Section 2 Specialties

**Chapter 4**

## Penetrating Craniocerebral Injury in Pediatric Patients

*Jillian Plonsker, Michael Brandel, Usman Khan and Michael L. Levy*

## **Abstract**

Penetrating head trauma is rare in the pediatric population, and rarer still in the civilian pediatric population. The high rehabilitation potential of children and the higher likelihood of a low-velocity, survivable injury necessitates careful management to minimize morbidity due to secondary injury from ischemia or infection. Management of penetrating injuries includes patient stabilization, appropriate imaging, and if surgery is needed, entry/exit site debridement with dural closure to prevent cerebrospinal fluid leak. Post-operative care includes infection prevention, intracerebral pressure management, and early identification of vasospasm and pseudoaneurysm formation.

**Keywords:** pediatric, penetrating head injury, low-velocity, non-missile, vasospasm, pseudoaneurysm

## **1. Introduction**

Although rare, penetrating craniocerebral injury is an increasingly recognized cause of emergent neurosurgical admissions in children and adolescents 17 years of age or younger [1]. Outside of war zones, these injuries can occur in the setting of gang-related violence in major metropolitan areas. Penetrating head injury may result from gunshot wounds or stabbings, and less commonly due to non-powder guns (Zip Guns) or transorbital penetration [2, 3]. In this review, we have defined high-velocity injuries as those that result from projectiles/objects traveling at velocities >600 meters per second. These are most commonly the result of rifle injuries, which are more prevalent in military conflicts. Low-velocity injuries are usually the result of handguns in civilian populations. The low-velocity equivalents in military conflicts include both handgun and shrapnel injuries. Additional low-velocity mechanisms of injury in children can include BB and pellet gun injuries, stab injuries, blunt penetrating injury, and trauma resulting from pencils, branches, nails, and other objects.

A relatively small number of case series in varied settings comprise the majority of the pediatric literature on penetrating craniocerebral injury.

Barlow et al. study of gunshot wounds in 108 children (nine cerebral injuries) at Harlem Hospital over 10 years was among the first series to examine the demographic, intentionality, and cause of these types of injuries in children [4]. Most worrisome was that 53% of the guns belonged to the children themselves, and 8% of injuries were inflicted by the police.

Beaver et al. reviewed 132 children under 16 years with fatal firearm injuries in the state of Maryland [5]. The cause of death was a homicide in 46%, accident in 25%, and suicide in 22%. Deaths occurred at home in 75% of cases. The perpetrator was a friend in 21%, family member in 20%, acquaintance in 7%, a bystander in 2%, and self-inflicted in 30%.

In 1993, Levy et al. published their experience with 105 pediatric patients at the University of Southern California/Los Angeles County Medical Center with a diagnosis of a gunshot wound to the brain during an 8-year period [1]. Most of these injuries (72%) were gang-related or secondary to murder-suicide, in contrast to a much higher rate of suicide in the adult population. These findings were contextualized by rising rates of gang-related murders in Los Angeles County and increasing numbers of gang members in that time frame. Similarly, a prior study by Ordog et al. [6] described 34 patients, 10 years of age or younger who were treated for gunshot wounds in Los Angeles between 1980 and 1987, noting that no children in this age range had been treated for gunshot wounds prior to 1980.

A retrospective review of traumatic injuries in children 16 years or younger in the San Francisco bay area from 2000 to 2009 revealed that the incidence of gunshot wounds to the head in children continued to increase over time. This represents another study documenting the vexatious number of these injuries each year in children [7]. These injuries were associated with a 63% mortality rate and were thought to represent mostly intentional injuries.

Bandt et al. reported their experience with 48 patients less than 18 years of age with penetrating intracranial gunshot injuries between 2002 and 2011 in St. Louis, MO [8]. The authors proposed a management paradigm involving more aggressive treatment compared to adults due to the more favorable outcomes experienced by children.

Seventy-one pediatric patients with an intracranial gunshot wound between 1996 and 2013 in Memphis, TN were analyzed by Decuypere et al. [9]. Nearly half of the victims died from their injuries, but over 80% of survivors had a good outcome. As noted in prior studies, the authors reported that variables related to the initial clinical exam and classification of CT findings were found to be the most important predictors of outcome.

Thirty patients under the age of 13 years who suffered craniocerebral gunshot injuries were treated at Red Cross War Memorial Children's Hospital in South Africa between 1989 and 2001 [10]. Over half of the victims were injured in the crossfire of civilian violence.

A case series from Mashhad, Iran reported 14 penetrating head injuries in children less than 10 years [11]. These injuries were primarily due to low-velocity objects, such as pencils, rods, silverware, and other miscellaneous objects. The authors noted that pediatric civilian low-velocity gunshot injuries were comparatively uncommon in some middle eastern countries and Japan as compared to the United States and Europe. These findings have supported the prior literature which documented the significant number of gunshot-related injuries to the head in the United States as compared to other countries.

