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Current SCI Clinical Trials 2002

Spinal Cord Injury Therapies In Clinical Trial 2002

Wise Young, Ph.D., M.D.

W. M. Keck Center for Collaborative Neuroscience

Rutgers University, Piscataway, NJ 08854

 

9 October 2002

 

Many people have asked what clinical trials are going on for spinal cord injury.  I will summarize below some trials that have been completed and some that are going on now.  In the 1990’s, only four major clinical trial of SCI therapies were carried out testing methylprednisolone, monosialic ganglioside, fetal spinal cord transplants, and peripheral nerve bridges of transected spinal cords.  Eight clinical trials of regenerative and remyelinative therapies are currently underway.  Three of the trials are focussing on therapies that are started within the first two weeks after injury:  activated macrophage transplants, alternating current stimulation, and AIT-082.  Five of the trials are concerned with therapies of chronic SCI:  4-AP, porcine fetal neural stem cell transplants, peripheral nerve bridging and growth factor cocktail, human fetal olfactory ensheating glia, and human mucosal autografts.  There is one trial attempting alternating electrical current stimulation in Ireland.  In addition, many rehabilitative therapies are being tested in clinical trials, including locomotor training on treadmills, spinal cord stimulation to activate locomotion, and treatments of chronic neuropathic pain.  Many controversial experimental surgeries are being carried out around the world, including omentum transposition, decompression-nerve-omentum transplants, peripheral nerve bridging to leg and bladder, and even shark embyro transplants. 


 

Completed Clinical Trials

 

1.  National Acute Spinal Cord Injury Study (NASCIS).  Methylprednisolone (MP) is the high dose steroid drug that improvs recovery when given within 8 hours after spinal cord injury.  The third NASCIS trial was published in 1997, showing the patients that received 30 mg/kg of MP between 3-8 hours after injury showed better recovery when the treatment was continued for 48 hours rather than 24 hours.  However, people that received the first dose within 3 hours recovered similarly whether they received a 24- or 48-hour course of the drug.   [Bracken, 2001; Bracken and Holford, 2002; Bracken, et al., 1997]

 

2.  Sygen (Fidia) clinical trial.  This multicenter trial compared MP alone and MP followed by Sygen (GM1) for 6 weeks.  GM1 is monosialic ganglioside, a molecule that apparently stimulates axons to grow.  This multi-center trial by Fred Geisler showed that the MP+GM1 treated group recovered faster during the first six weeks but both groups had similar recovery at 6-12 months after injury.   [Geisler, et al., 2001]

 

3.  Fetal spinal cord transplants.  This phase 1 trial at the University of Florida at Gainesville evaluated the safety and feasibility of transplanting fetal spinal cords obtained from aborted fetuses into the spinal cord of patients with progressive syringomyelic cysts.  This trial assessed 10 patients and showed that the transplants survived when the patient received a period of immunosuppression and that the treatment stopped progression of their syringomyelic cysts.  [Thompson, et al., 2001]

 

4.  Peripheral nerve bridges of transected spinal cords.  Tarcisio Barros at the University of São Paulo used peripheral nerves to bridge the spinal cords of several patients with spinal cord transections resulting from gunshot wounds.  Although the patients did not show recovery of motor or sensory function, the peripheral nerve bridges survived and appeared to reconnect the transected spinal cords.  (unpublished data)

 

Current Subacute Spinal Cord Injury Clinical Trials

 

4.  Activated macrophage transplants.  Michal Schwartz discovered in 1997 [Rapalino, et al., 1998; Schwartz and Moalem, 2001] that macrophages activated by exposure to peripheral nerves and injected into the spinal cord improves functional recovery in rats.  A phase 1 clinical trial in Israel sponsored by Proneuron showed that activated macrophage transplants may improve functional recovery in about 10 patients.  Further phase 1 clinical trials have started at Erasmus Hospital in Brussels (Belgium) and Craig Hospital in Denver (Colorado).

 

5.  Alternating current to stimulate regeneration.  Richard Borgens and his colleagues reported in 1999 [Borgens, et al., 1999] that alternating electrical currents applied to the spinal cord promotes functional recovery in dogs that had spinal cord injury.  They have begun a clinical trial at Purdue University (Indiana).   Note that there is another trial involving application of alternating currents to people with chronic spinal cord injury in Dublin, Ireland.

 

6.  AIT-082.  This drug is a modified guanosine analog, a small molecule that can be taken orally and penetrates the blood brain barrier [Grundman, et al., 2002; Yan and Taylor, 2002].  Several groups have reported that AIT-082 or neotrofin promotes axonal sprouting [Middlemiss, et al., 1995; Ramirez, et al., 2002] and stem cell proliferation in rats [Rathbone, et al., 1999].  Neotherapeutics is sponsoring a trial of oral AIT-082 starting within 2 weeks after spinal cord injury and continued for up to 3 months at three centers:  Ranchos Los Amigos in Downey CA, Gaylord Rehabilitation Center in Connecticut, Craig Hospital in Denver CO; and Thomas Jefferson in Philadelphia PA.

 

Current Chronic Spinal Cord Injury Clinical Trials

 

7.  4-aminopyridine (Fampridine).  4-aminopyridine or 4-AP works by blocking the fast voltage sensitive potassium channel to improve conduction in demyelinated axons [Blight and Gruner, 1987; Blight, et al., 1991; Bowe, et al., 1987; Gruner and Yee, 1999; Kocsis, 1985; Shi, et al., 1997] and increasing the amount of neurotransmitter that is released per signal that gets through the injury site [Smith, et al., 2000].  Several phase 2 clinical trials suggest beneficial effects of the drug in spinal cord injury [Hansebout, et al., 1993; Hayes, et al., 1993; Hayes, et al., 1994; Potter, et al., 1998; Qiao, et al., 1997; Segal and Brunnemann, 1997; Segal and Brunnemann, 1998; Segal, et al., 1999; Wolfe, et al., 2001] and multiple sclerosis [Davis, et al., 1990; Fujihara and Miyoshi, 1998; Jones, et al., 1983; Rossini, et al., 2001; Smits, et al., 1994; Stefoski, et al., 1987; Van Diemen, et al., 1993; van Diemen, et al., 1993], although one recent trial did not [van der Bruggen, et al., 2001].  The drug improves conduction of spared axons in injured spinal cord [Yu, et al., 2001a; Yu, et al., 2001b].  A sustained release oral formulation has been developed by Elan and is being developed by Acorda Therapeutics [Darlington, 2000; Segal, et al., 2000].  A phase 3 "pivotal" trial of the sustained release version of 4-aminopyridine has started.  About 75 spinal cord injury centers in the United States and Canada are participating in this trial.

 

8.  Porcine fetal neural stem cell transplants.  This is a phase 1 trial sponsored by Diacrin at Washington University in St. Louis and Albany Medical Center in New York. The cells were obtained from the brains of fetal pigs and transplanted into the spinal cord. All the patients are more than 2 years after injury.  These cells have been transplanted in more than 200 patients with stroke, Parkinson's disease, and Huntington's disease over the past five years [Savitz, et al., 2002].

 

9.  Peripheral nerve bridging and growth factor treatment of chronic injured spinal cords.  This is a trial being conducted in Taiwan by Henreich Cheng, a neurosurgeon who worked with Lars Olson and published a study in 1995 [Cheng, et al., 1997; Cheng, et al., 1996; Cheng and Olson, 1995] showing that such peripheral nerve bridges can result in functional regeneration in rats.  In patients with transected spinal cords, he does peripheral nerve bridges and a growth factor cocktail.  In others, he will treat with growth factor cocktail.  Such bridging therapies are being tried in Beijing China, as well.

 

10.  Human fetal olfactory ensheathing glial (OEG) transplants.  Several groups have reported that OEG transplants facilitate regeneration in rats with partially lesioned [Li, et al., 1997; Ramon-Cueto and Nieto-Sampedro, 1994] and transected spinal cords [Ramon-Cueto, 2000; Ramon-Cueto, et al., 2000; Ramon-Cueto, et al., 1998].  A neurosurgeon by the name of Samueil Rabinovich has transplanted mixtures of stem cells and OEG to the spinal cord of about 15 people with chronic spinal cord injury.  Another neurosurgeon Hongyun Huang is now transplanting OEG obtained from fetal olfactory bulbs into spinal cords of people with chronic spinal cord injury in Beijing.  He has reportedly done so in more than 150 patients so far.

 

11.  Human mucosal autografts.  Last year, Lu, et al. [Lu, et al., 2001; Lu, et al., 2002] in Australia reported that OEG from nasal mucosa (the lining of the nose) can regenerate the spinal cord of rats.  Two clinical trials have already started, one in Lisbon, Portugal.  The other is by Dr. Phil Waite in Brisbane Australia where several patients have received nasal mucosal autografts to the spinal cord.  The results are pending. 

 

Other Therapies

 

12.  Locomotor training.  Much animal research suggests that locomotor training may help improve recovery [Edgerton, et al., 2001].  In the early 1990’s, Wernig, et al. [Wernig and Muller, 1992; Wernig, et al., 1995; Wernig, et al., 1998; Wernig, et al., 1999] from Bonn Germany reported that they were able to train as many as 76% of wheel-chair bound people to walk independently, in some cases as long as 10 years after injury.  Several studies have confirmed and extended these results since in Europe [Abel, et al., 2002; Colombo, et al., 2001; Dietz, 2001; Wirz, et al., 2001] and the U.S. [Behrman and Harkema, 2000; Field-Fote, 2001; Protas, et al., 2001; Sullivan, et al., 2002; Trimble, et al., 2001; Wilson, et al., 2000].  Some researchers have attempted locomotor training without treadmill [Seif-Naraghi and Herman, 1999].  Many rehabilitation centers, have such trials ongoing.  Multi-center NIH clinical trial assessing the effects of treadmill training on locomotor recovery in chronic spinal cord injury:  UCLA [Dobkin, 2000], University of Ottawa in Ontario Canada, McGill University in Montreal, Rancho Los Amigos Medical Center in Downey CA, Shepard Center in Atlanta GA, Ohio State University in Columbus OH, Thomas Jefferson University Hospital in Philadelphia PA.  The Veteran Administration Medical Center in Houston likewise has a treadmill locomotor training trial.

 

13.  L2 locomotor center stimulation.  In 1998, Milan Dimitrijevic and colleagues reported success in stimulating a spinal cord center that activates locomotion in people with spinal cord injury.  In 2001, Richard Herman at the Good Samaritan Hospital in Phoenix Arizona reported that he successfully stimulated the spinal locomotor center at the L2 level to activate walking in a man with spinal cord injury, significantly improving the walking and also metabolic requirements for walking.  Dimitrijevic likewise reported a large series of studies on people, suggesting that L2 stimulation can recruit locomotor activity in people.  These studies are continuing at these two centers.

 

14.  Treatment of chronic pain after spinal cord injury.  Many trials are ongoing, assessing the effects of various treatments of neuropathic pain:

  NIH-funded clinical trial at the University of Pittsburgh, examining the efficacy of methadone as a treatment of chronic neuropathic pain.

  Massachusetts General Hospital is examining the effects of various combination drugs, including neurontin (gabapentin) and glutamate receptor blockers, and other durgs, on neuropathic pain after spinal cord injury.

  Randomized clinical trial of safety and efficacy of Viagra in women after spinal cord injury.  This is a clinical trial being held at the Spaulding Rehabilitation Hospital in Boston, examine the effects of Viagra on sexual arousal in women with spinal cord injury.

  Pain following SCI: Randomized cross-over trial of Neurontin, Methadone, and placebo.  This is a clinical trial at the University of Alabama at Birmingham.

 

15.  Experimental surgeries. 

  Omentum transposition.  For many years, Dr. Harry Goldsmith and others have been transplanting omentum (the vascular tissue that surrounds the guts) onto injured central nervous tissues, claiming that this can restore function in spinal cord injury [Goldsmith, 1997a], stroke [Goldsmith, et al., 1990; Goldsmith and Sax, 1999], and Alzheimer’s disease [Goldsmith, 1997b].  Some data suggest that the transposed omentum or meylosynangiosis may revasularize the spinal cord [Goldsmith, 1994; Khosla, et al., 1995] and may provide growth factors that promote recovery.  Several clinical studies have have found no significant benefit of the treatment [Baskov, et al., 1998; Clifton, et al., 1996; Duffill, et al., 2001; Sgouros and Williams, 1996; Spaic, et al., 2001] and some complications have been reported [Ignjatovic, et al., 1999; Schweighofer, et al., 1992].  A few positive cases of improvement have been published [Rafael, et al., 1992].  The controversial treatment is continuing to be applied in China, Cuba, and other countries.

  Decompression, untethering, peripheral nerve and omentum transplant.  Dr. Carl Kao has been operating on hundreds of people with chronic spinal cord injury in Ecuador, where he surgically decompresses and untethers the spinal cord, and transplants peripheral nerves and omentum to the spinal cord.   None of these results have been reported in the literature.

  Peripheral nerve bridging to the leg peripheral nerves.  Several years ago, Dr. Giorgio Brunelli reported that he had successfully connected peripheral nerve from the arm with peripheral nerve of the legs, restoring some motor function to legs.  More recently, he reported that he successfull bridged the sciatic nerves (the nerves that go from the spinal cord to the legs) to the spinal cord above the injury site in one patient.  This procedure may restore some motor function but the function is not yet coordinated nor associated with functional recovery.

  Peripheral nerve bridging to the bladder.  A number of researchers have shown that it is possible to use the peripheral nerve to bridge the spinal cord to the bladder and restore some function in animals.  Dr. S. M. Zhang in Shanghai has taken this to clinical trial and have carried out these procedures in people after spinal cord injury.  The results of this trial are not yet known.

  Shark embryo transplants to the spinal cord.  For nearly a decade, Dr. Ramirez del Rio and Dr. Carlos Romero Gaitán have been transplanting shark embryo cells into the spinal cord of people with chronic spinal cord injury.  In addition to the cells, they also decompress the spinal cord and shunt any cyst that may be present. 

 

References Cited

  Abel R, Schablowski M, Rupp R and Gerner HJ (2002). Gait analysis on the treadmill - monitoring exercise in the treatment of paraplegia. Spinal Cord. 40 (1): 17-22. Summary: STUDY DESIGN: A prospective study was performed to evaluate the gait training of seven consecutive spinal cord injured patients and 10 controls on a treadmill using instrumented gait analysis and video documentation. OBJECTIVES: To determine whether it is possible to maintain gait motion within physiological limits during treadmill training. SETTING: Primary and secondary care unit for spinal cord injury, Heidelberg, Germany. METHODS: Treadmill training was instituted as early as possible. Gait analysis was performed when the patients were stable enough to walk without manual aid from therapists and enough endurance to allow measurements. A control group of healthy volunteers were examined as well. Video documentation and a camera system using passive markers were employed. RESULTS: Treadmill training started with weight reduction of 25% of bodyweight (18 (0-35) kg), maximum walking speed 0.28 (0.15-0.7) m/s and maximum walking duration 4.7 (3-7) min. At the end of the training, weight reduction decreased to 9.3 (0-20) kg, maximum walking speed increased to 0.67 (0.23-1.1) ms with a maximum walking duration of 11 (8-15) min. 3-D motion analysis of hip, knee and ankle demonstrated joint excursions almost entirely within the limits of normal gait. Exceptions were due to fixed contractures. CONCLUSIONS: Our data suggests that it is possible to perform early gait training on a treadmill with no supportive orthoses within the physiologic range of joint motion. The risk for repetitive stress injuries or other negative effects is low. DOI: 10.1038/sj/sc/3101239. Stiftung Orthopadische Universitatsklinik Heidelberg, Heidelberg, Germany.

  Baskov AV, Shevelev IN, Iarikov DE, Iundin VI, Kolpachkov VA and Sokolova AA (1998). [The results of omentomyelopexy in the late period of traumatic spinal cord disease]. Zh Vopr Neirokhir Im N N Burdenko. (2): 17-9. Summary: The results of omental transplantation to the site of spinal cord lesion in 40 patients in late injury are given. Neurological deficit was alleviated in 17.5% of patients. Improvement of segmentary functions was observed in most cases and was recorded within 1 week to 3 months postoperatively. There was no neurological improvement after 6 months postoperatively. Patients with mild spinal cord injuries (D10- L1) had the best outcomes. Comparative analysis of the outcomes of omentomyelopexy with those of treatment in 115 patients undergone meningomyeloradicolysis did not demonstrate any significant difference. Thus, it is not justifiable to use omental transposition in late spinal cord injury.

  Behrman AL and Harkema SJ (2000). Locomotor training after human spinal cord injury: a series of case studies. Phys Ther. 80 (7): 688-700. Summary: Many individuals with spinal cord injury (SCI) do not regain their ability to walk, even though it is a primary goal of rehabilitation. Mammals with thoracic spinal cord transection can relearn to step with their hind limbs on a treadmill when trained with sensory input associated with stepping. If humans have similar neural mechanisms for locomotion, then providing comparable training may promote locomotor recovery after SCI. We used locomotor training designed to provide sensory information associated with locomotion to improve stepping and walking in adults after SCI. Four adults with SCIs, with a mean postinjury time of 6 months, received locomotor training. Based on the American Spinal Injury Association (ASIA) Impairment Scale and neurological classification standards, subject 1 had a T5 injury classified as ASIA A, subject 2 had a T5 injury classified as ASIA C, subject 3 had a C6 injury classified as ASIA D, and subject 4 had a T9 injury classified as ASIA D. All subjects improved their stepping on a treadmill. One subject achieved overground walking, and 2 subjects improved their overground walking. Locomotor training using the response of the human spinal cord to sensory information related to locomotion may improve the potential recovery of walking after SCI. Department of Physical Therapy and University of Florida Brain Institute, University of Florida, Gainesville 32510-0154, USA. abehrman@hp.ufl.edu.

