Archive for the ‘Care’ Category

Effects of Botox on Motoneurons

February 10, 2009

Effects of Botox on Motoneurons
Wise Young, Ph.D., M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey, Piscataway, NJ 08540
Originally posted  6/22/06, updated 2/11/09

Many people have asked questions about Botox or botulinum toxin that is now commonly used to treat spasticity and other conditions.

What is Botox? Botox is the trade name of a drug derived from botulinum toxins, a powerful family of neurotoxins that selectively affects acetylcholinergic neurons, produced by a family of bacteria called clostridium bolutinum. This bacteria grows under anaerobic conditions in canned foods and can cause a condition called botulism. One of the most powerful and dangerous neurotoxins in nature, it use to kill in over 50% of people who developed botulinism before respirators were available [1]. Ingestion, inhalation, or injection of 200-300 picograms per kilogram is a lethal dose. Because 100 grams of the toxin would be sufficient to kill every person on earth, it has been the target of some speculation as a terrorist weapon [2], particularly in milk [3] but, because the molecule is rapidly degraded when heated or exposed to air and difficult to produce in quantity, the concern has been largely theoretical [4].

Botulinum toxin therapy. Botulinum toxin has been studied for many years. In 1949, Justinus Burgen discovered that the toxin blocked neuromuscular transmission. In the 1950’s, it was used to eliminate facial wrinkles in actors. When injected in tiny amounts into muscle, the toxin binds to motor nerves, preventing release of neurotransmitters from the nerves to paralyze or weaken the muscle. The injection effects usually last only 3-4 months and repeated re-injections are necessary to maintain its effects for longe periods. Seven members of the botulinum toxin family (A-G) with three subtypes of the A group have been identified. In 1989, the U.S. FDA approved use of botulinum toxin A (BTX-A) to treat strabismus (eye movement), blepharospasm (spasmodic blinking), and hemifacial spasm (spasms of the face). In 2002, the FDA approved Botox use for treating facial wrinkles. BTX-A is marketed under the trade names of Botox and Dysport. Dysport is a different formulation of botulinum toxin A. Although not specifically approved for such indications, BTX-A is frequently used to treat urinary incontinence, anal fissures, spasticity, focal dystonias, and temporomandular joint pain. It has been used for treatment of neuromuscular pain, even though the toxin does not directly affect sensory nerves, because abnormal muscle activity may be associated with cramps [5], including bladder pain [6]. Some animal data suggest that botulinum toxins may affect activity of nociceptive neurons. In 2000, the U.S. FDA approved the use of botulinum toxin B (BTX-B) for cervical dystonia, a condition of hyperactive muscle groups in the neck. A cheaper but less potent Chinese version of Botox is also available. Although the other versions of botulinum toxin (C-G) have not been approved, several synthetic versions and fragments of the toxin being tested [7].

Mechanism of action. BTX-A has three components, a heavy chain and two light chains. Injected in small amounts into muscles, the heavy chain of botulinum binds to the surfaces of motor nerves where it is endocytosed (the membrane inverts and is taken back into the cell). A recent study [8] suggests that a membrane protein called SV2 is protein receptor for botulinum toxin. The heavy chain has turned out to be a useful tool for getting other molecules to be transported into cells [9]. The light chains of botulinum toxin are enzymes (proteases) that break down the SNAP-25 proteins in the SNARE family. These proteins are essential for release of acetylcholine (the neurotransmitter that activates muscles). Motor nerves treated with BTX-A tend to fill up and swell with unused acetylcholine vesicles. BTX-A and BTX-B reduce both all muscle activity, due to both voluntary and involuntary motor activity, usually within 24-48 hours and the paralysis lasts several months.

Side-effects of Botox Therapies. Botulinum toxin treatments are associated with some complications. Muscle weakness is the most commonly reported side-effect. The injection site may be sore and tender. Flu-like symptoms may occur. Pain may be present in neighboring muscles. Some 20-30% of patients may report these side effects [10]. Injection of the toxin into the wrong muscle is of course a possibility. When injected into the neck or nearby structures, the toxin may affect ability to swallow and dry mouths (a side-effect of the toxin on nerves that stimulate saliva secretion). The beneficial effects of the drug may not appear for 7-10 days and the effects may last 4-6 weeks. When used repeatedly and more frequently than 12 weeks, the body will develop antibodies against botulinum toxins, reducing their effectiveness. Antibodies against the serum (anti-toxin) is one treatment of botulinum toxicity.

Effect of Botox on Motoneurons. BTX-A is generally considered to be a very long-acting reversible toxin. However, BTX-A may have toxic effects on motoneurons. In neonatal rats, the toxin has been reported to increase electrotonic coupling between motoneurons and other neurons [11]. BTX-A is well known to stimulate motor axonal sprouting in muscle. This may have some unanticipated effects. For example, in 2002, Millecamps, et al. [12] reported that prior injection of BTX-A enhances locallly injected adenovirus retrograde gene transfer in motoneurons, apparently related to toxin-induced sprouting of the nerves and increasing the surface area of nerves exposed to virus. In 1977, Sumner [13] reported the BTX-A injected into the tongues of rats produced the same changes in motoneurons as cutting of the axon, with reductions in dendrite numbers and increase in abnormal dendrite appearance, increases in astrocytes around the motoneurons, and even presence of microglial cells that suggest an inflammatory response. Jung, et al. [14] reported changes in gene expression in rat spinal motoneurons after chemodenervation with botulinum toxin.

