- The importance of perfusion pressure is well established in the field of TBI treatment, as is that of monitoring blood pressure and intracranial pressure to optimize perfusion pressure. Numerous investigators have wondered whether the same approach may have value in the management of SCI. Indeed, in thoracoabdominal aortic aneurysm surgery, CSF drainage has been found to significantly reduce the incidence of ischemic paraplegia, presumably by lowering intrathecal pressure and improving spinal cord perfusion.
- In 2009 investigators at the University of British Columbia published results of a safety and feasibility study evaluating CSF drainage through a lumbar intrathecal line as a neuroprotective strategy after acute SCI. In 22 carefully selected patients randomly allocated to treatment, the investigators found no major adverse events related to CSF drainage, such as CSF leak, neurological worsening, and meningitis. The treatment did not, however, achieve a significant decrease in intrathecal pressure, although the investigators employed a conservative drainage protocol with a limit of 10mL/hour. Paradoxically, they found that intrathecal pressure was normal preoperatively and increased as a result of surgical decompression. Currently plans are being made for a new, larger trial involving CSF pressure monitoring only. A separate multicenter effort led by the University of Alabama at Birmingham will also explore spinal cord perfusion and CSF drainage.
震盪電場刺激(Oscillating Field Stimulation)
- Neurites grow toward the negative pole (cathode) in an electrical field. Researchers at Indiana University Medical Center thus developed an implantable “oscillating field stimulator” capable of generating an electrical field along the rostrocaudal axis of the spinal cord. In order to promote axonal growth in both directions, the device changes polarity every 15 minutes. Preliminary results of their trial were reported in 2005. Investigators implanted the device in 10 patients with complete SCI within 18 days of injury and removed it 15 weeks after injury. At 1 year, treated patients exhibited improvement in light touch (25.5 points; P = .02), and pinprick sensation (20.4 points; P = .02) over baseline performance. Motor improvement was also seen but it was only 6.3 points ( P = .02). A wound infection developed in 1 of the patients and device failure occurred in a second. Spontaneous neurological improvement from baseline examination is, of course, expected following SCI. On the basis of comparison with spontaneous improvement seen in historical controls from NASCIS III, the investigators of this study believe that device efficacy is suggested, but results of such a comparison with historical controls must be interpreted with caution, especially in such a small sample size.
- On the basis of the initial results, the U.S. Food and Drug Administration (FDA) approved enrollment of additional patients in this study. Cyberkinetics Neurotechnology Systems, Inc. (Foxboro, MA), purchased the intellectual property for this technology, and to our knowledge the trial is not active at this time. A similar trial involving pulsed electrical stimulation was reportedly conducted by investigators Xu and Liu in 100 patients in Beijing, 38 but the results have never been published to our knowledge.
- The remarkable tissue- and cell-preserving effects of hypothermia are well known to biologists and physicians. Indeed, it is said that patients “are not dead until they are warm and dead.” In addition to lowering metabolic rate, hypothermia appears to reduce extracellular glutamate, vasogenic edema, apoptosis, neutrophil and macrophage invasion and activation, and oxidative stress. Hypothermia has thus long been explored for its putative neuroprotective effects despite its risks, which include coagulopathy, sepsis, and cardiac dysrhythmia. Therapeutic hypothermia has become the standard of care for patients resuscitated from an out-of-hospital cardiac arrest, but animal models of traumatic SCI have demonstrated mixed results. Furthermore, some TBI trials had to be stopped early because of poor outcomes in patients treated with hypothermia.
- Later TBI guidelines sought to provide recommendations related to the use of hypothermia for human SCI, but insufficient human data exist. This approach must thus be considered experimental and subjected to scientific investigation; it should not be routinely employed by physicians until supportive evidence emerges. Researchers from the Miami Project to Cure Paralysis began a trial in 2007 exploring the role of systemic hypothermia in SCI. This trial involves rapid cooling with chilled intravenous saline to drop core body temperature to around 33°C and comparison with historical controls. The results of this case-controlled study were published in 2013 and were promising; however, more rigorous confirmatory studies are needed before this therapeutic approach is adopted.
