, U.S.A. Purpose: To examine the use of pregabalin in patients with painful neuropathic disorders under the care of general practitioners (GPs) in the U.K. Materials and Methods: Using a large U.K. database of GP encounters, we identified all persons aged >/= 18 years with at least one GP encounter with a diagnosis of a painful neuropathic disorder (eg, postherpetic neuralgia, diabetic peripheral neuropathy) between January 1, 2004 and July 31, 2006. Among these patients, we then identified those who initiated therapy with pregabalin; the date of initial receipt of pregabalin was designated the “index date.” We then examined use of pregabalin over the 6-month period following this date (“follow-up”), as well as changes in the use of other pain-related medications (eg, opioids, tricyclic antidepressants [TCAs], other antiepileptics [AEDs]) between the 6-month period preceding the index date (“pretreatment”) and follow-up. Patients with less than 6 months of pretreatment and follow-up data were excluded, as were those without any encounters during pretreatment for a painful neuropathic disorder. Results: A total of 1,400 patients (1.4% of all identified patients with painful neuropathic disorders) initiated therapy with pregabalin and met all other entry criteria; mean age was 62 years, and 58% were women. During pretreatment, most (54%) patients received three or more different types of pain-related medications. During follow-up, patients averaged four prescriptions for pregabalin, totaling 93 therapy days. Compared with pretreatment, fewer patients received other pain-related medications during follow-up, including TCAs (37% during pretreatment vs. 27% during follow-up), opioids (64% vs. 55%), and AEDs other than pregabalin (36% vs. 16%) (all P < 0.01). Conclusions: In the U.K., many patients prescribed pregabalin by their GPs may have been refractory to other pain-related medications. Use of these medications declined following initiation of pregabalin therapy.
  3. O’Connor AB, Noyes K and Holloway RG (2008).  A cost-utility comparison of four first-line medications in painful diabetic neuropathy.  Pharmacoeconomics.  26: 1045-64.  Department of Medicine, University of Rochester School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA. BACKGROUND: Painful diabetic neuropathy is common and adversely affects patients’ quality of life and function. Several treatment options exist, but their relative efficacy and value are unknown. OBJECTIVE: To determine the relative efficacy, costs and cost effectiveness of the first-line treatment options for painful diabetic neuropathy. METHODS: Published and unpublished clinical trial and cross-sectional data were incorporated into a decision analytic model to estimate the net health and cost consequences of treatment for painful diabetic peripheral neuropathy over 3-month (base case), 1-month and 6-month timeframes. Efficacy was measured in QALYs, and costs were measured in $US, year 2006 values, using a US third-party payer perspective.The patients included in the model were outpatients with moderate to severe pain associated with diabetic peripheral neuropathy and no contraindications to treatment with tricyclic antidepressants. Four medications were compared: desipramine 100 mg/day, gabapentin 2400 mg/day, pregabalin 300 mg/day and duloxetine 60 mg/day. RESULTS: Desipramine and duloxetine were both more effective and less expensive than gabapentin and pregabalin in the base-case analysis and through a wide range of sensitivity analyses. Duloxetine offered borderline value compared with desipramine in the base case ($US47 700 per QALY), but not when incorporating baseline-observation-carried-forward analyses of the clinical trial data ($US867 000 per QALY). The results were also sensitive to the probability of obtaining pain relief with duloxetine. CONCLUSIONS: Desipramine (100 mg/day) and duloxetine (60 mg/day) appear to be more cost effective than gabapentin or pregabalin for treating painful diabetic neuropathy. The estimated value of duloxetine relative to desipramine depends on the assumptions made in the statistical analyses of clinical trial data.
  4. Jones KL, Finn DP, Governo RJ, Prior MJ, Morris PG, Kendall DA, Marsden CA and Chapman V (2008).  Identification of discrete sites of action of chronic treatment with desipramine in a model of neuropathic pain.  Neuropharmacology.   