Promising neuroprotective strategies for traumatic spinal cord injury with a focus on the differential effects among anatomical levels of injury

Early surgical decompression

The popularized phrase coined by the senior author, “Time is spine”, highlights the preclinical^13,14 and clinical^15,16 success of early surgical decompression, which aims to realign the spinal column and relieve bony or ligamentous spinal cord compression. Decompression of intradural pressure, by durotomy alone or durotomy combined with duraplasty, has also been evaluated in experimental SCI^17,18. Yet mixed results warrant further research on the efficacy and standardization of these practices. In contrast, early extradural surgical decompression has been shown to reduce tissue damage and improve outcomes following SCI. Even with some concern regarding perioperative hemodynamic changes affecting cord perfusion, most spine surgeons have been, and continue to be, in favor of decompressing the acutely injured spinal cord^19,20. As a result, early decompression remains recommended in clinical management guidelines by the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons²¹. Similarly, the recent AOSpine guideline also recommends decompression within 24 hours of SCI²². While there may be differential efficacy between injury-level subpopulations²³, current evidence is limited by substantial clinical heterogeneity, loss to follow-up, unclear adjustment for baseline factors, and a lack of statistical power. For these reasons, more work is needed to develop customizable treatment regimens and prioritized surgical access to the most benefitting patient subtypes.

Support of mean arterial pressure

Hypotension, hypoxemia, pulmonary dysfunction, and cardiovascular instability are common within the first 7 to 10 days of SCI²⁴. Hemodynamic instability not only limits the opportunity for early surgical intervention but also increases spinal cord ischemia and therefore secondary damage. For this reason, the current AANS and Congress of Neurological Surgeons guideline recommends continuous hemodynamic monitoring, interventions correcting hypotension (such as by vasopressor administration), and maintenance of mean arterial blood pressure (MAP) between 85 and 90 mmHg for the first 7 days following cervical injury²⁵. While these recommendations are largely based on a small group of uncontrolled and underpowered studies²⁶, a recent retrospective assessment largely confirmed the published guidelines as well as the neuroprotective potential of vasopressor administration²⁷. As these results need further prospective validation, it will be important to stratify patient populations and identify potential treatment effect differences based on the anatomical level of injury. It is also important to note that MAP support principally aims to maintain appropriate spinal cord perfusion pressure (SCPP), determined by the difference between MAP and intraspinal pressure (ISP). However, as ISP may increase independently of MAP, maintenance of a low ISP or a high SCPP (or both) is gaining increasing attention as an important practice in the acute clinical management of SCI^28,29. While initial studies have shown encouraging results about the predictive value of low ISP or high SCPP in neurological recovery, larger multicenter studies are needed to validate these preliminary data²⁹.

Methylprednisolone sodium succinate

Methylprednisolone sodium succinate (MPSS) is a synthetic corticosteroid with potent anti-inflammatory effects and neuroprotective potential in acute traumatic SCI. Concerns about increased risk for infections following MPSS treatment have kept the drug at the forefront of continuous controversy. While it remains the only treatment option for acute SCI, debate regarding optimal dose, time of administration, efficacy, and adverse effects has dominated the field for decades and has dichotomized clinicians around the world. For this reason, there have been three National Acute Spinal Cord Injury Studies (NASCIS) to evaluate the clinical safety and efficacy of varying MPSS dose and timing. Moreover, NASCIS results have been retrospectively analyzed on numerous occasions to derive meaningful conclusions. One of the most recent publications on the topic concluded that MPSS does not increase the risk of infections and confers significant short-term effects when given within the first 8 hours of injury³⁰. Importantly, patients with cervical SCI and reduced baseline injury severity seem to benefit most from this treatment³¹. Given the particularly debilitating nature of cervical injuries, these improvements have tremendous impact on patients’ quality of life. Thus, the most recent AOSpine guideline currently recommends a 24-hour treatment of intravenous MPSS when initiated within the first 8 hours of SCI, independently of injury level²².

Riluzole

Secondary injury involves ionic dysregulation and excitotoxicity. As cell membranes become highly permeable to sodium ions, there is increased calcium influx. Subsequently, high sodium and calcium ion concentrations in neurons trigger the secretion of glutamate from nerve terminals. Increased synaptic glutamate leads to prolonged excitability in the postsynaptic neurons, driving eventual neuronal edema and death.

