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.

Anterior cervical disc arthroplasty versus anterior cervical discectomy and fusion

While anterior cervical discectomy and fusion (ACDF) has been the standard of care for 2-level disease, a randomized clinical trial (RCT) suggested similar outcomes.

There are also critical debates regarding the long-term effects of heterotopic ossification (HO) and the prevalence of adjacent-level degeneration.


One hundred-nine patients with one level cervical disc herniation, were randomized to one of the following treatments: Anterior cervical disc arthroplasty (ACDA), Anterior cervical discectomy and fusion (ACDF) with intervertebral cage, Anterior cervical discectomy (ACD) without fusion. Clinical and radiological outcome was measured by NDI, Visual Analogue Scale (VAS) neck pain, VAS arm pain, SF-36, EQ-5D, patients’ self-reported perceived recovery, radiographic cervical curvature, and adjacent segment degeneration (ASD) parameters at baseline and until two years after surgery. BBraun Medical paid €298.837 to cover the costs for research nurses.

The NDI declined from 41 to 47 points at baseline to 19±15 in the ACD group, 19± 18 in the ACDF group, and 20±22 in the ACDA group after surgery (p=0.929). VAS arm and neck pain declined to half its baseline value and decreased below the critical value of 40 mm. Quality of life, measured by the EQ-5D, increased in all three groups. ASD parameters were comparable in all three groups as well. No statistical differences were demonstrated between the treatment groups.

The hypothesis that ACDA would lead to superior clinical outcome in comparison to ACDF or ACD could not be confirmed during a two-year follow-up time period. Single level ACD without implanting an intervertebral device may be a reasonable alternative to ACDF or ACDA 1).


Findlay et al., from London and Edinburgh, researched for cervical total disc replacement versus anterior cervical discectomy and fusion.

Databases including Medline, Embase, and Scopus were searched. Inclusion criteria involved prospective randomized control trials (RCTs) reporting the surgical treatment of patients with symptomatic degenerative cervical disc disease. Two independent investigators extracted the data. The strength of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria. The primary outcome measures were overall and neurological success, and these were included in the meta-analysis. Standardized patient-reported outcomes, including the incidence of further surgery and adjacent segment disease, were summarized and discussed.

A total of 22 papers published from 14 randomized control trials (RCTs) were included, representing 3160 patients with follow-up of up to ten years. Meta-analysis indicated that TDR is superior to ACDF at two years and between four and seven years. In the short-term, patients who underwent TDR had better patient-reported outcomes than those who underwent ACDF, but at two years this was typically not significant. Results between four and seven years showed significant differences in Neck Disability Index (NDI), 36-Item Short-Form Health Survey (SF-36) physical component scores, dysphagia, and satisfaction, all favouring TDR. Most trials found significantly less adjacent segment disease after TDR at both two years (short-term) and between four and seven years (medium- to long-term).

TDR is as effective as ACDF and superior for some outcomes. Disc replacement reduces the risk of adjacent segment disease. Continued uncertainty remains about degeneration of the prosthesis. Long-term surveillance of patients who undergo TDR may allow its routine use 2).


Cervical total disc replacement (TDR) has been shown in a number of prospective clinical studies to be a viable treatment alternative to anterior cervical discectomy and fusion (ACDF) for symptomatic cervical degenerative disc disease. In addition to preserving motion, evidence suggests that cervical TDR may result in a lower incidence of subsequent surgical intervention than treatment with fusion.

One reason for this trend is the observation that in clinical studies, patients with a history of cervical arthrodesis seem to have a higher incidence of adjacent segment degeneration 3) 4) 5).

Furthermore, in biomechanical investigations, most authors have reported an increase in the segmental range of motion (ROM) and the intradiscal pressure (IDP) in the levels proximal and distal to a simulated mono- or bisegmental arthrodesis 6) 7) 8) 9) 10) 11) 12) 13) 14) 15).