  Blight AR and Gruner JA (1987). Augmentation by 4-aminopyridine of vestibulospinal free fall responses in chronic spinal-injured cats. J Neurol Sci. 82 (1-3): 145-59. Summary: This study examines the effect of the potassium channel blocker 4-aminopyridine (4-AP) on free fall responses (FFR) in the hindlimb muscles of chronically spinal injured cats. The thoracic spinal cord of 7 adult female cats was injured by a standardized contusion method. At 3-7 months post-injury the FFR in 6 hindlimb muscles was recorded electromyographically in each animal, under ketamine sedation. The normal short-latency response to a sudden drop was severely attenuated in all injured animals and practically undetectable in 2 cases. Within 15 min following intravenous administration of 1 mg/kg 4-AP, there was profound augmentation of the amplitude of the FFR and a tendency toward normalization of latency in all animals, though the normal amplitude range was not attained. The same 4-AP dose produced a relatively small increase of FFR amplitude in only 2 of 4 normal, uninjured animals tested. The data are consistent with previous observations that low doses of 4-AP restore conduction in some critically demyelinated axons, and provide support for the hypothesis that conduction block in surviving axons is responsible for a proportion of the dysfunction in chronic spinal injury. Augmentation of FFR in injured animals may also result partly from increased transmitter release in both spinal cord and periphery, due to the presynaptic effects of 4-AP. Department of Neurosurgery, New York University Medical Center, NY 10016.

  Blight AR, Toombs JP, Bauer MS and Widmer WR (1991). The effects of 4-aminopyridine on neurological deficits in chronic cases of traumatic spinal cord injury in dogs: a phase I clinical trial. J Neurotrauma. 8 (2): 103-19. Summary: A Phase I trial of 4-aminopyridine (4-AP) was carried out in 39 dogs referred to the veterinary teaching hospital with naturally occurring traumatic paraplegia or paraparesis. The rationale for the study was provided by the observation that 4-AP restores conduction in demyelinated nerve fibers in experimental spinal cord injury. Most injuries (77%) resulted from degenerative disk disease, occurring at or near the thoracolumbar junction, and producing chronic, complete paraplegia. Neurological examination of each dog was recorded on videotape before and at intervals after administration of 4-AP. The drug was administered systemically in total doses between 0.5 and 1 mg/kg body weight. Three areas of neurological status changed significantly at 15-45 minutes following administration of 4-AP: (a) striking improvements in hindlimb placing occurred in 18 animals; (b) increased awareness of painful stimuli to the hindlimb in 10 animals; (c) partial recovery of the cutaneus trunci muscle reflex of the back skin in 9 animals. These effects reversed within a few hours of administration. Other animals (36%) showed no change in neurological signs except a slight enhancement of hindlimb reflex tone. Significant side effects were seen in 6 dogs receiving higher intravenous doses, with elevation of body temperature and apparent anxiety, leading to mild seizures in 3 of the animals. These seizures were controlled with diazepam. The results indicate that conduction block may contribute significantly to functional deficits in closed-cord injuries and that potassium channel blockade may prove to be a valid, if limited approach to therapeutic intervention in chronic paraplegia and paraparesis. Center for Paralysis Research, School of Veterinary Medicine, Purdue University, West Lafayette, Indiana.

  Borgens RB, Toombs JP, Breur G, Widmer WR, Waters D, Harbath AM, March P and Adams LG (1999). An imposed oscillating electrical field improves the recovery of function in neurologically complete paraplegic dogs. J Neurotrauma. 16 (7): 639-57. Summary: We show that an applied electric field in which the polarity is reversed every 15 minutes can improve the outcome from severe, acute spinal cord injury in dogs. This study utilized naturally injured, neurologically complete paraplegic dogs as a model for human spinal cord injury. The recovery of paraplegic dogs treated with oscillating electric field stimulation (OFS) (approximately 500 to 600 microV/mm; n = 20) was compared with that of sham-treated animals (n = 14). Active and sham stimulators were fabricated in West Lafayette, Indiana. They were coded, randomized, sterilized, and packaged in Warsaw, Indiana, and returned to Purdue University for blinded surgical implantation. The stimulators were of a previously unpublished design and meet the requirements for phase I human clinical testing. All dogs were treated within 18 days of the onset of paraplegia. During the experimental applications, all received the highest standard of conventional management, including surgical decompression, spinal stabilization (if required), and acute administration of methylprednisolone sodium succinate. A radiologic and neurologic examination was performed on every dog entering the study, the latter consisting of standard reflex testing, urologic tests, urodynamic testing, tests for deep and superficial pain appreciation, proprioceptive placing of the hind limbs, ambulation, and evoked potential testing. Dogs were evaluated before and after surgery and at 6 weeks and 6 months after surgery. A greater proportion of experimentally treated dogs than of sham-treated animals showed improvement in every category of functional evaluation at both the 6-week and 6-month recheck, with no reverse trend. Statistical significance was not reached in comparisons of some individual categories of functional evaluation between sham-treated and OFS-treated dogs (ambulation, proprioceptive placing); an early trend towards significance was shown in others (deep pain), and significance was reached in evaluations of superficial pain appreciation. An average of all individual scores for all categories of blinded behavioral evaluation (combined neurologic score) was used to compare group outcomes. At the 6-month recheck period, the combined neurologic score of OFS-treated dogs was significantly better than that of control dogs (p = 0.047; Mann-Whitney, two-tailed). Department of Basic Medical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, Indiana 47907, USA. cpr@vet.purdue.edu.

  Bowe CM, Kocsis JD, Targ EF and Waxman SG (1987). Physiological effects of 4-aminopyridine on demyelinated mammalian motor and sensory fibers. Ann Neurol. 22 (2): 264-8. Summary: The selective response of demyelinated sensory fibers to 4-aminopyridine (4-AP) has been proposed as a mechanism underlying the reported paresthesias that complicate the use of this potassium-channel blocking agent in clinical trials for the treatment of multiple sclerosis and neuromuscular disorders. To identify differences in the electrophysiological response of specific fiber types to the application of 4-AP, rat ventral and dorsal spinal roots, demyelinated by intrathecal injections of lysophosphatidylcholine, were examined in vitro before and during potassium-channel blockade. The compound action potentials of demyelinated ventral roots showed a prominent postspike negativity associated with a broadening of single action potentials following application of 4-AP. Under similar conditions, whole root responses of demyelinated dorsal root axons also developed a late negativity, but individual fibers were observed to fire repetitively in response to a single stimulus. The data support the hypothesis that the prominent sensory dysfunctions reported in clinical trials of 4-AP are due to the selective response characteristics of sensory fibers. Department of Pediatrics, Brown University, Providence, RI 02912.

  Bracken MB (2001). Methylprednisolone and acute spinal cord injury: an update of the randomized evidence. Spine. 26 (24 Suppl): S47-54. Summary: OBJECTIVES: Randomized trials are widely recognized as providing the most reliable evidence for assessing efficacy and safety of therapeutic interventions. This evidence base is used to evaluate the current status of methylprednisolone (MPSS) in the early treatment of acute spinal cord injury. METHODS: Medline, CINAHL, and other specified databases were searched for MeSH headings "methylprednisolone and acute spinal cord injury." The Cochrane Library and an existing systematic review on the topic were also searched. RESULTS: Five randomized controlled trials were identified that evaluated high-dose MPSS for acute spinal cord injury. Three trials by the NASCIS group were of high methodologic quality, and a Japanese and French trial of moderate to low, methodologic quality. Meta-analysis of the final result of three trials comparing 24-hour high-dose MPSS with placebo or no therapy indicates an average unilateral 4.1 motor function score improvement (95% confidence interval 0.6-7.6, P = 0.02) in patients treated with MPSS. This neurologic recovery is likely to be correlated with improved functional recovery in some patients. The safety of this regimen of MPSS is evident from the spinal cord injury trials and a systematic review of 51 surgical trials of high-dose MPSS. CONCLUSION: High-dose MPSS given within 8 hours of acute spinal cord injury is a safe and modestly effective therapy that may result in important clinical recovery for some patients. Further trials are needed to identify superior pharmacologic therapies and to test drugs that may sequentially influence the postinjury cascade. Department of Epidemiology, Yale University School of Medicine, 60 College Street, New Haven, Connecticut 06520, USA. michael.bracken@yale.edu.

  Bracken MB and Holford TR (2002). Neurological and functional status 1 year after acute spinal cord injury: estimates of functional recovery in National Acute Spinal Cord Injury Study II from results modeled in National Acute Spinal Cord Injury Study III. J Neurosurg. 96 (3 Suppl): 259-66. Summary: OBJECT: In the second National Acute Spinal Cord Injury Study (NASCIS II) investigators evaluated several standard neurological parameters but not functional activity. This has led to questions concerning the clinical importance of the increase in neurological recovery observed following administration of methylprednisolone (MP) within 8 hours of acute spinal cord injury (SCI). The safety of the therapy has also been questioned. METHODS: Both neurological and functional recovery were assessed in NASCIS III, a trial that followed an almost identical protocol to NASCIS II. In the current analysis locally weighted scatterplot smoothing (LOESS) nonparametric regression is used to model the extent of recovery in the Functional Independence Measure (FIM) that is predicted by improvement in the NASCIS/American Spinal Cord Injury Association motor scores that were documented in NASCIS III 1 year after SCI, and the models are applied to the extent of motor recovery demonstrated in NASCIS II. The models predict improvement in FIM that would be expected from the motor function recovery observed in NASCIS II. Estimates are provided overall and for patients with complete and incomplete neurological loss at time of injury. The authors review recent evidence obtained from randomized studies documenting adverse effects that may result from high-dose MP therapy. The relationship between motor function and FIM is strongly nonlinear and dependent on initial level of injury and degree of injury severity. In the best statistical model, the expanded motor score could be used to explain 77.2% of the variability in the FIM. Based on the mean MP-related 3.6-unit improvement in the motor score for patients with complete injuries and 7.3 for those with incomplete injuries owed to MP in NASCIS II, 18.6% of patients would improve six or more FIM points and 9% nine or more points, respectively. In those with complete neurological injury, the mean motor improvement of 3.6 predicted that 63.9% of the patients would improve three or more FIM points and 12.1% six or more points to a maximum of eight points. Of those with incomplete neurological injury, a 7.3 mean improvement in motor function predicted that 27.4% would gain six or more FIM points and that 21% would gain nine or more points to a maximum of 15 points. Analysis of the current best evidence from SCI and other randomized surgical trials in which high-dose MP has been administered provides no grounds for concern about commonly studied adverse effects. CONCLUSIONS: The extent of MP therapy-related motor function recovery observed in NASCIS II predicted clinically important recovery in the FIM. Reasons to be cautious with regard to this prediction include the lack of robustness in statistical modeling, some loss of validity in the FIM, and considerable heterogeneity in the SCI population. Whatever functional activity is ascribed to high-dose MP therapy, it is does not appear to be associated with risk of adverse outcomes. Department of Epidemiology, School of Medicine, and Graduate School, Yale University, New Haven, Connecticut 06520-8034, USA. michael.bracken@yale.edu.

  Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings M, Herr DL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot PL, Jr., Piepmeier J, Sonntag VK, Wagner F, Wilberger JE, Winn HR and Young W (1997). Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. Jama. 277 (20): 1597-604. Summary: OBJECTIVE: To compare the efficacy of methylprednisolone administered for 24 hours with methyprednisolone administered for 48 hours or tirilazad mesylate administered for 48 hours in patients with acute spinal cord injury. DESIGN: Double-blind, randomized clinical trial. SETTING: Sixteen acute spinal cord injury centers in North America. PATIENTS: A total of 499 patients with acute spinal cord injury diagnosed in National Acute Spinal Cord Injury Study (NASCIS) centers within 8 hours of injury. INTERVENTION: All patients received an intravenous bolus of methylprednisolone (30 mg/kg) before randomization. Patients in the 24-hour regimen group (n=166) received a methylprednisolone infusion of 5.4 mg/kg per hour for 24 hours, those in the 48-hour regimen group (n=167) received a methylprednisolone infusion of 5.4 mg/kg per hour for 48 hours, and those in the tirilazad group (n=166) received a 2.5 mg/kg bolus infusion of tirilazad mesylate every 6 hours for 48 hours. MAIN OUTCOME MEASURES: Motor function change between initial presentation and at 6 weeks and 6 months after injury, and change in Functional Independence Measure (FIM) assessed at 6 weeks and 6 months. RESULTS: Compared with patients treated with methylprednisolone for 24 hours, those treated with methylprednisolone for 48 hours showed improved motor recovery at 6 weeks (P=.09) and 6 months (P=.07) after injury. The effect of the 48-hour methylprednisolone regimen was significant at 6 weeks (P=.04) and 6 months (P=.01) among patients whose therapy was initiated 3 to 8 hours after injury. Patients who received the 48-hour regimen and who started treatment at 3 to 8 hours were more likely to improve 1 full neurologic grade (P=.03) at 6 months, to show more improvement in 6-month FIM (P=.08), and to have more severe sepsis and severe pneumonia than patients in the 24-hour methylprednisolone group and the tirilazad group, but other complications and mortality (P=.97) were similar. Patients treated with tirilazad for 48 hours showed motor recovery rates equivalent to patients who received methylprednisolone for 24 hours. CONCLUSIONS: Patients with acute spinal cord injury who receive methylprednisolone within 3 hours of injury should be maintained on the treatment regimen for 24 hours. When methylprednisolone is initiated 3 to 8 hours after injury, patients should be maintained on steroid therapy for 48 hours.

  Cheng H, Almstrom S, Gimenez-Llort L, Chang R, Ove Ogren S, Hoffer B and Olson L (1997). Gait analysis of adult paraplegic rats after spinal cord repair. Exp Neurol. 148 (2): 544-57. Summary: This study presents a novel detailed method of analysis of rat gait and uses this method to demonstrate recovery of forward locomotion patterns in adult rats made paraplegic by surgical spinal cord transection and subjected to a novel strategy for spinal cord repair. Six normal rats were compared to five animals in which the cord was transected at T8- T9, and a 5-mm segment of the spinal cord removed, and to seven animals in which, following spinal cord transection and removal of a spinal cord segment, multiple intercostal peripheral nerve bridges were implanted, rerouting pathways from white to gray matter in both directions. The implanted area was filled with fibrin glue containing acidic fibroblast growth factor. Details of the repair strategy have been published (H. Cheng, Y. Cao, and L. Olson, 1996, Science 273: 510- 513). Gait analysis was carried out 3 and 4 months after surgery and once in the normal animals. Animals were allowed to walk across a runway with a transparent floor. Each test consisted of five trials, and each trial was videorecorded from underneath. Using frame-by-frame playback, individual footprints were then recorded regarding location and order of limb use, as well as step quality (degree of weight bearing, etc.). These data allowed measuring runway transit time, five different measures of step numbers, all possible temporal patterns of limb use, stride length, and base of support. Transected controls remained paralyzed in the hindlimbs with only occasional reflex hindlimb movements without weight bearing. Animals subjected to the full repair procedure were significantly faster than the controls, used their hindlimbs for 25-30% of the movements, and regained several of the specific limb recruitment patterns used by normal rats. Taken together, the gait analysis data demonstrate remarkable recovery of coordinated gait in the repaired animals, which was significantly better than controls for all relevant parameters, while at the same time clearly inferior to normal rats for most of the examined parameters. We conclude that normal rats use a multitude of interchangeable step sequence patterns, and that our spinal cord repair strategy leads to recovery of some of these patterns following complete spinal cord transection. These data suggest functionally relevant neuronal communication across the lesion. Copyright 1997 Academic Press. Department of Neuroscience, Karolinska Institute, Stockholm, S-171 77, Sweden.

  Cheng H, Cao Y and Olson L (1996). Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function [see comments]. Science. 273 (5274): 510-3. Summary: Complete spinal cord gaps in adult rats were bridged with multiple intercostal nerve grafts that redirected specific pathways from white to gray matter. The grafted area was stabilized with fibrin glue containing acidic fibroblast growth factor and by compressive wiring of posterior spinal processes. Hind limb function improved progressively during the first 6 months, as assessed by two scoring systems. The corticospinal tract regenerated through the grafted area to the lumbar enlargement, as did several bulbospinal pathways. These data suggest a possible repair strategy for spinal cord injury. Department of Neuroscience, Karolinska Institute, S-171 77 Stockholm, Sweden.