Riluzole is a benzothiazole (molecular weight of 234.2 Da) which inhibits voltage-gated sodium channels and glutamate release, thereby mitigating excitotoxicity. Riluzole has been reported to slow the progression of amyotrophic lateral sclerosis (ALS)—a progressive motor neuron disease—and currently is the only US Food and Drug Administration (FDA)-approved drug for ALS. In addition, riluzole has been shown to have neuroprotective potential in animal models of Parkinson’s disease³² and Huntington’s disease³³ and currently is being used in clinical studies of mild Alzheimer’s disease (ClinicalTrials.gov identifier NCT01703117). Importantly, riluzole was also shown to suppress spasticity³⁴, a frequent co-morbidity in patients with SCI, and to promote neural preservation in rats with high cervical spinal hemisection injury³⁵.

Capitalizing on the preclinical success of riluzole, a phase I/IIA clinical trial was launched in April 2010 to assess the safety and pharmacokinetics of riluzole in patients with acute traumatic SCI (ClinicalTrials.gov identifier NCT00876889). In this trial, 36 patients with SCI (28 cervical and eight thoracic SCI) received riluzole (50 mg) orally every 12 hours for 28 doses. A control group consisting of 36 patients with SCI—matched for neurological impairment, gender, and age—received the standard of care but no riluzole. Patients who received riluzole showed statistically significant improvement compared with the control group (P = 0.021). In particular, patients with incomplete cervical injury—American Spinal Injury Association (ASIA) Impairment Scale B—showed the highest improvement in the International Standards for Neurologic Classification of Spinal Cord Injury (ISNCSCI) motor score (P = 0.037). In addition to being efficacious, riluzole was shown to be safe for this patient cohort³⁶. Interestingly, there was no difference within the thoracic injury group, as patient numbers were small, patients had more severe injuries, and the ISNCSCI motor scoring is less sensitive to thoracic recovery³⁷.

Based on these results, a phase IIB/III was launched in 2013 to evaluate the efficacy and safety of riluzole in patients with cervical traumatic SCI, entitled “Riluzole in Acute SCI Study” (RISCIS) (estimated enrollment: 351 patients, ClinicalTrials.gov identifier NCT01597518). In this multicenter, randomized, placebo-controlled, double-blinded trial, riluzole (100 mg, twice daily) is administered orally to patients within 24 hours from injury, followed by two 50 mg daily doses for 14 days after SCI. A capsule identical in shape and size to riluzole is administered to patients in the control group. The primary outcome of the study is improvement in ISNCSCI motor scores at 180 days after injury. The study is estimated to be completed by 2021³⁷.

Therapeutic hypothermia

In response to trauma, increased metabolic rate can lead to excitotoxicity and cell death. Local or systemic cooling following insult has been shown to reduce the metabolic demand, thereby limiting cell death. Moreover, therapeutic hypothermia has been shown to reduce inflammatory cell infiltration, myeloperoxidase activity, and vasogenic edema and stabilize the blood-brain barrier³⁸. Despite these benefits, systemic hypothermia may have some serious side effects, including bradycardia, respiratory infections, and deep vein thrombosis. While local cooling of the spinal cord circumvents many of these concomitant issues, randomized controlled trials are still needed to prove the efficacy of local hypothermia in neurological recovery after SCI. However, in one study, acute (within 8 hours of injury) local hypothermia was shown to improve recovery among cervical and thoracic populations (n = 12 out of 14 cervical SCI, n = 4 out of 6 thoracic SCI) when compared with historical controls³⁹. Similarly, a pilot study of systemic hypothermia in patients with cervical complete SCI (n = 14) demonstrated fewer adverse effects and a trend toward improved recovery compared with age- and injury level-matched historical controls when systemic hypothermia was induced within 9 hours of trauma⁴⁰. Furthermore, a follow-up randomized controlled trial assessing the efficacy of intravascularly delivered systemic hypothermia in acute cervical SCI commenced in May 2017 (estimated enrollment: 120 patients, ClinicalTrials.gov identifier NCT02991690). Although previous multicenter randomized clinical trials found hypothermia to be ineffective in adults with traumatic brain injury⁴¹, expectations for SCI remain hopeful.

