AANS Neurosurgeon | Volume 28, Number 4, 2019


Abandoned Practices in the Medical Management of TBI

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Traumatic brain injury remains the leading cause of death and disability in people under the age of 35, while neuroprotection remains, to this day, the holy grail for neuroscientists. Researchers look for any promise in a drug or an intervention, then test the effects and outcomes for a list of neurodegenerative diseases. While success is not impossible, many therapeutic options do not live up to the promise of significant widespread or universal neuroprotection. We explore some of the interventions abandoned after disappointing clinical results.

Glucocorticoids in TBI

Glucocorticoids in traumatic brain injury (TBI) are a prime example of an abandoned practice. Maxwell and colleagues showed that glucocorticoids could reduce cerebral edema in an animal model of TBI by reducing abnormal vascular permeability.11 While glucocorticoids are used ubiquitously for vasogenic edema associated with brain and spine tumors, the recommendation against their use is the only Level 1 evidence in the Brain Trauma Foundation guidelines.3 The recommendation is based on the results of the MRC CRASH trial. Ten thousand adult patients with TBI were randomized to glucocorticoids versus standard of care and a significantly higher rate of death or disability occurred in the steroid-treated patients.6

Rilozule Failed to Deliver

Riluzole is a neuroprotective agent that reached attention in the 1990s, after becoming the standard of care for amyotrophic lateral sclerosis.13 Riluzole was originally developed as an antiepileptic medication with several proposed mechanisms of action and it was hoped that these multiple mechanisms would be a panacea for TBI.15,23,25,30 Beneficial effects were thought to be a result of reduced excitotoxicity.12 Mouse data showed that both motor and cognitive impairments resulting from TBI were significantly attenuated with administration of three doses of 8 mg/kg of riluzole at one week following injury.12 Similarly, improved motor responses were found in rats at three weeks after injury.24 Rat data also indicated that riluzole reduced brain edema and lesion size and exerted neuroprotection.2,21,30 Smith et. al advocated for its use within one hour of injury for maximal effect in rats.20 A human trial of riluzole for traumatic brain injury was not pursued despite some promising animal data, which lost momentum after the 1990s. Of possible relevance, Stutzman et. al indicates that the side effect profile may be formidable in this population.22 Within the neurosurgical community, riluzole is now being researched for its potential application in spinal cord injury.8,27

Minocycline Disappoints in Clinical Trials

Minocycline is a broad-spectrum antibiotic of the tetracycline family that was found to inhibit cytochrome c, thereby inhibiting caspase-mediated apoptosis.17 The drug is neuroprotective in different animal models of acute and chronic neurodegeneration, including TBI, acute ischemic stroke, amyotrophic lateral sclerosis, Parkinson’s disease and Huntington’s disease.1,9,16,26,28,29,31 Animal studies in mouse models of TBI showed that minocycline significantly attenuated histopathological changes in addition to preserving olfactory function and olfactory bulb volume, a common occurrence in mice post-TBI.18,19 Various clinical trials studied the clinical effects of minocycline on disease progression in patients. Unfortunately, the markedly impressive results in the animal models did not match the clinical results, with most of the trials showing either small neurological improvements or deleterious neurotoxic effects.4,5,7,10 The interest in minocycline diminished. Recently, a small phase I clinical trial established the safety of minocycline in patients with traumatic brain injuries and showed a trend towards improvement with higher doses.14 The pursuit of the detection of clinical minocycline-mediated neuroprotection has largely been abandoned.

Many Treatments Abandoned

Treatments tried and abandoned mark the history of TBI interventions. The key to universal neuroprotection and prevention of secondary injury remains an elusive target. It is worth noting that TBI cases are a heterogeneous group that will likely require a variety of different therapeutic approaches. Continued research and advanced neuromonitoring will further our understanding of the pathophysiology behind traumatic brain injury with the hope that novel therapies will prevent secondary injury and, perhaps, unlock the potential of the brain for recovery and regeneration.


