Diffuse axonal injury treatment

The National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled 1).


Treatment of patients with diffuse axonal injury are geared toward prevention of secondary injuries and facilitating rehabilitation. It appears to be the secondary injuries that lead to increased mortality. These can include hypoxia with coexistent hypotension, edema, and intracranial hypertension. Therefore, prompt care to avoid hypotension, hypoxia, cerebral edema, and elevated intracranial pressure (ICP) is advised.

Initial treatment priority in traumatic brain injury is focused on resuscitation. In a non-neuro trauma center, trauma surgeons and emergency physicians may perform the initial resuscitation and neurologic treatment to stabilize and transport the patient to a designated neurotrauma center expeditiously. ICP monitoring is indicated in patients with GCS of less than 8 after consultation with neurosurgery. Other considerations for ICP monitoring include patients that cannot have continual neurologic evaluations. These are typically in patients receiving general anesthesia, narcotic analgesia, sedation, and prolonged paralysis for other injuries. Cerebral oxygen saturation monitoring can be used with ICP monitoring to assess the degree of oxygenation. Short-term, usually seven days, anticonvulsant treatment can be used to prevent early post-traumatic seizures. There is no evidence that this will prevent long-term post-traumatic seizures however. There is emerging evidence that progesterone treatment in acute traumatic brain injury may reduce morbidity and mortality. This cannot be routinely recommended at this time.

Overall, the goal of diffuse axonal injury patients’ treatment is supportive care and prevention of secondary injuries 2).


Immediate measures will be taken to reduce swelling inside the brain, which can cause additional damage. In most cases, a course of steroids or other medications designed to reduce inflammation and swelling will be administered, and the patient will be monitored.


Findings of a study suggest that progesterone may be neuroprotective in patients with DAI. However, large clinical trials are needed to assess progesterone as a promising drug in DAI 3).


Diffuse axonal injury (DAI) patients are frequently accompanied by adverse sequelae and psychiatric disorders, such as anxiety, leading to a decreased quality of life, social isolation, and poor outcomes. However, the mechanisms regulating psychiatric disorders post-DAI are not well elucidated. Previous studies showed that endoplasmic reticulum stress functions as a pivotal factor in neurodegeneration disease. In a study, Huang et al., showed that DAI can trigger ER stress and unfolded protein response (UPR) activation in both the acute and chronic periods, leading to cell death and anxiety disorder. Treatment with 4-phenylbutyrate (4-PBA) is able to inhibit the UPR and cell apoptosis and relieve the anxiety disorder in our DAI model. However, later (14 days post-DAI) 4-PBA treatment can only restore the related gene expression of ER stress and UPR but not the psychiatric disorder. Therefore, the early (5 mins after DAI) administration of 4-PBA might be a therapeutic approach for blocking the ER stress/UPR-induced cell death and anxiety disorder after DAI 4).

Surgery

Surgery is not an option for those who have sustained a diffuse axonal injury.

Rehabilitation

If the patient has sustained a mild or moderate diffuse axonal injury, the rehabilitation phase will follow once the patient is stabilized and awake.

During this phase of treatment, the patient and his or her family will work with a multidisciplinary staff including doctors, nurses, physical and occupational therapists, and other specialists to devise an individualized program designed to return the patient to the maximum level of function. The rehabilitation phase may include:

Speech therapy

Physical therapy

Occupational therapy

Recreational therapy

Adaptive equipment training

Counseling

References

1)

Smith DH, Hicks R, Povlishock JT. Therapy development for diffuse axonal injury. J Neurotrauma. 2013 Mar 1;30(5):307-23. doi: 10.1089/neu.2012.2825. Epub 2013 Feb 14. PubMed PMID: 23252624; PubMed Central PMCID: PMC3627407.
2)

Mesfin FB, Taylor RS. Diffuse Axonal Injury (DAI). 2018 Dec 2. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK448102/ PubMed PMID: 28846342.
3)

Soltani Z, Shahrokhi N, Karamouzian S, Khaksari M, Mofid B, Nakhaee N, Reihani H. Does progesterone improve outcome in diffuse axonal injury? Brain Inj. 2016 Nov 7:1-8. [Epub ahead of print] PubMed PMID: 27819489.
4)

Huang GH, Chen K, Sun YY, Zhu L, Sun ZL, Feng DF. 4-Phenylbutyrate ameliorates anxiety disorder by inhibiting endoplasmic reticulum stress following diffuse axonal injury. J Neurotrauma. 2018 Dec 22. doi: 10.1089/neu.2018.6048. [Epub ahead of print] PubMed PMID: 30582423.

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