Glibenclamide (Glyburide, DiaBeta)

Capillary fragmentation following SCI contributes to hemorrhage. This process is initiated in the capillary-rich gray matter of the injury epicenter and expands rostro-caudally, leading to progressive tissue necrosis, cavitation, and neurological dysfunction. In a rat model of unilateral cervical SCI, Simard et al. found that sulfonylurea receptor 1 (SUR1)-regulated Ca²⁺-activated [ATP]_i-sensitive non-specific cation (NC_Ca-ATP) channels of the capillary endothelium in the spinal cord are key to capillary fragmentation following SCI⁴². By blocking NC_Ca-ATP channels with the FDA-approved anti-diabetic drug glibenclamide (Glyburide), Simard et al. observed decreased lesion volumes and significant white matter preservation coupled with improved neurobehavioral outcomes⁴². Recently, a phase I/II clinical trial was initiated to assess the safety and neuroprotective effectiveness of Glyburide (DiaBeta) in patients with acute traumatic cervical SCI (estimated enrollment: 10 patients, ClinicalTrials.gov identifier NCT02524379), with an estimated completion date in early 2020.

Granulocyte colony-stimulating factor

Initially overlooked for its potential in the central nervous system (CNS), granulocyte colony-stimulating factor (G-CSF) has shown positive preclinical results for SCI (Table 1). In response to ischemia and CNS injury, G-CSF and its receptor (CD114; G-CSFR) are upregulated in neurons and endogenous stem cells, initiating a compensatory neuroprotective mechanism. By binding to its cognate receptor, G-CSF counteracts programmed cell death in mature neurons, induces neurogenesis, and promotes neuronal differentiation of adult neural stem cells⁴³. Moreover, angiogenesis⁴⁴ and reduced inflammation⁴⁵ have been attributed to the protective actions of G-CSF. Kamiya et al. administered G-CSF for 5 consecutive days after cervical SCI and assessed ASIA motor scores 3 months later⁴⁶. The improvements were significant compared with historical controls of patients with cervical SCI receiving high-dose MPSS⁴⁶. In a study by Inada et al., patients with cervical SCI who received G-CSF demonstrated improved recovery compared with a non-treated group⁴⁷. However, the treatment was administered in an open-label and non-randomized fashion⁴⁷. Interestingly, in a study by Saberi et al., in which G-CSF was administered in patients with chronic SCI, significant motor and sensory recovery was demonstrated, particularly in patients with incomplete cervical SCI⁴⁸. Despite these promising effects, a true double-blinded randomized control clinical trial for G-CSF has yet to be developed.

Minocycline

Inflammatory cytokines produced by resident microglia and astrocytes following trauma attract peripheral immune cells to the spinal cord. Neutrophils and monocytes are the first blood-derived cells to enter the injured parenchyma. While these cells are crucial in cleaning up the cellular debris, they produce inflammatory cytokines, such as tumor necrosis factor-alpha and interferon-gamma, as well as toxic by-products that exacerbate damage.

Minocycline is a tetracycline antibiotic with neuroprotective and anti-inflammatory properties. A single-center, placebo-controlled, double-blinded phase I/II clinical trial was initiated in 2004 to evaluate the efficacy and safety of intravenous minocycline within 12 hours of injury for 7 days. The study, which was completed in 2010 (27 patients received minocycline and 25 received placebo), showed a trend toward improved motor scores in incomplete cervical SCI cases in the absence of any serious adverse effects (P = 0.05) but no improvement in thoracic SCI⁴⁹ (ClinicalTrials.gov identifier NCT00559494). Based on these results, a phase III clinical trial, titled “Minocycline in Acute Spinal Cord Injury (MASC)”, was initiated in 2013 and is expected to finish by 2018 (estimated enrollment: 248 patients, ClinicalTrials.gov identifier NCT01828203). Interestingly, a clinical trial evaluating the efficacy of minocycline in reducing neuropathic pain has been successfully completed, but the results have yet to be published (ClinicalTrials.gov identifier NCT01869907). Given that neuropathic pain is a common and debilitating co-morbidity in patients with SCI, the study results will be of significant interest to the field.

