Letter to the Editor. The INSPIRE studies for spinal cord injury

Marios C. Papadopoulos MD, FRCS(SN)1 and Samira Saadoun PhD2
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  • 1 St. George’s Hospital NHS Foundation Trust, London, United Kingdom
  • | 2 St. George’s, University of London, United Kingdom
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TO THE EDITOR: We read with interest the results of the INSPIRE study,1 in which bioresorbable polymer Neuro-Spinal Scaffolds were implanted into the damaged spinal cords of patients with complete (ASIA Impairment Scale [AIS] grade A) thoracic traumatic spinal cord injuries (TSCIs) within 96 hours postinjury (Kim KD, Lee KS, Coric D, et al. A study of probable benefit of a bioresorbable polymer scaffold for safety and neurological recovery in patients with complete thoracic spinal cord injury: 6-month results from the INSPIRE study. J Neurosurg Spine. 2021;34[5]:808-817). The authors are currently recruiting patients into the INSPIRE 2 study, a randomized, controlled, single-blind, two-arm, multicenter trial comparing the safety and benefit of inserting the Neuro-Spinal Scaffold into the damaged spinal cord (treatment arm) versus standard-of-care open spine surgery (comparator arm) in patients with thoracic AIS grade A TSCIs.2

There is now evidence that, after a severe TSCI, the spinal cord swells and becomes compressed against the dura,3 thus generating high intraspinal pressure (ISP) and reduced spinal cord perfusion pressure (SCPP).4 ISP is local pressure at the injury site, which differs from cerebrospinal fluid (CSF) pressure above or below the site and is not effectively reduced by draining lumbar CSF.5 Spinal cord compression by the dura results in a compartment-like syndrome; therefore, after TSCI, osseous decompression alone may not effectively decompress the injured spinal cord. This is analogous to traumatic brain injury (TBI), in which decompressive craniectomy requires opening the dura to effectively decompress the brain. Several groups have recently proposed duroplasty to treat TSCI,6–8 and a randomized controlled multicenter trial, known as DISCUS, is underway to investigate whether bony decompression plus duroplasty improves outcome compared with bony decompression alone.9

Based on these observations, the authors’ claim that it is the Neuro-Spinal Scaffold that probably contributes to the neurological recovery in the INSPIRE study may be premature. The neurological improvements shown in INSPIRE, and any neurological benefits of the treatment arm of INSPIRE 2 over the comparator arm, are probably due to intradural decompression, as illustrated in the article’s video,1 rather than the Neuro-Spinal Scaffold. Durotomy plus myelotomy reduces ISP and increases SCPP, which probably improves patient outcome even without inserting the Neuro-Spinal Scaffold. There are analogies between TSCI and TBI (Fig. 1): the bony plus dural decompression for TSCI being evaluated in the DISCUS trial9 may be analogous to the decompressive craniectomy for TBI that was evaluated in the RESCUEicp trial.10 Durotomy plus myelotomy (including evacuation of compressive hemorrhagic/necrotic material from the contusion site, as shown in the video1) in the INSPIRE trials for TSCI may be analogous to removing traumatic hematoma/contusion to decompress the brain in TBI.

FIG. 1.
FIG. 1.

Analogy between traumatic brain injury (left) and traumatic spinal cord injury (right). A: Contusion/hematoma causes brain or spinal cord swelling with dural cord compression, resulting in high intracranial or intraspinal pressure (ICP and ISP, respectively). B: Bony and dural decompression (decompressive craniectomy for TBI, duroplasty for TSCI). C: Contusionectomy reduces ICP and ISP. Figure is available in color online only.

In our view, the comparator arm in INSPIRE 2 should include durotomy plus myelotomy in addition to standard bony decompression but without inserting the Neuro-Spinal Scaffold. The currently used comparator arm (bony decompression alone) does not account for the probable beneficial effect of intradural decompression (durotomy plus myelotomy). Without addressing this issue, it may be difficult to justify inserting the Neuro-Spinal Scaffold into the spinal cords of patients with TSCI, even if the findings of the INSPIRE studies show that the surgical procedure is safe and beneficial.