  Cheng H and Olson L (1995). A new surgical technique that allows proximodistal regeneration of 5-HT fibers after complete transection of the rat spinal cord. Exp Neurol. 136 (2): 149-61. Summary: Shortening of the spinal column has been regarded as one possible method to obtain cord-to-cord apposition after total transection of the spinal column. However, to further improve regenerative possibilities, the problems of inconstant bony fusion and cyst formations within the junctions must be resolved. Modifying the method of de Medinaceli on the rat thoracic spine, we attempted several fixation devices to achieve better interspinal fixation after spondylectomy and transection, including transpedicular miniscrews, wiring of the transverse processes, and wiring of the posterior spinal processes. A dynamic model, based on retracting and compressing the cut ends of the spinal cord by means of adjustable fixation devices to allow swelling and shrinking of the stumps was also attempted to better compensate pathophysiologic changes of the transected cord. The best regeneration, as indicated by regrowth of 5-HT fibers below the level of transection, was obtained following application of fibrin glue and compressive wiring of posterior spinal processes. In this group, the distance between proximal and distal GFAP-rich spinal cord tissue (gap consisting of GFAP-poor components such as cysts, phagocytic cells, and scar tissue) of the two spinal cord stumps was also the shortest. With better approximation, the numbers of regenerated 5-HT fibers improved remarkably, suggesting that this descending fiber system is able to bridge the transection under these conditions. Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.

  Clifton GL, Donovan WH, Dimitrijevic MM, Allen SJ, Ku A, Potts JR, 3rd, Moody FG, Boake C, Sherwood AM and Edwards JV (1996). Omental transposition in chronic spinal cord injury [see comments]. Spinal Cord. 34 (4): 193-203. Summary: The results of omental transposition in chronic spinal cord injury have been reported in 160 patients operated upon in the United States, Great Britain, China, Japan, India and Mexico, with detailed outcomes reported in few studies. Recovery of function to a greater degree than expected by natural history has been reported. In this series, 15 patients with chronic traumatic spinal cord injury (> 1.5 years from injury) underwent transposition of pedicled omentum to the area of the spinal cord injury. Of the first series of four patients who were operated upon in 1988, one died, one was lost to follow-up and two were followed with sequential neurological examinations and Magnetic Resonance Imaging (MRI) scans preoperatively, at 1 year post injury and 4 1/2 years post injury. Another 11 patients were operated in 1992 and underwent detailed neurological and neurophysiological examinations and had MRI scans preoperatively and every 4 months for at least 1 year after surgery. All patients completed a detailed self-report form. Of the total of 13 operated patients in both series followed for 1-4 1/2 years, six reported some enhanced function at 1 year and five of these felt the changes justified surgery primarily because of improved truncal control and decreased spasticity. MRI scans showed enlargement of the spinal cord as compared to preoperative scans in seven patients. Increased T2 signal intensity of the spinal cord was found by 1 year after surgery in eight of 13 operated patients. Neurophysiological examinations of 11 patients in the second series agreed with self- reports of increases or decreases in spasticity (r = 0.65, P < 0.03). Somatosensory evoked potentials and motor evoked potentials at 4 month intervals up to 1 year in these patients showed no change after surgery. Neurological testing, using the American Spinal Injury Association (ASIA) and International Medical Society of Paraplegia (IMSOP) international scoring standards, failed to show any significant changes when the 1-year post operative examination was compared to the first preoperative examination except for decreased sensory function after surgery which approached statistical significance. When the 11 patients in the second series were compared to eight non-operated matched patients, followed for a similar length of time, no significant differences were found. Complications encountered in the operated patients from both series included one postoperative death from a pulmonary embolus, one postoperative pneumonia, three chronic subcutaneous cerebrospinal fluid (CSF) fistulae requiring wound revision, and one patient who developed biceps and wrist extensor weakness bilaterally requiring graft removal. We conclude that the omental graft remains viable over time and this operation can induce anatomical changes in the spinal cord as judged by MRI. Some patients reported subjective improvement but this was not supported by objective testing. We, therefore, find no justification for further clinical trials of this procedure in patients who have complete or sensory incomplete lesions. Further testing in motor incomplete patients would seem appropriate only with compelling supportive data. Department of Neurosurgery, University of Texas-Houston Medical School, USA.

  Colombo G, Wirz M and Dietz V (2001). Driven gait orthosis for improvement of locomotor training in paraplegic patients. Spinal Cord. 39 (5): 252-5. Summary: DESIGN: Single cases. OBJECTIVE: To compare the effects of manually assisted locomotor training in paraplegic patients with the automated training by a driven gait orthosis. SETTING: ParaCare, University Hospital Balgrist in Zurich, Switzerland. METHODS: Treadmill training with manual assistance and by a driven gait orthosis was applied to two spinal cord injured patients. The first patient had an incomplete lesion at C3, the second a complete lesion at C5. They were selected by convenience sample. The EMG activity of the leg muscles rectus femoris, biceps femoris, gastrocnemius medials (GM) and tibialis anterior (TA) was visually compared for the two training methods. GM and TA activity was also quantified by calculating the variation ratio between the EMG of the patients and a set of healthy subjects. RESULTS: No significant difference between the two training methods was found according to the leg muscle EMG activity. CONCLUSION: Neuronal centers in the spinal cord become activated in a similar way by the manually assisted and the automated locomotor training. With the driven gait orthosis training sessions can be prolonged and workload of therapists can be reduced, and therefore, the automated training represents an alternative to the conventional therapy. Rehabilitation and Research Institute ParaCare, University Hospital Balgrist, Zurich, Switzerland.

  Darlington C (2000). Fampridine Acorda Therapeutics. Curr Opin Investig Drugs. 1 (3): 375-9. Summary: Fampridine (EL-970; 4-aminopyridine), a potassium channel blocker, is in phase II development by Acorda for the potential treatment of spinal cord injuries and multiple sclerosis (MS) [385529]. Originally, Elan was evaluating fampridine for the treatment of spinal cord injuries in collaboration with Acorda Therapeutics [243393]. The drug was licensed from Rush Medical Center and Elan holds worldwide rights with Rush to provide clinical and technical support. Elan has used its Intestinal Protective Drug Absorption System (IPDAS) drug delivery system to produce Neurelan, which is a controlled-release (twice daily) formulation of fampridine [223736]. However, it seems possible that production of Neurelan might be taken over by Acorda [381211]. Acorda completed preliminary phase II trials of the drug for spinal cord injury (SCI) in 1998 [303023]. In February 2000, the company predicted that it would begin the a late-stage phase II trial for chronic (long-term) SCI in the first quarter of 2000 [355696], [350955]. The trial, which will be double-blind, randomized and placebo-controlled, will enroll 90 people with chronic SCI at 10 US rehabilitation centers [355696]. As of July 2000, phase II studies for chronic SCI were underway and phase III studies are expected to begin in 2001 [376610]. Results presented at the EPHAR '99 congress showed that contractions induced by 4-AP in porcine coronary arteries, are likely to depend on the neuronal 5-HT, but not on the noradrenaline store in this tissue [334161]. Department of Psychology, University of Otago, Dunedin, New Zealand. cynthia@psy.otago.ac.nz.

  Davis FA, Stefoski D and Rush J (1990). Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis. Ann Neurol. 27 (2): 186-92. Summary: 4-Aminopyridine (4-AP), a potassium channel blocker, restores conduction in blocked, demyelinated animal nerve. Its administration to multiple sclerosis (MS) patients produces transient neurological improvements. Vision improves after either oral or intravenous administration, whereas motor function improvement has been reported only with the latter. To assess further its potential as a practical symptomatic treatment, we studied the efficacy of single, oral doses of 4-AP on both visual and motor signs in MS. Twenty temperature-sensitive male MS patients were given either 10 to 25 mg of 4-AP or identically appearing lactose placebo capsules. Static quantitative perimetry, critical flicker-fusion, visual acuity, visual evoked potentials, and videotaped neurological examinations were monitored. All of 15 MS patients given 4-AP mildly to markedly improved. Motor functions (power, coordination, gait) improved in 9 of 13 involved, vision in 11 of 13, and oculomotor functions in 1 of 2. Improvements developed gradually at doses as low as 10 mg, usually beginning within 60 minutes after drug administration, and reversed gradually over 4 to 7 hours. No serious adverse effects occurred. No significant changes were observed in 5 MS patients given placebo. We conclude that orally administered 4-AP produces clinically important improvements in multiple, chronic deficits in MS. Further studies are warranted to assess efficacy and safety of prolonged administration. Multiple Sclerosis Center, Chicago, IL 60612.

  Dietz V (2001). Spinal cord lesion: effects of and perspectives for treatment. Neural Plast. 8 (1-2): 83-90. Summary: Following central motor lesions, two forms of adaptation can be observed which lead to improved mobility: (1) the development of spastic muscle tone, and (2) the activation of spinal locomotor centers induced by specific treadmill training. Tension development during spastic gait is different from that during normal gait and appears to be independent of exaggerated monosynaptic stretch reflexes. Exaggerated stretch reflexes are associated with an absence or reduction of functionally essential polysynaptic reflexes. When supraspinal control of spinal reflexes is impaired, the inhibition of monosynaptic reflexes is missing in addition to a reduced facilitation of polysynaptic reflexes. Therefore, overall leg muscle activity becomes reduced and less well modulated in patients with spasticity. Electrophysiological and histological studies have shown that a transformation of motor units takes place following central motor lesions with the consequence that regulation of muscle tone is achieved at a lower level of neuronal organization which in turn enables the patient to walk. Based on observations of the locomotor capacity of the spinal cat, recent studies have indicated that spinal locomotor centers can be activated and trained in patients with complete or incomplete paraplegia when the body is partially unloaded. However, the level of electromyographic activity in the gastrocnemius (the main antigravity muscle during gait) is considerably lower in the patients compared to healthy subjects. During the course of a daily locomotor training program, the amplitude of gastrocnemius, electromyographic activity increases significantly during the stance phase, while inappropriate tibialis anterior activation decreases. Patients with incomplete paraplegia benefit from such training programs such that their walking ability on a stationary surface improves. The pathophysiology and functional significance of spastic muscle tone and the effects of treadmill training on the locomotor pattern underlying new attempts to improve the mobility of patients with paraplegia are reviewed. ParaCare, Paraplegic Centre, University Hospital Balgrist, Zurich, Switzerland. dietz@balgrist.unizh.ch.

  Dobkin BH (2000). Functional rewiring of brain and spinal cord after injury: the three Rs of neural repair and neurological rehabilitation. Curr Opin Neurol. 13 (6): 655-9. Summary: Gains in the use of the upper extremities and in walking after brain and spinal cord injury or stroke depend especially upon the effectiveness of spared sensorimotor nodes in the networks for motor control. Biological interventions for neural repair and motor recovery may involve strategies that replace cells or signalling molecules and stimulate the regrowth of axons. The greatest success of these interventions will depend upon the functional incorporation of spared and new cells and their processes into motor networks. The distributed and modular organization of the motor neurons of the cortex and spinal cord offer a substrate that arranges or represents particular patterns of movement, yet is highly adaptable to training. Neurological impairments and related disabilities can be reduced through rehabilitative retraining protocols that engage these critical components of the sensorimotor network to promote use-dependent adaptations and functional rewiring.

  Duffill J, Buckley J, Lang D, Neil-Dwyer G, McGinn F and Wade D (2001). Prospective study of omental transposition in patients with chronic spinal injury. J Neurol Neurosurg Psychiatry. 71 (1): 73-80. Summary: OBJECTIVES: This prospective study was designed to assess the effects of omental transposition in patients with a chronic spinal injury. METHODS: Neurological status was established to be stable and multiple baseline across patient studies were done preoperatively and repeated postoperatively. Assessments included activities of daily living (ADL), functional ability, degree of spasticity, motor power, sensation, pain perception, urodynamic studies, electromyography, sensory evoked potentials (SEPs), and infrared thermography to measure peripheral and general skin vascular responses. Each patient had MRI. Assessments were done at 3, 6, and 12 months after omental transposition in 17 patients. RESULTS: The detailed assessments failed to show significant improvement, although some patients showed minor objective and subjective change in some categories. Neurological deterioration occurred in one patient. There were 20 surgical complications including urinary tract infection, deep vein thrombosis, wound infection, and incisional hernia. CONCLUSIONS: Omental transposition has not been shown to improve neurological function in 17 patients with chronic spinal cord injury, and continued use of this operation in this situation is not supported by this study. Further advances in spinal cord repair may utilise the pedicled omental graft to provide an alternative vascular supply, but its current use should be limited to experimental models. Department of Neurosurgery, Wessex Neurological Centre, Southampton University Hospitals Trust, Tremona Road, Southampton SO16 6YD, UK.

  Edgerton VR, Leon RD, Harkema SJ, Hodgson JA, London N, Reinkensmeyer DJ, Roy RR, Talmadge RJ, Tillakaratne NJ, Timoszyk W and Tobin A (2001). Retraining the injured spinal cord. J Physiol. 533 (Pt 1): 15-22. Summary: The present review presents a series of concepts that may be useful in developing rehabilitative strategies to enhance recovery of posture and locomotion following spinal cord injury. First, the loss of supraspinal input results in a marked change in the functional efficacy of the remaining synapses and neurons of intraspinal and peripheral afferent (dorsal root ganglion) origin. Second, following a complete transection the lumbrosacral spinal cord can recover greater levels of motor performance if it has been exposed to the afferent and intraspinal activation patterns that are associated with standing and stepping. Third, the spinal cord can more readily reacquire the ability to stand and step following spinal cord transection with repetitive exposure to standing and stepping. Fourth, robotic assistive devices can be used to guide the kinematics of the limbs and thus expose the spinal cord to the new normal activity patterns associated with a particular motor task following spinal cord injury. In addition, such robotic assistive devices can provide immediate quantification of the limb kinematics. Fifth, the behavioural and physiological effects of spinal cord transection are reflected in adaptations in most, if not all, neurotransmitter systems in the lumbosacral spinal cord. Evidence is presented that both the GABAergic and glycinergic inhibitory systems are up-regulated following complete spinal cord transection and that step training results in some aspects of these transmitter systems being down-regulated towards control levels. These concepts and observations demonstrate that (a) the spinal cord can interpret complex afferent information and generate the appropriate motor task; and (b) motor ability can be defined to a large degree by training. Brain Research Institute and Departments of Physiological Science and Neurobiology, University of California, Los Angeles, CA 90095, USA.

  Field-Fote EC (2001). Combined use of body weight support, functional electric stimulation, and treadmill training to improve walking ability in individuals with chronic incomplete spinal cord injury. Arch Phys Med Rehabil. 82 (6): 818-24. Summary: OBJECTIVE: To assess the effect of an intervention combining body weight support (BWS), functional electric stimulation (FES), and treadmill training on overground walking speed (OGWS), treadmill walking speed, speed and distance, and lower extremity motor scores (LEMS). DESIGN: Before and after comparison. SETTING: Miami Project to Cure Paralysis. PARTICIPANTS: Nineteen subjects with American Spinal Injury Association class C injury who were at least 1 year postinjury and had asymmetrical lower extremity function. INTERVENTION: Subjects trained 1.5 hours per day, 3 days per week, for 3 months. The training consisted of body weight-supported treadmill walking assisted by electric stimulation. Stimulation was applied to common peroneal nerve of the weaker lower extremity (LE) and timed to assist with the swing phase of the step cycle. MAIN OUTCOME MEASURES: OGWS in the absence of both BWS and FES; LEMS, and treadmill training parameters of speed and distance. RESULTS: Over the course of training, there was a significant increase in OGWS (from.12 +/- 0.8m/s to .21 +/- .15m/s, p = .0008), treadmill walking speed (from .23 +/- .12m/s to.49 +/- .20m/s, p = .00003), and treadmill walking distance (from 93 +/- 84m to 243 +/- 139m, p = .000001). The median LEMS increased significantly for both the stimulated and nonstimulated leg (from 8 to 11 in the FES-assisted leg, from 15 to 18 in the nonassisted leg, p < .005 for each). CONCLUSIONS: All subjects showed improvement in OGWS and overall LE strength. Further research is required to delineate the essential elements of these particular training strategies. Division of Physical Therapy and the Miami Project to Cure Paralysis, University of Miami School of Medicine, Miami, FL, USA. edee@miami.edu.

  Fujihara K and Miyoshi T (1998). The effects of 4-aminopyridine on motor evoked potentials in multiple sclerosis. J Neurol Sci. 159 (1): 102-6. Summary: In order to study the effects of 4-aminopyridine (4-AP) on impulse conduction in multiple sclerosis (MS), we studied motor-evoked potentials (MEPs) in the upper (U/E) and lower extremities (L/E) of six MS patients with stable spastic paraparesis before and after intravenous administration of 4-AP. As a result, we found a significant increase in mean amplitudes in U/E and L/E (P = 0.008) and a significant decrease in the variability of onset latencies in L/E (P = 0.017) without any significant changes in mean and shortest onset latencies. In four limbs of three patients in whom there were no detectable MEP responses before 4-AP administration, definite responses were elicited after 4-AP administration. 4-AP seems to have its therapeutic effects by improving impulse conductivity in demyelinated nerve fibers or by enhancing central or peripheral synaptic transmission, which thus results in coordinated contractions of more muscle fibers in MS. Department of Neurology, Kyushu Rosai Hospital, Kitakyushu, Japan. fujikazu@neurol.med.tohoku.ac.jp.

