Hypoxic ischaemic brain injury

Hypoxic ischaemic brain injury

Hypoxic ischaemic brain injury is common and usually due to cardiac arrest or profound hypotension. The clinical pattern and outcome depend on the severity of the initial insult, the effectiveness of immediate resuscitation and transfer, and the post-resuscitation management on the intensive care unit. Clinical assessment is difficult and so often these days compromised by sedationneuromuscular-blocking drugventilationhypothermia and inotropic management. Investigations can add valuable information, in particular brain MRI shows characteristic patterns depending on the severity of the injury and the timing of imaging. EEG patterns may also suggest the possibility of a good outcome. There is no entirely reliable algorithm of clinical signs or investigations which allow a definitive prognosis but the combination of careful repeated observations and appropriate ancillary investigations allows the neurologist to give an informed and accurate opinion of the likely outcome, and to advise on management. Overall, the prognosis is extremely poor and only a quarter of patients survive to hospital discharge, and often even then with severe neurological or cognitive deficits 1).


In eleven patients (median age of 47 [range 20-71], 8 male and 3 female). There was a linear relationship between ICP and non-invasive estimators of ICP (nICP) with optic nerve sheath diameter ultrasonography (ONSD) (R = 0.53 [p < 0.0001]), JVP (R = 0.38 [p < 0.001]) and transcranial Doppler ultrasonography (TCD) (R = 0.30 [p < 0.01]). The ability to predict intracranial hypertension was highest for ONSD and TCD (AUC = 0.96 [95% CI: 0.90-1.00] and AUC = 0.91 [95% CI: 0.83-1.00], respectively). Jugular venous bulb pressure (JVP). presented the weakest prediction ability (AUC = 0.75 [95% CI: 0.56-0.94]).

ONSD and TCD methods demonstrated agreement with invasively-monitored ICP, suggesting their potential roles in the detection of intracranial hypertension in hypoxic ischaemic brain injury (HIBI) after cardiac arrest 2).

References

1)

Howard RS, Holmes PA, Koutroumanidis MA. Hypoxic-ischaemic brain injury. Pract Neurol. 2011 Feb;11(1):4-18. doi: 10.1136/jnnp.2010.235218. Review. PubMed PMID: 21239649.
2)

Cardim D, Griesdale DE, Ainslie PN, Robba C, Calviello L, Czosnyka M, Smielewski P, Sekhon MS. A comparison of non-invasive versus invasive measures of intracranial pressure in hypoxic ischaemic brain injury after cardiac arrest. Resuscitation. 2019 Jan 7. pii: S0300-9572(18)30912-2. doi: 10.1016/j.resuscitation.2019.01.002. [Epub ahead of print] PubMed PMID: 30629992.

Neurologic Injury after Lateral Lumbar Interbody Fusion

Since the first description of LLIF in 2006, the indications for LLIF have expanded and the rate of LLIF procedures performed in the USA has increased. LLIF has several theoretical advantages compared to other approaches including the preservation of the anterior and posterior annular/ligamentous structures, insertion of wide cages resting on the dense apophyseal ring bilaterally, and augmentation of disc height with indirect decompression of neural elements. Favorable long-term outcomes and a reduced risk of visceral/vascular injuries, incidental dural tears, and perioperative infections have been reported. However, approach-related complications such as motor and sensory deficits remain a concern. In well-indicated patients, LLIF can be a safe procedure used for a variety of indications 1).

Hijji et al. published a systematic review analyzing the complication profile of LLIF. Their study included a total of 63 articles and 6819 patients. The most commonly reported complications were transient neurologic injury (36.07%). The clinical significance of those transient findings, however, is unclear since the rate of persistent neurologic complications was much lower (3.98%) 2)

The risk of lumbar plexus injury is particularly concerning at the L4-5 disc space. Although LLIF is associated with an increased prevalence of anterior thigh/groin pain as well as motor and sensory deficits immediately after surgery, our results support that pain and neurologic deficits decrease over time. The level treated appears to be a risk factor for lumbosacral plexus injury 3).

Interestingly, the use of rhBMP-2 was associated with higher rates of persistent motor deficits, which might be explained by a direct deleterious effect of this agent on the lumbosacral plexus 4).

In a retrospective chart review of 118 patients, Cahill et al. determined the incidence of femoral nerve injury, which is considered one of the worst neurological complications after LLIF. The authors reported an approximate 5% femoral nerve injury rate of all the LLIF procedures performed at L4-5. There were no femoral nerve injuries at any other levels 5).

During a 6-year time period of performing LLIF Aichmair et al., noted a learning curve with a decreasing proportional trend for anterior thigh pain, sensory as well as motor deficits 6)

Le et al. also observed a learning curve with a significant reduction in the incidence of postoperative thigh numbness during a 3-year period (from 26.1 to 10.7%) 7).

Levi AD from the University of Miami Hospital, adopted an exclusive mini-open muscle-splitting approach in LLIF with first-look inspection of the lumbosacral plexus nerve elements taht may improve motor and sensory outcomes in general and the incidence of postoperative groin/thighsensory dysfunction and psoas-pattern weakness in particular 8).

References

1)

Salzmann SN, Shue J, Hughes AP. Lateral Lumbar Interbody Fusion-Outcomes and Complications. Curr Rev Musculoskelet Med. 2017 Dec;10(4):539-546. doi: 10.1007/s12178-017-9444-1. Review. PubMed PMID: 29038952; PubMed Central PMCID: PMC5685966.
2)

Hijji FY, Narain AS, Bohl DD, Ahn J, Long WW, DiBattista JV, Kudaravalli KT, Singh K. Lateral lumbar interbody fusion: a systematic review of complication rates. Spine J. 2017 Oct;17(10):1412-1419. doi: 10.1016/j.spinee.2017.04.022. Epub 2017 Apr 26. Review. PubMed PMID: 28456671.
3)