A series from Tel Aviv concluded that pediatric craniocerebral gunshot injuries from plastic projectiles resembled those of low-velocity missiles, with similar treatment algorithms and outcomes compared to other penetrating craniocerebral injuries in civilians [12].

*Penetrating Craniocerebral Injury in Pediatric Patients DOI: http://dx.doi.org/10.5772/intechopen.106549*

Low-velocity penetrating injuries in children are not as common in armed conflict. Given the nature of the high-velocity injuries associated with rifles, most low-velocity injuries are the result of penetrating shrapnel. Low-velocity injuries are those associated with projectiles traveling less than 600 m/sec. This is consistent with the prevalence of handgun injuries in civilian populations. Wani et al. reported on 51 children with penetrating brain injuries who were the victims of armed conflict [13]. Nearly all injuries were from roadside grenade attacks. Victims of grenade attacks had better outcomes than those who suffered bullet injuries to the head. The authors noted that being upright and running away from an audible attack may have predisposed patients to craniocerebral injury, which perhaps could have been prevented by lying down.

A large series of cranial stab wounds was published by Domingo et al. in 1994, including 54 patients less than 14 years. Injuries were due to assault in 58% and accidental in 42%. All patients survived their injury and required surgical debridement [14]. A large series on pediatric penetrating brain injury in Durban, South Africa included more stab wounds (57%) than gunshot wounds (43%) [15]. Interestingly, neurological deficits did not significantly differ by the mechanism of injury when accounting for age and other clinical information.

Irfan et al. reported their experience with four patients in the 2–3 year age range who experienced gunshot wounds to the head, only one of whom did not survive [16]. Penetrating craniocerebral injuries to patients in this age range have the additional nuance of developmental and neurobehavioral impact among survivors [17].

## **2. Epidemiology**

Due to the rarity of penetrating craniocerebral injury in children, it is challenging to identify epidemiological data. This is particularly true given the diversity of data sources reported in the aforementioned case series.

The incidence of pediatric TBI ranges from 12 to 700 per 100,000 population, with most studies reporting between 47 and 280 [18–20]. While the incidence of penetrating TBI in children remains unknown, it represents a small fraction of those likely between 1% and 7%, and varies significantly by country and setting [15, 21].

An analysis of the National Trauma Data Bank, a curated United States trauma registry, demonstrated that gunshot wounds to the head represented 1.4% of pediatric TBI cases, with increasing incidence over time (from 275 per 100,000 in 2003 to 315 per 100,000 in 2012). The mean age was 14.8 years and 79.2% were male. Most victims were African American (43%) or white (35%). Assault was the most common mechanism (63%), followed by suicide (18.3%) and accident (12.6%). There was a time trend for increasing suicides, decreasing accidental injuries, and a stable assault rate. The location of injury was commonly residential (40.6%) or street (24.9%), and less often a public building (1.9%) or recreational location (0.9%). Mortality was 45.1% overall, and 71.5% in the setting of suicidal intent.

In general, pediatric gunshot wound victims were primarily males with mortality rates ranging from 47.9–65% [1, 6, 8–10, 15, 22–25].

Among TBI patients, children in racial minority groups or of low-income status are more likely to be the victim of assault or firearms and are more likely to have poor clinical outcomes [26]. This is likely also true, specifically, for victims of penetrating TBI [21], although data are limited.

## **3. Management**

Initial management of both high- and low-velocity penetrating injury in children involves emergent and aggressive hemodynamic stabilization, correction of coagulopathies, and neurologic assessment. Neurologic imaging after stabilization should include brain computed topography (CT) [27]. CT angiography should be considered to rule out vascular injury. An intracranial pressure monitor is indicated in patients with a low Glasgow coma score (GCS) ≤ 7 or signs of elevated intracranial pressure.

The rate of surgical intervention ranges from 51 to 100% for injuries due to gunshot wounds or explosives [9, 10, 22–24], 70–94% in pellet gun injuries [28, 29], 60% in dog bites [30], and up to100% in stab wounds [14]. Lower rates of intervention among high-velocity injuries likely reflect nonsurvivors or those with inoperable injuries.

Goals of surgery depend on the extent of the injury [31]. Small head wounds without significant intracranial pathology may simply require local wound care and closure, whereas devitalized scalp or compromised bone and dura may require more extensive debridement. Intracranial injuries with hematomas and/or mass effect may require debridement of necrotic brain tissue and accessible bone fragments, or hematoma evacuation. Debridement of the missile tract and the aggressive pursuit of bone/metallic fragments is not recommended when there is no significant mass effect (**Figure 1**). As noted in adult populations a primary goal of surgical intervention in children is dural closure to avoid CSF leaks. Antiepileptic and antimicrobial recommendations are discussed in the following section.