  Geisler FH, Coleman WP, Grieco G and Poonian D (2001). The Sygen multicenter acute spinal cord injury study. Spine. 26 (24 Suppl): S87-98. Summary: STUDY DESIGN: Randomized, double-blind, sequential, multicenter clinical trial of two doses of Sygen versus placebo. OBJECTIVES: To determine efficacy and safety of Sygen in acute spinal cord injury. SUMMARY OF BACKGROUND DATA: An earlier, single-center trial in 28 patients showed an improvement (50.0% vs. 7.1%, P = 0.034) in marked recovery with Sygen. METHODS: Standard clinical trial techniques. RESULTS: The prospectively planned analysis at the prespecified endpoint time for all patients was negative. There was a significant effect in all patients in the primary outcome variable (the percentage of marked recovery) at week 8, the end of the dosing period. There was a significant effect in all patients in the time at which marked recovery is first achieved. Restricted to severity Group B, which has small sample size, the primary efficacy analysis showed a trend but did not reach significance. There is a large, consistent and, at some time points, significant effect in the primary outcome variable in the nonoperated patients through week 26. The American Spinal Injury Association motor, light touch, and pinprick scores showed a consistent trend in favor of Sygen, as also did bowel function, bladder function, sacral sensation, and anal contraction. The less severely injured patients appeared to have a greater beneficial drug effect. Evidence against an effect of Sygen was minimal and scattered. CONCLUSIONS: Although not proven in the primary efficacy analysis of this trial, Sygen appears to be beneficial in patients with severe spinal cord injury. Medical Group, S.C., Chicago Institute of Neurosurgery and Neuroresearch, 2515 North Clark Street, Suite 800, Chicago, Illinois 60614, USA. fgeisler@concentric.net.

  Goldsmith HS (1994). Brain and spinal cord revascularization by omental transposition. Neurol Res. 16 (3): 159-62. Summary: It has been learned over the years that placement of the pedicled omentum onto the brain and the spinal cord results in the rapid development of blood vessels that penetrate directly, vertically and deeply into the underlying CNS structure. Rapid clinical changes in some patients following omental transposition to the CNS raised the question as to whether the changes might be due not only to increased vascular perfusion, but to neurochemicals within omental tissue. Subsequent studies have shown that the omentum incorporates in its tissue neurotransmitters, nerve growth substances, gangliosides and angiogenic factors of high activity. These neurochemical and angiogenic substances are undoubtedly involved in some manner in the ability of axons in a transected spinal cord to grow at 1 mm/day and apparently make appropriate connections with distal spinal cord target tissue. Department of Neurosurgery, Boston University School of Medicine, MA 02118.

  Goldsmith HS (1997a). Omental transposition in chronic spinal cord injury. Spinal Cord. 35 (3): 189-90. Summary:

  Goldsmith HS (1997b). Omental transposition to the brain for Alzheimer's disease. Ann N Y Acad Sci. 826: 323-36. Summary: Omental transposition (OT) to revascularize the brain was first performed in animals in the late 1960s, where it was shown that blood vessels originating from the omentum crossed through the omental- cerebral interface prior to developing into large-sized vessels that penetrated directly and deeply into the underlying brain. The additional cerebral blood flow coming from the omentum was of sufficient volume to protect an animal's brain from cerebral infarction even in the presence of middle cerebral artery ligation. It was also learned that the omentum was a rich source for neurotransmitters and omentum-derived nerve growth substance. OT to the brain is now being done for a variety of conditions which include strokes, TIAs, epilepsy, and Parkinson's disease. Of recent interest is the published information that OT may play some role in Alzheimer's disease (AD). The placement of the omentum on an AD brain has led to a profound decrease in senile plaque formation. The omentum may ultimately prove to be beneficial in reversing or at least stabilizing the dementia associated with the devastation of AD. University of Nevada School of Medicine, Reno, USA.

  Goldsmith HS, Bacciu P, Cossu M, Pau A, Rodriguez G, Rosadini G, Ruju P, Sehrbundt Viale E, Turtas S and Viale GL (1990). Regional cerebral blood flow after omental transposition to the ischaemic brain in man. A five year follow-up study. Acta Neurochir. 106 (3-4): 145-52. Summary: Regional cerebral blood flow, recorded by the 133Xenon inhalation method, was measured preoperatively and over a five years postoperative period in six patients with completed stroke and stabilized neurological deficits, who had undergone omental transposition for revascularization of the ischaemic brain. Comparisons of the preoperative blood flow values with those recorded following surgery demonstrate a postoperative increase of blood flow in five patients, with a high statistical degree of significance in four of them at the final examination. The flow increase was noted over the infarcted areas of the brain, upon which the omentum had been placed, as well as areas of the ischaemic hemisphere without omental placement and the contralateral hemisphere. Out of the five patients who demonstrated preoperative flow values below the expected norm for age, four showed final postoperative cerebral blood flow within the normal limits for their age. The results are consistent with the assumption that the transposed omentum played a role in postoperative blood flow increase, by adding collateral circulation to the ischaemic brain. Department of Surgery, Boston University Medical School.

  Goldsmith HS and Sax DS (1999). Omental transposition for cerebral infarction: a 13-year follow-up study. Surg Neurol. 51 (3): 342-5; discussion 345-6. Summary: BACKGROUND: During the past decade there has been increasing use of omental transposition to the brain of patients who experienced neurologic sequelae after a cerebral infarction. This paper reports the long-term neurologic effects seen in a patient who underwent omental transposition 31 months after a stroke. Her postoperative follow-up period has been 13 years. CASE DESCRIPTION: The patient had an expressive aphasia, a right hemiparesis and the inability to read which occurred immediately after her stroke. After surgery she demonstrated subjective and objective improvement in her speech and mobility. She also regained her ability to read shortly after surgery. CONCLUSION: The patient demonstrated that omental transposition to the brain can improve neurologic function in the presence of a long-standing cerebral infarction and that the clinical improvement can be maintained over an extended period. Department of Surgery, University of Nevada School of Medicine, Reno, USA.

  Grundman M, Farlow M, Peavy G, Kim HT, Capparelli E, Schultz AN, Salmon DP, Ferris SH, Mobs R, Thomas RG, Schafer K, Campbell K, Hake AM, Schoos B and Thal LJ (2002). A phase I study of AIT-082 in healthy elderly volunteers. J Mol Neurosci. 18 (3): 283-93. Summary: A Phase I, double-blind, placebo-controlled, single-dose, escalation study of the purine derivative, AIT-082 (Neotrofin, NeoTherapeutics, Inc.) was conducted in healthy elderly volunteers. This trial was designed to evaluate single-dose safety, tolerability, and pharmacokinetics. Potential cognitive domains that might benefit from AIT-082 were preliminarily investigated. AIT-082 is currently being developed as a potential treatment for Alzheimer's disease (AD). Preclinical studies indicate that AIT-082 has memory-enhancing properties, stimulates neuritogenesis, and upregulates neurotrophic factors. Subjects received a single oral dose of AIT-082 or placebo on a weekly basis for 5 wk. All patients received a placebo dose at baseline. Six subjects received increasing doses of AIT-082 over the next 4 wk at doses of 0.6, 2.0, 6.0, and 20.0 mg of AIT-082 per kilogram of body weight. Two subjects received placebo throughout the trial. Nine subjects were recruited. One subject was withdrawn after the third treatment visit owing to poor venous access. There were no serious adverse events. The drug was well-tolerated. The time to peak drug concentration was approx 85 min with an elimination half-life of approx 17.6 h. Performance on the Number Comparison, Symbol Digit, and Trails A tests improved with AIT-082 dosing compared to baseline (placebo). In conclusion, AIT-082 was rapidly absorbed by the oral route with a half-life suitable for once daily dosing. No problems with tolerability or safety were demonstrated. Department of Neurosciences, University of California, San Diego, La Jolla 92037, USA. mgrundman@ucsd.edu.

  Gruner JA and Yee AK (1999). 4-Aminopyridine enhances motor evoked potentials following graded spinal cord compression injury in rats. Brain Res. 816 (2): 446-56. Summary: Although several experimental and clinical studies have demonstrated the ability of 4-aminopyridine (4-AP) to restore electrophysiological and/or behavioral function following chronic spinal cord injury, the mechanism by which this occurs remains unclear. Demonstration of efficacy in rat spinal cord injury has not been reported, evidently because even relatively mild spinal cord contusions that produce only minor permanent locomotor disturbances abolish hind limb myoelectric motor evoked potentials (mMEPs). In this study, mMEPs were recorded acutely 25 days following graded thoracic spinal cord compression in rats. mMEP amplitudes were significantly enhanced by a single, 2 mg/kg i.v. dose of 4-AP. mMEPs were increased in all rats showing some evoked responses initially, and also in some animals which had no responses prior to treatment. 4-AP was further found to increase the maximum following frequency of mMEPs in both normal and injured rats from about 0.1 Hz to between 1 and 10 Hz. These data suggest that 4-AP might act by enhancing synaptic efficacy, as well as enhancing conduction in spinal axons whose myelination has been rendered dysfunctional by trauma. Cephalon, Department of Experimental Pharmacology, 145 Brandywine Pkwy., West Chester, PA 19380-4245, USA. jgruner@cephalon.com.

  Hansebout RR, Blight AR, Fawcett S and Reddy K (1993). 4-Aminopyridine in chronic spinal cord injury: a controlled, double-blind, crossover study in eight patients. J Neurotrauma. 10 (1): 1-18. Summary: The potassium channel blocking drug 4-aminopyridine (4-AP) was administered to eight patients with chronic spinal cord injury, in a therapeutic trial based on the ability of the drug to restore conduction of impulses in demyelinated nerve fibers. The study was performed using a randomized, double-blind, crossover design, so that each patient received the drug and a vehicle placebo on different occasions, separated by 2 weeks. Drug and placebo were delivered by infusion over 2 h. An escalating total dose from 18.0 to 33.5 mg was used over the course of the study. Subjects were evaluated neurologically before and after the infusion. Two subjects returned for a second trial after 4 months and were examined daily for 3 to 4 days following drug infusion. Side effects were consistent with previous reports. Administration of the drug was associated with significant temporary neurologic improvement in five of six patients with incomplete spinal cord injury. No effect was detected in two cases of complete paraplegia and one of two severe incomplete cases (Frankel class B). Improvements in neurologic status following drug administration included increased motor control and sensory ability below the injury, and reduction in chronic pain and spasticity. The effects persisted up to 48 h after infusion of the drug, and patients largely returned to preinfusion status by 3 days. Compared with the more rapid elimination of the drug, these prolonged neurologic effects appear to involve a secondary response and are probably not a direct expression of potassium channel blockade. Department of Surgery, McMaster University, Hamilton, Ontario, Canada.

  Hayes KC, Blight AR, Potter PJ, Allatt RD, Hsieh JT, Wolfe DL, Lam S and Hamilton JT (1993). Preclinical trial of 4-aminopyridine in patients with chronic spinal cord injury. Paraplegia. 31 (4): 216-24. Summary: 4-Aminopyridine (4-AP) is a K+ channel blocking agent that enhances nerve conduction through areas of demyelination by prolonging the duration of the action potential and increasing the safety factor for conduction. We have investigated the effects of 4-AP (24 mg total dose-intravenous) in 6 patients with spinal cord injury (3 complete, 3 incomplete) with the intent of overcoming central conduction block, or slowing, due to demyelination. Vital signs remained stable and only mild side effects were noted. The 3 patients with incomplete injuries all demonstrated enhanced volitional EMG interference patterns and one patient exhibited restored toe movements. The changes were reversed on drug washout. There were no changes in segmental reflex activities. These results are consistent with those obtained from 4-AP trials with animal models of spinal cord injury, showing modest therapeutic benefit attributable to enhanced central conduction. Department of Physical Medicine & Rehabilitation, Parkwood Hospital, London, Ontario, Canada.

  Hayes KC, Potter PJ, Wolfe DL, Hsieh JT, Delaney GA and Blight AR (1994). 4-Aminopyridine-sensitive neurologic deficits in patients with spinal cord injury. J Neurotrauma. 11 (4): 433-46. Summary: 4-Aminopyridine (4-AP) is a potassium channel blocking agent with the ability to restore conduction in demyelinated internodes of axons of the spinal cord. The present investigation sought to obtain electrophysiologic evidence of the effect of 4-AP in ameliorating central conduction deficits in a group of patients (n = 6) with spinal cord injury (SCI). The group was selected on the basis of having temperature-dependent central conduction deficits. 4-AP (24-25 mg total dose) was delivered intravenously at 6 mgh-1 or 15 mgh-1 while somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) were recorded as indices of central conduction. Two patients exhibited marked increases in the amplitude of cortical SEPs, and in one of these, 4-AP brought about a reduced central conduction time from L1 to cortex. Four patients revealed increased amplitude MEPs with concomitant reduction in latency indicative of enhanced conduction in corticospinal or corticobulbospinal pathways. Two of these patients demonstrated increased voluntary motor unit recruitment following 4-AP. Clinical examination revealed reduced spasticity (n = 2), reduced pain (n = 1), increased sensation (n = 1), improved leg movement (n = 3), and restored voluntary control of bowel (n = 1). These results support the hypothesis that 4-AP induces neurologic benefits in some patients with SCI. They are also consistent with the emerging concept that pharmaceutical amelioration of central conduction deficits caused by focal demyelination may contribute to the management of a select group of patients with compressive or contusive SCI. Department of Physical Medicine & Rehabilitation, Parkwood Hospital, University of Western Ontario, London, Canada.

  Ignjatovic M, Zivotic-Vanovic M, Cuk V, Ignjatovic D, Stankovic N, Minic L and Tadic R (1999). [Necrosis of the omental flap]. Acta Chir Iugosl. 46 (1-2): 33-7. Summary: The aim of this research is to review the frequency of the omental flap necrosis comparing the vascularized omental flaps based on the left or right gastroepiploic vessels. The first 100 patients, with injuries of spinal cord on different levels, are included in this prospective clinical study with follow-up from 12 to 24 months. The special surgical technique was used for preparation of omental pedicled graft, for its lengthening and transposition to the level of the spinal cord injury and direct and indirect signs of the omental flap necrosis were studied. In our patients there was no necrosis of the omental grafts based on the left gastroepiploic artery. The insufficiency of the left gastroepiploic artery was not present in any patient and so it was not the reason of the omental flap necrosis. Devascularisation of the great gastric curvature until to the root of the left gastroepiploic artery, administration of the prophylactic doses of the Heparin and to put gently pressure on the omental flap do not contribute to the appearance of the omental flap necrosis. Based on our experiences and on results of this research we conclude that this way of forming the omental graft can be used for the other omentopexies. Vojnomedicinska akademija, Klinika za opstu i vaskularnu hirurgiju, Beograd.

  Jones RE, Heron JR, Foster DH, Snelgar RS and Mason RJ (1983). Effects of 4-aminopyridine in patients with multiple sclerosis. J Neurol Sci. 60 (3): 353-62. Summary: 4-Aminopyridine (4-AP) was administered to two groups of patients with multiple sclerosis (MS). The first group consisted of 5 patients with labile visual symptoms, 2 of whom had arcuate scotomata. 4-AP improved visual performance of most patients in this group and reduced the size of scotomata. The second group consisted of 5 patients with the spinal form of MS who were in a stable state; in this group 4-AP had little effect clinically or on tests of visual function.

  Khosla A, Bowen BC, Falcone S, Quencer RM and Green B (1995). MR of omental myelosynangiosis. AJNR Am J Neuroradiol. 16 (2): 275-9. Summary: PURPOSE: To describe MR findings in patients who have undergone omental transposition (omental myelosynangiosis) for spinal cord revascularization. METHODS: Spin-echo MR images, without and with intravenous gadolinium, were obtained before and after surgery in three patients using a quadrature spine coil. Three-dimensional time-of- flight spinal MR angiography was also performed. RESULTS: On routine MR, the transposed omentum is an irregular, lobulated fat-equivalent mass, containing serpiginous areas of flow void, which extends through the laminectomy site to lie directly adjacent to the cord surface. MR angiography demonstrated small omental vessels, some coursing to the omentum-cord interface; however, no definite extension into the cord was detected. In all patients, there was alteration in cord size and contour after transposition, but no change in cord signal. Clinical improvement was observed in one of the three patients. The signal characteristics of the transposed omentum changed, showing less homogeneity and a gradual loss of the signal over a period of 4 months. CONCLUSIONS: MR delineates transposed omentum and associated postoperative changes in omental myelosynangiosis. MR angiography is useful as an adjunct to demonstrate the small vessels near the omentum- cord interface, but lacks sufficient resolution to demonstrate neoangiogenesis within the cord. Department of Radiology, University of Miami Fla School of Medicine, USA.

  Kocsis JD (1985). Aminopyridine-sensitivity of spinal cord white matter studied in vitro. Exp Brain Res. 57 (3): 620-4. Summary: Sections of dorsal columns of the spinal cord were removed from rats of various ages and studied in a sucrose gap chamber. The potassium channel blocking agent, 4-aminopyridine (4-AP), led to a pronounced increase in the area of the compound action potential of immature dorsal column axons. During the course of maturation this effect was attenuated but not lost. Occlusion experiments indicate that the 4-AP-elicited increase in area of the response was likely the result of multiple action potential discharge, an effect also present in dorsal root but not ventral root fibers (Bowe et al. 1985). These results indicate that the 4-AP-elicited changes in action potential characteristics previously described for sensory fibers in the peripheral nervous system are also present in the central nervous system extensions of these axons.