References

1)

Vleggeert-Lankamp CLA, Janssen TMH, van Zwet E, Goedmakers CMW, Bosscher L, Peul W, Arts MP. The NECK trial: Effectiveness of anterior cervical discectomy with or without interbody fusion and arthroplasty in the treatment of cervical disc herniation; a double-blinded randomised controlled trial. Spine J. 2018 Dec 21. pii: S1529-9430(18)31322-6. doi: 10.1016/j.spinee.2018.12.013. [Epub ahead of print] PubMed PMID: 30583108.
2)

Findlay C, Ayis S, Demetriades AK. Total disc replacement versus anterior cervical discectomy and fusion. Bone Joint J. 2018 Aug;100-B(8):991-1001. doi: 10.1302/0301-620X.100B8.BJJ-2018-0120.R1. PubMed PMID: 30062947.
3)

Goffin J, Geusens E, Vantomme N, Quintens E, Waerzeggers Y, Depreitere B, et al. Long-term follow-up after interbody fusion of the cervical spine. J Spinal Disord Tech. 2004;17:79–85. doi: 10.1097/00024720-200404000-00001.
4)

Gore DR, Sepic SB. Anterior discectomy and fusion for painful cervical disc disease: a report of 50 patients with an average follow-up of 21 years. Spine. 1998;23:2047–2051. doi: 10.1097/00007632-199810010-00002.
5)

Hilibrand AS, Carlson GD, Palumbo MA, Jones PK, Bohlman H. Radiculopathy and myelopathy at segments adjacent to the site of a previous anterior cervical arthrodesis. J Bone Joint Surg. 1999;81-A:519–528.
6)

Chang U-K, Kim DH, Lee MC, Willenberg R, Kim S-H, Lim J. Changes in adjacent-level disc pressure and facet joint force after cervical arthroplasty compared with cervical discectomy and fusion. J Neurosurg Spine. 2007;7:33–39. doi: 10.3171/SPI-07/07/033.
7)

Chang U-K, Kim DH, Lee MC, Willenberg R, Kim S-H, Lim J. Range of motion change after cervical arthroplasty with ProDisc-C and Prestige artificial discs compared with anterior cervical discectomy and fusion. J Neurosurg Spine. 2007;7:40–46. doi: 10.3171/SPI-07/07/040.
8)

DiAngelo DJ, Foley KT, Morrow BR, Schwab JS, Song J, German JW, et al. In vitro biomechanics of cervical disc arthroplasty with the ProDisc-C total disc implant. Neurosurg Focus. 2004;17(E7):44–54. doi: 10.3171/foc.2004.17.3.7.
9)

DiAngelo DJ, Robertson JT, Metcalf NH, McVay BJ, Davis RC. Biomechanical testing of an artificial cervical joint and an anterior plate. J Spinal Disord Tech. 2003;16:314–323. doi: 10.1097/00024720-200308000-00002.
10)

Dmitriev AE, Cunningham BW, Hu N, Sell G, Vigna F, McAfee PC. Adjacent level intradiscal pressure and segmental kinematics following a cervical total disc arthroplasty. An in vitro human cadaveric model. Spine. 2005;30:1165–1172. doi: 10.1097/01.brs.0000162441.23824.95.
11)

Eck JC, Humphreys SC, Lim T-H, Jeong ST, Kim JG, Hodges SD, et al. Biomechanical study on the effect of cervical spine fusion on adjacent-level intradiscal pressure and segmental motion. Spine. 2002;27:2431–2434. doi: 10.1097/00007632-200211150-00003.
12)

Fuller DA, Kirkpatrick JS, Emery SE. A kinematic study of the cervical spine before and after segmental arthrodesis. Spine. 1998;23:1649–1656. doi: 10.1097/00007632-199808010-00006.
13)

Park D-H, Ramakrishnan P, Cho T-H, Lorenz E, Eck JC, Humphreys SC, et al. Effect of lower two-level anterior cervical fusion on the superior adjacent level. J Neurosurg Spine. 2007;7:336–340. doi: 10.3171/SPI-07/09/336.
14)

Pospiech J, Stolke D, Wilke HJ, Claes LE. Intradiscal pressure recordings in the cervical spine. Neurosurgery. 1999;44:379–384. doi: 10.1097/00006123-199902000-00078.
15)

Ragab AA, Escarcega AJ, Zdeblick TA. A quantitative analysis of strain at adjacent segments after segmental immobilization of the cervical spine. J Spinal Disord Tech. 2006;19:407–410. doi: 10.1097/00024720-200608000-00006.

Posterior communicating artery injury

Intracranial pseudoaneurysm is a rare complication of endoscopic endonasal surgery. Herein, Morinaga et al., from Fukuoka University Chikushi Hospital describe two-staged stent assisted coil embolization for posterior communicating artery pseudoaneurysm after endoscopic endonasal surgery for pituitary adenoma.