## **4. Complications**

### **4.1 Structural**

Direct impact from the penetrating object can cause a variety of damage to tissue. Skull fracture and cerebrospinal fluid leak due to dural laceration are common. Children's skulls do not become fully ossified until two years of age; therefore, they are more susceptible to skull fracture after non-missile or low-velocity penetrating trauma. The most common entry locations are the thin-walled orbit and the squamous temporal bone [32–34]. Bihemispheric injury and ventricular transgression are associated with worse outcomes (**Figure 2**).

Low-velocity objects are, however, less likely to cause contra-coup injuries, thermal or blast injuries than are high-velocity or missile objects [34]. Depending on the course of the object through brain tissue, there may be a hematoma or cerebral contusion causing a mass effect.

### **4.2 Neurologic**

The significance of the trajectory of the object/projectile is that it has been found to be a powerful determinant of outcome (both morbidity and mortality) as previously noted. The trajectory of the object impacts the likelihood of a transient or permanent neurologic deficit, which most commonly are weakness and cranial

*Penetrating Craniocerebral Injury in Pediatric Patients DOI: http://dx.doi.org/10.5772/intechopen.106549*

#### **Figure 1.**

*A–D. Entry wound and exit wound should be debrided in the operating room with removal of superficial foreign material and repair of any dural injury.*

**Figure 2.** *A–B. Bihemispheric injury is associated with a worse prognosis.*

neuropathy. A review of 223 patients with a near-even mix of high and low-velocity injury found that the mean age of children with the neurologic deficit was higher (11.72 years) than those who were neurologically intact (8.96 years) [15].

The routine use of antiepileptics is controversial. Trauma literature supports the use of antiepileptics for the prevention of early (<7 days) post-traumatic epilepsy but not late post-traumatic epilepsy [34, 35]. Low GCS is independently associated with developing post-traumatic seizures in pediatric patients [36]. Left-sided injury is also reported to be associated with a higher likelihood of seizures [15].

Newer antiepileptics, such as levetiracetam, have not been as rigorously studied for use in this patient population despite their popularity. Additionally, there is a disparity in pediatric literature compared to adult literature regarding the routine use of antiepileptics after traumatic brain injury. It seems to be routine practice in moderate to severe penetrating head trauma to administer prophylactic antiepileptics due to the low-risk profile, though this remains at the discretion of the treating neurosurgeon and there is not enough literature support to define management standards.

Blunt traumatic brain injury has been associated with a high rate of new diagnoses of ADHD, oppositional defiant disorder, mood disorders, PTSD, OCD, bipolar disorder, and antisocial or aggressive behaviors. Although perhaps of less importance in the acute period, penetrating head trauma, particularly to the frontal lobe, may cause devastating neuropsychiatric sequelae in children. Neuropsychiatric evaluation and referral to child psychiatry should always be considered [37].

## **4.3 Infectious**

The routine use of broad-spectrum empiric antibiotics after penetrating head trauma is common but not universally agreed upon. Complications of grossly contaminated wounds include cerebritis, intracerebral abscess, ventriculitis, and meningitis. The most common pathogens are *Staphylococcus* species and gram-negative bacteria, though anaerobic species have been reported in both pediatric and adult cases with high mortality [34, 38]. Empiric antibiotic therapy should cover for these most common pathogens. There is considerable variability in the literature as to the exact type of antibiotics and the length of therapy. Early surgical intervention and debridement <12 hours from presentation decrease the risk of subsequent infection, with watertight dural closure being one of the most significant variables related to minimizing infection [34, 39].

Pediatric series of penetrating head trauma report a higher rate of infection than adults, up to 40–50% [40]. Risk factors for infection include the foreign body being a porous material, such as wood, fragmentation of the object, cerebrospinal fluid leak, nasal or mastoid sinus involvement, and gross contamination of the entry or exit site (**Figure 3**).

Low-velocity penetrating injuries, which are more common in young patients, are more likely to be grossly contaminated with skin, hair, and bone along the projectile tract. They are also more likely to involve porous material that can fragment, further increasing the risk of infection.

While most studies recommend immediate initiation of broad-spectrum antibiotics on arrival to the emergency department, a large retrospective review of adult trauma patients in Cleveland, OH described a very low incidence of infection despite most patients only receiving one dose of Ancef [39].

#### **Figure 3.**

*Dural laceration and the cerebrospinal fluid leak should be addressed urgently in the operating room to reduce the likelihood of infection.*

### **4.4 Vascular**

Morbidity after penetrating head trauma can be significantly impacted by both immediate and delayed vascular pathology. Immediate injury to the vasculature or direct tissue injury can lead to significant blood loss, space-occupying hematoma, or cerebral ischemia, all of which may cause neurologic deficit or secondary injury due to cerebral edema and elevated intracranial pressure [41].