  Li Y, Field PM and Raisman G (1997). Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells [see comments]. Science. 277 (5334): 2000-2. Summary: The upper cervical corticospinal tract was transected on one side in adult rats. A suspension of ensheathing cells cultured from adult rat olfactory bulb was injected into the lesion site. This induced unbranched, elongative growth of the cut corticospinal axons. The axons grew through the transplant and continued to regenerate into the denervated caudal host tract. Rats with complete transections and no transplanted cells did not use the forepaw on the lesioned side for directed reaching. Rats in which the transplanted cells had formed a continuous bridge across the lesion exhibited directed forepaw reaching on the lesioned side. The Norman and Sadie Lee Research Centre, Division of Neurobiology, National Institute for Medical Research, Medical Research Council, London NW7 1AA, UK.

  Lu J, Feron F, Ho SM, Mackay-Sim A and Waite PM (2001). Transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats. Brain Res. 889 (1-2): 344-57. Summary: Recent reports have highlighted the potential therapeutic role of olfactory ensheathing cells for repair of spinal cord injuries. Previously ensheathing cells collected from the olfactory bulbs within the skull were used. In humans a source of these cells for autologous therapy lies in the nasal mucosa where they accompany the axons of the olfactory neurons. The aim of the present study was to test the therapeutic potential of nasal olfactory ensheathing cells for spinal cord repair. Olfactory ensheathing cells cultured from the olfactory lamina propria or pieces of lamina propria from the olfactory mucosa were transplanted into the transected spinal cord. Three to ten weeks later these animals partially recovered movement of their hind limbs and joints which was abolished by a second spinal cord transection. Control rats, receiving collagen matrix, respiratory lamina propria or culture medium, did not recover hind limb movement. Recovery of movement was associated with recovery of spinal reflex circuitry, assessed using the rate-sensitive depression of the H-reflex from an interosseous muscle. Histological analysis of spinal cords grafted with olfactory tissue demonstrated nerve fibres passing through the transection site, serotonin-positive fibres in the spinal cord distal to the transection site, and retrograde labelling of brainstem raphe and gigantocellularis neurons from injections into the distal cord, indicating regeneration of descending pathways. Thus, olfactory lamina propria transplantation promoted partial restoration of function after relatively short recovery periods. This study is particularly significance because it suggests an accessible source of tissue for autologous grafting in human paraplegia. Neural Injury Research Unit, School of Anatomy, University of New South Wales, 2052, Sydney, Australia.

  Lu J, Feron F, Mackay-Sim A and Waite PM (2002). Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord. Brain. 125 (Pt 1): 14-21. Summary: We demonstrated recently that transplantation of olfactory ensheathing cells from the nasal olfactory mucosa can promote axonal regeneration after complete transection of the spinal cord in adult rat. Ten weeks after transection and transplantation there was significant recovery of locomotor behaviour and restoration of descending inhibition of spinal cord reflexes, accompanied by growth of axons across the transection site, including serotonergic axons arising from the brainstem raphe nuclei. The present experiment was undertaken to determine whether olfactory ensheathing cells from the olfactory mucosa are capable of promoting regeneration when transplanted into the spinal cord 4 weeks after transection. Under general anaesthesia, thoracic spinal cord at the T10 level was transected completely in adult rats. Four weeks later, the scar tissue and cavities at the transection site were removed to create a 3-4 mm gap. Into this gap, between the cut surfaces of the spinal cord, pieces of olfactory lamina propria were placed. Ten weeks later, the locomotor activity of these animals was significantly improved compared with control animals, which received implants of either pieces of nasal respiratory lamina propria or collagen (Basso, Beattie, Bresnahan Locomotor Rating Scale scores 4.3 + 0.8, n = 6 versus 1.0 + 0.2, n = 10, respectively; P < 0.001). Ten weeks after transplantation the behavioural recovery was still improving. Regrowth of brainstem raphe axons across the transplant site was shown by the presence of serotonergic axons in the spinal cord caudal to the transection site, and by retrograde labelling of cells in the nucleus raphe magnus after injections of fluorogold into the caudal spinal cord. Neither serotonergic axons nor labelled brainstem cells were observed in the control animals. These results indicate that olfactory ensheathing cells from the nasal olfactory lamina propria have the ability to promote spinal cord regeneration when transplanted 4 weeks after complete transection. Olfactory ensheathing cells are accessible and available in the human nose; the present study further supports clinical use of these cells in repairing the human spinal cord via autologous transplantation. Neural Injury Research Unit, School of Anatomy, University of New South Wales, Sydney Australia.

  Middlemiss PJ, Glasky AJ, Rathbone MP, Werstuik E, Hindley S and Gysbers J (1995). AIT-082, a unique purine derivative, enhances nerve growth factor mediated neurite outgrowth from PC12 cells. Neurosci Lett. 199 (2): 131-4. Summary: AIT-082 is a novel, metabolically stable, derivative of the purine hypoxanthine. Addition of AIT-082 to cultured PC12 cells enhanced significantly nerve growth factor (NGF)-mediated neurite outgrowth from PC12 cells. These results suggest a cellular mechanism, the enhancement of NGF-action, that might account for the ability of AIT-082 to restore age-induced working memory deficits in mice. Department of Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. middlems@fhs.csu.mcmaster.ca.

  Potter PJ, Hayes KC, Hsieh JT, Delaney GA and Segal JL (1998). Sustained improvements in neurological function in spinal cord injured patients treated with oral 4-aminopyridine: three cases. Spinal Cord. 36 (3): 147-55. Summary: Preclinical trials of intravenously administered 4-Aminopyridine (4-AP) have demonstrated transient improvements in neurological function in patients with longstanding spinal cord injury (SCI). The present report describes three patients with SCI who responded favourably in preclinical trials and who were subsequently administered oral (capsule) 4-AP (10 mg b.i.d. or t.i.d.) over a 4 month interval. The three patients (two male: 1 female) all had incomplete tetraplegia (ASIA levels C and D) with the neurological level of the lesion between C5-C7. Following the administration of 4-AP the patients demonstrated marked and sustained reductions in upper (n = 1) or lower extremity (n = 2) spasticity. Other clinical benefits of 4-AP were reduced pain (n = 1), restored muscle strength (n = 3), improved sensation (n = 2), voluntary control of bowel function (n = 1), and sustained penile tumescence (n = 2). The patients exhibited improved hand function (n = 1), enhanced mobility in transfers and gait (n = 2), with improved energy and endurance. Only trivial side effects (transient light-headedness) were observed. In one case, the enhanced neurological function allowed the patient to stand with support for the first time post injury (16 years). The time course of therapeutic response to the initial dose matched the pharmacokinetic elimination profile derived from serum and urine analysis. There was no evidence of renal or hepatic toxicity with prolonged use. These results indicate a therapeutic benefit of oral 4-Aminopyridine in the management of various neurological deficits in a select group of SCI patients. Department of Physical Medicine & Rehabilitation, Parkwood Hospital, London, Ontario, Canada.

  Protas EJ, Holmes SA, Qureshy H, Johnson A, Lee D and Sherwood AM (2001). Supported treadmill ambulation training after spinal cord injury: a pilot study. Arch Phys Med Rehabil. 82 (6): 825-31. Summary: OBJECTIVES: To conduct a pilot study of weight-supported ambulation training after incomplete spinal cord injury (SCI), and to assess its safety. DESIGN: Quasiexperimental, repeated measures, single group. SETTING: Veterans Affairs medical center. PATIENTS: Three subjects with incomplete, chronic, thoracic SCIs; 2 classified as D on the American Spinal Injury Association (ASIA) impairment scale and 1 as ASIA impairment scale C. INTERVENTION: Subjects participated in 12 weeks of training assisted by 2 physical therapists. The training consisted of walking on a treadmill while supported by a harness and a pneumatic suspension device. Support started at 40% of body weight and a treadmill speed of.16kmph, and progressed by reducing support and increasing treadmill speed and continuous treadmill walking time up to 20 minutes. Training was conducted for 1 hour per day, 5 days per week for 3 months. Treadmill walking occurred for 20 minutes during the sessions. MAIN OUTCOME MEASURES: Gait function (speed, endurance, walking status, use of assistive device and orthotics); oxygen costs of walking; brain motor control assessment; self-report indices; ASIA classification; muscle function test; and safety. RESULTS: All 3 subjects increased gait speed (.118m/s initially to.318m/s after training 12wk), and gait endurance (20.3m/5min initially to 63.5m/5min). The oxygen costs decreased from 1.96 to 1.33mL x kg(-1) x m(-1) after 12 weeks of training. CONCLUSIONS: This pilot study suggests that supported treadmill ambulation training can improve gait for individuals with incomplete SCIs by using objective gait measures. The self-report indices used have promise as patient-centered outcome measures of this new form of gait training. A larger, controlled study of this technique is warranted. School of Physical Therapy, Texas Woman's University, Houston 77030-2897, USA. hf_protas@twu.edu.

  Qiao J, Hayes KC, Hsieh JT, Potter PJ and Delaney GA (1997). Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury. J Neurotrauma. 14 (3): 135-49. Summary: The potassium (K+) channel-blocking agent 4-aminopyridine (4-AP) is currently being investigated for its potential therapeutic value in patients with spinal cord injury (SCI). The present study was designed to test the hypothesis that 4-AP ameliorates central motor conduction deficits in individuals with SCI. Oral 4-AP (10 mg) was administered to 19 (n = 19) SCI subjects with stable neurological deficits. Their response to the drug was monitored using motor evoked potentials (MEPs) following transcranial magnetic stimulation of motor cortex and various measures of segmental or peripheral reflex activity (F-waves, H-reflex, and M-response) recorded from lower limb muscles. The mean MEP amplitude in the extensor digitorum brevis muscle (left) was significantly (p < .05) increased from x = .25 +/- .42 mV to x = .59 +/- 1.04 mV at 2 h after drug administration, and the cortical stimulation threshold was reduced (p < .05) by 5.8%. Similar results were obtained in all subjects exhibiting MEPs (n = 13) and in all muscles (n = 6) studied. These changes were maintained at 4 h postdrug. MEP latencies were reduced in all subjects who initially exhibited abnormally prolonged MEP latencies relative to control group (n = 13) values. F-wave, H-reflex, and M-response values (latency and amplitude) were not systematically altered by 4-AP, leading to the conclusion that it was central motor conduction that was enhanced. This interpretation was supported by observed reductions in central motor conduction time (CMCT) in the majority of SCI subjects from whom CMCT measurements were obtained, two of whom anecdotally reported improved motor control after 4-AP, and by increased MEP:M-wave amplitude ratios. The MEP:M-wave ratios indicated that the magnitude of the effect of 4-AP on motoneuron recruitment was not large, in absolute terms (<4% motoneuron pool), but was appreciable relative to the initial level of motoneuron recruitment. These results provide the first statistically significant, objective evidence of improved functioning of the neuromuscular system in chronically injured SCI subjects receiving 4-AP and suggest that the improvements are mediated through enhanced central conduction. The results further support the emerging view that pharmaceutical management of central conduction deficits may prove to be a useful therapeutic strategy for some patients with long-standing SCI. Program in Neuroscience, The University of Western Ontario, London, Canada.

  Rafael H, Malpica A, Espinoza M and Moromizato P (1992). Omental transplantation in the management of chronic traumatic paraplegia. Case report. Acta Neurochir. 114 (3-4): 145-6. Summary: A 27 year old male patient with chronic traumatic paraplegia received an omental transplant to the spinal cord. During surgery we found 40 percent of the spinal cord hypotrophied, with vascular alterations and abundant scar tissue. Some neurological improvement already started a few days postoperatively. After 36 months of postoperative follow-up he presents with right crural monoparesis (grade 1-4), deep sensation and with sphincter control. Instituto Mexicano del Seguro Social (IMSS), Mexico city.

  Ramirez JJ, Parakh T, George MN, Freeman L, Thomas AA, White CC and Becton A (2002). The effects of Neotrofin on septodentate sprouting after unilateral entorhinal cortex lesions in rats. Restor Neurol Neurosci. 20 (1-2): 51-9. Summary: PURPOSE: Recent research on the purine derivative of hypoxanthine Neotrofin (4-[[3-(1,6-dihydro-6-oxo-9-purin-9-yl)-1-oxopropyl]amino]benzoic acid; AIT-082) has indicated that Neotrofin treatment elevates the mRNA levels of various neurotrophic factors, including nerve growth factor (NGF), in the CNS. Several previous studies have indicated that NGF may regulate septodentate sprouting after entorhinal cortex lesions in rats. Thus, the objective of this investigation was to determine whether Neotrofin treatment would enhance lesion-induced septodentate sprouting from 4 to 15 days postlesion. METHODS: Sham-operated rats or rats with EC lesions were injected (i.p.) with either Neotrofin (30 mg/kg) or saline (0.9%) immediately after surgery and every day thereafter until the end of the treatment regimen. Septodentate sprouting, as indicated by intensity of acetylcholinesterase (AChE) label in the dentate gyrus, was assessed with optical densitometry. RESULTS: We observed that Neotrofin elevated the AChE-label in the outer molecular layer of the ventral dentate gyrus at 4 days postlesion and of the dorsal dentate gyrus at 15 days postlesion. CONCLUSIONS: Neotrofin appears to have exerted limited stimulatory effects on lesion-induced sprouting by a cholinergic pathway. Laboratory of Behavioral Neuroscience, Department of Psychology, Davidson College, Davidson, North Carolina 28035-7017, USA. juramirez@davidson.edu.

  Ramon-Cueto A (2000). Olfactory ensheathing glia transplantation into the injured spinal cord. Prog Brain Res. 128: 265-72. Summary: Institute of Biomedicine, Spanish Council for Scientific Research (CSIC), Valencia, Spain. aramon@ibv.csic.es.

  Ramon-Cueto A, Cordero MI, Santos-Benito FF and Avila J (2000). Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron. 25 (2): 425-35. Summary: Axonal regeneration in the lesioned mammalian central nervous system is abortive, and this causes permanent disabilities in individuals with spinal cord injuries. In adult rats, olfactory ensheathing glia (OEG) transplants successfully led to functional and structural recovery after complete spinal cord transection. From 3 to 7 months post surgery, all OEG-transplanted animals recovered locomotor functions and sensorimotor reflexes. They presented voluntary hindlimb movements, they supported their body weight, and their hindlimbs responded to light skin contact and proprioceptive stimuli. In addition, relevant motor axons (corticospinal, raphespinal, and coeruleospinal) regenerated for long distances within caudal cord stumps. Therefore, OEG transplantation provides a useful repair strategy in adult mammals with traumatic spinal cord injuries. Our results with these cells could lead to new therapies for the treatment of spinal cord lesions in humans. Centro de Biologia Molecular Severo Ochoa (CSIC-UAM), Facultad de Ciencias, Universidad Autonoma de Madrid, Cantoblanco, Spain. aramon@ibv.csic.es.

  Ramon-Cueto A and Nieto-Sampedro M (1994). Regeneration into the spinal cord of transected dorsal root axons is promoted by ensheathing glia transplants. Exp Neurol. 127 (2): 232-44. Summary: The permissivity of adult olfactory bulb to the ingrowth of olfactory axons could be due to the unique properties of ensheathing glia. To test whether these glial cells could be used to promote axonal regeneration in a spontaneously nonregenerating system, we transplanted suspensions of pure ensheathing cells into a rhizotomized spinal cord segment. Ensheathing cells were purified away from other cell types by immunoaffinity, using anti-p75 nerve growth factor receptor. After laminectomy at the lower thoracic level, the spinal cord was exposed and one dorsal root (T10) was completely transected at the cord entry point. The root stump was microsurgically anastomosed to the cord and a suspension of ensheathing cells was transplanted in the spinal cord at the dorsal root entry zone. Three weeks after transplantation, numerous regenerating dorsal root axons were observed reentering the spinal cord. Ingrowth of dorsal root axons was observed using DiI and antibodies against calcitonin gene-related peptide and growth- associated protein. Primary sensory afferents invaded laminae 1, 2, and 3, grew through laminae 4 and 5, and reached the dorsal grey commissure and lamina 4 of the contralateral side. We did not observe regenerating axons within the ipsilateral ventral horn and dorsal column. Transplanted ensheathing cells reached the same laminae as axons. Neither ensheathing cells nor regenerating axons invaded those laminae they did not innervate under normal circumstances. In conclusion, the regeneration of injured dorsal root axons into the adult spinal cord was possible after ensheathing glia transplantation. The use of ensheathing cells as stimulators of axonal growth might be generalized to other central nervous system injuries. Neural Plasticity Department, Instituto Cajal, Madrid, Spain.