A 68-year-old man had a history of severe adult growth hormone secretion deficiency, requiring growth hormone replacement therapy; secondary adrenal hypofunction; hyperthyroidism; hypertension; constipation; glaucoma; and hyperuricemia. Five years ago, after initial endoscopic transsphenoidal surgery for pituitary adenoma, he was hospitalized for reoperation. Posterior communicating artery injury was observed during second endoscopic trans-sphenoidal surgery and pressure hemostasis was performed using a hemostatic preparation. Immediately post-surgery, a localized subarachnoid hemorrhage was observed. Sudden-onset impaired consciousness and respiratory disturbances ensued on postoperative day 7, and computed tomography of the head was performed. Recurrent subarachnoid hemorrhage was confirmed, and acute hydrocephalus secondary to third ventricular blockage was identified. Cerebral angiography was performed after urgent bilateral cerebral ventricular drainage under general anesthesia. A pseudoaneurysm was identified in the left posterior communicating artery, and coil embolization was performed. Six weeks post-surgery, LVIS® Jr. stent was placed in the posterior communicating artery. Recurrence of the aneurysm was not detected 6 months post-surgery. He underwent lumboperitoneal shunting for secondary normal pressure hydrocephalus after dual antiplatelet therapy discontinuation and is being followed-up as an outpatient with a modified Rankin Scale of 2 10 months post-surgery.

Two-staged stent-assisted coil embolization using LVIS® stent was effective for a posterior communicating artery pseudoaneurysm occurring after posterior communicating artery injury following endoscopic trans-sphenoidal surgery for Follicle stimulating hormone secreting pituitary adenoma 1).


Traumatic injury of the posterior communicating artery or the basilar artery causing arteriovenous fistulae is rare.

Ko et al., report an unusual case of the coincidence of a posterior communicating artery-cavernous sinus fistula and a basilar artery-cavernous sinus fistula associated with traumatic pseudoaneurysms of the posterior communicating and basilar arteries. The fistulas and pseudoaneurysms were obliterated completely after staged endovascular surgery via a transarterial and transvenous route.

This is the first such report worldwide 2).


A middle-aged patient presented with a rapidly growing right dural-based extra-axial posterior clinoid mass extending to the right cavernous sinus that was surgically resected. Histological examination showed solid growth of primitive neuroectodermal tumor arising from the third nerve. Following surgical resection, the patient was further managed by radiation and chemotherapy. Two years later the patient developed new intracranial hemorrhage in the area adjacent to the previous surgical cavity. A cerebral angiogram showed contrast extravasation at the junction of the posterior communicating artery (Pcom) and the right posterior cerebral artery (PCA), with an expanding pseudoaneurysm. This was managed with N-butyl cyanoacrylate embolization. Autopsy showed microscopic recurrence of tumor into the PCA/PCom region with invasion of the wall of the Pcom. This case report illustrates the concept of vascular blowout in intracranial cerebral vasculature. It appears that, in the presence of risk factors that contribute to weakening of vessel walls (surgery, radiation, tumor recurrence), a blowout can occur intracranially 3).

1)

Morinaga Y, Nii K, Sakamoto K, Inoue R, Mitsutake T, Hanada H. Stent-assisted Coil Embolization for a Ruptured Posterior Communicating Artery Pseudoaneurysm after Endoscopic Trans-sphenoidal Surgery for Pituitary Adenoma. World Neurosurg. 2018 Dec 21. pii: S1878-8750(18)32870-5. doi: 10.1016/j.wneu.2018.12.047. [Epub ahead of print] PubMed PMID: 30583130.
2)

Ko HC, Koh JS, Shin HS, Lee SH, Ryu CW. Staged Endovascular Occlusion of a Posterior Communicating Artery-Cavernous Sinus Fistula and a Basilar Artery-Cavernous Sinus Fistula Associated with Traumatic Pseudoaneurysms: Technical Consideration and Literature Review. World Neurosurg. 2017 Nov;107:1051.e7-1051.e11. doi: 10.1016/j.wneu.2017.08.070. Epub 2017 Aug 24. Review. PubMed PMID: 28842235.
3)

Alaraj A, Behbahani M, Valyi-Nagy T, Aardsma N, Aletich VA. Rare presentation of intracranial vascular blowout after tumor resection and radiation therapy. J Neurointerv Surg. 2015 May;7(5):e18. doi: 10.1136/neurintsurg-2014-011192.rep. Epub 2014 Apr 24. PubMed PMID: 24763549.
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