Traumatic intracranial pseudoaneurysms are a relatively common sequelae of both blunt and penetrating head trauma; 20% of traumatic aneurysms are related to penetrating head trauma. The most common vessels involved are the MCA, followed by the ACA and the ICA [Alvis]. The rupture risk of traumatic pseudoaneurysms resultant from penetrating injury is not well quantified, and they may grow or shrink with time. However, the presence of subarachnoid hemorrhage after penetrating head trauma has been significantly associated with mortality (**Figure 4**). At 48 hours post-injury, 17% of survivors and 68% of nonsurvivors had SAH on imaging [42]. Vascular imaging should be strongly considered for any penetrating trauma in which the object tract traverses the Sylvian fissure or any major subarachnoid space or is adjacent to vascular structures. CTA is rapid and convenient, however, may be obscured by an artifact of metallic objects and, therefore, formal angiography might be necessary. Aneurysms can form in the days following trauma or may form in a delayed fashion. Surgical or interventional treatment is recommended due to the high risk of rupture [43, 44].

Vasospasm after penetrating pediatric head trauma may be an underrecognized phenomenon contributing to preventable "secondary" brain injury by reducing cerebral perfusion. A prospective study of pediatric patients with blunt traumatic brain

#### **Figure 4.** *Subarachnoid hemorrhage is a significant predictor of mortality.*

injury demonstrated a moderately high prevalence of vasospasm on transcranial doppler (TCD), which was correlated with the severity of the injury. This study further identified post-resuscitation GCS < 8, mechanism of injury (motor vehicle accident), and fever at admission as significant predictors of subsequent development of vasospasm [45]. In adults with penetrating trauma, the incidence of vasospasm is as high as 40% and has a strong association with the presence of subarachnoid hemorrhage [46]. Vasospasm occurs in 21% of blunt moderate to severe TBI patients, and 33.5% of severe TBI patients studied with TCD. Peak onset is 2–4 days post-injury and resolves in 2–3 days [45]. Vasospasm following low-velocity penetrating trauma has also been described. Given that these injuries are less likely to be lethal and have the potential for a good outcome, prevention of secondary injury is paramount [47].

The anticipation and presumptive treatment to avoid concomitant infection are essential. Associated cerebritis, abscess, or sepsis can be additionally associated with stroke. This is an important consideration in an immunocompromised patient. Additionally, stroke-associated pneumonia (SAP) can increase morbidity and mortality following these injuries.

## **5. Conclusions**

Pediatric penetrating head trauma in civilian populations is rare. Children in these settings are more likely to be struck by low-velocity or non-missile objects than by

*Penetrating Craniocerebral Injury in Pediatric Patients DOI: http://dx.doi.org/10.5772/intechopen.106549*

firearms, which confer a higher likelihood of survival. Therefore, surgical debridement or decompression, closure of dural violations to prevent infection, and diligent medical management to prevent secondary injury are critical to maximizing recovery in this resilient patient population.

## **Author details**

Jillian Plonsker1 , Michael Brandel1 , Usman Khan1 and Michael L. Levy1,2\*

1 Department of Neurological Surgery, University of California San Diego Health, La Jolla, CA, USA

2 Pediatric Neurosurgery Division, Rady Children's Hospital, San Diego, CA, USA

\*Address all correspondence to: mlevy@rchsd.org

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Levy ML et al. Penetrating craniocerebral injury resultant from gunshot wounds: Gang-related injury in children and adolescents. Neurosurgery. 1993;**33**(6):1018-1024 discussion 1024-5

[2] Santiago-Dieppa DR et al. BB gunshot wound to the head. The Journal of Pediatrics. 2019;**210**:237

[3] Di Roio C et al. Craniocerebral injury resulting from transorbital stick penetration in children. Child's Nervous System. 2000;**16**(8):503-506 discussion 507

[4] Barlow B, Niemirska M, Gandhi RP. Ten years' experience with pediatric gunshot wounds. Journal of Pediatric Surgery. 1982;**17**(6):927-932

[5] Beaver BL et al. Characteristics of pediatric firearm fatalities. Journal of Pediatric Surgery. 1990;**25**(1):97-99 discussion 99-100

[6] Ordog GJ et al. Gunshot wounds in children under 10 years of age. A new epidemic. American Journal of Diseases of Children. 1988;**142**(6):618-622

[7] Schecter SC et al. Pediatric penetrating trauma: The epidemic continues. Journal of Trauma and Acute Care Surgery. 2012;**73**(3):721-725

[8] Bandt SK et al. Management of pediatric intracranial gunshot wounds: Predictors of favorable clinical outcome and a new proposed treatment paradigm. Journal of Neurosurgery. Pediatrics. 2012;**10**(6):511-517