  Ramon-Cueto A, Plant GW, Avila J and Bunge MB (1998). Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants. J Neurosci. 18 (10): 3803-15. Summary: The lack of axonal regeneration in the injured adult mammalian spinal cord leads to permanent functional impairment. To induce axonal regeneration in the transected adult rat spinal cord, we have used the axonal growth-promoting properties of adult olfactory bulb ensheathing glia (EG). Schwann cell (SC)-filled guidance channels were grafted to bridge both cord stumps, and suspensions of pure (98%) Hoechst-labeled EG were stereotaxically injected into the midline of both stumps, 1 mm from the edges of the channel. In EG-transplanted animals, numerous neurofilament-, GAP-43-, anti-calcitonin gene-related peptide (CGRP)-, and serotonin-immunoreactive fibers traversed the glial scars formed at both cord-graft interfaces. Supraspinal serotonergic axons crossed the transection gap through connective tissue bridges formed on the exterior of the channels, avoiding the channel interior. Strikingly, after crossing the distal glial scar, these fibers elongated in white and periaqueductal gray matter, reaching the farthest distance analyzed (1.5 cm). Tracer-labeled axons present in SC grafts were found to extend across the distal interface and up to 800 microm beyond in the distal cord. Long-distance regeneration (at least 2.5 cm) of injured ascending propriospinal axons was observed in the rostral spinal cord. Transplanted EG migrated longitudinally and laterally from the injection sites, reaching the farthest distance analyzed (1.5 cm). They moved through white matter tracts, gray matter, and glial scars, overcoming the inhibitory nature of the CNS environment, and invaded SC and connective tissue bridges and the dorsal and ventral roots adjacent to the transection site. Transplanted EG and regenerating axons were found in the same locations. Because EG seem to provide injured spinal axons with appropriate factors for long-distance elongation, these cells offer new possibilities for treatment of CNS conditions that require axonal regeneration. The Chambers Family Electron Microscopy Laboratory, The Miami Project to Cure Paralysis, University of Miami School of Medicine, Miami, Florida 33101, USA.

  Rapalino O, Lazarov-Spiegler O, Agranov E, Velan GJ, Yoles E, Fraidakis M, Solomon A, Gepstein R, Katz A, Belkin M, Hadani M and Schwartz M (1998). Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med. 4 (7): 814-21. Summary: Postinjury recovery in most tissues requires an effective dialog with macrophages; however, in the mammalian central nervous system, this dialog may be restricted (possibly due to its immune-privileged status), which probably contributes to its regeneration failure. We circumvented this by implanting macrophages, pre-exposed ex vivo to peripheral nerve segments, into transected rat spinal cord. This stimulated tissue repair and partial recovery of motor function, manifested behaviorally by movement of hind limbs, plantar placement of the paws and weight support, and electrophysiologically by cortically evoked hind-limb muscle response. We substantiated these findings immunohistochemically by demonstrating continuity of labeled nerve fibers across the transected site, and by tracing descending fibers distally to it by anterograde labeling. In recovered rats, retransection of the cord above the primary transection site led to loss of recovery, indicating the involvement of long descending spinal tracts. Injection of macrophages into the site of injury is relatively non-invasive and, as the cells are autologous, it may be developed into a clinical therapy. Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.

  Rathbone MP, Middlemiss PJ, Gysbers JW, Andrew C, Herman MA, Reed JK, Ciccarelli R, Di Iorio P and Caciagli F (1999). Trophic effects of purines in neurons and glial cells. Prog Neurobiol. 59 (6): 663-90. Summary: In addition to their well known roles within cells, purine nucleotides such as adenosine 5' triphosphate (ATP) and guanosine 5' triphosphate (GTP), nucleosides such as adenosine and guanosine and bases, such as adenine and guanine and their metabolic products xanthine and hypoxanthine are released into the extracellular space where they act as intercellular signaling molecules. In the nervous system they mediate both immediate effects, such as neurotransmission, and trophic effects which induce changes in cell metabolism, structure and function and therefore have a longer time course. Some trophic effects of purines are mediated via purinergic cell surface receptors, whereas others require uptake of purines by the target cells. Purine nucleosides and nucleotides, especially guanosine, ATP and GTP stimulate incorporation of [3H]thymidine into DNA of astrocytes and microglia and concomitant mitosis in vitro. High concentrations of adenosine also induce apoptosis, through both activation of cell-surface A3 receptors and through a mechanism requiring uptake into the cells. Extracellular purines also stimulate the synthesis and release of protein trophic factors by astrocytes, including bFGF (basic fibroblast growth factor), nerve growth factor (NGF), neurotrophin-3, ciliary neurotrophic factor and S-100beta protein. In vivo infusion into brain of adenosine analogs stimulates reactive gliosis. Purine nucleosides and nucleotides also stimulate the differentiation and process outgrowth from various neurons including primary cultures of hippocampal neurons and pheochromocytoma cells. A tonic release of ATP from neurons, its hydrolysis by ecto-nucleotidases and subsequent re-uptake by axons appears crucial for normal axonal growth. Guanosine and GTP, through apparently different mechanisms, are also potent stimulators of axonal growth in vitro. In vivo the extracellular concentration of purines depends on a balance between the release of purines from cells and their re-uptake and extracellular metabolism. Purine nucleosides and nucleotides are released from neurons by exocytosis and from both neurons and glia by non-exocytotic mechanisms. Nucleosides are principally released through the equilibratory nucleoside transmembrane transporters whereas nucleotides may be transported through the ATP binding cassette family of proteins, including the multidrug resistance protein. The extracellular purine nucleotides are rapidly metabolized by ectonucleotidases. Adenosine is deaminated by adenosine deaminase (ADA) and guanosine is converted to guanine and deaminated by guanase. Nucleosides are also removed from the extracellular space into neurons and glia by transporter systems. Large quantities of purines, particularly guanosine and, to a lesser extent adenosine, are released extracellularly following ischemia or trauma. Thus purines are likely to exert trophic effects in vivo following trauma. The extracellular purine nucleotide GTP enhances the tonic release of adenine nucleotides, whereas the nucleoside guanosine stimulates tonic release of adenosine and its metabolic products. The trophic effects of guanosine and GTP may depend on this process. Guanosine is likely to be an important trophic effector in vivo because high concentrations remain extracellularly for up to a week after focal brain injury. Purine derivatives are now in clinical trials in humans as memory-enhancing agents in Alzheimer's disease. Two of these, propentofylline and AIT-082, are trophic effectors in animals, increasing production of neurotrophic factors in brain and spinal cord. Likely more clinical uses for purine derivatives will be found; purines interact at the level of signal-transduction pathways with other transmitters, for example, glutamate. They can beneficially modify the actions of these other transmitters. Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

  Rossini PM, Pasqualetti P, Pozzilli C, Grasso MG, Millefiorini E, Graceffa A, Carlesimo GA, Zibellini G and Caltagirone C (2001). Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-aminopyridine. Mult Scler. 7 (6): 354-8. Summary: Previous studies suggest that aminopyridine may play a role in the symptomatic treatment of fatigue in multiple sclerosis. Although the mechanism underlying the beneficial effect on fatigue remains unclear, it has been proposed that aminopyridines may help to improve conduction in demyelinated central pathways, implicating both axonal and synaptic mechanisms. The objective of the present study is to determine whether 4-AP decreases daily-living fatigue in progressive multiple sclerosis. The effect of 4-AP on other neurophysiological and neuropsychological parameters was also considered. A 'double-blind', randomized, 'placebo-controlled', crossover trial was conducted on 54 patients with progressive multiple sclerosis. All patients received treatment with placebo and 32 mg per day of 4-AP, each for 6 months. The main outcome measure was the Fatigue Severity Scale. Secondary measures were EDSS, cognitive functions and neurophysiological parameters. Forty-nine patients (91%) completed the study. Changes in fatigue scores, EDSS and cognitive functions were not significantly different between 4-AP and placebo. However, when patients treated with 4-AP were divided into two groups according to the serum level of 4-AP, a significant effect on fatigue compared with placebo was observed in the 'high level' (>30 ng/ml) group (P=0.05). Synchronization of motor evoked potentials improved during 4-AP with respect to placebo (P=0.019) and this correlated positively with fatigue reduction (P=0.010). No relevant side effects were observed. AFaR-Ospedale San Giovanni Calibita Fatebenefratelli, Rome, Italy.

  Savitz SI, Rosenbaum DM, Dinsmore JH, Wechsler LR and Caplan LR (2002). Cell transplantation for stroke. Ann Neurol. 52 (3): 266-75. Summary: Cell transplantation has emerged as an experimental approach to restore brain function after stroke. Various cell types including porcine fetal cells, stem cells, immortalized cell lines, and marrow stromal cells are under investigation in experimental and clinical stroke trials. This review discusses the unique advantages and limitations of the different graft sources and emphasizes the current, limited knowledge about their biology. The survival, integration, and efficacy of neural transplants in stroke patients will depend on the type, severity, chronicity, adequacy of circulation, and location of the stroke lesion. Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.

  Schwartz M and Moalem G (2001). Beneficial immune activity after CNS injury: prospects for vaccination. J Neuroimmunol. 113 (2): 185-92. Summary: A recent study in our laboratory showed, against all expectations, that macrophages and a particular type of T cell, by promoting regrowth and reducing the post-traumatic spread of damage in the injured rat optic nerve or spinal cord, have a beneficial effect on the injured CNS. Macrophages in the CNS have long been thought to have predominantly destructive effects. Autoimmunity in general, and in the CNS in particular, has never been documented as a purposeful physiological response of benign character. Our results suggest that after traumatic injury to the central nervous system (CNS), both of these immune cell types potentially have beneficial effects: macrophages can promote repair and T cells of a particular specificity can reduce the spread of damage. However, possibly because of the immune-privileged character of the CNS, the spontaneously evoked physiological activities of both macrophages and T cells in the CNS are restricted, and appear to need well-controlled boosting in order to be effective. It thus appears that (i) a stress signal transmitted from the traumatized tissue (in this case the CNS) for recruitment of the adaptive immune system does not have to be pathogen-related in order to evoke a response, (ii) a response to self is not necessarily a quirk of nature, and (iii) an autoimmune response, provided that it is well-regulated, helps the individual to cope with stress signals from the traumatized CNS, and thus plays a role in maintenance of the injured tissue without posing a threat to the organism. Department of Neuroimmunology, The Weizmann Institute of Science, Rehovot, Israel. michal.schwartz@weizmann.ac.il.

  Schweighofer F, Fellinger M, Schippinger G, Peicha G and Passler JM (1992). Complications after an unusual procedure in the treatment of a cervical spine burst fracture. A case report. Langenbecks Arch Chir. 377 (4): 235-6. Summary: A 21-year-old man sustained a burst fracture of the 7th cervical vertebral body complicated by a complete loss of sensory and motor functions. He was treated with a pedicled greater omentum flap interposed between the cervical and thoracic spine in a Latin American country. The purpose of this paper is to point out the atypical way of the initial mismanagement. By applying basic principles of fracture management, open reduction and internal fixation was performed resulting in spinal stability which should enhance any chance of recovery of the patient. University Clinic of Surgery, Department of Traumatology, Graz.

  Segal JL and Brunnemann SR (1997). 4-Aminopyridine improves pulmonary function in quadriplegic humans with longstanding spinal cord injury. Pharmacotherapy. 17 (3): 415-23. Summary: STUDY OBJECTIVE: To test the hypothesis that 4-aminopyridine (4-AP) might cause clinically evident improvement in pulmonary function in humans with chronic spinal cord injury (chronic SCI). DESIGN: Balanced, open-label study with subjects consecutively enrolled. SETTING: Spinal Cord Injury Service, university-affiliated tertiary level care Department of Veterans Affairs Medical Center. PATIENTS: Seventeen healthy men and women suffering from traumatic SCI (11 quadriplegic, 6 paraplegic patients) for more than 1 year. INTERVENTIONS: Each subject was given a single dose of 4-AP 10 mg orally in an immediate-release formulation. MEASUREMENTS AND MAIN RESULTS: Significant increases in mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) that persisted for at least 12 hours were demonstrated in quadriplegic patients beginning 6 hours after 4-AP administration. Tests of pulmonary function that demonstrated statistically significant increases at any time were also numerically, if not statistically, increased at 24 hours compared with pretreatment values obtained in 4-AP-naive subjects. CONCLUSIONS: The administration of a single dose of an immediate-release formulation of 4-AP to humans with longstanding, traumatic quadriplegia is associated with sustained, clinically meaningful, and statistically significant improvements in pulmonary function. We suggest that the administration of 4-AP may have a salutary effect in patients suffering from SCI and appears to be associated with potentially clinically significant reductions in the pathophysiologic pulmonary sequelae of SCI. Medicine Service, Department of Veterans Affairs Medical Center, Long Beach, CA 90822, USA.

  Segal JL and Brunnemann SR (1998). 4-Aminopyridine alters gait characteristics and enhances locomotion in spinal cord injured humans. J Spinal Cord Med. 21 (3): 200-4. Summary: Recovery of useful motor function in humans with spinal cord injury (SCI) is a primary and elusive goal. In this preliminary study, we describe efforts to delineate the pharmacological effects of 4-aminopyridine (4-AP) on gait parameters in spinal cord injured humans who have retained some capacity to ambulate bipedally. A sequential entry, open label study was made of the effects of a single oral administration of an immediate-release formulation of 4-AP on the time-course profile of changes in component parameters of bipedal gait in ambulatory volunteers with chronic SCI. Nine healthy, rehabilitated, community-adapted male volunteers (six tetraparetic, three paraparetic), who sustained their injuries more than one year prior to entry into the study, ingested a single 10-mg dose of 4-aminopyridine after an overnight fast. Gait analysis parameters included velocity (meters/min), cadence (steps/min), stride length (meters), gait cycle (seconds), and double limb support (percent of gait cycle). They were measured for 24 hours using a sampling-rich strategy (nine duplicate measurements over 24 hrs). Repeated measures (randomized block) analysis of variance (ANOVA) and paired t-tests were used to test for the significance of differences between means and variances. The apparent pharmacological effect of 4-AP is associated with statistically significant changes in one or more of the component elements used to assess the characteristics and efficiency of bipedal gait. These changes in gait analysis parameters correspond temporally with the improvements in pulmonary function and heart rate variability previously described by us. 4-AP appears to enhance gait in a subset of humans with SCI. In this preliminary study we report, for the first time, an apparent effect of 4-AP on gait in spinal cord injured humans and suggest that the pharmacological effects of 4-AP may have clinically significant application in the restoration of useful motor function. Department of Veterans Affairs Medical Center, Long Beach, CA 90822, USA.

  Segal JL, Hayes KC, Brunnemann SR, Hsieh JT, Potter PJ, Pathak MS, Tierney DS and Mason D (2000). Absorption characteristics of sustained-release 4-aminopyridine (fampridine SR) in patients with chronic spinal cord injury. J Clin Pharmacol. 40 (4): 402-9. Summary: Fampridine SR (4-aminopyridine) is a potassium channel-blocking drug currently being investigated for its therapeutic efficacy in ameliorating central conduction deficits due to demyelination in patients with spinal cord injury (SCI). The present open-label pharmacokinetic trial examined the absorption characteristics of a sustained-release form of the drug in 25 SCI subjects with chronic incomplete injuries. The overall group mean Cmax of 27.7 +/- 6.2 ng/mL occurred at a tmax of 3.4 +/- 1.4 hours. AUC0-12 was 210.5 +/- 49.5 ng/mL.h. For paraplegics, AUCtmax was 76.02 +/- 33.28 and for tetraplegics was significantly less at 51.25 +/- 20.36 (p = 0.037). A statistically significant difference in the initial rate and extent of absorption, but not in total 4-AP bioavailability over the 12-hour study period, was evident between tetraplegic patients, 0.60 +/- 0.23, and paraplegic patients, 0.39 +/- 0.14 (p = 0.02). There was a linear correlation (p < 0.05) between the neurological level of injury and Cmax/AUCtmax. These results confirm and extend previous observations of different rates of drug absorption among SCI patients with lesions above and below the sympathetic outflow (T6) and provide evidence of the absorption characteristics of this sustained-release form of 4-aminopyridine, which is helpful for optimal dosing. Department of Veterans Affairs Medical Center, Long Beach, California 90822, USA.

  Segal JL, Pathak MS, Hernandez JP, Himber PL, Brunnemann SR and Charter RS (1999). Safety and efficacy of 4-aminopyridine in humans with spinal cord injury: a long-term, controlled trial. Pharmacotherapy. 19 (6): 713-23. Summary: STUDY OBJECTIVE: To determine the effects of the long-term administration of 4-aminopyridine (4-AP) on sensorimotor function in humans with long-standing spinal cord injury (SCI). DESIGN: Randomized, open-label, active-treatment control, dosage-blinded study. SETTING: University-affiliated, tertiary-level care, Department of Veterans Affairs Medical Center. PATIENTS: Twenty-one healthy men and women outpatients suffering from traumatic SCI (14 tetraplegic, 7 paraplegic) for 2 years or more. INTERVENTIONS: Dosages of an immediate-release formulation of 4-AP were titrated. At 3 months, 16 subjects were receiving 4-AP 30 mg/day (high dose); 5 subjects were receiving 4-AP 6 mg/day (low dose) and served as an active-treatment control group. MEASUREMENTS AND MAIN RESULTS: Composite motor and sensory scores had statistically significant increases at 3 months. Maximal expiratory pressure, maximal inspiratory pressure, forced vital capacity, and forced expiratory volume in 1 second showed clinically meaningful and/or statistically significant increases among patients receiving 4-AP 30 mg/day. These subjects also had significant decreases in spasticity (modified Ashworth Scale). Serial biochemical profiles and electroencephalographs were unchanged from baseline, and no clinically significant drug toxicity was encountered. CONCLUSIONS: Long-term oral administration of immediate-release 4-AP was associated with improvement in and recovery of sensory and motor function, enhanced pulmonary function, and diminished spasticity in patients with long-standing SCI. 4-Aminopyridine appears to be safe and relatively free from toxicity when administered orally over 3 months. Each patient who received immediate-release 4-AP 30 mg/day showed a response in one or more of the outcome measures. Department of Medicine, Department of Veterans Affairs Medical Center, Long Beach, California 90822, USA.

