Archive for December, 2008

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.

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.


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.


  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!


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

Tricylic Antidepressant Therapy for Depression and Neuropathic Pain

December 16, 2008

Tricyclic Antidepressant Therapy for Depression and Neuropathic Pain
by Wise Young, PhD MD
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, 604 Allison Rd, Piscataway, NJ 08854-8082
16 December 2008, last revised 20 December 2008

Many people take tricyclic antidepressant drugs for neuropathic pain and for depression. They are called tricyclic antidepressant (TCA) because they are small molecules with three rings.  The original tricyclic antidepressant was imipramine.  Members of the drug family include amitriptyline (also called Elavil, Endep, Tryptanol, Tripiline, Amyzol) , desipramine (norpramin, pertograne), doxepin (Adapin, Sinequan), nortriptyline (Aventyl, Pamelor, Noritren), and many others.  In this article, I will review their use, mechanism, toxicity, and withdrawal.

Mechanisms of Action

The mechanisms of tricyclic antidepressants were not well understood until recently. They are believed to block the re-uptake of neurotransmitters norepinephrine and serotonin by neurons but not dopamine.  They may also bind to muscarinic and histamine H1 receptors.  While the pharmacological effects of the drugs can often be seen immediately, anti-depressive effects are typically not seen for several weeks.

When neurons release catecholaminergic neurotransmitters (e.g. serotonin, norepinephrine), the length of time that they act depends on the speed with which they are broken down (by monoamine oxidase) and are taken up the neurons (re-uptake).  A family of proteins called biogenic amine transporters take up catecholaminergic neurotransmitters.

Tricyclic antidepressants bind to biogenic amine transporters and interfere with re-uptake of neurotransmitters.  Thus, these drugs are like the serotonin uptake blockers except that they are less selective.   It is possible that they may have other mechanisms of action at lower doses.

Treatment for Depression

In 2004, Moncrieff, et al. [1] did a Cochrane Review of 9 clinical trials from 1990-2000, involving 751 participants and comparing TCA drugs.  Combining the studies showed consistent and significant effects of antidepressant drugs.  One the trials was strongly positive, skewing the other results.  If this trial were removed, this reduced the effect. Conservative analyses suggest small drug effects and a large placebo effect on depression.

In 2007, Bramness, et al. [2] assessed the relationship between antidepressant sales and suicide rates in Norway.  Sales of non-tricyclic antidepressants (non-TCA) and suicides were clearly negatively related, i.e. increased sales of the non-TCA was associated with decreases of suicide.  Mottram, et al. [3] examined elderly patients and found that TCA compared less favorably due to high withdrawal rate from side-effects.

In 2008, Nieuwenhuijsen, et al. [4] did a Cochrane Review of 2556 participants in randomized clinical trials examining interventions in depressed workers.  They found no evidence of an effect of medication alone, enhanced primary care, psychological interventions, or combinations of these.

Treatment for Neuropathic Pain

In 2007, Saarto & Wiffen [5] updated a 2005 Cochrane Review on the effects of antidepressant drugs on neuropathic pain.  The review included  61 trials of 20 antidepressants (3293 participants) and concluded that  TCA drugs provided significant but moderate pain relief.  There was limited evidence for efficacy of selective serotonin uptake blockers for treatment of neuropathic pain.  One of three patients given a TCA drug or venlafaxine achieved moderate pain relief.

In 2006, the European Federation of Neurological Societies [6] reviewed clinical trial evidence and concluded that there was level A evidence for efficacy of TCA, gabapentin, pregabalin, and opioids for neuropathic pain.  In addition, some evidence supported the use of topical lidocaine for post-herpetic syndrome and venlafaxine and duloxetine for diabetic neuropathy.

In 2005, Namaka, et al. [7] proposed a treatment algorithm whereby the first-line therapies included tricyclic antidepressants, anti-epileptic drugs, topical anti-neuralgics, and analgesics.  If the patient does not respond to treatment with at least 3 different agents within a drug class, agents from a second drug class may be tried.  Patients that do not respond to monotherapy may respond to combinations.  This is now widely accepted.

Toxicity of TCA

Because TCA is the lowest cost first-line therapy, they are tried in almost all patients with depression and neuropathic pain.  From this perspective, it is paramount that the toxicity and interaction of TCA drugs with other drugs be considered in planning treatment programs.

