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

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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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References

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