  Seif-Naraghi AH and Herman RM (1999). A novel method for locomotion training. J Head Trauma Rehabil. 14 (2): 146-62. Summary: This article describes a novel therapeutic system for locomotion training and learning for patients with a wide range of neurological and musculoskeletal disorders. The technique embraces the notion that locomotion therapy should be goal oriented and task specific. The task specificity includes a partial weight-bearing device that permits the posture/equilibrium, movement, and weight-bearing components of gait function to operate concurrently, even in patients with serious deficits. In addition, it allows interaction with therapists and others to facilitate locomotion control, particularly during the early stages of gait therapy. Neurobiological bases for this technique and early clinical results are discussed, and two case studies of patients with traumatic brain injury (TBI) are presented. Although well-designed efficacy studies are needed, clearly this therapeutic approach to locomotor disorders among TBI patients meets the various criteria for recovery of gait function established in this article. Mobility Research LLC, Tempe, Arizona, USA.

  Sgouros S and Williams B (1996). A critical appraisal of pediculated omental graft transposition in progressive spinal cord failure. Br J Neurosurg. 10 (6): 547-53. Summary: A critical review of patients who had pediculated omental grafting for progressive spinal cord failure was performed in order to assess the impact of this procedure on the natural history of the spinal cord function after spinal cord injury. Ten patients were reviewed; all had complete or partial paraplegia. Mean age at injury was 29.1 years. There was an average interval of 9.7 years between injury and onset of progressive worsening of symptoms, and 5.6 years between onset of such symptoms and diagnosis. Average follow-up was 24.5 months. Five patients underwent omental grafting as primary surgical treatment whereas the other five had earlier procedures. One patient died on the postoperative period. Significant morbidity was also observed. All the surviving patients were asked to score themselves by answering a questionnaire exploring the effect of surgery in limb function and performance on activities of daily living. Only two patients improved following the procedure. Two others remained unchanged, while the remaining six continued to deteriorate. There was no difference in clinical outcome between the primary surgery group and the ones that had had previous procedures. Delayed omental grafting done as tried in this clinic did not seem to improve the prognosis of the injured cord and was associated with significant morbidity. Midland Centre for Neurosurgery and Neurology, Birmingham, UK.

  Shi R, Kelly TM and Blight AR (1997). Conduction block in acute and chronic spinal cord injury: different dose-response characteristics for reversal by 4-aminopyridine. Exp Neurol. 148 (2): 495-501. Summary: The effect of the potassium channel blocker, 4-aminopyridine (4-AP), on conduction of action potentials in injured guinea pig spinal cord axons was measured using isolated tracts in oxygenated Krebs' solution at 37 degrees C. The dose-response characteristics of acutely and chronically injured axons were compared. The maximal improvement of conduction occurred in acutely injured axons at a concentration of 100 microM 4-AP, but in chronically injured spinal cord at 10 microM. The threshold for significant response to 4-AP was between 0.5 and 1 microM in chronically injured cords, and between 1 and 10 microM following acute compression injury. The difference in susceptibility to potassium channel blockade may be related to underlying differences in the mechanism of conduction block at the two stages of injury. Initially, junctions between axons and myelin are acutely disrupted, altering primarily the leakage resistance of the myelin sheath and periaxonal space. In chronically injured cords, there is widespread but incomplete process of repair in the lesion site, which leaves many axons partially myelinated. The difference in sensitivity to 4-AP suggests there is also some modification of the accessibility of axonal potassium channel or a change in their affinity for the drug. Division of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

  Smith KJ, Felts PA and John GR (2000). Effects of 4-aminopyridine on demyelinated axons, synapses and muscle tension. Brain. 123 ( Pt 1): 171-84. Summary: Several clinical trials have demonstrated that 4-amino-pyridine (4-AP), a potassium channel-blocking agent, improves symptoms in some patients with multiple sclerosis. The beneficial effects have typically been attributed to the restoration of conduction to demyelinated axons, since this effect was previously demonstrated experimentally. However, the clinical dose is approximately 250-1000 times lower than that used experimentally, potentially making extrapolation of the experimental findings unreliable. To examine the action(s) of 4-AP in demyelinating disorders, the drug was administered at clinical doses, both in vivo and in vitro, to rat dorsal column axons which had been experimentally demyelinated by the intraspinal injection of ethidium bromide. 4-AP had no consistent effect in restoring conduction to demyelinated axons, even to axons which were held just on the verge of conducting by adjusting the lesion temperature. However, 4-AP had prominent effects that did not involve demyelinated axons, including the potentiation of synaptic transmission and an increase in skeletal muscle twitch tension. We propose that these latter effects may be largely responsible for the beneficial action of 4-AP in multiple sclerosis patients. If so, the dominant effects of 4-AP in multiple sclerosis patients are independent of demyelination, and it follows that 4-AP may be beneficial in other neurological disorders in which function is diminished. Neuroinflammation Research Group, Department of Neuroimmunology, Guy's, King's and St Thomas' School of Medicine, Guy's Campus, London SE1 9RT, UK. kenneth.smith@kcl.ac.uk.

  Smits RC, Emmen HH, Bertelsmann FW, Kulig BM, van Loenen AC and Polman CH (1994). The effects of 4-aminopyridine on cognitive function in patients with multiple sclerosis: a pilot study. Neurology. 44 (9): 1701-5. Summary: 4-Aminopyridine (4-AP) has a favorable effect on the disability of certain patients with MS. We investigated the effect of 4-AP on neuropsychological performance in 20 MS patients using a randomized, double-blind, placebo-controlled, crossover design. Although there was a trend for improved performance with 4-AP for two of the tests, we could not demonstrate significant effects of 4-AP on cognitive function. Department of Neurology, Free University Hospital, Amsterdam, The Netherlands.

  Spaic M, Minic L, Djitic R, Lukic Z and Tadic R (2001). [Omentomyelosynangiosis--a direct intraoperative observation]. Vojnosanit Pregl. 58 (3): 249-54. Summary: The late outcome of implantation of the vascular omental pedicle on the injured spinal cord performed in 7 patients to improve functional recovery through revascularization of the injured cord tissue is reported. All the patients were reoperated at the same spinal level 2-5 years after the omental pedicle implantation for the treatment of chronic neuropathic spinal pain by employing DREZ (Dorsal Root Entry Zone lesion) surgery. From the technical standpoint it was necessary to mobilize the implanted omental pedicle from the cord surface to provide the access to dorsolateral cord sulcus for the DREZ operation. Mobilization of the omental pedicle provided unique opportunity to observe omental-cord contact surface (omentomielosinangiosis) that is believed to stimulate revascularization of the cord tissue. In our report particular attention was paid to the specificity of the omental-cord contact surface and the late tissue changes of the cord as well as omental tissue knowing the fact that the capacity of omental tissue to stimulate neoangiogenesis still represents the actual doubt in neurobiological theory and practice. Detailed analysis of the actual neurological condition of these patients compared to neurological condition assessed before the implantation of the pediculated-vascular omental graft revealed neither sensory nor motoric improvement (in the postimplantation period). The effect of DREZ surgery of the chronic neuropathic spinal pain was not a topic of this report.

  Stefoski D, Davis FA, Faut M and Schauf CL (1987). 4-Aminopyridine improves clinical signs in multiple sclerosis. Ann Neurol. 21 (1): 71-7. Summary: Twelve temperature-sensitive male patients with multiple sclerosis and 5 normal men were monitored before, during, and after the intravenous injection of 7 to 35 mg of 4-aminopyridine (4-AP) in 1- to 5-mg doses, every 10 to 60 minutes. Static quantitative perimetry, flicker-fusion frequency, visual acuity, and videotaped neurological examinations were performed. Ten of the 12 patients showed mild to marked improvement. Vision improved in 7 patients, oculomotor function in 5, and motor function (power, coordination, gait) in 5. Improvements developed gradually within minutes of drug injection at doses as low as 2 mg, and gradually reversed around 2 to 4 hours after the peak drug effect. No effects were observed in 5 patients given saline injections. No serious side effects occurred in either the normal subjects or the patients receiving 4-AP. It is concluded that 4-AP lessens multiple neurological deficits in multiple sclerosis and, furthermore, that the K+ channel is functional in demyelinated central nervous system axons in humans. The improvements with 4-AP are substantial enough to be of transient therapeutic benefit in selected patients.

  Sullivan KJ, Knowlton BJ and Dobkin BH (2002). Step training with body weight support: effect of treadmill speed and practice paradigms on poststroke locomotor recovery. Arch Phys Med Rehabil. 83 (5): 683-91. Summary: OBJECTIVE: To investigate the effect of practice paradigms that varied treadmill speed during step training with body weight support in subjects with chronic hemiparesis after stroke. DESIGN: Randomized, repeated-measures pilot study with 1- and 3-month follow-ups. SETTING: Outpatient locomotor laboratory. PARTICIPANTS: Twenty-four individuals with hemiparetic gait deficits whose walking speeds were at least 50% below normal. INTERVENTION: Participants were stratified by locomotor severity based on initial walking velocity and randomly assigned to treadmill training at slow (0.5mph), fast (2.0mph), or variable (0.5, 1.0, 1.5, 2.0mph) speeds. Participants received 20 minutes of training per session for 12 sessions over 4 weeks. MAIN OUTCOME MEASURE: Self-selected overground walking velocity (SSV) was assessed at the onset, middle, and end of training, and 1 and 3 months later. RESULTS: SSV improved in all groups compared with baseline (P<.001). All groups increased SSV in the 1-month follow-up (P<.01) and maintained these gains at the 3-month follow-up (P=.77). The greatest improvement in SSV across training occurred with fast training speeds compared with the slow and variable groups combined (P=.04). Effect size (ES) was large between fast compared with slow (ES=.75) and variable groups (ES=.73). CONCLUSIONS: Training at speeds comparable with normal walking velocity was more effective in improving SSV than training at speeds at or below the patient's typical overground walking velocity. Department of Neurology, University of California, Los Angeles, CA 90095, USA.

  Thompson FJ, Reier PJ, Uthman B, Mott S, Fessler RG, Behrman A, Trimble M, Anderson DK and Wirth ED, 3rd (2001). Neurophysiological assessment of the feasibility and safety of neural tissue transplantation in patients with syringomyelia. J Neurotrauma. 18 (9): 931-45. Summary: The feasibility and safety of a procedure involving fetal spinal cord tissue transplantation in patients with syringomyelia was assessed using a neurophysiological protocol designed to quantitate peripheral nerve function, spinal cord reflex excitability, and spinal cord conduction pathways essential for somatosensory evoked potentials. We report here data obtained before and for 18 months following the transplantation procedure performed on the first two patients in this study. The neurophysiological assessment protocols included measures of cortical and spinal cord evoked potentials, H-reflex excitability, and peripheral nerve conduction. Prior to the procedure, both patients had significant deficits on some of the neurophysiological measures, for example, lower extremity cortical evoked potentials. However, robust measures of intact pathways, such as upper extremity cortical evoked potentials, were also observed preoperatively in both patients. Thus, it was anticipated that conduction in these intact pathways could be at risk either from complications from the transplantation procedure and/or from continued expansion of the syrinx. Following the transplantation procedure, no negative changes were observed in any of the neurophysiological measures in either patient. In addition, patient 1 showed a decrease in the rate potentiation of tibial H-reflexes on the right side and an increase in the response probability of left tibial H-reflexes. The results of this postoperative longitudinal assessment provide a first-level demonstration of the safety of the intraspinal neural tissue transplantation procedure. However, the consideration of safety is currently limited to the grafting procedure itself, since the long-term fates of the donor tissue in these two patients remain to be shown more definitively. Department of Neuroscience, University of Florida College of Medicine, Gainesville, USA. Thompson@ufbi.ufl.edu.

  Trimble MH, Behrman AL, Flynn SM, Thigpen MT and Thompson FJ (2001). Acute effects of locomotor training on overground walking speed and H-reflex modulation in individuals with incomplete spinal cord injury. J Spinal Cord Med. 24 (2): 74-80. Summary: OBJECTIVE: The purpose of this study was to assess the effect of a single bout of a locomotor-training paradigm on overground walking speed and H-reflex modulation of individuals with incomplete spinal cord injury (SCI). METHODS: Self-selected and maximum walking speeds and soleus H-reflexes (H/M ratios) during standing and stance and swing phases of walking (self-selected velocity) were obtained from 4 individuals with American Spinal Injury Association impairment classification D. Data were collected immediately before and after a single bout of locomotor training with body weight support on a treadmill. The pretraining H/M ratios of the SCI subjects were also compared with values from 4 able-bodied subjects who did not receive the intervention. Maximum H/M ratios while standing and during midstance and midswing phases of overground walking were considerably greater in the SCI subjects than in the control subjects. RESULTS: After the single bout of training, self-selected and maximum overground walking speeds of the subjects with SCI increased by 26% and 25%, respectively. Furthermore, H-reflexes were significantly more depressed in the SCI subjects during overground walking (28% less during stance, 34% less during swing). CONCLUSIONS: Although preliminary, these findings indicate that a single bout of locomotor training produced immediate increases in walking velocity and acute neurophysiologic changes in individuals with incomplete SCI. Department of Physical Therapy, University of Florida, Gainesville, USA.

  van der Bruggen MA, Huisman HB, Beckerman H, Bertelsmann FW, Polman CH and Lankhorst GJ (2001). Randomized trial of 4-aminopyridine in patients with chronic incomplete spinal cord injury. J Neurol. 248 (8): 665-71. Summary: OBJECTIVE: To test the efficacy of 4-aminopyridine (4-AP) on functional status, walking speed and vibration perception in patients with chronic, incomplete spinal cord injury. METHODS: Twenty SCI patients were randomized in a trial with a double-blind, crossover design to receive four weeks of orally administered 4-AP, followed by a two-week wash-out period and four weeks of placebo, or vice versa. The total daily dose of 4-AP during the four weeks of treatment was systematically increased to a maximum of 0.5 mg/kg body weight. Evaluation of (side-)effects took place at the beginning, after one week, and at the end of each four-week study period. RESULTS: No significant benefit was found on functional status (COOP-WONCA). A statistically significant treatment effect was found on the vibration perception threshold (VPT) in the left fingers, during the first study period. On average, patients receiving 4-AP treatment responded less favourably (mean increase in VPT of 0.29 (0.31) microm) than patients receiving placebo (mean decrease in VPT of 0.05 (0.35) microm) (p=0.04). Neither comfortable nor maximum walking speed altered significantly following 4-AP treatment. CONCLUSIONS: No statistically significant, functional benefit from 4-AP was found for patients in the present study. Furthermore, no support was found for the possibility that an a priory selection of responsive patients would have yielded more favourable results. Department of Rehabilitation Medicine, University Hospital Vrije Universiteit Amsterdam, The Netherlands. h.beckerman@azvu.nl.

  Van Diemen HA, Polman CH, Koetsier JC, Van Loenen AC, Nauta JJ and Bertelsmann FW (1993). 4-Aminopyridine in patients with multiple sclerosis: dosage and serum level related to efficacy and safety. Clin Neuropharmacol. 16 (3): 195-204. Summary: In a recent randomized, double-blind, placebo-controlled crossover trial, we demonstrated efficacy of 4-aminopyridine (4-AP) in improving disability of patients with multiple sclerosis (MS). Here we describe the relationship between dosage, serum level, efficacy, and safety of intravenously and orally administered 4-AP in the same group of 70 MS patients. After both intravenous and oral administration there was a significant relationship between serum levels and 4-AP doses used (p < 0.001 and p < 0.01, respectively). The use of 4-AP in oral doses three times a day showed a large variation and fluctuation in serum levels. After 12 weeks of oral treatment (maximum daily dosage 0.5 mg/kg body weight), a statistically significant improvement was found for the smooth pursuit gain of the eye movements (estimated effect 0.14, 95% confidence interval 0.06-0.23, p < 0.001). The amount of improvement was significantly related to 4-AP serum levels (p = 0.0013). Side effects after intravenous 4-AP occurred frequently and were very troublesome (pain in infusion arm, dizziness). Side effects during oral treatment (dizziness, paresthesias) were very mild and occurred 30-45 min after intake of the medication and could be related to high serum levels. Department of Neurology, Free University Hospital, Amsterdam, The Netherlands.

  van Diemen HA, Polman CH, van Dongen MM, Nauta JJ, Strijers RL, van Loenen AC, Bertelsmann FW and Koetsier JC (1993). 4-Aminopyridine induces functional improvement in multiple sclerosis patients: a neurophysiological study. J Neurol Sci. 116 (2): 220-6. Summary: This study reports on the neurophysiological measurements that were performed in the context of a randomized, double-blind, placebo-controlled, cross-over study with intravenously administered 4-aminopyridine (4-AP) in 70 patients with definite multiple sclerosis (MS). A beneficial effect of 4-AP was found for both visual evoked response and eye movement registration parameters. This study extends the experimental data obtained on animal nerve fibers, showing that 4-AP can improve impulse conduction in demyelinated nerve, to clinical data which indicate that 4-AP induces an objective improvement in the central nervous system function in MS-patients. It thereby also provides a theoretical basis for clinical efficacy of 4-AP in MS. Department of Neurology, Free University Hospital, Amsterdam, The Netherlands.