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1. Arvin, K. L., Han, B. H., Du, Y., Lin, S., Paul, S. M., & Holtzman, D. M. (2002). Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Annals of Neurology, 52(1), 54-61.

2. Bareyre, F., Wahl, F., Mcintosh, T. K., & Stutzmann, J. (1997). Time Course of Cerebral Edema after Traumatic Brain Injury in Rats: Effects of Riluzole and Mannitol. Journal of Neurotrauma, 14(11), 839-849.

3. Carney, N., Totten, A. M., O?reilly, C., Ullman, J. S., Hawryluk, G. W., Bell, M. J., . . . Ghajar, J. (2016). Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery, 1.

4. Casha, S., Zygun, D., Mcgowan, D., Yong, V. W., & Hurlbert, R. J. (2009). Neuroprotection with Minocycline after Spinal Cord Injury. Neurosurgery, 65(2), 410-411.

5. Casha, S., Zygun, D., Mcgowan, M. D., Bains, I., Yong, V. W., & Hurlbert, R. J. (2012). Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain, 135(4), 1224-1236.

6. Edwards P, Arango M, Balica L, Cottingham R, El-Sayed H, Farrell B, et al. (2005). Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury—outcomes at 6 months. The Lancet, 365(9475), 1957-1959.

7. Gordon, P. H., Moore, D. H., Miller, R. G., Florence, J. M., Verheijde, J. L., Doorish, C., . . . Tandan, R. (2007). Efficacy of minocycline in patients with amyotrophic lateral sclerosis: A phase III randomised trial. The Lancet Neurology, 6(12), 1045-1053.

8. Grossman, R. G., Fehlings, M. G., Frankowski, R. F., Burau, K. D., Chow, D. S., Tator, C., . . . Wilson, J. R. (2014). A Prospective, Multicenter, Phase I Matched-Comparison Group Trial of Safety, Pharmacokinetics, and Preliminary Efficacy of Riluzole in Patients with Traumatic Spinal Cord Injury. Journal of Neurotrauma, 31(3), 239-255.

9. Guegan, C. (2002). Instrumental Activation of Bid by Caspase-1 in a Transgenic Mouse Model of ALS. Molecular and Cellular Neuroscience, 20(4), 553-562.

10. Lampl, Y., Boaz, M., Gilad, R., Lorberboym, M., Dabby, R., Rapoport, A., . . . Sadeh, M. (2007). Minocycline treatment in acute stroke: An open-label, evaluator-blinded study. Neurology, 69(14), 1404-1410.

11. Maxwell, R. E., Long, D. M., & French, L. A. (1971). The effects of glucosteroids on experimental cold-induced brain edema. Journal of Neurosurgery, 34(4), 477-487.

12. McIntosh, T. K., Smith, D. H., Voddi, M., Perri, B. R., & Stutzmann, J. (1996). Riluzole, a Novel Neuroprotective Agent, Attenuates Both Neurologic Motor and Cognitive Dysfunction Following Experimental Brain Injury in the Rat. Journal of Neurotrauma, 13(12), 767-780.

13. Meininger, V., Lacomblez, L., & Salachas, F. (2000). What has changed with riluzole? Journal of Neurology, 247(S6).

14. Meythaler, J., Fath, J., Fuerst, D., Zokary, H., Freese, K., Martin, H. B., . . . Roskos, P. T. (2019). Safety and feasibility of minocycline in treatment of acute traumatic brain injury. Brain Injury, 33(5), 679-689.

15. Mizoule, J., Meldrum, B., Mazadier, M., Croucher, M., Ollat, C., Uzan, A., . . . Fur, G. L. (1985). 2-Amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid neurotransmission—I. Neuropharmacology, 24(8), 767-773.

16. Sanchez, Mejia, R.O., Ona, V.O., Li, M., & Friedlander, R.M. (2001). Minocycline Reduces Traumatic Brain Injury-mediated Caspase-1 Activation, Tissue Damage, and Neurological Dysfunction. Neurosurgery.