[9] DeCuypere M et al. Pediatric intracranial gunshot wounds: The Memphis experience. Journal of Neurosurgery. Pediatrics. 2016;**17**(5):595-601

[10] Coughlan MD et al. Craniocerebral gunshot injuries in children. Child's Nervous System. 2003;**19**(5-6):348-352

[11] Faraji M, Ashrafzadeh F. Penetrating head injuries in children. Neurosurgery Quarterly. 2005;**15**(3):160-163

[12] Paret G et al. Pediatric craniocerebral wounds from plastic bullets: Prognostic implications, course, and outcome. The Journal of Trauma. 1996;**41**(5):859-863

[13] Wani AA et al. Missile injury to the pediatric brain in conflict zones. Journal of Neurosurgery. Pediatrics. 2011;**7**(3):276-281

[14] Domingo Z, Peter JC, de Villiers JC. Low-velocity penetrating craniocerebral injury in childhood. Pediatric Neurosurgery. 1994;**21**(1):45-49

[15] Muballe KD, Hardcastle T, Kiratu E. Neurological findings in pediatric penetrating head injury at a university teaching hospital in Durban, South Africa: A 23-year retrospective study. Journal of Neurosurgery. Pediatrics. 2016;**18**(5):550-557

[16] Irfan FB et al. Craniocerebral gunshot injuries in preschoolers. Child's Nervous System. 2010;**26**(1):61-66

[17] Ewing-Cobbs L et al. Gunshot wounds to the brain in children and adolescents: Age and neurobehavioral development. Neurosurgery. 1994;**35**(2):225-233 discussion 233

[18] Mikhael M, Frost E, Cristancho M. Perioperative Care for Pediatric Patients with Penetrating Brain Injury: A review. *Penetrating Craniocerebral Injury in Pediatric Patients DOI: http://dx.doi.org/10.5772/intechopen.106549*

Journal of Neurosurgical Anesthesiology. 2018;**30**(4):290-298

[19] Dewan MC et al. Epidemiology of global Pediatric traumatic brain injury: Qualitative review. World Neurosurgery. 2016;**91**:497-509.e1

[20] Thurman DJ. The epidemiology of traumatic brain injury in children and youths: A review of research since 1990. Journal of Child Neurology. 2016;**31**(1):20-27

[21] Hansen D, Yue JK, Winkler EA, Dhall SS, Manley GT, Tarapore PE. Pediatric firearm-related traumatic brain injury in United States trauma centers. Journal of Neurosurgery: Pediatrics PED. 2019;**24**(5):498-508

[22] Klimo P et al. Severe Pediatric head injury during the Iraq and Afghanistan conflicts. Neurosurgery. 2015;**77**(1):1-7 discussion 7

[23] Mathew P et al. Operative treatment of paediatric penetrating head injuries in southern Afghanistan. British Journal of Neurosurgery. 2013;**27**(4):489-496

[24] Paret G et al. Gunshot wounds in brains of children: Prognostic variables in mortality, course, and outcome. Journal of Neurotrauma. 1998;**15**(11):967-972

[25] Miner ME et al. The results of treatment of gunshot wounds to the brain in children. Neurosurgery. 1990;**26**(1):20-24 discussion 24-5

[26] Kelly KA, Patel PD, Salwi S, Lovvorn HN III, Naftel R. Socioeconomic health disparities in pediatric traumatic brain injury on a national level. Journal of Neurosurgery: Pediatrics. 2022;**29**(3):335-341

[27] Alvis-Miranda HR et al. Craniocerebral gunshot injuries; a review of the current literature. Bulletin of Emergency and Trauma. 2016;**4**(2):65-74

[28] Kumar R et al. Penetrating head injuries in children due to BB and pellet guns: A poorly recognized public health risk. Journal of Neurosurgery. Pediatrics. 2016;**17**(2):215-221

[29] Amirjamshidi A, Abbassioun K, Roosbeh H. Air-gun pellet injuries to the head and neck. Surgical Neurology. 1997;**47**(4):331-338

[30] Steen T et al. Intracranial injuries from dog bites in children. Pediatric Neurosurgery. 2015;**50**(4):187-195

[31] Surgical Management of Penetrating Brain Injury. The Journal of Trauma: Injury, Infection, and Critical Care. 2001;**51**(2):S16-S25

[32] Torche VE, Rojas VP, Vera FF, Vigueras A. Lesión penetrante intracraneana transorbitaria, con compromiso de seno cavernoso en paciente pediátrico. Neurocirugia. 2021

[33] Varutti R, Mosca A, Latronico N. Non-visible penetrating brain trauma: A case report. Journal of Emergency Practice and Trauma. 2020;**6**(1):50-52