Disclosures

The authors report no conflict of interest.

References

  • 1

    Kim KD, Lee KS, Coric D, et al. A study of probable benefit of a bioresorbable polymer scaffold for safety and neurological recovery in patients with complete thoracic spinal cord injury: 6-month results from the INSPIRE study. J Neurosurg Spine. 2021;34(5):808817.

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  • 2

    InVivo Therapeutics. Study of probable benefit of the neuro-spinal scaffold™ in subjects with complete thoracic AIS A spinal cord injury as compared to standard of care (INSPIRE 2). May 26, 2021.Accessed June 21, 2021.https://clinicaltrials.gov/ct2/show/NCT03762655

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  • 3

    Saadoun S, Werndle MC, Lopez de Heredia L, Papadopoulos MC. The dura causes spinal cord compression after spinal cord injury. Br J Neurosurg. 2016;30(5):582584.

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    • Export Citation
  • 4

    Werndle MC, Saadoun S, Phang I, et al. Monitoring of spinal cord perfusion pressure in acute spinal cord injury: initial findings of the injured spinal cord pressure evaluation study. Crit Care Med. 2014;42(3):646655.

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    • Export Citation
  • 5

    Hogg FRA, Gallagher MJ, Kearney S, Zoumprouli A, Papadopoulos MC, Saadoun S. Acute spinal cord injury: monitoring lumbar cerebrospinal fluid provides limited information about the injury site. J Neurotrauma. 2020;37(9):11561164.

    • Search Google Scholar
    • Export Citation
  • 6

    Phang I, Werndle MC, Saadoun S, et al. Expansion duroplasty improves intraspinal pressure, spinal cord perfusion pressure, and vascular pressure reactivity index in patients with traumatic spinal cord injury: injured spinal cord pressure evaluation study. J Neurotrauma. 2015;32(12):865874.

    • Search Google Scholar
    • Export Citation
  • 7

    Grassner L, Winkler PA, Strowitzki M, Buhren V, Maier D, Bierschneider M. Increased intrathecal pressure after traumatic spinal cord injury: an illustrative case presentation and a review of the literature. Eur Spine J. 2017;26(1):2025.

    • Search Google Scholar
    • Export Citation
  • 8

    Zhu F, Yao S, Ren Z, et al. Early durotomy with duroplasty for severe adult spinal cord injury without radiographic abnormality: a novel concept and method of surgical decompression. Eur Spine J. 2019;28(10):22752282.

    • Search Google Scholar
    • Export Citation
  • 9

    National Institute for Health Research (EME). Duroplasty for injured cervical spinal cord with uncontrolled swelling (DISCUS): a randomised controlled trial. Accessed June 21, 2021.https://fundingawards.nihr.ac.uk/award/NIHR130048

    • Search Google Scholar
    • Export Citation
  • 10

    Hutchinson PJ, Kolias AG, Timofeev IS, et al. Trial of decompressive craniectomy for traumatic intracranial hypertension. N Engl J Med. 2016;375(12):11191130.

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    • Export Citation
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  • 1 Johns Hopkins University, Baltimore, MD
  • | 2 UC Davis, Sacramento, CA
  • | 3 Vidant Health, Greenville, NC
  • | 4 Atrium Healthcare, Charlotte, NC, Atrium Musculoskeletal Institute, Charlotte, NC
  • | 5 Delaware Valley SCI Center, Thomas Jefferson University, Philadelphia, PA
  • | 6 InVivo Therapeutics Corporation, Cambridge, MA