Institute of Neuroscience, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, UK. Tricyclic antidepressants (TCAs) are an important analgesic treatment for neuropathic pain, though the neural substrates mediating these effects are poorly understood. We have used an integrative approach combining behavioural pharmacology with functional magnetic resonance imaging (fMRI) to investigate the effects of chronic treatment with the TCA desipramine, on touch-evoked pain (mechanical allodynia) and brain regional activity in the selective spinal nerve ligation (SNL) model of neuropathic pain. SNL and sham-operated rats received once daily i.p. administration of 10 mg/kg DMI, or saline, for 14 days. Withdrawal responses to the application of a normally non-noxious (10 g) stimulus were recorded in SNL and sham-operated rats over this period. On the final day of the study, SNL and sham-operated rats received a final challenge dose of DMI (10 mg/kg i.p.) during fMRI scanning. Chronic administration of desipramine (DMI) significantly attenuated mechancial allodynia in SNL rats. DMI challenge in chronic DMI-treated neuropathic rats produced significantly greater activation of the deep mesencephalic nucleus, primary somatosensory cortex, insular cortex, medial globus pallidus, inferior colliculus, perirhinal cortex and cerebellum compared to sham-operated rats and saline controls. By contrast, the spatial pattern of brain regional activation by chronic DMI treatment in sham controls encompassed a number of other areas including those associated with learning and memory processes. These novel findings identify key brain regions implicated in the analgesic and mood altering effects associated with chronic treatment with DMI.
  5. Hackworth RJ, Tokarz KA, Fowler IM, Wallace SC and Stedje-Larsen ET (2008).  Profound pain reduction after induction of memantine treatment in two patients with severe phantom limb pain.  Anesth Analg.  107: 1377-9.  Naval Medical Center San Diego, Department of Anesthesiology, 34800 Bob Wilson Drive, San Diego, CA 92134, USA. We present the cases of two patients who suffered severe lower extremity injuries and subsequently developed phantom limb pain (PLP) that was refractory to high dose opioids and adjunctive pain medications. Both patients were receiving large doses of oral methadone, IV hydromorphone via a patient-controlled analgesia delivery system, and adjunctive medications including tricyclic antidepressants, nonsteroidal anti-inflammatory medications, and anti-epileptics. Despite these treatments, the patients had severe PLP. Upon induction of the oral N-methyl-D-aspartate receptor antagonist memantine, both patients had a profound reduction in their PLP without any apparent side effects from the medication.
  6. Yamamoto T (2008).  [Mechanisms of the development of neuropathic pain and its treatment].  Nihon Hansenbyo Gakkai Zasshi.  77: 215-8.  Department of Anesthesiology, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto-shi, Kumamoto 860-8556, Japan. yamamoto@fc.kh.kumamoto-u.ac.jp. Neuropathic pain has been known to be refractory to traditional analgesics, such as opioids and non-steroidal anti-inflammatoy drugs. Some mechanisms of the development of neuropathic pain have been proposed; 1) sprouting of A beta fibers to the superficial layer of the dorsal horn, 2) ectopic discharge in the dorsal root ganglion and/or in neuroma at the nerve stump, 3) spinal sensitization. Ectopic discharge has been reported to be inhibited by Na+ channel blocker, such as lidocaine, and anticonvulsant. Lidocaine and anticonvulsant are used in the management of neuropathic pain. Activation of NMDA receptor is usually involved in the development of spinal sensitization and NMDA receptor antagonist, such as ketamine, is used in the management of neuropathic pain. Recently, alpha2delta subunit blocker, new class of anticonvulsant, is introduced to the management of neuropathic pain. alpha2delta subunit is the subunit of Ca2+ channel and modulate the influx of Ca2+. This Ca2+ influx induces release of neurotransmitter in the neuron. alpha 2 delta subunit blockers, such as gabapentin and pregabalin, may reduce the release of neurotransmitter and elicit analgesic effect in the treatment of neuropathic pain.
  7. Ploppa A, Ayers DM, Johannes T, Unertl KE and Durieux ME (2008).  The inhibition of human neutrophil phagocytosis and oxidative burst by tricyclic antidepressants.  Anesth Analg.  107: 1229-35.  Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls University Tuebingen, Hoppe-Seyler-Str. 3, 72 076 Tuebingen, Germany. annette.ploppa@uni-tuebingen.de. BACKGROUND: Tricyclic antidepressants are being investigated as long-acting analgesics for topical application in wounds or IV for postoperative pain relief. However, it remains unclear if tricyclic antidepressants affect the host defense and if reported toxic effects on neutrophils are of relevance in this setting. We therefore investigated the effects of amitriptyline, nortriptyline, and fluoxetine on human neutrophil phagocytosis, oxidative burst, and neutrophil toxicity in a human whole blood model. METHODS: Heparinized blood samples from healthy volunteers were incubated with amitriptyline, nortriptyline, or fluoxetine (10(-6) to 10(-3) M) for 0, 1, or 3 h. Staphylococcus aureus in a bacteria:neutrophil ratio of 5:1 and dihydroethidium (for the determination of oxidative burst) were added. Phagocytosis was stopped after 5, 10, 20, and 40 min. After lysis of red blood cells, samples were analyzed by flow cytometry. RESULTS: In concentrations up to 10(-4) M, none of the compounds