[34] Drosos E et al. Pediatric nonmissile penetrating head injury: Case series and literature review. World Neurosurgery. 2018;**110**:193-205

[35] Aarabi B et al. Antiseizure prophylaxis for penetrating brain injury (vol 51, pg S41, 2001). Journal of Trauma and Acute Care Surgery. 2017;**83**(6):1218-1218

[36] Lewis RJ et al. Clinical predictors of post-traumatic seizures in children with head trauma. Annals of Emergency Medicine. 1993;**22**(7):1114-1118

[37] Badhiwala JH, Blackham JR, Bhardwaj RD. Neuropsychiatric changes following penetrating head injury in children. Surgical Neurology International. 2014;**5**:154-154

[38] Kazim SF et al. Management of penetrating brain injury. Journal of Emergencies, Trauma, and Shock. 2011;**4**(3):395-402

[39] Marut D et al. Evaluation of prophylactic antibiotics in penetrating brain injuries at an academic level 1 trauma center. Clinical Neurology and Neurosurgery. 2020;**193**:105777

[40] Heiferman DM, Hayward DM, Ashley WW Jr. Bilateral through-andthrough trajectory of a low-velocity transcranial penetrating foreign object in a twelve-month-old. Pediatric Neurosurgery. 2016;**51**(1):25-29

[41] Levy ML et al. Outcome prediction after penetrating Craniocerebral injury in a civilian population: Aggressive surgical Management in Patients with admission Glasgow coma scale scores of 3, 4, or 5. Neurosurgery. 1994;**35**(1):77-85

[42] Levy ML et al. The significance of subarachnoid Hemorrhage after penetrating Craniocerebral injury: Correlations with angiography and outcome in a civilian population. Neurosurgery. 1993;**32**(4):532-540

[43] Diaz A et al. Trauma-induced arterial aneurysm in childhood. Report of a case and review of the literature. Neurochirurgie. 1998;**44**(1):46-49

[44] Levy ML. Economic, ethical, and outcome-based decisions regarding aggressive surgical Management in Patients with Penetrating Craniocerebral Injury. Journal of Health Communication. 1996;**1**(3):301-308

[45] O'Brien NF, Maa T, Yeates KO. The epidemiology of vasospasm in children with moderate-to-severe traumatic brain injury\*. Critical Care Medicine. 2015;**43**(3):674-685

[46] Kordestani RK et al. Cerebral arterial spasm after penetrating craniocerebral gunshot wounds: Transcranial Doppler and cerebral blood flow findings. Neurosurgery. 1997;**41**(2):351-359 discussion 359-360

[47] Almojuela A et al. Vasospasm following low-velocity penetrating pediatric intracranial trauma. Journal of Medical Case Reports. 2022;**16**(1):48

## **Chapter 5**

## Traumatic Optic Neuropathy

*Ainat Klein and Wahbi Wahbi*

## **Abstract**

Traumatic optic neuropathy (TON) is a specific neurological sequence of traumatic brain injury (TBI). It has a different mechanism than other most neurologic complications of head trauma and its consequences can be devastating. The damage can be from direct penetrating trauma or bone fracture injuring the optic nerve directly or secondary to indirect blunt trauma (usually causing traction). The diagnosis of TON is based on the clinical history and examination findings indicative of optic neuropathy, especially the presence of defective pupillary light response. TON can cause only mild vision loss but, in some cases, severe vision loss is present. Imaging findings can support the diagnosis, and provide information on the mechanism as well as treatment options. The treatment options include observation alone, systemic steroids, erythropoietin, surgical decompression of the optic canal, or combination. The evidence base for these various treatment options is controversial and each treatment has its side effects and risks. Poor prognostic factors include poor visual acuity at presentation, loss of consciousness, no improvement in vision in the first 48 hours, and evidence of optic canal fractures on neuroimaging.

**Keywords:** trauma, optic neuropathy, vision loss, steroids, erythropoietin

## **1. Introduction**

Traumatic optic neuropathy (TON) is an acute injury of the optic nerve secondary to blunt or penetrating head injuries, in which dysfunction of the optic nerve, vision impairment, is caused secondary to direct or indirect trauma to the nerve. Traumatic optic neuropathy can be isolated but usually, it is part of more widespread head trauma. Historic studies report an incidence of 0.5–2% of head injuries [1, 2]. A recent national epidemiological survey of TON in the UK found a minimum prevalence in the general population of 1 in 1,000,000 [3].

TON might be present after vehicle accidents (car and bicycle), falls from heights, falling debris, assault, stab, and gunshot wounds (**Figure 1**). Iatrogenic injuries are also reported (mainly secondary to endoscopic sinus surgeries or suprasellar neurosurgeries) [3]. It is important to note that all patients with TON have head injuries and 66% of them have a significant head injury [4]. TON can be present after apparently otherwise mild injuries, but it is most common in the setting of craniofacial fractures [5].

