Updates in the Early Management of Acute Spinal Cord Injury

Mark J. Lambrechts, MD; Tariq Ziad Issa, BA; Alan S. Hilibrand, MD

J Am Acad Orthop Surg. 2023;31(17):e619-e632.

Abstract and Introduction

Abstract

Spinal cord injury (SCI) is a leading cause of disability worldwide, and effective management is necessary to improve clinical outcomes. Many long-standing therapies including early reduction and spinal cord decompression, methylprednisolone administration, and optimization of spinal cord perfusion have been around for decades; however, their efficacy has remained controversial because of limited high-quality data. This review article highlights studies surrounding the role of early surgical decompression and its role in relieving mechanical pressure on the microvascular circulation thereby reducing intraspinal pressure. Furthermore, the article touches on the current role of methylprednisolone and identifies promising studies evaluating neuroprotective and neuroregenerative agents. Finally, this article outlines the expanding body of literature evaluating mean arterial pressure goals, cerebrospinal fluid drainage, and expansive duroplasty to further optimize vascularization to the spinal cord. Overall, this review aims to highlight evidence for SCI treatments and ongoing trials that may markedly affect SCI care in the near future.

Introduction

Acute spinal cord injury (ASCI) remains a major cause of disability worldwide with an incidence of 21 cases per 100,000 individuals in the United States.^[1]Although the global incidence has decreased markedly over the past 30 years, the global age standardized prevalence has increased by 0.1% each year.

Abstract and Introduction
Acute Spinal Cord Injury Pathophysiology
Early Spinal Cord Decompression
Methylprednisolone
Other Neuroprotective Agents
Cellular Transplantation
Cellular Adjuncts and Biomaterials
Other Investigational Modalities
Summary
References

Table 1. Studies Evaluating the Effect of Early Surgical Decompression on Neurologic Recovery
Study	Patients	Design	Injury	Time to Decompression	Conclusion
Fehlings et al, 2012⁵	313	Multicenter, prospective	Traumatic cervical ASCI	Early: <24h Late: >24h	Early surgery is associated with 2.8 greater odds improvement of at least two AIS grades.
Dvorak et al, 2015⁴¹	888	Multicenter, retrospective^a	Traumatic ASCI	Early: <24h Late: >24h	Early surgery is associated with 6.3 motor points additional recovery in patients with AIS grade B, C, or D, but not AIS A. Early surgery also reduces LOS.
Badhiwala et al, 2021⁸	1,548	Multicenter, retrospective^a	Traumatic ASCI	Early: <24h Late: >24h	Early surgery is associated with improved sensorimotor recovery.
Badhiwala et al, 2022⁶	186	Multicenter, retrospective^a	Central cord syndrome	Early: <24h Late: >24h	Early surgery is associated with improved upper limb motor recovery in all patients and overall motor function in AIS Grade C patients.
Wutte et al, 2020⁴²	43	Single-center, retrospective	Traumatic thoracic ASCI	Early: <8h Late: >8h	Although early surgery was not associated with greater AIS improvement, patients experienced significantly improved functional bladder and mobility outcomes.
Burke et al, 2019¹¹	48	Single-center, retrospective	Traumatic cervical ASCI	Ultra-early: <12h Early: 12–24h Late: >24h	Ultra-early surgery was associated with greater improvement in AIS grades compared with early group (1.3 vs 0.5, P = 0.02). 88.8% of AIS A patients converted to better AIS grade in the ultra-early group, compared with only 38.4% in the early and late groups.
Nasi et al, 2019⁴³	81	Single-center, retrospective	Traumatic cervical ASCI	Ultra-early: <12h Early: 12–48h	Ultra-early surgical decompression was associated with greater neurologic improvement.
Jug et al, 2019⁹	64	Single-center, retrospective	Traumatic cervical ASCI	ROC analysis to determine optimal timing among patients operated on within 24	Decompression within 4 hours (95% CI: 4–9 hours) was the optimal window for patients to experience improvement of at least 2 AIS grades.

^aRetrospective analyses were done on prospectively collected and maintained data sets
ASCI = acute spinal cord injury, AIS = American Spinal Injury Association Impairment Scale, LOS = length of stay