affected neutrophil phagocytosis and oxidative burst. At 10(-3) M, all three compounds were highly toxic for neutrophils. Amitriptyline preserved morphological integrity, but completely suppressed neutrophil function. Nortriptyline and fluoxetine caused a marked disruption of neutrophils. The effects of the investigated antidepressants were not time-dependent. CONCLUSIONS: Phagocytosis and intracellular host defense are largely unaffected by antidepressants in concentrations of 10(-4) M and below. Our results confirm that antidepressants are highly toxic to neutrophils in millimolar concentrations. The neurotoxic effects and clinical side effects, but not effects on neutrophil functions, therefore, are likely to be the limiting factors in using antidepressants as analgesics.
  8. Bouras EP, Talley NJ, Camilleri M, Burton DD, Heckman MG, Crook JE and Richelson E (2008).  Effects of amitriptyline on gastric sensorimotor function and postprandial symptoms in healthy individuals: a randomized, double-blind, placebo-controlled trial.  Am J Gastroenterol.  103: 2043-50.  Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida 32211, USA. BACKGROUND: Low-dose tricyclic antidepressants have been used to treat chronic somatic and gastrointestinal pain disorders, including refractory functional dyspepsia. However, there are only limited data on the effects of these drugs on upper gastrointestinal function. AIM: To compare the effects of two doses of amitriptyline (AMT) and placebo on gastric accommodation, emptying, satiation, and postprandial symptoms in healthy volunteers. METHODS: Using a parallel-group, double-blind, placebo-controlled design, 41 healthy volunteers were randomized to AMT 25 mg, AMT 50 mg, or placebo for 2 wk. During the final 3 days of therapy, the following end points were assessed: fasting and postprandial gastric volumes, 2- and 4-h gastric emptying, time and volume to maximum satiation using a nutrient drink test, and postprandial symptoms 30 min later using 10-cm visual analog scales. AMT and metabolite levels were measured. RESULTS: AMT slowed gastric emptying at 2 h (median 75% for placebo, 57% for AMT 25 mg, 67% for AMT 50 mg; P= 0.037) and 4 h (median 98% for placebo, 96% for AMT 25 mg, 92% for AMT 50 mg; P= 0.003). AMT did not affect gastric volumes or satiation volume, but it did reduce nausea scores at 30 min in a dose-dependent manner (median 2.1 for placebo, 0.9 for AMT 25 mg, and 0.0 for AMT 50 mg; P= 0.009). CONCLUSION: In healthy volunteers, AMT slows gastric emptying of solids, but it does not significantly affect gastric volumes or satiation. AMT reduces nausea after challenge with a high calorie liquid load.
  9. Allen SC (2008).  Neuropathic pain – the case for opioid therapy.  Oncology.  74 Suppl 1: 76-82.  Royal Berkshire Hospital, Reading, UK. stephenallen@lineone.net. For many patients, neuropathic pain (NeP) is arguably more difficult to control than nociceptive or ‘normal’ pain. We also now recognise the great burden that NeP has on the lives of patients – it is not only a matter of treating pain in isolation, but managing all of the issues that affect the patient’s quality of life. Until relatively recently we have had little understanding of the pathophysiology causing NeP and have relied on the secondary effects of non-analgesic drugs as the mainstays of treatment. Greater understanding of the pathophysiology of NeP has led to more appropriate therapy and an increased use of multiple drug therapy – ‘rational polypharmacy’. Traditional opinions concerning the treatment of NeP have been challenged and it is because of this that the use of opioids in NeP has been re-evaluated. Opioids will never replace tricyclic antidepressants and anti-epileptic drugs as first-line therapy for NeP. However, they are now fully established as effective and useful second- or third-line drugs. Many patients in the past have been potentially undertreated as a result of our inertia to use opioids. The case for opioid therapy in NeP has been firmly established.
  10. Dobecki DA, Schocket SM and Wallace MS (2006).  Update on pharmacotherapy guidelines for the treatment of neuropathic pain.  Curr Pain Headache Rep.  10: 185-90.  Center for Pain and Palliative Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Neuropathic pain is a common problem in our society affecting nearly 1.5% of the US population. There currently are five medications approved by the US Food and Drug Administration (FDA) for the treatment of neuropathic pain, which include gabapentin, pregabalin, duloxetine, 5% lidocaine patch, and carbamazepine. Other agents with proven efficacy in multiple randomized, placebo-controlled trials include opioids, tricyclic antidepressants, venlafaxine, and tramadol. All of these agents, both FDA-approved and off-label, have been recommended as first-line treatments for neuropathic pain. This article discusses these agents in detail as they relate to the treatment of neuropathic pain.
Blogged with the Flock Browser