  1. Monoamine oxidase (MAO) inhibitors.  Nortriptyline should not be used in concurrently with a MAO inhibitor because the combination can cause high body temperatures (hyperpyretic crisis), severe convulsions, and fatalities.  All MAO inhibitors should be discontinued at least two weeks for Nortriptyline is started.  Some MAO drugs include isoarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate).
  2. Hypersensitivity.  Patients that are hypersensitive to dibenzazepine may also be allergic to nortriptyline.
  3. Myocardial infarction. Nortriptyline should not be given during the acute recovery period after MI.
  4. Alcohol consumption.  Alcohol potentiates the effects of nortriptyline and may lead to increased suicide attempts or overdoses.
  5. Schizophrenia.  Patients with schizophrenia may have an exacerbation of their psychosis.
  6. Manic depression.  Nortriptyline may cause symptoms of the manic phase to emerge, as well as patient hostility and epilepiform seizures.
  7. Anti-cholinergic and sympathomimetic drugs.  Close supervision is required when nortriptyline is used with anti-cholinegic and sympathomimetic drugs since TCA drugs influence the effects of these drugs on multiple systems.
  8. Suicide.  If a depressed patient has a history of suicide, it is important that the least possible quantity of drug be dispensed at any given time because depressed patients often take high doses of tricyclic antidepressants for suicide.
  9. Diabetes.  Both elevation and lowering of blood sugar levels have been reported with nortriptyline.

The major difference between TCA use for depression and neuropathic pain is dose.  For example, the typical doses of amitriptyline used for depression and neuropathic pain are 125 mg/day and 25 mg/day respectively.  Rintala, et al. [8] found that amitriptyline (25-50 mg/day) was significantly better than placebo or gabapentin for relieving chronic neuropathic pain in persons with spinal cord. At the doses, side effects should be less.

Drug Interactions and Adverse Reactions

Tricyclic antidepressants enhances the effects of many drugs because it interferes with neurotransmitter uptake.  However, some drugs interfere with metabolism of tricyclic antidepressants.

  • Cimetidine increases plasma concentrations of tricyclic antidepressants.
  • Chlorporamide (250 mg/day) and nortriptyline (125 mg/day) may be associated with significant hypoglycemia in a patient with type II diabetes.
  • Amitriptyline enhances the effects of alcohol and other CNS depressants.
  • Amitriptyline and disulfiram may cause delirium.

Common side-effects include drowsiness, dizziness, insomnia, blurred vision, rash, and dry moth.  High doses of tricyclic antidepressants have the following adverse reactions:

  • Cardiovascular:  hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, and stroke.
  • Psychiatric:  confusion states with hallucination, disorientation, delusions, anxiety, restlessness, agitation, insomnia, panic, nightmares, hypomania, exacerbation of psychosis.
  • Neurologic:  numbness and tingling (paresthesias) of the limbs, discoodination, ataxia, tremors, peripheral neuropathy, extrapyramidal symptoms, seizures, EEG alterations, and tinnitus
  • Anticholinergic:  Dry mouth, sublingual adenitis, blurred vision, changes in accomodation, mydriasis, constipation, paralytic ileus, urinary retention, delayed micturition (urination).
  • Allergy.  skin rash, petechiae, urticaria, photosensitization, edema (face and tongue), drug fever, cross-sensitivity to related drugs.
  • Hematologic.  Bone marrow depression, agranulocytosis, eosinophilia, purpura, thrombocytopenic purpura.
  • Gastrointestinal.  Nausea, vomiting, anorexia, epigastric distress, diarrhea, strange taste,
  • Endocrine
  • Others

Abrupt withdrawal of tricyclic antidepressants can cause withdrawal symptoms and the drug should be slowly discontinued over a period of time.  However, this is usually for relatively high doses of the drug, i.e. 125 mg/day.  At the low doses (10-20 mg/day) that are used for neuropathic pain, ramping down may not be necessary.

Summary and Conclusions

Tricyclic antidepressant (TCA) drugs are commonly used for depression and neuropathic pain.  In depression, they do have significant but modest effects on depression, in part because of strong placebo effects.  In neuropathic pain, however, tricyclic antidepressants have been found to be as good or better than other therapies, including anti-epileptic drugs like gabapentin and pregabalin.  However, only about a third of patients responded to TCA drugs and it provides only moderate pain relief.  On the other hand, TCA drugs are often used in combination with other drugs.  In general, TCA has more side-effects than selective serotonin re-uptake inhibitors (SSRI) and the drugs are deadly when taken in overdose.  The TCA dose of neuropathic pain is much lower than for depression and therefore should cause less side-effects and may not require systematic staged withdrawal.  On the other hand, TCA drugs interact with many drugs even at low doses and therefore treatment programs with TCA must be carefully designed and regularly reviewed.    