Lykissas MG, Aichmair A, Hughes AP, Sama AA, Lebl DR, Taher F, Du JY, Cammisa FP, Girardi FP. Nerve injury after lateral lumbar interbody fusion: a review of 919 treated levels with identification of risk factors. Spine J. 2014 May 1;14(5):749-58. doi: 10.1016/j.spinee.2013.06.066. Epub 2013 Sep 5. PubMed PMID: 24012428.
4)

Lykissas MG, Aichmair A, Hughes AP, Sama AA, Lebl DR, Taher F, Du JY, Cammisa FP, Girardi FP. Nerve injury after lateral lumbar interbody fusion: a review of 919 treated levels with identification of risk factors. Spine J. 2014 May 1;14(5):749-58. doi: 10.1016/j.spinee.2013.06.066. Epub 2013 Sep 5. PubMed PMID: 24012428.
5)

Cahill KS, Martinez JL, Wang MY, Vanni S, Levi AD. Motor nerve injuries following the minimally invasive lateral transpsoas approach. J Neurosurg Spine. 2012 Sep;17(3):227-31. doi: 10.3171/2012.5.SPINE1288. Epub 2012 Jun 29. PubMed PMID: 22746272.
6)

Aichmair A, Lykissas MG, Girardi FP, Sama AA, Lebl DR, Taher F, Cammisa FP, Hughes AP. An institutional six-year trend analysis of the neurological outcome after lateral lumbar interbody fusion: a 6-year trend analysis of a single institution. Spine (Phila Pa 1976). 2013 Nov 1;38(23):E1483-90. doi: 10.1097/BRS.0b013e3182a3d1b4. PubMed PMID: 23873231.
7)

Le TV, Burkett CJ, Deukmedjian AR, Uribe JS. Postoperative lumbar plexus injury after lumbar retroperitoneal transpsoas minimally invasive lateral interbody fusion. Spine (Phila Pa 1976). 2013 Jan 1;38(1):E13-20. doi: 10.1097/BRS.0b013e318278417c. PubMed PMID: 23073358.
8)

Sellin JN, Brusko GD, Levi AD. Lateral Lumbar Interbody Fusion Revisited: Complication Avoidance and Outcomes with the Mini-Open Approach. World Neurosurg. 2019 Jan;121:e647-e653. doi: 10.1016/j.wneu.2018.09.180. Epub 2018 Oct 3. PubMed PMID: 30292030.

Traumatic spinal cord injury treatment

Early decompression surgery post-SCI can enhance patient outcomes, but does not directly facilitate neural repair and regeneration. Currently, there are no U.S. Food and Drug Administration-approved pharmacological therapies to augment motor function and functional recovery in individuals with traumatic SCI.

Acute traumatic spinal cord injury (SCI) is a devastating event with far-reaching physical, emotional, and economic consequences for patients, families, and society at large. Timely delivery of specialized care has reduced mortality; however, long-term neurological recovery continues to be limited. In recent years, a number of exciting neuroprotective and regenerative strategies have emerged and have come under active investigation in clinical trials, and several more are coming down the translational pipeline. Among ongoing trials are RISCIS (riluzole), INSPIRE study (Neuro-Spinal Scaffold), MASC (minocycline), and SPRING (VX-210). Microstructural MRI techniques have improved our ability to image the injured spinal cord at high resolution. This innovation, combined with serum and cerebrospinal fluid (CSF) analysis, holds the promise of providing a quantitative biomarker readout of spinal cord neural tissue injury, which may improve prognostication and facilitate stratification of patients for enrollment into clinical trials. Given evidence of the effectiveness of early surgical decompression and growing recognition of the concept that “time is spine,” infrastructural changes at a systems level are being implemented in many regions around the world to provide a streamlined process for transfer of patients with acute SCI to a specialized unit. With the continued aging of the population, central cord syndrome is soon expected to become the most common form of acute traumatic SCI; characterization of the pathophysiologynatural history, and optimal treatment of these injuries is hence a key public health priority. Collaborative international efforts have led to the development of clinical practice guidelines for traumatic SCI based on robust evaluation of current evidence 1).

1)

Badhiwala JH, Ahuja CS, Fehlings MG. Time is spine: a review of translational advances in spinal cord injury. J Neurosurg Spine. 2018 Dec 20;30(1):1-18. doi: 10.3171/2018.9.SPINE18682. Review. PubMed PMID: 30611186.

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.

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.

Traumatic cervical spinal cord injury outcome

Injury to the spine and spinal cord is one of the common cause of disability and death. Several factors affect the outcome; but which are these factors (alone and in combination), are determining the outcomes are still unknown.

Based on parameters from the International Standards, physicians are able to inform patients about the predicted long-term outcomes, including the ability to walk, with high accuracy. In those patients who cannot participate in a reliable physical neurological examination, magnetic resonance imaging and electrophysiological examinations may provide useful diagnostic and prognostic information. As clinical research on this topic continues, the prognostic value of the reviewed diagnostic assessments will become more accurate in the near future. These advances will provide useful information for physicians to counsel tSCI patients and their families during the catastrophic initial phase after the injury 1).

Preclinical and class III clinical data suggest improved outcomes by maintaining the mean arterial pressure > 85 mm Hg and avoiding hypoxemia at least for 7 days following cervical SCI, and this level of monitoring and support should occur in the ICU 2).


100 cases of patients under 18 years at accident with acute traumatic cervical spinal cord injury admitted to spinal cord injury SCI centers participating in the European Multi-center study about SCI (EMSCI) between January 2005 and April 2016 were reviewed. According to their age at accident, age 13 to 17, patients were selected for the adolescent group. After applying in- and exclusion criteria 32 adolescents were included. Each adolescent patient was matched with two adult SCI patients for analysis.

ASIA Impairment scale (AIS) grade, neurological, sensory, motor level, total motor score, and Spinal Cord Independence Measure (SCIM III) total score.

Mean AIS conversion, neurological, motor and sensory levels as well as total motor score showed no significantly statistical difference in adolescents compared to the adult control group after follow up of 6 months. Significantly higher final SCIM scores (p < 0.05) in the adolescent group compared to adults as well as a strong trend for a higher gain in SCIM score (p < 0.061) between first and last follow up was found.