The vast majority of affected patients are young males (79–85%) in their early thirties. Children constitute a large portion as about 20% of patients are younger than 18 years [6]. In this age group, falls (50%) and motor vehicle accidents (40%) are the most common causes of TON.

TON is classified as direct when the nerve is injured directly by a projectile object that penetrates the orbit to damage the optic nerve, or indirect injury when it results from the non-penetrating effects of trauma.

The mechanism of TON is multifactorial. In the case of direct TON damage is caused directly to the nerve by laceration or impingement of the nerve from various causes, including penetrating a foreign body, displaced bone fragment, or optic canal fracture (**Figure 1**). In indirect trauma, compression forces from the superior orbital rim are transferred and concentrated in the orbital roof and optic canal, where the nerve is most vulnerable since it is fixed within the bony optic canal; Coup-contrecoup forces whip mobile portions of the optic nerve against fixed structures, causing injury [7, 8]. Shearing injury to the axons and microvasculature can also play a role, leading to necrosis [9, 10]. Violent rotation of the globe can also result in partial or complete optic nerve avulsion (**Figure 2**) [11]. Depending on the nature of the event, the shock wave can also fracture the optic canal and bone fragments can impinge on the nerve, [8] (occasionally being referred to as direct injury). Diffuse axonal injury is another mechanism that is thought to be involved in TON. As previously reported [12, 13], following head injury, axons of the brain white matter are deformed, swelling, cytoskeleton damage, and impaired axoplasmic transmission led to the disconnection of axons, regression, reorganization, and degeneration.

Orbital compartment syndrome (OCS), in which acute severe bleeding is maintained within the orbit, is another specific subgroup of TON. The orbit is a confined, cone-shaped space, which is bound on all sides by bony walls, except anteriorly, where it is limited by the orbital septum and tarsal plates of the upper and lower eyelid. These structures have limited elasticity and thereby the orbit has limited compliance. Any increase in the orbital content, secondary to bleeding blood vessels, or trapped air, will result in an increase in intra-orbital pressure [14]. Besides

#### **Figure 1.**

*A 37-year-old female was admitted after gunshot wounds. Upon admission, she was intubated and unconscious. She had multi-compartment hemorrhages, parenchymal, subdural, and subarachnoid and secondary mass effect with midline displacement to the left (not shown). In plain radiograph (A) two metallic foreign bodies were seen. The bottom one is in the right maxillary sinus, with hyperdense small fragments in its track. The second one is adjacent to the right orbital apex. Lateral orbital wall fractures, as well as apical fractures, were noted (B + C). On the first ophthalmologic evaluation, she had pinpoint pupils (secondary to sedative agents) but still, a right RAPD was documented. It was not possible to have dilated fundus exam (DFE). She had no signs of orbital compartment syndrome (no proptosis, free eye movements, and normal intraocular pressure). Multidisciplinary consultation of neurosurgeon, oculoplastic surgeon and ENT, concluded that any surgical intervention aimed to remove the apical foreign body will have a high risk of bleeding and life-threatening complications—It was decided on conservative follow up. Endoscopic sinus surgery was done, removing the maxillary sinus foreign body. Upon regaining consciousness, the patient was evaluated again and had a vision of 20/30 and nonspecific visual field defects. DFE was unremarkable. On her 2 months follow-up, there was no RAPD, and vision improved to 20/20 with no visual field defects.*

#### **Figure 2.**

*A 39-year-old male suffered from severe trauma from a surfboard. On first evaluation, he had lacerations of the inferior and superior eyelids with limited eye movements in elevation, suppression and adduction. He had a dilated unresponsive pupil on the left and a vision of NLP in his left eye with RAPD+4. DFE revealed vitreous hemorrhage, and the optic nerve could not be identified in the posterior pole. Besides medial and inferior orbital wall fractures with down displacement into the maxillary sinus (B), the intraconal orbital fat appeared infiltrated and the left optic nerve was thickened and irregular in its course (A). Discontinuity of the posterior aspect of the globe, adjacent to the optic nerve head was noted. A diagnosis of optic nerve avulsion was made, and it was unfortunately impossible to regain vision in this case. Attempts were made to reconstruct the orbit by suturing the lacerations involving the medial cantal folds with excellent cosmetic results, which were important for a young patient.*

the possibility of direct compressing on the nerve, it results in disturbing the orbital blood flow and thereby causes acute ischemic damage to the nerve [14, 15].

Post-injury, biochemical cascades exacerbate the initial damage and different treatment modalities are intended to limit this secondary injury. Most cases of visual loss are immediate; however, delayed visual loss is documented in 10% of cases.