Table 2. - Summary of the 2017 AO Spine Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury
Category	Recommendation	Quality of Evidence	Recommendation Strength	Rationale
Surgery⁴⁴	We suggest that early surgery (<24 hr) be considered as an option in adult patients with traumatic CCS.	Low	Weak	In the absence of strong evidence, the potential for neurologic and functional benefit identified in studies is likely of enough importance that the potential benefits likely outweigh possible harms.
Surgery⁴⁴	We suggest that early surgery be offered as an option for adult patients with ASCI, regardless of level.	Low	Weak	The included studies were downgraded for imprecision or risk of bias. Although the studies identified benefits to surgery at all levels, many members of the GDG were uncertain if these reported benefits met clinical significance. However, without differences in complications, the benefits likely outweigh costs.
Steroids²²	We suggest not offering a 24 hr infusion of high-dose MPSS to adult patients who present after 8 hours with ASCI.	Moderate	Weak	The anticipated desirable effects are probably not large relative to the undesirable effects, given that MPSS administered after 8 hours of injury does not result in statistically or clinically significant improvements.Considering all these factors, the GDG voted that the undesirable consequences probably outweigh the desirable consequences in most settings.
	We suggest a 24-hour infusion of high-dose MPSS be offered as an option to adult patients with ASCI within 8 hours of injury.	Moderate	Weak	Pooled results at 6- or 12-month follow-up indicated improvement in mean motor scores in the treatment group compared with control subjects with a clinically important effect size.Because of the positive effects, the GDG voted that the clinically significant benefits probably outweigh the low risk all these factors, the GDG voted that the undesirable consequences probably outweigh the low risk of undesirable consequences.
	We suggest not offering a 48 hr infusion of high-dose MPSS to adult patients with ASCI.	N/A	Weak	No studies have demonstrated the efficacy of 48 vs 24 hr infusion, but NASCIS III demonstrated a higher risk of complications. The risk for harm therefore outweighs any unknown efficacy.
Anticoagulant thromboprophylaxis⁴⁵ (PPX)	We suggest that PPX be offered routinely to reduce the risk of VTE in the acute period after SCI.	Low	Weak	All evidence was rated as low quality. Despite an absence of significant findings, the GDG stated that PPX should be prescribed routinely to reduce the risk of VTE. The anticipated undesirable effects, specifically treatment-associated bleeding, are uncertain and vary between prophylaxis strategies.
	We suggest that PPX, consisting of either subcutaneous LMWH or fixed, low-dose UFH, be offered to VTE risk in the acute period after SCI. We suggest against adjusted-dose UFH due to the increased risk of bleeding events.	Low	Weak	The GDG believed that for the comparisons of enoxaparin, dalteparin, LMWH, and UFH, the anticipated benefits and adverse effects were similar.However, when comparing adjusted-dose, fixed-dose, and low-dose UFH, the bleeding consequences of adjusted-dose UFH are higher.
	We suggest commencing PPX within the first 72 hours after injury, if possible.	Low	Weak	The GDG unanimously agreed that the anticipated desirable effects to early PPX are probably large, but the recommendation is weak no VTE events occurred in early or late groups to be able identify any difference in risk.
The role of MRI in decision making⁴⁶	We suggest that MRI be performed in adult patients with ASCI before surgery, when feasible, to facilitate improved clinical decision making.	Very low	Weak	The GDG considered that despite no direct evidence that MRI influences decision making, a weak recommendation is warranted because MRI can identify features that, if present, could alter clinical management and, in turn, have a beneficial effect on outcomes.
The role of MRI in decision making⁴⁶	We suggest that MRI should be done in adult patients with ASCI, before or after surgical intervention, to improve prediction of neurologic and functional outcome.	Low	Weak	Although the desirable effects are probably small, MRI can help manage expectations and inform patient's potential outcomes. In addition, the undesirable effects of obtaining an MRI are small and providing MRI is feasible to implement.

Clinical Practice Guidelines were abstracted from the AO Spine Clinical Practice Guidelines. Although guidelines regarding the role of therapy were also published, these were not included in our review.
ASCI = acute spinal cord injury, CCS = central cord syndrome, GDG = guideline development group, MPSS = methylprednisolone sodium succinate, LMWH = low-molecular-weight heparin, MRI = magnetic resonance imaging, NASCIS = National Acute Spinal Cord Injury Study, UFH = unfractionated heparin, VTE = venous thromboembolic event

Table 3. Selected Trials Involving the Role of Bone Marrow–derived Mesenchymal Stem Cells
Study	Number of Experimental Patients	Route of Delivery	Key Findings	Adverse Effects
Vaquero et al, 2018⁴⁷	11	Intrathecal	3/9 patients demonstrated improvement in AIS grade, 6/9 demonstrated improved bladder function, and 4/9 improved voluntary muscle contractions.	None
Oh et al, 2016²⁹	16	Intramedullary, intradural	Only 2/16 patients demonstrated improvement in neurologic status.	None
Jarocha et al, 2015⁴⁸	1	Intrathecal, intravenous	The single patient demonstrated improvement from AIS A to C/D.	None
El-Kheir et al, 2014²⁸	50	Intrathecal	17/50 patients (34%) treated with cell therapy + physiotherapy showed improvement in AIS grade compared with 0/20 control subjects.At 18 months, 23/50 cell therapy-treated cases (46%) showed sustained functional improvement.	None
Mendonca et al, 2014⁴⁹	14	Intraspinal	7/14 experienced improvement from AIS A to B or C.	None
Dai et al, 2013⁵⁰	20	Intraspinal	10/20 patients had a significant clinical improvement in motor, light touch, pin prick sensory, and residual urine volume, and 9/20 demonstrated improvement from AIS A to B.	None
Jiang et al, 2013⁵¹	20	Intraspinal	4/8 AIS A, 3/4 AIS B, and 8/8 AIC C patients demonstrated neurologic improvement.	None
Karamouzian et al, 2012⁵²	11	Intrathecal	5/11 (45.5%) in the study group and three patients in the control group (15%) improved from AIS A to C compared with 3/20 control subjects (15%).	None
Saito et al, 2012⁵³	5	Intrathecal	Patients with AIS grade B or C demonstrated neurologic improvement, whereas those with AIS a did not.	None
Park et al, 2012⁵⁴	10	Intramedullary	6/10 showed neurologic improvement in upper extremity.3/10 showed improvement upper extremity power, activities of daily living, and significant MRI changes at long-term follow-up.	None
Pal et al, 2009⁵⁵	30	Intrathecal	No changes in AIS grade, SSEP, MEP, or NCV.	None

AIS = American Spinal Injury Association Impairment Scale, BM-MSC = bone marrow–derived mesenchymal stem cell, SSEP = somatosensory-evoked potential, MEP = motor-evoked potential, NCV = nerve conduction velocity