Neurological outcome after traumatic cervical SCI is not superior in adolescents compared to adults in this cohort. Significantly higher SCIM scores indicate more functional gain for the adolescent patients after traumatic cervical SCI. Juvenile age appears to be an independent predictor for a better functional outcome. 3).


A prospective observational study at single-center with all patients with cervical spinal cord injury (SCI), attending our hospital within a week of injury during a period of October 2011 to July 2013 was included for analysis. Demographic factors such as age, gender, etiology of injury, preoperative American Spinal Injury Association (ASIA) grade, upper (C2-C4) versus lower (C5-C7) cervical level of injury, imageological factors on magnetic resonance imaging (MRI), and timing of intervention were studied. Change in neurological status by one or more ASIA grade from the date of admission to 6 months follow-up was taken as an improvement. Functional grading was assessed using the functional independence measure (FIM) scale at 6 months follow-up.

A total of 39 patients with an acute cervical spine injury, managed surgically were included in this study. Follow-up was available for 38 patients at 6 months. No improvement was noted in patients with ASIA Grade A. Maximum improvement was noted in ASIA Grade D group (83.3%). The improvement was more significant in lower cervical region injuries. Patient with cord contusion showed no improvement as opposed to those with just edema wherein; the improvement was seen in 62.5% patients. Percentage of improvement in cord edema ≤3 segments (75%) was significantly higher than edema with >3 segments (42.9%). Maximum improvement in FIM score was noted in ASIA Grade C and patients who had edema (especially ≤3 segments) in MRI cervical spine.

Complete cervical SCI, upper-level cervical cord injury, patients showing MRI contusion, edema >3 segments group have worst improvement in neurological status at 6 months follow-up 4).


A total of 66 patients diagnosed with traumatic cervical SCI were selected for neurological assessment (using the International standards for neurological classification of spinal cord injury [ISNCSCI]) and functional evaluation (based on the Korean version Modified Barthel Index [K-MBI] and Functional Independence Measure [FIM]) at admission and upon discharge. All of the subjects received a preliminary electrophysiological assessment, according to which they were divided into two groups as follows: those with cervical radiculopathy (the SCI/Rad group) and those without (the SCI group).

A total of 32 patients with cervical SCI (48.5%) had cervical radiculopathy. The initial ISNCSCI scores for sensory and motor, K-MBI, and total FIM did not significantly differ between the SCI group and the SCI/Rad group. However, at discharge, the ISNCSCI scores for motor, K-MBI, and FIM of the SCI/Rad group showed less improvement (5.44±8.08, 15.19±19.39 and 10.84±11.49, respectively) than those of the SCI group (10.76±9.86, 24.79±19.65 and 17.76±15.84, respectively) (p<0.05). In the SCI/Rad group, the number of involved levels of cervical radiculopathy was negatively correlated with the initial and follow-up motors score by ISNCSCI.

Cervical radiculopathy is not rare in patients with traumatic cervical SCI, and it can impede neurological and functional improvement. Therefore, detection of combined cervical radiculopathy by electrophysiological assessment is essential for accurate prognosis of cervical SCI patients in the rehabilitation unit 5).

References

1)

van Middendorp JJ, Goss B, Urquhart S, Atresh S, Williams RP, Schuetz M. Diagnosis and prognosis of traumatic spinal cord injury. Global Spine J. 2011 Dec;1(1):1-8. doi: 10.1055/s-0031-1296049. PubMed PMID: 24353930; PubMed Central PMCID: PMC3864437.
2)

Schwartzbauer G, Stein D. Critical Care of Traumatic Cervical Spinal Cord Injuries: Preventing Secondary Injury. Semin Neurol. 2016 Dec;36(6):577-585. Epub 2016 Dec 1. Review. PubMed PMID: 27907962.
3)

Geuther M, Grassner L, Mach O, Klein B, Högel F, Voth M, Bühren V, Maier D, Abel R, Weidner N, Rupp R, Fürstenberg CH; EMSCI study group, Schneidmueller D. Functional outcome after traumatic cervical spinal cord injury is superior in adolescents compared to adults. Eur J Paediatr Neurol. 2018 Dec 11. pii: S1090-3798(18)30247-2. doi: 10.1016/j.ejpn.2018.12.001. [Epub ahead of print] PubMed PMID: 30579697.
4)

Srinivas BH, Rajesh A, Purohit AK. Factors affecting outcome of acute cervical spine injury: A prospective study. Asian J Neurosurg. 2017 Jul-Sep;12(3):416-423. doi: 10.4103/1793-5482.180942. PubMed PMID: 28761518; PubMed Central PMCID: PMC5532925.
5)

Kim SY, Kim TU, Lee SJ, Hyun JK. Prognosis for patients with traumatic cervical spinal cord injury combined with cervical radiculopathy. Ann Rehabil Med. 2014 Aug;38(4):443-9. doi: 10.5535/arm.2014.38.4.443. Epub 2014 Aug 28. PubMed PMID: 25229022; PubMed Central PMCID: PMC4163583.

Update: Intentional traumatic brain injury

Intentional traumatic brain injury

Epidemiology

Intentional injury has been associated with certain demographics and socioeconomic groups. Less is known about the relationship of intentional traumatic brain injury (TBI) to injury severity, mortality, and demographic and socioeconomic profile.


A planned secondary analysis of a prospective multicentre cohort study was conducted in 10 emergency departments EDs in Australia and New Zealand, including children aged <18 years with head injury (HI). Epidemiology codes were used to prospectively code the injuries. Demographic and clinical information including the rate of clinically important traumatic brain injury (ciTBI: HI leading to death, neurosurgery, intubation >1 day or admission ≥2 days with abnormal computed tomography [CT]) was descriptively analysed.