Flock: Blogging Browser

December 15, 2008

Flock: Blogging Browser
by Wise Young, PhD MD
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, Piscataway, NJ 08854-8082
14 December 2008

For over a decade, I have been administering web-based forums, starting first with Spinewire in 1997-98, then Cando.com from 1999 to 2001, and Carecure.org from July 2001 to now.  I spend much time posting onto web sites with a Mac.  So, I have become a connoisseur/user of web browsers and have tried almost every one that has come out, at least for the Mac.  My current favorite browser is one that is called Flock (http://flock.com/).  It has many special features and some frustrations.  I thought that I would review my experience here.

What is Flock?

Flock calls itself “The Social Web Browser”.  Based on Mozilla’s Firefox 3, the Flock browser is free and available in multiple languages (American English, Chinese, German, Russian, Spanish, and a few other languages.  I am using version 2.02 for Mac and there are versions for Windows and Linux.

The browser comes equipped with built-in software to interact with each of the major networking, blogging, news, image, and video sites.  It has all the capabilities of Firefox 3 and can use its extensions.  For example, I installed Stumble on Flock with no difficulty.  In fact, it loads Firefox’s preferences and bookmarks.

Most of Flock’s new functions are available on a little bar of icons located on the left hand side of the favorites menu.  In addition, Flock has a “media bar” that downloads and displays image feed from each web site.  Clicking each icon changes a left-sided menu bar which gives access to specific web sites.