Cethrin (VX-210)

The injured spinal cord niche contains growth-inhibitory molecules, such as myelin debris and chondroitin sulfate proteoglycans, that lead to neuron growth cone collapse, thereby inhibiting regeneration. These molecules bind to respective receptors on regenerating neurons, where they initiate a phosphorylation cascade. At the converging point of this cascade are Rho GTPases, a family of intracellular enzymes that regulate cytoskeletal mechanisms and cellular mobility. Cethrin (VX-210) is a recombinant deactivator of RhoA (a member of the Rho family) with dura and cell membrane penetrance. An open-label uncontrolled phase I/IIa clinical trial showed significant neurological improvement in patients with SCI who received Cethrin (48 patients, ClinicalTrials.gov identifier NCT00500812). Benefits were particularly enhanced in patients with cervical SCI compared with their thoracic counterparts⁵⁰, a finding that incentivized the initiation of larger controlled double-blinded clinical trials for patients with cervical SCI. This phase IIb/III clinical trial will evaluate the safety and efficacy of two doses of VX-210 (formerly known as Cethrin) compared with placebo (a fibrin sealant) when applied extradurally at the site of injury, acutely after cervical SCI (estimated enrollment: 150 patients, ClinicalTrials.gov identifier NCT02669849).

Anti-Nogo-A antibody (ATI-355)

Anti-Nogo-A antibody is a monoclonal antibody against Nogo-A, a protein inhibitor of neurite growth found on adult CNS myelin. Widely assessed at the thoracic level in rodents^51–53, in addition to several studies in primate models of cervical SCI^54,55, anti-Nogo-A antibody has been shown to promote axonal sprouting and improve functional recovery following injury. A non-randomized, open-label phase I clinical trial of humanized anti-Nogo-A antibody (ATI-355; Novartis Pharmaceuticals) was initiated to assess the feasibility, tolerability, and safety of either repeated intrathecal bolus injections of AT1-355 or continuous intrathecal delivery in acute SCI (4–14 days after injury). In total, 52 cervical and thoracic patients with traumas between C5 and T12 level were recruited in the study, and results are pending dissemination (ClinicalTrials.gov identifier NCT00406016). A phase IIb trial, led by Armin Curt, is expected to begin in Europe shortly.

Intravenous immunoglobulin G

Intravenous immunoglobulin G (IVIG) consists of serum immunoglobulin G (IgG) pooled from thousands of healthy donors. Independent laboratory studies in cervical and thoracic models of SCI have shown that IVIG improves recovery by targeting the detrimental inflammatory response in the spinal cord after trauma^56–58. While the efficacy of IVIG for SCI has not been assessed in clinical trials, the exciting preclinical results coupled with IVIG’s long-term clinical use for the treatment of autoimmune and immunodeficiency conditions make it a promising candidate for SCI clinical trials.

Cell therapies

With cell transplantation as an attractive treatment approach for SCI, a diverse range of cells has been evaluated in preclinical studies, resulting in a plethora of potential mechanisms. In short, transplanted cells have been used for immune modulation, trophic support, scaffolding, re-myelination, and cell replacement⁵⁹. Yet, predominantly applied in the subacute and chronic phases of injury, only a few cell transplantation strategies are thought to have neuroprotective potential for the acutely injured spinal cord.

Mesenchymal stem/stromal cells. Mesenchymal stem/stromal cells (MSCs) are multipotent mesodermal progenitors defined by their in vitro adhesion to plastic and their cell surface antigen profile⁶⁰. Readily accessible from various adult tissues such as bone marrow, cartilage, and fat, MSCs are among the most commonly studied cells in regenerative medicine. This popularity has led to significant heterogeneity in MSC isolation, cultivation, and purification procedures, further resulting in mixed therapeutic efficacy among preclinical studies and the increasing number of clinical studies⁶¹. In SCI, MSCs have been reported to dampen inflammation, modulate the immune response, and secrete neuroprotective factors⁵⁹. A 2013 systematic meta-analysis of preclinical studies, involving intrathecal, intraparenchymal, and intravenous infusion of MSCs in various models of cervical and thoracic SCI, determined that the cells, overall, result in improved functional recovery after injury⁶². While this is encouraging, a lot remains to be understood about the identity and function of MSCs. Furthermore, additional mechanistic studies are needed to effectively tailor their therapeutic application for SCI and identify differences in efficacy between anatomical levels of injury.