Intentional injuries were identified in 372 of 20 137 (1.8%) head-injured children. Injuries were caused by caregivers (103, 27.7%), by peers (97, 26.1%), by siblings (47, 12.6%), by strangers (35, 9.4%), by persons with unknown relation to the patient (21, 5.6%), other intentional injuries (8, 2.2%) or undetermined intent (61, 16.4%). About 75.7% of victims of assault by caregivers were <2 years, whereas in other categories, only 4.9% were <2 years. Overall, 66.9% of victims were male. Rates of CT performance and abnormal CT varied: assault by caregivers 68.9%/47.6%, by peers 18.6%/27.8%, by strangers 37.1%/5.7%. ciTBI rate was 22.3% in assault by caregivers, 3.1% when caused by peers and 0.0% with other perpetrators.

Intentional HI is infrequent in children. The most frequently identified perpetrators are caregivers and peers. Caregiver injuries are particularly severe 1).


A study identified 1,409 (8.0%) intentional TBIs and 16,211 (92.0%) unintentional TBIs. Of the intentional TBIs, 389 (27.6%) was self-inflicted TBI (Si-TBI) and 1,020 (72.4%) was other-inflicted TBI (Oi-TBI). The most common cause of Si-TBI was “jumping from high places” (32.1%), followed by “firearms” (30.6%). About half of Oi-TBI was because of “fight and brawl” (48.3%), followed by “struck by objects” (26.1%). Si-TBI was associated with younger age, female gender, and having more alcohol/drug abuse history. For Oi-TBI, younger age, male gender, having more alcohol/drug abuse history were independently associated.

This research provides the first comprehensive overview of intentional TBI based in Canada.

The comprehensive data set (CDS) of the Ontario trauma registry (OTR) provided the ability to identify who is at risk for intentional TBI. Prevention programs and more targeted rehabilitation services should be designed for this vulnerable population 2).

Outcome

Intentional injury is associated with significant morbidity and mortality.

Caregiver injuries are particularly severe in children 3).

Prospective data were obtained for 2,637 adults sustaining TBIs between January 1994 and September 1998. Descriptive, univariate, and multivariate analyses were conducted to determine the predictive value of intentional TBI on injury severity and mortality.

Gender, minority status, age, substance abuse, and residence in a zipcode with low average income were associated with intentional TBI. Multivariate analysis found minority status and substance abuse to be predictive of intentional injury after adjusting for other demographic variables studied. Intentional TBI was predictive of mortality and anatomic severity of injury to the head. Penetrating intentional TBI was predictive of injury severity with all injury severity markers studied.

Many demographic variables are risk factors for intentional TBI, and such injury is a risk factor for both injury severity and mortality. Future studies are needed to definitively link intentional TBI to disability and functional outcome 4).

References

1) , 3)

Babl FE, Pfeiffer H, Dalziel SR, Oakley E, Anderson V, Borland ML, Phillips N, Kochar A, Dalton S, Cheek JA, Gilhotra Y, Furyk J, Neutze J, Lyttle MD, Bressan S, Donath S, Hearps SJ, Crowe L; Paediatric Research in Emergency Departments International Collaborative (PREDICT). Paediatric intentional head injuries in the emergency department: A multicentre prospective cohort study. Emerg Med Australas. 2018 Nov 26. doi: 10.1111/1742-6723.13202. [Epub ahead of print] PubMed PMID: 30477046.
2)

Kim H, Colantonio A. Intentional traumatic brain injury in Ontario, Canada. J Trauma. 2008 Dec;65(6):1287-92. doi: 10.1097/TA.0b013e31817196f5. PubMed PMID: 19077615.
4)

Wagner AK, Sasser HC, Hammond FM, Wiercisiewski D, Alexander J. Intentional traumatic brain injury: epidemiology, risk factors, and associations with injury severity and mortality. J Trauma. 2000 Sep;49(3):404-10. Erratum in: J Trauma 2000 Nov;49(5):982. PubMed PMID: 11003315.

UpToDate: Brachial plexus injury epidemiology

Brachial plexus injury epidemiology

Epidemiological studies of traumatic brachial plexus injuries are few and most of them focus on treatment and prognosis.

A study of 2018 from Rasulić et al., in surgically treated civilian traumatic brachial plexus injuries in Serbia, there were seven different etiological factors. The road traffic accidents were the most common-41 (60.3%), while the motorcycle accidents were the most dominant subtype (53.7%) of all road traffic accidents, and also representing 32.4% of all causes of trauma. Supraclavicular elements of the brachial plexus were injured in more than 80% of patients. A total of 49 (72.1%) patients from the study had one or more associated injuries. The most common associated injuries were bone fractures, cerebral contusions, and vascular injuries 1).

In 2014 a analysis of the epidemiological characteristics of patients with traumatic brachial plexus lesions in São Paulo, Brazil, the sixth largest city in the world.

This was a retrospective analysis of the epidemiological characteristics of patients submitted to surgical treatment of traumatic brachial plexus lesions in the Peripheral Nerve Surgery Unit of the Department of Neurosurgery of the University of São Paulo Medical School.

In the period from 2004 to 2012, 406 patients underwent surgery. There were 384 (94.6 %) men and 22 (5.4 %) women. In 45.9 % the compromised plexus was the right and in 54.1 %, the left. The average age was 28.38 years. Among the causes, the most frequent was motorcycle accidents (79 %). Most of the lesions were supraclavicular. In 46.1 % of cases the lesions were complete, in 30.1 % the lesions compromised C5/C6 roots, in 20.9 % the C5/C6/C7 roots were lesioned and in 2.9 % the lesion was in the lower roots, C8/T1. Among the associated lesions the most prevalent were head trauma, observed in 34.2 % of the cases; lesions of long bones in 38.8 %; clavicle fractures in 25.9 %; and thoracic trauma in 12.9 %.

In a population of adult patients with brachial plexus lesions with surgical indication, most of them comprise young male adults involved in high-energy motorcycle accidents 2).

Jain in 2012 wanted to know the situation in an Indian centre. Data regarding age, sex, affected side, mode of injury, distribution of paralysis, associated injuries, pain at the time of presentation and the index procedure they underwent were collected from 304 patients. Additional data like the vehicle associated during the accident, speed of the vehicle during the accident, employment status and integration into the family were collected in 144 patients out of the 304 patients.