  1. Moncrieff J, Wessely S and Hardy R (2004).  Active placebos versus antidepressants for depression.  Cochrane Database Syst Rev CD003012.
  2. Bramness JG, Walby FA and Tverdal A (2007).  The sales of antidepressants and suicide rates in Norway and its counties 1980-2004.  J Affect Disord 102: 1-9.
  3. Mottram P, Wilson K and Strobl J (2006).  Antidepressants for depressed elderly.  Cochrane Database Syst Rev CD003491.
  4. Nieuwenhuijsen K, Bultmann U, Neumeyer-Gromen A, Verhoeven AC, Verbeek JH and van der Feltz-Cornelis CM (2008).  Interventions to improve occupational health in depressed people.  Cochrane Database Syst Rev CD006237.
  5. Saarto T and Wiffen PJ (2007).  Antidepressants for neuropathic pain.  Cochrane Database Syst Rev CD005454.
  6. Attal N, Cruccu G, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, Sampaio C, Sindrup S and Wiffen P (2006).  EFNS guidelines on pharmacological treatment of neuropathic pain.  Eur J Neurol 13: 1153-69.
  7. Namaka M, Gramlich CR, Ruhlen D, Melanson M, Sutton I and Major J (2004).  A treatment algorithm for neuropathic pain.  Clin Ther 26: 951-79.
  8. Rintala DH, Holmes SA, Courtade D, Fiess RN, Tastard LV and Loubser PG (2007).  Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury.  Arch Phys Med Rehabil 88: 1547-60.

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.


  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. 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. 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. 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.
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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 from 1999 to 2001, and 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 (  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.

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Sacral Tarlov Cysts: Diagnosis and Treatment

December 14, 2008

Sacral Tarlov Cysts: Diagnosis and Treatment
By Wise Young, Ph.D., M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey, Piscataway, NJ 08854-8082
13 December 2008

Someone recently asked for an explanation of Tarlov cysts, what they are, how they are diagnosed, and the best way to treat them. I will describe below the criteria for diagnosis, the prevalence of the cysts, the symptoms, and recommended treatments.

What are Tarlov Cysts?

Tarlov cysts are fluid-filled cysts associated with sacral nerve roots, at the junction of the nerve root and root ganglion. First described by Tarlov [1] in 1938, when he was at the Montreal Institute of Neurology, he was careful to call these cysts perineural and to distinguish them from meningeal cysts, which would be extensions of subarachnoid space.

Computerized tomographic (CT) myelography where dye is injected into the cerebrospinal fluid (CSF) showed that Tarlov cysts are true meningeal cysts that communicate with spinal subarachnoid space [2, 3]. To demonstrate communication of Tarlov cysts with subarachnoid space, CT scans should be obtained 30-60 minutes after injection of subarachnoid dye.

In 1988, Nabors et al. [4] classified Tarlov cysts as a kind of extradural meningeal cyst.  A Tarlov perineural cyst differs from other meningeal cysts in that there are spinal root axons within the cyst walls or the cavity of the cyst. The cysts may surround the nerve or extend into the nerve. For this reason, simple excision of the Tarlov cysts will damage the spinal root.

Prevalence and Symptoms

In his original 1938 communication, Tarlov had found these cysts in 5 of 30 cadavers (17%). In 1994, Paulsen, et al. [5] found 23 patients with perineural cysts out of 500 sequential lumbosacral magnetic resonance scans (4.6%). In 2005, Langdown, et al. [6] in Australia reported that 54 patients out of 3535 MRI scans (1.5%) obtained for lumbosacral symptoms had Tarlov cysts.

Most Tarlov cysts are asymptomatic. Tarlov initially thought that the cysts are innocuous. However, in 1948, he [7] reported a case of sciatica associated with a sacral perineural cyst. Paulsen, et al. [5] found that five of 23 patients with the cysts were symptomatic (22%) and that CT-guided cyst puncture reduced pain. In the Langdown study [6], 7 of 54 patients (13%) had symptoms due to the cyst.

Symptoms are variable, ranging from radicular pain [8] and paresthesia to urinary and bowel dysfunction [9, 10], cauda equina syndrome [11], and even abdominal pain [12], depending on the level of sacral roots involved. Pain is the most common presentation.