- Minocycline is a synthetic tetracycline derivative commonly used as an antibiotic in dermatology. It has also been noted to inhibit microglial activation and to have anti-apoptotic properties. Preclinical testing in various animal models of SCI reported enhanced functional recovery with its use.
- In 2012 researchers from the University of Calgary published a phase 2 placebo-controlled randomized study examining the utility of intravenous minocycline for human SCI. The 52 patients involved in the study were randomly allocated to treatment groups within 12 hours of their injury and were treated for 7 days. The investigators verified the presence of minocycline in the CSF and noted transient liver enzyme elevation in one patient as the only adverse event attributable to the drug. In patients treated with minocycline, motor recovery was 6 points higher than in those receiving placebo; however, this difference was not statistically significant ( P = .20). No improvement was found in patients with thoracic SCI, although patients with cervical injuries exhibited motor recovery of 14 points ( P = .05). According to the principal investigators a phase 3 trial is under way.
- A similar study is reportedly being conducted by investigators in Saudi Arabia. This SCI trial is studying the efficacy of minocycline when coadministered with the immunosuppressant tacrolimus (FK506) ; we are uncertain of the trial's status at this time.
- Riluzole (Rilutek, Sanofi-Aventis, Bridgewater, NJ) is a benzothiazole anticonvulsant that has been licensed for use in patients with amyotrophic lateral sclerosis (ALS) for approximately 10 years. Riluzole is the only drug to date approved for use as a neuroprotectant. Studies suggest that it prolongs the lives of those with ALS by 2 to 3 months. Its neuroprotective effects appear to result from blockade of voltage-sensitive sodium channels as well as from antagonism of presynaptic calcium-dependent glutamate release. Of interest to the treatment of SCI, synergy with MPSS has been suggested for this agent, and animal models of SCI have demonstrated neuroprotective effects when riluzole was administered as late as 10 days following injury.
- A phase 1 multicenter trial examining the safety of riluzole in acute SCI (RISCIS) was completed by the North American Clinical Trials Network, and the results were published in February 2014. The 36 enrolled patients in this matched comparison group trial were administered riluzole 50mg PO (by mouth) every 12 hours, starting within 12 hours of injury and continuing for 14 days. Although some patients exhibited liver enzyme elevation, no serious adverse events were attributed to riluzole. Riluzole-treated patients with cervical injuries had an additional 15.5 points of improvement in mean ISNCSCI motor score from admission to 90 days in comparison with registry patients used as controls ( P = .021). A phase 2/3 study is now recruiting patients with ASIA Impairment Scale grades A to C who present to the hospital within 12 hours of a cervical SCI. This placebo-controlled trial will evaluate a dose of riluzole of 2 × 100mg in the first 24 hours followed by 2 × 50mg daily for the following 13 days after injury and will assess change between ISNCSCI motor scores at baseline and at 180 days. Secondary outcomes will include overall neurological recovery, sensory recovery, functional outcomes, quality of life outcomes, health utilities, mortality, and adverse events.
- Magnesium has long been explored in neurotrauma for its neuroprotective properties and has shown benefit in preliminary studies. Magnesium blocks NMDA receptors, a process that may at least in part account for its beneficial effects. In human TBI magnesium is ineffective. Polyethylene glycol is believed to stabilize and repair injured cell membranes by functioning as a membrane “fusogen.” After receiving received fast track designation from the FDA for its proprietary magnesium/polyethylene glycol formulation, named AC105, Accorda Therapeutics (Ardsley, NY) has initiated a phase 2 trial designed to optimize penetration into the injured spinal cord. The first patient was enrolled in September 2013. In this placebo-controlled trial, participants will receive six intravenous doses, with the first administered within 12 hours of injury.
- Fortunately, the previously described barrier to CNS regeneration imposed by Nogo and more newly discovered myelin inhibitors does not seem insurmountable. Schwab's group not only discovered Nogo but also developed a neutralizing antibody for it. This antibody, which sequesters Nogo, is now being investigated in a human clinical trial (ATI355, Novartis Pharmaceuticals Corporation, East Hanover, NJ). A second and potentially more potent therapy has been developed by McKerracher and Higuchi in Montreal. Their group created VX-210 (Vertex Pharmaceuticals, Boston, MA), which targets the final common pathway of all known myelin and ECM inhibitors.