Road traffic accidents accounted for 94% of patients and of the road traffic accidents 90% involved two wheelers. Brachial plexus injury formed a part of multitrauma in 54% of this study group and 46% had isolated brachial plexus injury. Associated injuries like fractures, vascular injuries and head injuries are much less probably due to the lower velocity of the vehicles compared to the western world. The average time interval from the date of injury to exploration of the brachial plexus was 127 days and 124 (40.78%) patients presented to us within this duration. Fifty-seven per cent had joined back to work by an average of 8.6 months. It took an average of 6.8 months for the global brachial plexus-injured patients to write in their non-dominant hand 3).

In 2010 the aim of a study of Dorsi et al., was to estimate the prevalence of brachial plexus injury (BPI) in pediatric multitrauma patients.

The National Pediatric Trauma Registry was queried using the ICD-9 code 953.4, injury to brachial plexus, to identify cases of BPI. The patient demographics, mechanism of trauma, and associated ICD-9 diagnoses were analyzed.

Brachial plexus injuries were identified in 113 (0.1%) of the 103,434 injured children entered in the registry between April 1, 1985, and March 31, 2002. Sixty-nine patients (61%) were male. Injuries were most often caused by motor vehicle accidents involving passengers (36 cases [32%]) or pedestrians (19 cases [17%]). Head injuries were diagnosed in 47% of children and included concussion in 27%, intracranial bleeds in 21%, and skull fractures in 14%. Upper-extremity vascular injury occurred in 16%. The most common musculoskeletal injuries were fractures of the humerus (16%), ribs (16%), clavicle (13%), and scapula (11%). Spinal fractures occurred in 12% of patients, and spinal cord injury occurred in 4%. The Injury Severity Score ranged from 1 to 75, with a mean score of 10, and 6 patients (5%) died as a result of injuries sustained during a traumatic event.

Brachial plexus injuries occur in 0.1% of pediatric multitrauma patients. Motor vehicle accidents and pedestrians struck by a motor vehicle are the most common reasons for BPIs in this population. Common associated injuries include head injuries, upper-extremity vascular injuries, and fractures of the spine, humerus, ribs, scapula, and clavicle 4).

In 2006 a study of Flores from the Unidade de Neurocirurgia, Hospital de Base do Distrito Federal, Brasília, Brazil most of the lesions were supraclavicular (62%). Twenty-one cases occurred due to traction (60%), 9 to gun shot wound (25%), 3 to compression (8.5%) and two perforation/laceration (5.7%). Motorcycle accidents were the cause of trauma in 54% of patients. CT myelography demonstrated root avulsion in 16 cases (76%). Partial spontaneous neurological recovery was observed in 43% of the patients. Neuropathic pain occurred in 25 (71%) cases, and the use of some oral intake drugs (as amitriptyline or carbamazepine) controlled it in 64% of times.

Traction is the most frequent mechanism related to brachial plexus injuries, and root avulsions are common in this cases. Pain and concomitant lesions are frequently observed in these group. In this series, the rate of incidence to the local population was 1.75/100000/year. 5).

In 1997 Midha published that Brachial plexus injury afflict slightly more than 1% of multitrauma victims. Motorcycle and snowmobile accidents carry especially high risks, with the incidence of injury approaching 5%. Head injuries, thoracic injuries, and fractures and dislocations affecting the shoulder girdle and cervical spine are particularly common associated injuries. Supraclavicular injuries are more common, are of more severe grade, more often require surgery, and are associated with worse prognosis, compared with infraclavicular injuries 6).

References

1)

Rasulić L, Savić A, Lepić M, Puzović V, Karaleić S, Kovačević V, Vitošević F, Samardžić M. Epidemiological characteristics of surgically treated civilian traumatic brachial plexus injuries in Serbia. Acta Neurochir (Wien). 2018 Jul 29. doi: 10.1007/s00701-018-3640-7. [Epub ahead of print] PubMed PMID: 30056518.
2)

Faglioni W Jr, Siqueira MG, Martins RS, Heise CO, Foroni L. The epidemiology of adult traumatic brachial plexus lesions in a large metropolis. Acta Neurochir (Wien). 2014 May;156(5):1025-8. doi: 10.1007/s00701-013-1948-x. Epub 2013 Dec 7. PubMed PMID: 24318512.
3)

Jain DK, Bhardwaj P, Venkataramani H, Sabapathy SR. An epidemiological study of traumatic brachial plexus injury patients treated at an Indian centre. Indian J Plast Surg. 2012 Sep;45(3):498-503. doi: 10.4103/0970-0358.105960. PubMed PMID: 23449838; PubMed Central PMCID: PMC3580349.
4)

Dorsi MJ, Hsu W, Belzberg AJ. Epidemiology of brachial plexus injury in the pediatric multitrauma population in the United States. J Neurosurg Pediatr. 2010 Jun;5(6):573-7. doi: 10.3171/2010.3.PEDS09538. PubMed PMID: 20515329.
5)

Flores LP. [Epidemiological study of the traumatic brachial plexus injuries in adults]. Arq Neuropsiquiatr. 2006 Mar;64(1):88-94. Epub 2006 Apr 5. Portuguese. PubMed PMID: 16622560.
6)

Midha R. Epidemiology of brachial plexus injuries in a multitrauma population. Neurosurgery. 1997 Jun;40(6):1182-8; discussion 1188-9. PubMed PMID: 9179891.

UpToDate: Diffuse axonal injury outcome

Diffuse axonal injury outcome

Diffuse axonal injury, and more generally TBI, often results in physical, cognitive, and behavioral impairments that can be temporary or permanent1) 2) 3) 4) 5) 6) 7) 8) 9) 10).


The outcome of patients after DAI has been linked to the number of lesions identified through imaging. A longitudinal study that analyzed the evolution of traumatic axonal injury using magnetic resonance imaging (MRI) of 58 patients with moderate or severe TBI showed that the greater the number of lesions observed early after trauma, the greater the impairment of functionality after 12 months 11).