Effects of Botox on Muscle. Botox parayzes muscle by stopping acetylcholine release. Because the toxin is injected in small amounts that only affect the muscle in the immediate vicinity of the injection site, there is a decrease in muscle activity and strength. The toxin effect lasts for 4-6 weeks and the injections must be repeated to retain the effect. The mechanisms by which the muscle recovers strength from the toxin are not well understood but may be due to some or all of the following possibilities. First, the recovery of muscle strength may be due to sprouting axons from surrounding non-paralyzed motor nerves. After botox injections, motor axons do sprout extensively in the muscle. Second, the nerves may take several weeks to get rid of the BTX-A and transport additional SNAP-25 proteins to the end of the axon so that acetylcholine can be released. Third, surrounding muscle fibers may hypertrophy to make up for the paralysis of the muscle. Permanent weakness of muscle may occur, especially in muscles with already compromised voluntary activity.

Advantage and Disadvantage. The advantage of Botox is its ease of administration. The doctor simply injects a tiny amount of the toxin into the muscle deemed to be overactive. Depending on the vantage point, the fact that Botox’s effects are not permanent may be an advantage or a disadvantage. To doctors and the companies that make money from the procedure, it is an advantage. For the patients, the reversibility of botox effects is also an advantage, particularly if the injection is made into the wrong place. To have to receive repeated injections every 3 months, however, is disadvantageous. A second disadvantage is botox paralyzes both voluntary and involuntary (spasticity and spasms) muscle activity. For patients who use or anticipate using the muscles, the weakness due to botox may contribute further dysfunction. Finally, the side-effects and the development of immune responses to the toxin are significant drawbacks of repeated injections.

Limitations and Alternatives. Botox is useful only in situations where one or at most a few groups of muscles are overactive. It is not suitable as a treatment of widespread spasticity, spasms, and other abnormal activity affecting many muscle groups. Alternatives to botox for treatment of spasticity fall into three broad categories. The first are anti-spasticity, ant-epileptic/spasm, and other drugs that suppress central nervous system and muscle activity. These include baclofen and tizanidine. The second are surgical methods, such as lengthening tendons or even denervation. The third are chemical methods of damaging peripheral nerve connections to the muscle, such as phenol.

Of note to afficionados of spinal cord injury therapies, bacteria are a rich source of other toxins [15] that may be of benefit for spinal cord injury. For example, clostridia bacteria produce C2 toxin, which binds to actin [16]. Others, such as C3, bind to proteins of the Rho family [17] that are responsible for mediating inhibitory effects of Nogo receptor activation on axonal growth [18], a mechanism that has been hypothesized to be one of the reasons why axons cannot regenerate in the central nervous system.

In summary, botox is botulinum toxin A, a potent neurotoxin made by the bacterium clostridium botulinus that grows in spoiled foods and still kills people. The toxin binds selectively to the surface of motor nerves and transfers inside the nerve where it breaks down proteins required for release of acetylcholine, the neurotransmitter responsible for muscle and secretory activity. The toxin selectively paralyzed muscles where it has been injected but the effects wear off.

References

1.  http://www.cdc.gov/NCIDOD/DBMD/diseaseinfo/botulism_g.htm

2.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15839401&query_hl=1

3.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15985558

4.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15163234

5.  http://www.emedicine.com/pmr/topic218.htm

6.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15371885

7.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15721769

8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16543415

9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15584922

1o.  http://www.emedicine.com/pmr/topic216.htm

11.  http://jn.physiology.org/cgi/content/full/89/2/793

12.  http://www.liebertonline.com/doi/abs/10.1089/10430340252769752;jsessionid=ncUerq8lS67bYfsF9V?cookieSet=1&journalCode=hum

13.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=202476

14.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9145803

15.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15517984

16.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15549605

17.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16472654

18.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15751583

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Tendon Lengthening for Muscle Contractures

February 10, 2009

TENDON LENGTHENING FOR MUSCLE CONTRACTURES
Wise Young, Ph.D., M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey, Pisacataway, NJ 08854
Email: wisey@pipeline.com, Updated: 21 June 2006

[This is an article that I originally wrote for CareCure in 2006.  Because people have continued to ask questions about tendon lengthening, I reproduce it here for easier citation]  Several people have written to me about tendon lengthening to relieve spasticity. I thought that it might be useful to describe and comment on the procedure.

Spasticity and Contractures. Spasticity induces and is aggravated by muscle contractures. Muscles contain receptors called spindles that monitor tension and feeds back to the spinal cord to maintain muscle length. Injury to the spinal cord increases excitabilty of neural circuits that control muscle tension. Spastic muscles resist changes of tension by contracting. Prolonged and continuous muscle spasticity may lead to muscle contracture or shortening of muscles. Contractures interfere with standing and walking. While drugs such as baclofen and tizanidine moderates spasticity, they usually cannot moderate muscle contractures.