- As discussed, Schwab's group demonstrated that oligodendrocytes and their myelin membranes are major inhibitors of axonal growth within the CNS. They employed a monoclonal antibody, IN-1, to isolate and characterize inhibitory fractions within CNS myelin. IN-1 also had the noteworthy property of lessening myelin inhibition in vitro. Subsequent in vivo application of IN-1 resulted in substantial axonal sprouting and some long-distance corticospinal axonal regeneration within the adult mammalian CNS and was associated with improved functional recovery.
- The humanized anti-Nogo antibody, ATI355, has been shown to promote axonal sprouting and functional recovery following SCI in numerous animal models; it is a rare therapeutic to have demonstrated functional improvement in a primate model. In a phase 1 human trial initiated by Novartis Pharmaceuticals in 2006, ATI355 was administered via continuous intrathecal infusion in four increasing dose regimens, with the highest dose being delivered over 28 days. The trial was completed in Europe and Canada because the FDA expressed concerns about the external nature of the infusion pump. The trial enrolled patients with complete SCI between C5 and T12 due to injuries incurred 4 to 14 days previously. Although the trial has been completed its account has not been published; we await word on a phase 2 trial.
- Cethrin involves a toxin produced by Clostridium botulinum , C3 transferase, which is a specific inhibitor of the guanosine triphosphatase Rho, through which all known myelin and ECM inhibitors identified thus far signal. Additionally, animal studies suggest not only that this agent facilitates axonal growth and functional recovery but also that C3 transferase has additional neuroprotective effects. To improve cellular permeability and permit delivery to the spinal cord via application on intact dura at the time of spinal decompression, McKerracher and Higuchi created a recombinant version of C3 transferase that incorporates a transport sequence. The resulting protein is referred to as VX-210. In the human application, VX-210 is mixed with the fibrin sealant Tisseel (Baxter Healthcare Corporation, Deerfield, IL) before being applied to the dura. The resulting combination, Cethrin, was commercialized by Bioaxone Biosciences, Inc., and was studied in a human clinical trial.
- A phase 2/3a multicenter, dose-escalation human trial was initiated under the leadership of this chapter's senior author (MGF) at the University of Toronto, and its results have been published. This trial sequentially recruited patients with ASIA Impairment Scale grade A thoracic (T2-T12) or cervical (C4-T1) SCI to receive escalating doses of Cethrin ranging from 0.3mg to 9mg. Forty-eight patients were enrolled and followed up for 1 year. No serious adverse events were attributed to the drug. Patients with cervical SCI who were treated with 3mg of Cethrin showed an improvement in ASIA (ISNCSCI) motor score of 27.3 ± 13.3 points at 12 months. Approximately 6% of patients with thoracic SCI experienced enough improvement to be moved from ASIA Impairment Scale grade A to grade C or D, compared with 31% of patients with cervical SCI and 66% of patients with cervical SCI who received 3mg of Cethrin. These findings suggests that VX-210 may increase neurological recovery after complete SCI. Further clinical trials with Cethrin in patients with SCI are being planned.
- After obtaining phase 1 safety data in healthy human controls, Asubio Pharmaceuticals, Inc. (Edison, NJ), is conducting a 164-patient phase 2 randomized, placebo-controlled multicenter trial for its molecule SUN13837. It will be administered to persons with C4 to C7 injuries within 12 hours after injury and for a total of 30 days. SUN13837 is an analog of fibroblast growth factor that has demonstrated neuroprotective and angiogenic properties. Unlike fibroblast growth factor, SUN13837 is designed to not stimulate cellular proliferation because this effect has the potential to induce neoplasia.
- Granulocyte colony-stimulating factor (G-CSF) drives the differentiation, proliferation, and survival of granulocytic lineage cells and is well known to clinicians for its use in febrile neutropenia and other conditions. G-CSF has also been shown to increase both the mobilization of bone marrow stromal cells from the bone marrow and their presence at sites of SCI. In a rodent model this effect was also associated with white matter sparing and improved hind-limb locomotor function. In a mouse model it was additionally shown to reduce apoptosis of cells within the spinal cord. Like other drugs currently under investigation, G-CSF has the advantage of a known track record in human application. It is currently in early-phase human clinical trials in Japan; few published details are available regarding the trials, however.