A study of 26 DAI patients indicated that the volume and number of lesions identified by MRI performed within 48 h of hospital admission strongly correlated with the level of disability observed at the time of hospital discharge 12).


DAI with hypoxia, as measured by peripheral oxygen saturation, and hypotension with New Injury Severity Score (NISS) value – had a statistically significant association with patient mortality; on the other hand, severity of DAI and length of hospital stay were the only significant predictors for dependence. Therefore, severity of DAI emerged as a risk factor for both mortality and dependence 13).


Clinical evidence of DAI on MRI may only be useful for predicting short-term in-hospital functional outcome. Given no association of DAI and long-term TBI outcomes, providers should be cautious in attributing DAI to future neurologic function, quality of life, and/or survival 14).


Brain atrophy progresses over time, but patients showed better executive function (EF) and verbal episodic memory (EVM) in some of the tests, which could be due to neuroplasticity 15).

References

1)

Gennarelli TA. Cerebral concussion and diffuse brain injuries. 2nd ed In: Cooper PR, editor. , editor. Head Injury. Baltimore: Williams & Wilkins; (1987). p. 108–24.
2)

Gennarelli TA. Cerebral concussion and diffuse brain injuries. 3rd ed In: Cooper PR, editor. , editor. Head Injury. Baltimore: Williams & Wilkins; (1993). p. 137–58.
3)

Lagares A, Ramos A, Alday R, Ballenilla F, Pérez-Nuñez A, Arrese I, et al. Magnetic resonance in moderate and severe head injury: comparative study of CT and MR findings. Characteristics related to the presence and location of diffuse axonal injury in MR. Neurocirugia (Astur) (2006) 17(2):105–18.10.1016/S1130-1473(06)70351-7
4)

Esbjörnsson E, Skoglund T, Sunnerhagen KS. Fatigue, psychosocial adaptation and quality of life one year after traumatic brain injury and suspected traumatic axonal injury; evaluations of patients and relatives: a pilot study. J Rehabil Med (2013) 45:771–7.10.2340/16501977-1170
5)

Chelly H, Chaari A, Daoud E, Dammak H, Medhioub F, Mnif J, et al. Diffuse axonal injury in patients with head injuries: an epidemiologic and prognosis study of 124 cases. J Trauma (2011) 71(4):838–46.10.1097/TA.0b013e3182127baa
6)

Jeong JH, Kim YZ, Cho YW, Kim JS. Negative effect of hypopituitarism following brain trauma in patients with diffuse axonal injury. J Neurosurg (2010) 113(3):532–8.10.3171/2009.10.JNS091152
7)

Ham TE, Sharp DJ. How can investigation of network function inform rehabilitation after traumatic brain injury? Curr Opin Neurol (2012) 25(6):662–9.10.1097/WCO.0b013e328359488f
8)

Sousa RMC. Comparisons among measurement tools in traumatic brain injury outcomes. Rev Esc Enferm USP (2006) 40(2):203–13.10.1590/S0080-62342006000200008
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Scholten AC, Haagsma JA, Andriessen TM, Vos PE, Steyerberg EW, van Beeck EF, et al. Health-related quality of life after mild, moderate and severe traumatic brain injury: patterns and predictors of suboptimal functioning during the first year after injury. Injury (2015) 46(4):616–24.10.1016/j.injury.2014.10.064
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Liew BS, Johari SA, Nasser AW, Abdullah J. Severe traumatic brain injury: outcome in patients with diffuse axonal injury managed conservatively in hospital Sultanah Aminah, Johor Bahru – an observational study. Med J Malaysia (2009) 64(4):280–8.
11)

Moen KG, Skandsen T, Folvik M, Brezova V, Kvistad KA, Rydland J, et al. A longitudinal MRI study of traumatic axonal injury in patients with moderate and severe traumatic brain injury. J Neurol Neurosurg Psychiatry (2012) 83(12):1193–200.10.1136/jnnp-2012-302644
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Schaefer PW, Huisman TA, Sorensen AG, Gonzalez RG, Schwamm LH. Diffusion-weighted MR imaging in closed head injury: high correlation with initial Glasgow Coma Scale score and score on modified Rankin scale at discharge. Radiology (2004) 233(1):58–66.10.1148/radiol.2323031173
13)

Vieira RC, Paiva WS, de Oliveira DV, Teixeira MJ, de Andrade AF, de Sousa RM. Diffuse Axonal Injury: Epidemiology, Outcome and Associated Risk Factors. Front Neurol. 2016 Oct 20;7:178. eCollection 2016. PubMed PMID: 27812349; PubMed Central PMCID: PMC5071911.
14)

Humble SS, Wilson LD, Wang L, Long DA, Smith MA, Siktberg JC, Mirhoseini MF, Bhatia A, Pruthi S, Day MA, Muehlschlegel S, Patel MB. Prognosis of diffuse axonal injury with traumatic brain injury. J Trauma Acute Care Surg. 2018 Jul;85(1):155-159. doi: 10.1097/TA.0000000000001852. PubMed PMID: 29462087; PubMed Central PMCID: PMC6026031.
15)

Stewan Feltrin F, Zaninotto AL, Guirado VMP, Macruz F, Sakuno D, Dalaqua M, Magalhães LGA, Paiva WS, Andrade AF, Otaduy MCG, Leite CC. Longitudinal changes in brain volumetry and cognitive functions after moderate and severe diffuse axonal injury. Brain Inj. 2018 Jul 19:1-10. doi: 10.1080/02699052.2018.1494852. [Epub ahead of print] PubMed PMID: 30024781.