Special Features

Flock has ten special features, that you can access from icons from the minibar, i.e.
•   World.  This opens up a page which contains multiple columns that you can configure.  One column, for example, is called Favorite Feeds, which contains news feeds from various web sites that you can add or delete.  Another column is Friend Activity which lists all the updates from Facebook, MySpace, etc. and other sites that you may be a member of.  Then there is a column called Favorite Media, which lists media that you select, including facebook pictures.
•  People.  This sets your left-hand column to list status and other updates from Facebook, MySpace, Digg, Flickr, Pownce, Twitter, and YouTube.  In Facebook, for example, clicking on a person shown on the left side-bar will take you to their profile or show you their pictures in a scrolling media bar on the top.  You can upload photographs directly to Flickr or post a link to your facebook profile without having to navigate through facebook, poke a friend, and answer friend requests.
•  Media. This opens (or closes) the media bar which contains pictures from all the various sites that you may belong to and have images, including Digg, Facebook, Flickr, TrueVeo, and Youtube.  One nice feature is that it shows little pictures that automatically enlarges when you put your cursor over them.  If you click, it goes to the site to show the full-size image.  I have not encountered a more convenient and efficient way to view internet pictures, videos, news clips, movie trailers, etc.
•  Feeds.  This allows you to select any news or website to get feeds from.  To add a feed, just go to the site, press the feed icon by the URL address, and the browser automatically adds the web site to your feed sidebar.  For example, I went to the CareCure front page, pressed the feed icon, and it automatically gave me a CareCure Forum icon on the side-bar, showing 14 posts with images.  You can indicate which one you have viewed, want to save, blog, email, or digg it.  There are buttons to refresh, mark all as viewed, show an excerpt or in full, in one or two columsn.
•  Mail.  So far, I have used it only for G-mail and Yahoo mail.  Apparently, it will also work with AOL but Flock is not yet able to collect mail from Earthlink or other mail services.  It will collect and display your latest mail in a dropdown menu.  The primary mail service can set to always change to the one that was last accessed.
•  Favorites.  This is like the favorites bar of most browsers except that you can enter and move items on the menu directly by dragging and dropping.  It also comes preloaded with the sites that Flock is specially designed to interact with.
•  Actions and Services.    This shows all the major sites that Flock can interact with and that you have signed up on.  It will log into all these sites simultaneously and allow you to flip through them.   Each time you have activated an account, it goes to the top of the left window menu.
•  Web Clipboard.  This is a drag and drop clipboard, where you can store, text, links, and images for later use.  Once stored, the material can be viewed, emailed, put into a blog file, or deleted.
•  Blog. This opens up a serviceable blog window which will upload to whichever blog service you use.  It doesn’t have all the bells and whistles of WordPress but it is not bad.  It has an <edit>, a <source>, and a <preview> mode.  I use wordpress and can attest that it uploads the files quickly to the web site with no fuss.
•  Uploader.  This program provides drag and drop uploading of picture files onto facebook of other services.  The Flock uploader works better than the applets from Facebook or the Facebook App for iPhoto.  For example, the Facebook App for Uploading directly from iPhoto will not create the album for some reason.  In addition, the uploader has cropping and some other simple tools for manipulating the picture.

Some Frustrations

Big windows.  This is not a browser for computers with small screens.  The top menu/url bar, the favorites bar, any special bar (like Stumble, the tab bar, and the media bar take up 5 cm of window space.  If you have the left menu bar active, that adds another 2-3 cm to each window.

Site limitations.  There are of course many web sites and services besides the ones that Flock is currently able to access.  Unfortunately, only the Flock developers can put these features in.  This problem will abate as more sites adopt standardized interfaces but at the moment, Flock cannot access a number of my favorite sites.

Slowdowns.  A browser can only do so much.  Because Flock interacts with multiple sites at a time, all this activity can make the browser feel sluggish.  On the other hand, I am watching a movie, working on Facebook and Linkedin, posting on carecure, blogging of WordPress, and surfing the web on Flock at the same time.

Summary and Conclusions

The Flock browser is a Firefox 3 browser with special features designed for three types of activities.  First, it automates interactions with networking sites such as Facebook, MySpace, Digg, Flickr, Pownce, Twitter, and YouTube.  Second, it automates collection of text, images, and video from websites, displaying these for rapid viewing and actions.  Third, the browser is designed for blogging.  It will take image and text, place them in a blogging window, email them, and post them to major blogging sites, including Blogger, Blogsome, LiveJournal, Typepad, WordPress, and Xanga.  These functions operate together seamlessly and better than third party applications, at least on the Mac.

Please comment on CareCure.

Blogged with the Flock Browser