Most surgeons agree that asymptomatic Tarlov cysts should not be treated [13] and that symptomatic cysts should be treated. Several treatment options are available:

Lumbar drainage. Bartels & Overbeeke [14] reported that lumbar CSF drainage relieved pain in 2 of 3 patients with symptomatic Tarlov cysts. Subsequently, they did a lumbar-peritoneal shunt in one patient to relieve the pressure. This suggests that CSF pressure contributes to the size of Tarlov cysts and that they are true meningeal cysts.

CT-guided percutaneous decompression. Paulsen, et al. [5] did percutaneous CT-guided decompression of the cysts, reporting rapid reduction in symptoms and relief of pain but the symptoms returned in 3 weeks to 6 months. Patel, et al. [15] used CT-guidance decompression but injected fibrin glue after the decompression, finding no recurrence over 23 months.

Decompressive laminectomy. Siqueira, et al. [16] did decompressive laminectomies in two patients. Sa & Sa [17] treated four cases with a sacral laminectomy, reporting resolution of the pain. However, the pain often recurred. Tanaka, et al. [18] treated 12 consecutive patients with laminectomies and imbrications of the sacral cysts.

Laminectomy and cyst resection. Voyadzis, et al. [9] operated on 10 patients, carrying out sacral laminectomies and resections of the cysts. Seven of 10 patients had complete resolution of their pain but 3 (30%) showed no benefit. These three all had cysts smaller than 1.5 cm in diameter. Histology revealed nerve fibers in 75% of the cases, ganglion cells in 25%, and evidence of old hemorrhage in half.

Laminectomy, partial cyst excision, duroplasty or plication of the cyst walls. Total cyst resection is unnecessary [19]. Caspar, et al. [20] excised the cysts with duroplasty or plication of cyst wall in 15 patients with no complications and relief of pain in 13 (87%).

Laminectomy, fenestration of cyst wall, partial resectio, and myofascial flap. Acosta, et al. [13] stimulated the cyst wall to find motor axons, resected parts did not have nerves, and then used a muscle flap to close the cyst. Guo, et al. [21] used a similar approach to resect the cyst wall, imbricated the remaining sheath, and repaired the defect with muscle and Gelfoam.

Summary and Conclusions

Tarlov cysts are fluid-filled meningeal cysts on spinal roots.  Although present in 1-5% of the population, only 10% to 20% of cysts are symptomatic, manifesting as sciatica or other radicular pains, bowel and bladder problems, and other complaints. Lumbar CSF drainage and percutaneous CT-guided drainage of the cysts will relieve the symptoms temporarily. Injecting fibrin glue postpones recurrence. Resection of the cyst resolves the pain but histology revealed nerve fibers and sensory ganglion in the cyst walls. Laminectomy, fenestration and partial resection with careful neurophysiological testing to avoid motor fibers, and closure with a muscle flap is the preferred approach.


1. Tarlov I (1938). Perineural cysts of the spinal nerve roots. Arch Neurol Psychiatry. 40: 1067-1074.

2. Goyal RN, Russell NA, Belanger JM, Benoit BG and Rawa M (1987). Metrizamide CT scanning in spinal nerve root cysts. Can J Neurol Sci. 14: 149-52.

3. Goyal RN, Russell NA, Benoit BG and Belanger JM (1987). Intraspinal cysts: a classification and literature review. Spine. 12: 209-13.

4. Nabors MW, Pait TG, Byrd EB, Karim NO, Davis DO, Kobrine AI and Rizzoli HV (1988). Updated assessment and current classification of spinal meningeal cysts. J Neurosurg. 68: 366-77.

5. Paulsen RD, Call GA and Murtagh FR (1994). Prevalence and percutaneous drainage of cysts of the sacral nerve root sheath (Tarlov cysts). AJNR Am J Neuroradiol. 15: 293-7; discussion 298-9.

6. Langdown AJ, Grundy JR and Birch NC (2005). The clinical relevance of Tarlov cysts. J Spinal Disord Tech. 18: 29-33.

7. Tarlov IM (1948). Cysts, perineurial, of the sacral roots; another cause, removable, of sciatic pain. J Am Med Assoc. 138: 740-4.

8. Chaiyabud P and Suwanpratheep K (2006). Symptomatic Tarlov cyst: report and review. J Med Assoc Thai. 89: 1047-50.

9. Voyadzis JM, Bhargava P and Henderson FC (2001). Tarlov cysts: a study of 10 cases with review of the literature. J Neurosurg. 95: 25-32.