Update: Curcumin for Traumatic Brain Injury

A study determined whether the neuroprotective role of curcumin in mouse TBI is dependent on the NF-E2-related factor (Nrf2) pathway. The Feeney weight-drop contusion model was used to mimic TBI. Curcumin was administered intraperitoneally 15 min after TBI induction, and brains were collected at 24 h after TBI. The levels of Nrf2 and its downstream genes (Hmox-1, Nqo1, Gclm, and Gclc) were detected by Western blot and qRT-PCR at 24 h after TBI. In addition, edema, oxidative damage, cell apoptosis and inflammatory reactions were evaluated in wild type (WT) and Nrf2-knockout (Nrf2-KO) mice to explore the role of Nrf2 signaling after curcumin treatment. In wild type mice, curcumin treatment resulted in reduced ipsilateral cortex injury, neutrophil infiltration, and microglia activation, improving neuron survival against TBI-induced apoptosis and degeneration. These effects were accompanied by increased expression and nuclear translocation of Nrf2, and enhanced expression of antioxidant enzymes. However, Nrf2 deletion attenuated the neuroprotective effects of curcumin in Nrf2-KO mice after TBI. These findings demonstrated that curcumin effects on TBI are associated with the activation the Nrf2 pathway, providing novel insights into the neuroprotective role of Nrf2 and the potential therapeutic use of curcumin for TBI 1).


The protective effect of tetrahydrocurcumin (THC) after experimental traumatic brain injury (TBI) has been demonstrated, as demonstrated by the inhibition of oxidative stress, mitochondrial dysfunction, and apoptosis. However, the mechanisms underlying this effect are still not well understood.
A study was to investigate the neuroprotective effects of THC, and its potential mechanisms, in a rat model of TBI. To this end, rats were divided into 4 groups: the sham group, the TBI group, the TBI + vehicle (V) group, and the TBI + THC group. THC or V was administered via intraperitoneal injection to rats in the TBI + V and TBI + THC groups 30 min after TBI. After euthanasia (24 h after TBI), neurological scores, brain water content, and neuronal cell death in the cerebral cortex were recorded. Brain samples were collected after neurological scoring for further analysis. THC treatment alleviated brain edema, attenuated TBI-induced neuronal cell apoptosis, and improved neurobehavioral function. In addition, NFE2-related factor 2 (Nrf2) expression was upregulated following TBI. These results suggest that THC improves neurological outcome after TBI, possibly by activating the Nrf2 signaling pathway 2).


The aim of a study was to investigate the potential neuroprotection of curcumin and the possible role of Nrf2-ARE pathway in the weight-drop model of TBI. The administration of curcumin significantly ameliorated secondary brain injury induced by TBI, such as brain water content, oxidative stress, neurological severity score, and neuronal apoptosis. Curcumin possessed anti-apoptotic character evidenced by elevating Bcl-2 content and reducing that of cleaved caspase-3. Moreover, curcumin markedly enhanced the translocation of Nrf2 from the cytoplasm to the nucleus, proved by the results of western blot and immunohistochemistry, subsequently increased the expression of downstream factors such as heme oxygenase 1 (HO1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) and prevented the decline of antioxidant enzyme activities. In conclusion, curcumin could increase the activities of antioxidant enzymes and attenuate brain injury in the model of TBI, possibly via the activation of the Nrf2-ARE pathway 3).


In a study, Huang et al., evaluated the therapeutic potential of curcumin for the treatment of DAI and investigated the mechanisms underlying the protective effects of curcumin against neural cell death and axonal injury after DAI. Rats subjected to a model of DAI by head rotational acceleration were treated with vehicle or curcumin to evaluate the effect of curcumin on neuronal and axonal injury. We observed that curcumin (20 mg/kg intraperitoneal) administered 1 h after DAI induction alleviated the aggregation of p-tau and β-APP in neurons, reduced ER-stress-related cell apoptosis, and ameliorated neurological deficits. Further investigation showed that the protective effect of curcumin in DAI was mediated by the PERK/Nrf2 pathway. Curcumin promoted PERK phosphorylation, and then Nrf2 dissociated from Keap1 and was translocated to the nucleus, which activated ATF4, an important bZIP transcription factor that maintains intracellular homeostasis, but inhibited the CHOP, a hallmark of ER stress and ER-associated programmed cell death. In summary, we demonstrate for the first time that curcumin confers protection against abnormal proteins and neuronal apoptosis after DAI, that the process is mediated by strengthening of the unfolded protein response to overcome ER stress, and that the protective effect of curcumin against DAI is dependent on the activation of Nrf2 4).


Neurological function, brain water content and cytokine levels were tested in TLR4⁻/⁻ mice subjected to weight-drop contusion injury. Wild-type (WT) mice were injected intraperitoneally with different concentrations of curcumin or vehicle 15 minutes after TBI. At 24 hours post-injury, the activation of microglia/macrophages and TLR4 was detected by immunohistochemistry; neuronal apoptosis was measured by FJB and TUNEL staining; cytokines were assayed by ELISA; and TLR4, MyD88 and NF-κB levels were measured by Western blotting. In vitro, a co-culture system comprised of microglia and neurons was treated with curcumin following lipopolysaccharide (LPS) stimulation. TLR4 expression and morphological activation in microglia and morphological damage to neurons were detected by immunohistochemistry 24 hours post-stimulation.
The protein expression of TLR4 in pericontusional tissue reached a maximum at 24 hours post-TBI. Compared with WT mice, TLR4⁻/⁻ mice showed attenuated functional impairment, brain edema and cytokine release post-TBI. In addition to improvement in the above aspects, 100 mg/kg curcumin treatment post-TBI significantly reduced the number of TLR4-positive microglia/macrophages as well as inflammatory mediator release and neuronal apoptosis in WT mice. Furthermore, Western blot analysis indicated that the levels of TLR4 and its known downstream effectors (MyD88, and NF-κB) were also decreased after curcumin treatment. Similar outcomes were observed in the microglia and neuron co-culture following treatment with curcumin after LPS stimulation. LPS increased TLR4 immunoreactivity and morphological activation in microglia and increased neuronal apoptosis, whereas curcumin normalized this upregulation. The increased protein levels of TLR4, MyD88 and NF-κB in microglia were attenuated by curcumin treatment.
The results suggest that post-injury, curcumin administration may improve patient outcome by reducing acute activation of microglia/macrophages and neuronal apoptosis through a mechanism involving the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages in TBI 5).