Response

We would like to thank Drs. Papadopoulos and Saadoun for their thoughtful comments. The recent increased interest in spinal cord pathophysiology has opened up an exciting opportunity to explore potential therapies for traumatic spinal cord injury (SCI). While Drs. Papadopoulos and Saadoun are correct in stating that the spinal cord swells following injury, leading to increased intraspinal pressure and reduced perfusion,1,2 the most efficacious treatment for this devastating condition has not been established. The preclinical work leading to the INSPIRE study (ClinicalTrials.gov identifier NCT02138110) was compelling3–6—so much so that the US FDA approved a clinical trial. The insertion of an inert biodegradable scaffold following myelotomy has the benefit of releasing pressure and removing the necrohemorrhagic material found at the time of acute injury, and the scaffold has been shown to have an acceptable risk profile when implanted in patients with complete thoracic SCI. While a study comparing myelotomy versus myelotomy and scaffold implantation would be ideal, given the current climate and expense associated with surgical trials it may never be done. Therefore, we might have to rely on the INSPIRE and INSPIRE 2.0 (ClinicalTrials.gov identifier NCT03762655; currently recruiting patients) clinical trials as well as large animal studies to better inform us of the ideal strategy to optimize perfusion and recovery following spinal cord injury.

Acknowledgments

We thank Nikki Moreland of Nous Healthcare Communications Ltd. for medical writing and editorial assistance funded by InVivo Therapeutics Corporation.

References

  • 1

    Werndle MC, Saadoun S, Phang I, et al. Monitoring of spinal cord perfusion pressure in acute spinal cord injury: initial findings of the injured spinal cord pressure evaluation study. Crit Care Med. 2014;42(3):646655.

    • Search Google Scholar
    • Export Citation
  • 2

    Martirosyan NL, Kalani MY, Bichard WD, et al. Cerebrospinal fluid drainage and induced hypertension improve spinal cord perfusion after acute spinal cord injury in pigs. Neurosurgery. 2015;76(4):461469.

    • Search Google Scholar
    • Export Citation
  • 3

    Teng YD, Lavik EB, Qu X, et al. Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci U S A. 2002;99(5):30243029.

    • Search Google Scholar
    • Export Citation
  • 4

    Pritchard CD, Slotkin JR, Yu D, et al. Establishing a model spinal cord injury in the African green monkey for the preclinical evaluation of biodegradable polymer scaffolds seeded with human neural stem cells. J Neurosci Methods. 2010;188(2):258269.

    • Search Google Scholar
    • Export Citation
  • 5

    Slotkin JR, Pritchard CD, Luque B, et al. Biodegradable scaffolds promote tissue remodeling and functional improvement in non-human primates with acute spinal cord injury. Biomaterials. 2017;123(63):76.

    • Search Google Scholar
    • Export Citation
  • 6

    Guest JD, Moore SW, Aimetti AA, et al. Internal decompression of the acutely contused spinal cord: differential effects of irrigation only versus biodegradable scaffold implantation. Biomaterials. 2018;185(284):300.

    • Search Google Scholar
    • Export Citation

Images from Shimizu et al. (pp 616–623).

  • View in gallery

    Analogy between traumatic brain injury (left) and traumatic spinal cord injury (right). A: Contusion/hematoma causes brain or spinal cord swelling with dural cord compression, resulting in high intracranial or intraspinal pressure (ICP and ISP, respectively). B: Bony and dural decompression (decompressive craniectomy for TBI, duroplasty for TSCI). C: Contusionectomy reduces ICP and ISP. Figure is available in color online only.

  • 1

    Kim KD, Lee KS, Coric D, et al. A study of probable benefit of a bioresorbable polymer scaffold for safety and neurological recovery in patients with complete thoracic spinal cord injury: 6-month results from the INSPIRE study. J Neurosurg Spine. 2021;34(5):808817.

    • Search Google Scholar
    • Export Citation
  • 2

    InVivo Therapeutics. Study of probable benefit of the neuro-spinal scaffold™ in subjects with complete thoracic AIS A spinal cord injury as compared to standard of care (INSPIRE 2). May 26, 2021.Accessed June 21, 2021.https://clinicaltrials.gov/ct2/show/NCT03762655

    • Search Google Scholar
    • Export Citation
  • 3

    Saadoun S, Werndle MC, Lopez de Heredia L, Papadopoulos MC. The dura causes spinal cord compression after spinal cord injury. Br J Neurosurg. 2016;30(5):582584.