  Wernig A and Muller S (1992). Laufband locomotion with body weight support improved walking in persons with severe spinal cord injuries. Paraplegia. 30 (4): 229-38. Summary: After low transection of the spinal cord mammalian quadrupeds can be trained to walk on a driven surface indicating that coordinating neuronal circuits persist in the spinal cord segments caudal to the lesion. We trained 8 persons with incomplete spinal cord lesion on a Laufband (driven treadmill) for 1 1/2 to 7 months (5 days a week, 30-60 minutes daily) starting 5 to 20 months after injury and found significant improvement in the utilisation of the paralysed limbs during locomotion. Locomotion is described in one additional patient who had trained independently on parallel bars for several years. Five patients had complete functional paralysis in one lower limb when tested in a resting position. In EMG recordings voluntary activity (ie activity induced upon command) was absent or residual in the main flexor and extensor muscles of this limb. In contrast, during locomotion flexion and extension movements were performed and phasic EMG activity was present. In these 5 patients, and in all others reported here, skin sensibility and proprioception are preserved to different degrees in all limbs. In the course of locomotive training of 4 severely paralysed patients the initially habituating flexion reflexes could be entrained in the paralysed limbs as was the case for knee extension during stance. Subsequently, initial body weight support (BWS) of 40% could be reduced to 0%. The distance covered on the Laufband (0-104 m in the first week) increased significantly (200-410 m) in the last week of training as did speed (0-10 to 14-23 m/min). More importantly, this training subsequently allowed patients to walk on a static surface for 100 to 200 meters while voluntary activity remained absent in the paralysed limb when tested at rest. Similar progress was achieved in the 4 less severely paralysed patients. The one patient who had trained independently on parallel bars for several years is described walking on a static surface for 40 meters with the help of a walker, though he had one completely and one near completely paralysed lower limb. It appears that bipedal stepping with consequent knee extension and stabilisation can be taught after unilateral complete or near complete loss of voluntary activity, suggesting the manifestation of complex reflex motor patterns at the spinal level. Department of Physiology, University of Bonn, FRG.

  Wernig A, Muller S, Nanassy A and Cagol E (1995). Laufband therapy based on 'rules of spinal locomotion' is effective in spinal cord injured persons [published erratum appears in Eur J Neurosci 1995 Jun 1;7(6):1429]. Eur J Neurosci. 7 (4): 823-9. Summary: Rehabilitation of locomotion in spinal cord (s.c.) injured patients is unsatisfactory. Here we report the effects of a novel 'Laufband (LB; treadmill) therapy' based on 'rules of spinal locomotion' derived from lower vertebrates. Eighty-nine incompletely paralysed (44 chronic and 45 acute) para- and tetraplegics underwent this therapy, then were compared with 64 patients (24 chronic and 40 acute) treated conventionally. The programme consisted of daily upright walking on a motor driven LB initially with body weight support (BWS) provided by a harness and assisted limb movements by the therapists when necessary. Forty-four chronic patients with different degrees of paralysis undertook the programme for 3-20 weeks (median = 10.5), 0.5-18 years after s.c. damage. At the onset of LB therapy 33/44 patients were wheelchair-bound (no standing and/or walking without help by others) whereas at the end of therapy 25 patients (76%) had learned to walk independently, 7 patients with help [corrected]. Only 1 subject did not improve. It was striking that voluntary muscle activity in the resting position was still low in several patients who had gained walking capability. Eleven patients who could already walk before LB therapy improved in speed and endurance. Of the 44 patients, six were capable of staircase walking before LB therapy compared with 34 afterwards. In order to validate the apparent superiority of LB therapy two types of comparisons were performed. In a 'temporal' control 12 spastic paretic patients, still wheelchair-bound after the period of postacute conventional therapy, performed LB immediately thereafter. After completion of LB therapy nine of these patients had learned to walk without help from others.(ABSTRACT TRUNCATED AT 250 WORDS). Department of Physiology, University of Bonn, Germany.

  Wernig A, Nanassy A and Muller S (1998). Maintenance of locomotor abilities following Laufband (treadmill) therapy in para- and tetraplegic persons: follow-up studies. Spinal Cord. 36 (11): 744-9. Summary: Recent reports indicate that walking capabilities in spinal cord damaged persons significantly improve--as compared to conventional rehabilitation therapy--after intensive training of aided (Laufband) treadmill-stepping. In the present report, follow up investigations on two collectives of spinal cord injured (sci) persons are described who had undergone (Laufband) treadmill therapy either during a period of renewed rehabilitation months or years after spinal cord injury (35 chronic patients) or during their first postacute rehabilitation period (41 acute patients). Among the initially chronic patients, 20 from 25 still wheelchair-bound before the onset of (Laufband) treadmill therapy, ie not capable of raising from the wheelchair and walking without help by other persons, became independent walkers after therapy. Assessment of voluntary muscle activity in resting position before and after the period of therapy had shown only small increases in most patients, indicating the involvement of motor automatisms and better utilisation of remaining muscle function during walking. Follow- up assessments performed 6 months to 6 1/2 years after discharge from the hospital revealed that the walking capabilities achieved by (Laufband) treadmill therapy in the 35 initially chronic patients were maintained in 31 persons, in three they had further improved, in only one it was reduced. These results indicate that the improvements achieved under clinical conditions can be maintained in every day life under domestic surroundings. From 41 initially acute patients, 15 had further improved and none had reduced his walking capability 6 months to 6 years after discharge from the hospital. Department of Physiology, University of Bonn, Germany.

  Wernig A, Nanassy A and Muller S (1999). Laufband (treadmill) therapy in incomplete paraplegia and tetraplegia. J Neurotrauma. 16 (8): 719-26. Summary: Recent reports indicate that intensive training of upright walking on a treadmill (German: Laufband, LB), significantly improves walking capability in spinal cord-damaged persons. The aids provided initially are body weight support by a harness and passive setting of one or both limbs by therapists. To facilitate stepping and evoke motor automatisms, "rules of spinal locomotion" need to be applied during training. The effects of this novel locomotion therapy on patients with chronic and acute incomplete paralysis are summarized and discussed here. Many patients with chronic paralysis, still wheelchair-bound and not capable of walking without help from others, became independent and learned to walk for some distance without help. Assessment of voluntary muscle activity in resting position before and after the period of therapy often showed only small increases, rendering the involvement of complex motor reflexes (motor programs) and better utilization of remaining muscle function during walking as main sources for the improvements in locomotion. This idea is supported by electromyographic recordings. Follow-up assessments performed 0.5 to 6.5 years after discharge from the hospital show that the significant improvements achieved by LB-therapy in patients with initially chronic paralysis can be maintained under domestic surrounding. Patients with initially acute paralysis improved their walking capabilities even further. It is suggested that LB therapy may be generally applied in the motor rehabilitation of persons with acute and chronic incomplete paraplegia and tetraplegia. Its use in other diseases is discussed.

  Wilson MS, Qureshy H, Protas EJ, Holmes SA, Krouskop TA and Sherwood AM (2000). Equipment specifications for supported treadmill ambulation training. J Rehabil Res Dev. 37 (4): 415-22. Summary: Supported Treadmill Ambulation Training (STAT) is a mode of therapy for gait retraining for patients with spinal cord injuries or other upper motor neuron dysfunction. The STAT program involves simultaneously supporting a portion of the patient's weight while gait training on a treadmill. STAT has been successful in improving the gait of many research subjects, but has not been widely applied in clinical practice. The goal of this study was to acquire practical, clinically useful information regarding this therapeutic intervention in order to remove barriers to its use. This manuscript enumerates equipment specifications for the treadmill, body weight support (BWS) system, and harness. The ergonomics of the work space are also considered, since the therapist(s) will need access to the patient's legs during therapy. The specific recommendations were determined through prior clinical experience, consultation of anthropometric tables, and application of engineering principles. The guidelines listed are intended to facilitate safe and effective application of the therapy at minimum hardware cost. VA Medical Center, Houston, TX 77030, USA.

  Wirz M, Colombo G and Dietz V (2001). Long term effects of locomotor training in spinal humans. J Neurol Neurosurg Psychiatry. 71 (1): 93-6. Summary: The long term effects of locomotor training in patients with spinal cord injury (SCI) were studied. In patients with complete or incomplete SCI coordinated stepping movements were induced and trained by bodyweight support and standing on a moving treadmill. The leg extensor muscle EMG activity in both groups of patients increased significantly over the training period, associated with improved locomotor ability in those with incomplete SCI. During a period of more than 3 years after training, the level of leg extensor EMG remained about constant in incomplete SCI in those who regularly maintained locomotor activity. By contrast the EMG significantly fell in those with complete SCI. The results suggest a training induced plasticity of neuronal centres in the isolated spinal cord which may be of relevance for future interventional therapies. ParaCare, Paraplegic Centre of the University Hospital Balgrist, Forchstrasse 340, CH-8008 Zurich, Switzerland.

  Wolfe DL, Hayes KC, Hsieh JT and Potter PJ (2001). Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury: a double-blinded, placebo-controlled crossover trial. J Neurotrauma. 18 (8): 757-71. Summary: 4-Aminopyridine (4-AP) is a potassium (K+) channel blocking agent that has been shown to reduce the latency and increase the amplitude of motor evoked potentials (MEPs) elicited with transcranial magnetic stimulation (TMS) in patients with chronic spinal cord injury (SCI). These effects on MEPs are thought to reflect enhanced conduction in long tract axons brought about by overcoming conduction deficits due to focal demyelination and/or by enhancing neuroneuronal transmission at one or more sites of the neuraxis. The present study was designed to obtain further evidence of reduced central motor conduction time (CMCT) and to determine whether MEPs could be recorded from paretic muscles in which they were not normally elicited. MEPs were elicited with TMS being delivered to subjects (n = 25) pre- and post-administration of 4-AP (10 mg capsule) or placebo. The principal finding was that 4-AP lowered the stimulation threshold, increased the amplitude and reduced the latency of MEPs in all muscles tested, including those that were unimpaired, but did not alter measures of the peripheral nervous system (i.e., M-wave, H-reflex, F-wave). These 4-AP-induced changes in MEPs were significantly greater than those seen with placebo (p < 0.05). The primary implication of these results is that a low dose of 4-AP (immediate-release formulation) appears to improve the impaired central motor conduction of some patients with incomplete SCI. This is most likely attributable to overcoming conduction deficits at the site of injury but may also involve an increase in cortical excitability. Department of Physical Medicine and Rehabilitation, University of Western Ontario, London, Canada. dwolfe@uwo.ca.

  Yan R and Taylor EM (2002). Neotrofin is transported out of brain by a saturable mechanism: possible involvement of multidrug resistance and monocarboxylic acid transporters. Drug Metab Dispos. 30 (5): 513-8. Summary: Neotrofin (AIT-082; leteprinim potassium) is transported out of brain by a saturable mechanism and in this study the mechanisms mediating this efflux were evaluated. Intracerebroventricular coadministration of [(14)C]Neotrofin with verapamil, a P-glycoprotein inhibitor, probenecid, an organic anion transporter inhibitor, 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsul fanyl)methylsulfanyl] propionic acid (MK571), a multidrug resistance-associated protein inhibitor, and salicylate or benzoate, both monocarboxylic acid transporter substrates, inhibited the efflux of [(14)C]Neotrofin. Additionally, Neotrofin inhibited the efflux of [(3)H]quinidine from brain. Compounds can diffuse from cerebrospinal fluid (CSF) into extracellular fluid of brain parenchyma and thus, efflux of [(14)C]Neotrofin after intracerebroventricular administration may indicate active transport across choroid plexus epithelium, brain capillary endothelium, or both. To determine whether [(14)C]Neotrofin efflux occurs at the brain capillary endothelium, experiments were performed in which [(14)C]Neotrofin was administered intraparenchymally. The t(1/2) for [(14)C]Neotrofin disappearance from brain after intraparenchymal administration was significantly lower than that for [(3)H]sucrose and the efflux of Neotrofin was inhibited by 600-fold excess of unlabeled Neotrofin, verapamil, MK571, and salicylate. Together, these data suggest that a saturable mechanism for the efflux of Neotrofin is located at the blood-brain barrier and possibly the blood-CSF barrier. It is likely that multiple transporters are involved in the efflux of Neotrofin and these may include multidrug resistance and monocarboxylic acid transporters. These data are discussed in detail with respect to the site of transporter expression, the recent identification of numerous multidrug resistance-associated protein and monocarboxylic acid transporter homologs, the existence of other potential brain efflux transporters, and the availability of specific pharmacological agents with which to distinguish these transporters. NeoTherapeutics, Inc., Irvine, California 92618, USA.

  Yu K, Li J, Rong W, Jia L, Yuan W, Ye X, Shi Z and Dai B (2001a). Recording of spared motor evoked potentials and its augmentation by 4-aminopyridine in chronic spinal cord-injured rats. Chin Med J (Engl). 114 (2): 155-61. Summary: OBJECTIVE: To research the direct electrophysiological evidence of discomplete spinal cord injury (SCI) and the effect of 4-aminopyridine on it. METHODS: Motor evoked potentials (MEPs), both spinal cord recorded MEPs (scMEPs) and extracellularly recorded MEPs (exMEPs) were recorded and characterized on a T13 epidural electrode (scMEPs) and an extracellular microelectrode (exMEPs) for 10 normal rats and 40 rats with lesions of various severity (sham, 35 g.cm force (gcf), 70 gcf, 100 gcf impact injury) at the T8-T9 cord using the Allen's drop model. The incline plane and Tarlov techniques were used to assess clinical neurological function. RESULTS: MEPs in the normal rats were elicited by applying transcortical suprathreshold stimulation consisting of 3-4 early negative peaks (N1, N2, N3 and N4) followed by several late waves. The N1 and N2 peaks were largest in the anterior and ventrolateral funiculus, respectively, which was indicative of extrapyramidal pathways. The 100 gcf impact injuries and the cord transection abolished the MEP distal to the lesion, whereas the 35 gcf injuries resulted in a latency shift and amplitude decrement of the MEP peaks. Eighteen of the 20 rats with 70 gcf-injuries showed clinical paraplegia. Among them, 7 rats had neurophysiological evidence of residual conduction pathways through the lesioned cord segment, such as the presence of N1 and N2 peaks in the scMEPs or exMEPs. After 4-aminopyridine (4-AP) administrations (1 mg/kg), the amplitude of the spared exMEP increased significantly and spread more widely. CONCLUSIONS: MEPs evoked by transcortical stimulation travel mostly in the extrapyramidal tract. MEP monitoring could provide an excellent method of detecting the functional integrity of the motor tracts after SCI, and could even detect spared motor fibers after discomplete SCI. Furthermore, the use of 4-AP or other K+ channel blocking agents may be a potential treatment for patients with chronic moderate to severe SCI. Department of Orthopedics, Shanghai Municipal Corps Hospital, Chinese People's Armed Police Forces, Shanghai 201103, China. kwyu@sh163b.sta.net.cn.

  Yu K, Rong W, Li J, Jia L, Yuan W, Yie X and Shi Z (2001b). Neurophysiological evidence of spared upper motor conduction fibers in clinically complete spinal cord injury: discomplete SCI in rats. J Neurol Sci. 189 (1-2): 23-36. Summary: Motor evoked potentials (MEP) were recorded and characterized by epidural electrodes (scMEP) and extracellular microelectrodes (exMEP) on T(13) level from 10 normal rats and 40 rats with chronic spinal cord injury (SCI). The spinal cord of 40 anesthetized rats were injured with various severity (sham, 35, 70, and 100 g/cm impact injury) at T(8)-T(9) cord using Allen's drop model. The incline plane and Tarlov techniques were investigated to assess clinical neurological function. MEPs in the normal rats elicited by applying transcortical suprathreshold stimulation consisted of 3-4 early negative peaks (N(1), N(2), N(3), N(4)) followed by several late waves. The N(1) and N(2) peaks had their maximal amplitudes in the anterior and ventrolateral funiculus, respectively, irrespective of the polarity of stimulation, which indicated that these impulses were conducted mostly through the extrapyramidal pathways. The 100 g/cm impact injury or transection of the cord caused abolishment of the MEP signals distal to the lesion, whereas the 35 g/cm injury resulted in a latency shift and amplitude decrement of the MEP peaks. Out of 20 rats with 70 g/cm injuries, 18 showed clinically paraplegia. Among them, seven had neurophysiological evidence of residual conduction pathways through the injured cord segment, such as the presence of N(1) and N(2) peaks in scMEP or exMEP. After 4-aminopyridine (4-AP) administration (1 mg/kg), the amplitude of spared exMEP increased significantly and spread more widely. These results suggest that MEPs evoked by transcortical stimulation travel mostly in the extrapyramid tract. The present study provides further direct and objective electrophysiological evidences of spared functional axons after discomplete SCI, since many other studies on this field have achieved similar results previously. Furthermore, pharmaceutical treatment with 4-AP or other K(+) channel blocking agents proved to be a potential therapeutic strategy for patient with chronic SCI. Deparment of Orthopaedic Surgery, Changzheng Hospital, Feng Yang Road 415#, Shanghai 200003, People's Republic of China. kwyu@sh163b.sta.net.cn.

 



©Wise Young PhD, MD


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