The neuroprotective effects of curcumin were evaluated in a weight drop model of cortical contusion trauma in rat. Male Wistar rats (350-400 g, n=9) were anesthetized with sodium pentobarbital (60 mg/kg i.p.) and subjected to head injury. Five days before injury, animals randomly received an i.p. bolus of either curcumin (50 and 100 mg/kg/day, n=9) or vehicle (n=9). Two weeks after the injury and drug treatment, animals were sacrificed and a series of brain sections, stained with hematoxylin and eosin (H&E) were evaluated for quantitative brain lesion volume. Two weeks after the injury, oxidative stress parameter (malondialdehyde) was also measured in the brain. Curcumin (100 mg/kg) significantly reduced the size of brain injury-induced lesions (P<0.05). Neurological examinations (rotarod and inclined-plane tests) were performed on days 1, 3, 7 and 14 post-brain injury. Control injured rats had a significant neurological deficit during 2 weeks (P<0.001). The injury increased brain levels of the malondialdehyde by 35.6% and these increases were attenuated by curcumin (100 mg/kg). Curcumin treatment significantly improved the neurological status evaluated during 2 weeks after brain injury. The study demonstrates the protective efficacy of curcumin in rat traumatic brain injury model 6).


In a study, pre-treatment with curcumin (75, 150 mg/kg) or 30 min post-treatment with 300 mg/kg significantly reduced brain water content and improved neurological outcome following a moderate controlled cortical impact in mice. The protective effect of curcumin was associated with a significant attenuation in the acute pericontusional expression of interleukin-1beta, a pro-inflammatory cytokine, after injury. Curcumin also reversed the induction of aquaporin-4, an astrocytic water channel implicated in the development of cellular edema following head trauma. Notably, curcumin blocked IL-1beta-induced aquaporin-4 expression in cultured astrocytes, an effect mediated, at least in part, by reduced activation of the p50 and p65 subunits of nuclear factor kappaB. Consistent with this notion, curcumin preferentially attenuated phosphorylated p65 immunoreactivity in pericontusional astrocytes and decreased the expression of glial fibrillary acidic protein, a reactive astrocyte marker. As a whole, these data suggest clinically achievable concentrations of curcumin reduce glial activation and cerebral edema following neurotrauma, a finding which warrants further investigation 7).


In a study Rats were exposed to a regular diet or a diet high in saturated fat, with or without 500 ppm curcumin for 4 weeks (n = 8/group), before a mild fluid percussion injury (FPI) was performed. The high-fat diet has been shown to exacerbate the effects of TBI on synaptic plasticity and cognitive function. Supplementation of curcumin in the diet dramatically reduced oxidative damage and normalized levels of BDNF, synapsin I, and CREB that had been altered after TBI. Furthermore, curcumin supplementation counteracted the cognitive impairment caused by TBI. These results are in agreement with previous evidence, showing that oxidative stress can affect the injured brain by acting through the BDNF system to affect synaptic plasticity and cognition. The fact that oxidative stress is an intrinsic component of the neurological sequel of TBI and other insults indicates that dietary antioxidant therapy is a realistic approach to promote protective mechanisms in the injured brain 8).
1)

Dong W, Yang B, Wang L, Li B, Guo X, Zhang M, Jiang Z, Fu J, Pi J, Guan D, Zhao R. Curcumin plays neuroprotective roles against traumatic brain injury partly via Nrf2 signaling. Toxicol Appl Pharmacol. 2018 May 1;346:28-36. doi: 10.1016/j.taap.2018.03.020. Epub 2018 Mar 21. PubMed PMID: 29571711.
2)

Wei G, Chen B, Lin Q, Li Y, Luo L, He H, Fu H. Tetrahydrocurcumin Provides Neuroprotection in Experimental Traumatic Brain Injury and the Nrf2 Signaling Pathway as a Potential Mechanism. Neuroimmunomodulation. 2018 Apr 18. doi: 10.1159/000487998. [Epub ahead of print] PubMed PMID: 29669346.
3)

Dai W, Wang H, Fang J, Zhu Y, Zhou J, Wang X, Zhou Y, Zhou M. Curcumin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE signaling pathway. Brain Res Bull. 2018 Apr 4. pii: S0361-9230(17)30417-3. doi: 10.1016/j.brainresbull.2018.03.020. [Epub ahead of print] PubMed PMID: 29626606.
4)

Huang T, Zhao J, Guo D, Pang H, Zhao Y, Song J. Curcumin mitigates axonal injury and neuronal cell apoptosis through the PERK/Nrf2 signaling pathway following diffuse axonal injury. Neuroreport. 2018 Mar 22. doi: 10.1097/WNR.0000000000001015. [Epub ahead of print] PubMed PMID: 29570500.
5)

Zhu HT, Bian C, Yuan JC, Chu WH, Xiang X, Chen F, Wang CS, Feng H, Lin JK. Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury. J Neuroinflammation. 2014 Mar 27;11:59. doi: 10.1186/1742-2094-11-59. PubMed PMID: 24669820; PubMed Central PMCID: PMC3986937.
6)

Samini F, Samarghandian S, Borji A, Mohammadi G, bakaian M. Curcumin pretreatment attenuates brain lesion size and improves neurological function following traumatic brain injury in the rat. Pharmacol Biochem Behav. 2013 Sep;110:238-44. doi: 10.1016/j.pbb.2013.07.019. Epub 2013 Aug 7. PubMed PMID: 23932920.
7)

Laird MD, Sukumari-Ramesh S, Swift AE, Meiler SE, Vender JR, Dhandapani KM. Curcumin attenuates cerebral edema following traumatic brain injury in mice: a possible role for aquaporin-4? J Neurochem. 2010 May;113(3):637-48. doi: 10.1111/j.1471-4159.2010.06630.x. Epub 2010 Jan 20. PubMed PMID: 20132469; PubMed Central PMCID: PMC2911034.
8)

Wu A, Ying Z, Gomez-Pinilla F. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition. Exp Neurol. 2006 Feb;197(2):309-17. Epub 2005 Dec 20. PubMed PMID: 16364299
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