    • Search Google Scholar
    • Export Citation
  • 4

    Werndle MC, Saadoun S, Phang I, et al. Monitoring of spinal cord perfusion pressure in acute spinal cord injury: initial findings of the injured spinal cord pressure evaluation study. Crit Care Med. 2014;42(3):646655.

    • Search Google Scholar
    • Export Citation
  • 5

    Hogg FRA, Gallagher MJ, Kearney S, Zoumprouli A, Papadopoulos MC, Saadoun S. Acute spinal cord injury: monitoring lumbar cerebrospinal fluid provides limited information about the injury site. J Neurotrauma. 2020;37(9):11561164.

    • Search Google Scholar
    • Export Citation
  • 6

    Phang I, Werndle MC, Saadoun S, et al. Expansion duroplasty improves intraspinal pressure, spinal cord perfusion pressure, and vascular pressure reactivity index in patients with traumatic spinal cord injury: injured spinal cord pressure evaluation study. J Neurotrauma. 2015;32(12):865874.

    • Search Google Scholar
    • Export Citation
  • 7

    Grassner L, Winkler PA, Strowitzki M, Buhren V, Maier D, Bierschneider M. Increased intrathecal pressure after traumatic spinal cord injury: an illustrative case presentation and a review of the literature. Eur Spine J. 2017;26(1):2025.

    • Search Google Scholar
    • Export Citation
  • 8

    Zhu F, Yao S, Ren Z, et al. Early durotomy with duroplasty for severe adult spinal cord injury without radiographic abnormality: a novel concept and method of surgical decompression. Eur Spine J. 2019;28(10):22752282.

    • Search Google Scholar
    • Export Citation
  • 9

    National Institute for Health Research (EME). Duroplasty for injured cervical spinal cord with uncontrolled swelling (DISCUS): a randomised controlled trial. Accessed June 21, 2021.https://fundingawards.nihr.ac.uk/award/NIHR130048

    • Search Google Scholar
    • Export Citation
  • 10

    Hutchinson PJ, Kolias AG, Timofeev IS, et al. Trial of decompressive craniectomy for traumatic intracranial hypertension. N Engl J Med. 2016;375(12):11191130.

    • Search Google Scholar
    • Export Citation
  • 1

    Werndle MC, Saadoun S, Phang I, et al. Monitoring of spinal cord perfusion pressure in acute spinal cord injury: initial findings of the injured spinal cord pressure evaluation study. Crit Care Med. 2014;42(3):646655.

    • Search Google Scholar
    • Export Citation
  • 2

    Martirosyan NL, Kalani MY, Bichard WD, et al. Cerebrospinal fluid drainage and induced hypertension improve spinal cord perfusion after acute spinal cord injury in pigs. Neurosurgery. 2015;76(4):461469.

    • Search Google Scholar
    • Export Citation
  • 3

    Teng YD, Lavik EB, Qu X, et al. Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci U S A. 2002;99(5):30243029.

    • Search Google Scholar
    • Export Citation
  • 4

    Pritchard CD, Slotkin JR, Yu D, et al. Establishing a model spinal cord injury in the African green monkey for the preclinical evaluation of biodegradable polymer scaffolds seeded with human neural stem cells. J Neurosci Methods. 2010;188(2):258269.

    • Search Google Scholar
    • Export Citation
  • 5

    Slotkin JR, Pritchard CD, Luque B, et al. Biodegradable scaffolds promote tissue remodeling and functional improvement in non-human primates with acute spinal cord injury. Biomaterials. 2017;123(63):76.

    • Search Google Scholar
    • Export Citation
  • 6

    Guest JD, Moore SW, Aimetti AA, et al. Internal decompression of the acutely contused spinal cord: differential effects of irrigation only versus biodegradable scaffold implantation. Biomaterials. 2018;185(284):300.

    • Search Google Scholar
    • Export Citation

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