17. Scott, G., Zetterberg, H., Jolly, A., Cole, J. H., Simoni, S. D., Jenkins, P. O., . . . Sharp, D. J. (2017). Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration. Brain, 141(2), 459-471.

18. Siopi, E., Calabria, S., Plotkine, M., Marchand-Leroux, C., & Jafarian-Tehrani, M. (2012). Minocycline Restores Olfactory Bulb Volume and Olfactory Behavior after Traumatic Brain Injury in Mice. Journal of Neurotrauma, 29(2), 354-361.

19. Siopi, E., Cho, A. H., Homsi, S., Croci, N., Plotkine, M., Marchand-Leroux, C., & Jafarian-Tehrani, M. (2011). Minocycline Restores sAPP? Levels and Reduces the Late Histopathological Consequences of Traumatic Brain Injury in Mice. Journal of Neurotrauma, 28(10), 2135-2143.

20. Smith, S. L., & Hall, E. D. (1998). Tirilazad Widens the Therapeutic Window for Riluzole-Induced Attenuation of Progressive Cortical Degeneration in an Infant Rat Model of the Shaken Baby Syndrome. Journal of Neurotrauma, 15(9), 707-719.

21. Stover, J. F., Beyer, T. F., & Unterberg, A. W. (2000). Riluzole Reduces Brain Swelling and Contusion Volume in Rats Following Controlled Cortical Impact Injury. Journal of Neurotrauma, 17(12), 1171-1178.

22. Stutzmann, J., Pratt, J., Boraud, T., & Gross, C. (1996). The effect of riluzole on post-traumatic spinal cord injury in the rat. NeuroReport, 7(2), 387-392.

23. Vorwerk, C. K., Zurakowski, D., Mcdermott, L. M., Mawrin, C., & Dreyer, E. B. (2004). Effects of axonal injury on ganglion cell survival and glutamate homeostasis. Brain Research Bulletin, 62(6), 485-490.

24. Wahl, F., Renou, E., Mary, V., & Stutzmann, J. (1997). Riluzole reduces brain lesions and improves neurological function in rats after a traumatic brain injury. Brain Research, 756(1-2), 247-255.

25. Wahl, F. & Stutzmann, J.M. (1999). Neuroprotective effects of riluzole in neurotrauma models: a review. Acta Neurochir Suppl, 73, 103-110.

26. Wang, X., Zhu, S., Drozda, M., Zhang, W., Stavrovskaya, I. G., Cattaneo, E., . . . Friedlander, R. M. (2003). Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntingtons disease. Proceedings of the National Academy of Sciences, 100(18), 10483-10487.

27. Wu, Y., Satkunendrarajah, K., Teng, Y., Chow, D. S., Buttigieg, J., & Fehlings, M. G. (2013). Delayed Post-Injury Administration of Riluzole Is Neuroprotective in a Preclinical Rodent Model of Cervical Spinal Cord Injury. Journal of Neurotrauma, 30(6), 441-452.

28. Yrjanheikki, J., Keinanen, R., Pellikka, M., Hokfelt, T., & Koistinaho, J. (1998). Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proceedings of the National Academy of Sciences, 95(26), 15769-15774.

29. Yrjanheikki, J., Tikka, T., Keinanen, R., Goldsteins, G., Chan, P. H., & Koistinaho, J. (1999). A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proceedings of the National Academy of Sciences, 96(23), 13496-13500.

30. Zhang, C., Raghupathi, R., Saatman, K. E., Smith, D. H., Stutzmann, J., Wahl, F., & Mcintosh, T. K. (1998). Riluzole attenuates cortical lesion size, but not hippocampal neuronal loss, following traumatic brain injury in the rat. Journal of Neuroscience Research, 52(3), 342-349.

31. Zhu, S., Stavrovskaya, I. G., Drozda, M., Kim, B. Y., Ona, V., Li, M., . . . Friedlander, R. M. (2002). Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature, 417(6884), 74-78.

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