Treatments of Contractures. Clnicians use three ways to relieve spasticity muscle contractures. One is to inject a toxin called Botox which damages motor nerves and, in high doses, the motoneurons that innervate muscles. The other is to inject phenol, a chemical, that damages both motor and sensory nerves. A third way is to cut the muscle tendon and lengthen the tendon to relieve the tension on the muscle. The first two methods damage motoneurons or axons, sometimes irreversibly, and may cause weakness of muscles. For people who have some muscle function, tendon lengthening is the method of choice.

Tendon Lengthening. The basic tendon lengthening procedure involves cutting the tendon partway at two points and a cut down the middle of the tendon. This allows the two halves of the tendon to be slid along each other and then sewed together, as illustrated in the diagram below. The procedure is simplified for illustrative purposes but it shows how the cuts (left image) can allow two strands of tendon to be slid alongside each other (middle image), and sewed together (right image). Note that there are other ways to cut the tendon, including methods that involving creating four strands and splicing these strands together. Once healed, the tendon is longer and the cut parts will fill out with scar tissues.

Strength of Repaired Tendons. Tendon lengthening procedures have been carried out for many decades. In fact, I use to participate in such surgeries for children with cerebral palsy and idiopathic toe walking (Source). Children who undergo tendon lengthening even of big musles such as the leg flexors (Source) can return to athletic activities. Many athletes of course rupture their tendons, undergo tendon repair, and then return to their previous activity. Repaired tendons have a scar and the strength of the scar depends on how it healed. The tendon should be immobilized for about four weeks the healing to take place (Source). Properly healed tendons are reasonably strong.

Complications. Making the tendons too long or not lengthening the tendon sufficiently can result in weakening of the muscle (Source) or insufficient resolution of the spasticity. Both surgical experience and judgment is required to get the proper lengthening without significantly weaking the muscle. For obvious reasons, it is not good to go in numerous times to repair the tendon. Repeated surgeries and scar tissues will cause stiffening of the tendon and lost of elastic recoil. Muscle weakness due to immobilization and non-use may be a problem and full function may not return to pre-operative levels for as long as 9 months after surgery, even with intensive physical therapy (Source). The change in one muscle group may affect the balance of other muscles, resulting in abnormal gait (Source).

In summary, tendon lengthening surgery has been practiced for many decades. The procedure does reduce spasticity of major muscle groups and well-healed tendons are strong enough to permit renewal of athletic activity. However, the operation requires experience and good surgical judgment. Like all operations of this nature, complications may occur. Immobilization of the tendon is important for proper healing. Overlengthening, repeated operations, and muscle weakness may occur. The advantages of tendon lengthening is that it may correct specific orthopedic problems and spasticity without damaging nerves or motoneurons.

Figure 1.  Schematic diagream of tendon lengthening.  The surgeon cuts the tendon partway at two points and then a longitudinal cut down the midline of the tendon.  The tendon can then be slid along each other and then sewn together at the appropriate place.  Scar tissue will fill in the rest.

See discussion in http://sci.rutgers.edu/forum/showthread.php?t=64704

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

January 13, 2009

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

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

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

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

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

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

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

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

Reversing Muscle Atrophy

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

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

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

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

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

Reversing Osteoporosis

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

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

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

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

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

Reversible Surgery

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

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

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

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

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

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

Locomotor Training

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

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

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

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

Spinal Cord Stimulation

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

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

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

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

Plasticity

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

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

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

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

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

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

Education

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

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

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

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

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

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

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

Summary and Conclusions

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

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

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

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

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

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

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Ten Frequently Asked Questions Concerning Cure of Spinal Cord Injury

December 21, 2008

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

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

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

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

2. When will a cure be available?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Spinal Cord Injury Levels and Classification

December 19, 2008

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

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

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

Vertebral vs. Cord Segmental Levels

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

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

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

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

spinalcord01
Figure 1. Spinal cord and vertebral levels.

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

Motor and Sensory Examination

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

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

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

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

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

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

Spinal Cord Injury Levels

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

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

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

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

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

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

Complete versus Incomplete Injury

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

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

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

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

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

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

Classification of Spinal Cord Injury

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

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

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

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

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

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

Figure 4. ASIA Impairment Scale and Clinical Syndromes.

Conclusions

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

© Wise Young

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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.    

References

  1. Moncrieff J, Wessely S and Hardy R (2004).  Active placebos versus antidepressants for depression.  Cochrane Database Syst Rev CD003012.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14974002
  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.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17223200
  3. Mottram P, Wilson K and Strobl J (2006).  Antidepressants for depressed elderly.  Cochrane Database Syst Rev CD003491.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16437456
  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.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18425942
  5. Saarto T and Wiffen PJ (2007).  Antidepressants for neuropathic pain.  Cochrane Database Syst Rev CD005454.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17943857
  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.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17038030
  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.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15336464
  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.  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18047869


Treatment of Neuropathic Pain Disorder: A Review of Recent Studies

December 15, 2008

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

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

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

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

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

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

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

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

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

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

References

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

Treatment

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.

References

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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