10. Kumpers P, Wiesemann E, Becker H, Haubitz B, Dengler R and Zermann DH (2006). [Sacral nerve root cysts–a rare cause of bladder dysfunction. Case report and review of the literature]. Aktuelle Urol. 37: 372-5.

11. Nicpon KW, Lasek W and Chyczewska A (2002). [Cauda equina syndrome caused by Tarlov’s cysts–case report]. Neurol Neurochir Pol. 36: 181-9.

12. Slipman CW, Bhat AL, Bhagia SM, Issac Z, Gilchrist RV and Lenrow DA (2003). Abdominal pain secondary to a sacral perineural cyst. Spine J. 3: 317-20.

13. Acosta FL, Jr., Quinones-Hinojosa A, Schmidt MH and Weinstein PR (2003). Diagnosis and management of sacral Tarlov cysts. Case report and review of the literature. Neurosurg Focus. 15: E15.

14. Bartels RH and van Overbeeke JJ (1997). Lumbar cerebrospinal fluid drainage for symptomatic sacral nerve root cysts: an adjuvant diagnostic procedure and/or alternative treatment? Technical case report. Neurosurgery. 40: 861-4; discussion 864-5.

15. Patel MR, Louie W and Rachlin J (1997). Percutaneous fibrin glue therapy of meningeal cysts of the sacral spine. AJR Am J Roentgenol. 168: 367-70.

16. Siqueira EB, Schaffer L, Kranzler LI and Gan J (1984). CT characteristics of sacral perineural cysts. Report of two cases. J Neurosurg. 61: 596-8.

17. Sa MC and Sa RC (2004). [Tarlov cysts: report of four cases]. Arq Neuropsiquiatr. 62: 689-94.

18. Tanaka M, Nakahara S, Ito Y, Nakanishi K, Sugimoto Y, Ikuma H and Ozaki T (2006). Surgical results of sacral perineural (Tarlov) cysts. Acta Med Okayama. 60: 65-70.

19. Yucesoy K, Naderi S, Ozer H and Arda MN (1999). Surgical treatment of sacral perineural cysts. A case report. Kobe J Med Sci. 45: 245-50.

20. Caspar W, Papavero L, Nabhan A, Loew C and Ahlhelm F (2003). Microsurgical excision of symptomatic sacral perineurial cysts: a study of 15 cases. Surg Neurol. 59: 101-5; discussion 105-6.

21. Guo D, Shu K, Chen R, Ke C, Zhu Y and Lei T (2007). Microsurgical treatment of symptomatic sacral perineurial cysts. Neurosurgery. 60: 1059-65; discussion 1065-6.

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The Cost of a Cure for Spinal Cord Injury

December 11, 2008

The Cost of a Cure for Spinal Cord Injury
by Wise Young, Ph.D. M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers University Piscataway, NJ 08854-8082

12 December 2008

In a recent post on CareCure, Random asked “What is the Cost of Cure?” This reasonable question is devilishly hard to answer for three reasons.  First, the question assumes that the definition of “cure” is well-accepted.  It is not.  Before we can answer the question, we must agree on what the or a cure is.  Second, cost depends on many factors, including where the funds are coming from, who is spending the funds, and what type of research the funds will be spent for.  Third, cost depends on time.  To know how much, we need to know how long it will take.  Time is money.

Definition of Cure

To some people, a cure is eradication of a disease or condition.  If we define cure of spinal cord injury as eradication of the condition, I don’t think that it is likely that we will be able to achieve this in the forseeable future.  People are vulnerable to trauma and damage to our spinal cord will occur as long as there is bad luck or stupidity.  Also, we are unlikely to develop a therapy that will restore people to the way they were before their accident.  We can’t reverse aging, at least not yet.

On the other hand, it is conceivable and very likely that we will have a therapy that can restore function sufficiently so that a third party, who does not know you, would not be able to tell that you had spinal cord injury.  This happens to a majority of people with so-called “incomplete” spinal cord injuries.  A feasible goal of therapies is to make the person as “incomplete” as possible and allow the spinal cord plasticity to do the rest.

Let us agree that the cure for spinal cord injury is sufficient restoration of function so that a person who has not met you before could not readily tell that you had spinal cord injury.  This definition does not mean that you have been restored to “normal” or even the way you were before injury.  While some might disagree that such situation could be called a cure, I think that most people would agree that it is a worthwhile and feasible.


Cost of research is a complex factor that depends on the source of funds, who is spending it, and the type of research.  The funding source is important because funding are seldom dedicated to one condition.  For example, rehabilitation will be spread out amongst spinal cord injury and other conditions.  Funding for basic science will be scattered as well.

Who is spending the funds is also important.  Academic laboratories tend to emphasize basic research, with a greater likelihood of discovery and general solutions to problems.  Small biotech companies tend to focus on applied science with an emphasis on proof-of-concept research for patents.   Large pharmaceutical or therapeutic companies tend to do preclinical testing and clinical trials.

Research can be divided into three phases:  discovery, preclinical, and clinical.  Let’s say that discovery research is the least costly and one laboratory project typically costs about US$250,000 per year.   Preclinical research, such as therapy development and animal testings, is more expensive, typically $2.5 million per year.  Clinical trials are the most expensive, on the order of $25 million per year.


Time is a crucial factor.  On average, the pharmaceutical industry estimates that it takes an average of about 11 years and $1.1 billion to move a therapy from discovery to market.  The timing of the phases of research depends on the therapy and often overlap with each other.  For example, the discovery phase may be 3-4 years, the preclinical phase may be 3-4 years, and the clinical phase may be 3-4 years.

The bench-to-beside time can vary from 3 years for a me-too drug which bypasses discovery and preclinical phases to over 12 years for a new drug that has to go through full-length discovery, preclinical, and clinical trial phases.  Of course, complications or failures along the way mean that one must start all over, adding to the therapy development time.

Four years is quite reasonable for each phase.  The discovery phase, for example, can easily exceed four years, depending on the treatment.  The preclinical phase includes testing in animals and this may take several years as well.  The clinical trial phase must go through the standard three phases.  Phase 1 is for assessing safety and feasibility, phase 2 is for optimizing the therapy and outcomes, and phase 3 is the pivotal trial.


If a therapy requires 4 years per phase at full cost, i.e. 4 years of discovery research at $250,000/year ($1 million), 4 years of preclinical research at $2.5 million/year ($10 million), and 4 years of clinical trials at $25 million/year ($100 million), the cost adds up to $111 million per treatment.  If only 10% of therapies the gauntlet, the total cost of getting a therapy to market is about $1.1 billion over 12 years.

The total treatment costs can be defrayed significantly in several ways.  The first and the most important approach is to do rigorous preclinical studies that would increase the likelihood of success in the phase 3 studies.  While this may add a year or two to the preclinical phase, reducing the risk of a catastrophic failure at the clinical trial phase is worthwhile.

A second and very effective approach is to have NIH-funded clinical trial networks.  Such networks substantially reduce costs of clinical trials by providing already vetted and trained centers that are ready and able to test therapies.  The time and expense of organizing the trials can easily waste a year and add more than 10% to the costs of the trials.


In theory, a clinical trial should have a 50% chance of success.  The ethics of clinical trials require “clinical equipoise”, i.e. the probabilities that the treatment and control groups are effective should be balanced. If 10 trials were carried out, each with a 50% chance of success, the likelihood of at least one successful trial is about 95%.  Thus, a program to test ten treatments has a 95% chance of yielding one therapy that works.

If the cost of one developing and testing one therapy is $111 million over 12 years, then testing ten therapies should cost about $1.11 billion over 12 years.   That is about $100 million per year.   If we have at least ten therapies that have passed their discovery phase and are in their preclinical trial phase, the cost and time should be less, i.e. about a billion dollars and four years.

Let us assume that NIH invests $100 million per year over the next four years into a spinal cord injury clinical trial network and that industry spends $125 million per year over the same period on clinical trials of ten therapies.  If so, we have a 95% probability of having at least one positive clinical trial in four years with a $500 million investment by industry and $400 million by NIH.

Summary and Conclusions

To estimate the cost of curing spinal cord injury, I defined “cure” as a condition where a third party cannot tell that you had spinal cord injury.  I then assumed that the path for each therapy involves sequential four-year phases of discovery, preclinical, and clinical research.   I further assumed that discovery research has a cost of $250,000/year compared to preclinical research cost of $2.5 million/year and clinical trial cost of $25 million/year.  Thus, one treatment will cost  $111 million and 12 years to move from discovery to market.  Finally, I assumed that it would take ten therapies to have a 95% chance of achieving a “cure”.  Given these assumptions, if we were starting from scratch, it would take $1.2 billion and 12 years.  However, if we already have ten therapies that are ready for clinical trial, it would cost about a billion dollar and four years.  A clinical trial network would lower costs and accelerate the progress.

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