## **2. Diagnosis**

Since TON can develop even due to minor head trauma, it should be suspected if any evidence of impaired vision exists following head or facial trauma. In the conscious patient, a detailed history accounting for the mechanism of injury and previous visual status is mandatory. Visual function assessment and comprehensive eye examination should be carried out ruling out other causes of visual loss.

Clinical signs supporting the diagnosis of optic neuropathy include: 1) Impaired visual acuity: about 40–60% of patients present with only light perception vision, or worse [3, 16, 17], although, the visual acuity may range from normal to no light perception. Late deterioration of vision may occur secondary to intra-sheath hematoma and should raise again the diagnosis of TON [16]. 2) Relative afferent pupilar defect (RAPD), an asymmetrical pupillary response to light, which is a very specific sign of optic neuropathy, is very important in the assessment of TON patients; it may be the only subjective evidence at presentation in mild cases and more importantly in the unconscious patient and nonverbal children. A negative RAPD due to symmetric optic nerve injury should always be considered [2]. To note, in the settings of head trauma some patients may have dilated pupils which interferes with the pupillary examination. Alcohol, illicit drugs, narcotics, paralyzing agents, hypothermia, oculomotor nerve neuropathy, and sympathetic injury (Horner's syndrome), can all interfere with pupillary testing [18]. 3) Color vision impairment indicating optic neuropathy.

Visual field defect with variable field defects is another helpful adjunct in the diagnosis and monitoring of TON patients. Unfortunately, in the acute setting, many trauma patients are unable to cooperate and have formal computerized visual field exams.

Visual evoked potentials (VEP) are another important tool in the diagnosis of TON in unconscious and nonverbal patients, providing evidence of visual pathway status and predicting the visual outcome. Patients with better VEP amplitudes have favorable visual outcomes [19].

The optic disc appearance in the early course of TON depends on the site of injury along with the optic nerve. When the injury is anterior to the entry site of the CRA a swollen optic disc with retinal hemorrhages is expected. However, in the majority of the patients, the disc appearance is normal since most of the cases have a more posterior injury. Late in the course of TON, a clinically evident optic atrophy usually develops within 4–6 weeks following the trauma. Kanamori et al. demonstrated that RNFL thinning and RGC complex loss began 2 weeks after trauma and plateaued at 20 weeks [20].

Radiologic studies (CT and MRI) may demonstrate bony fractures, optic sheath hematoma or intra-orbital air, and bleeding (orbital compartment). CT scan with coronal reconstruction images is an excellent imaging modality for demonstrating optic canal fractures [13–15, 21–23]. Multiplayer spiral computed tomographic (MSCT) with spatial stereo reconstruction is an advanced imaging tool that can better evaluate the optic canal status and diagnose combined injuries in other craniofacial tissues [24]. Nevertheless, the role of neuroimaging in the diagnosis of TON is still controversial since the majority of TON patients do not demonstrate relevant findings and the diagnosis can be made on clinical grounds only. However, in a patient with progressive visual loss, repeated neuroimaging is crucial for identifying surgical candidates and directing the surgical treatment.

## **3. Treatment**

Currently, the most common treatments used for TON include 1) systemic steroids; 2) surgical optic nerve decompression; 3) a combination of steroids and surgical decompression. Nevertheless, the treatment of TON remains controversial as spontaneous visual improvement occurs in about 25–50% of TON patients [25, 26]. On the other hand, no medical or surgical treatment was proved until now with a clear advantage over observation only.

Systemic steroid therapy for TON has been extrapolated from the National Acute Spinal Cord Injury Study (NASCIS), a randomized controlled trial comparing steroid treatment to placebo for acute spinal injury, in which increased recovery of neurological function was seen in patients treated with methylprednisolone [27]. The rationale for their use in the treatment of TON is their anti-inflammatory and anti-oxidative effect. Typically, a regimen of very high (megadose) intravenous methylprednisolone is used to treat TON followed by oral steroid with tapering down. The International Optic Nerve Trauma Study (IONTS) is the largest comparative study comparing systemic steroids to surgical decompression and observation using different dosing and timing regimens failed to show any significant difference between the three groups [16]. In addition, there was no clear benefit for any timing or dosage regimen of corticosteroids on the final visual outcome. Lai et al. analyzed the risk factors for visual outcome in a small series of 20 TON patients with initial visual acuity of NLP and found that patients treated with methylprednisolone less than 24 hours from the injury showed better final visual acuity [28]. In another series, Sitaula et al. compared observation to oral prednisone (1 mg/kg for 7 days with 6 weeks taper) and high-dose intravenous

#### *Traumatic Optic Neuropathy DOI: http://dx.doi.org/10.5772/intechopen.104731*

methylprednisolone (1 g/d for 3 days followed by oral prednisone taper) found significant visual improvement in the high-dose group compared to the other two groups [29].

Other authors compared different regimes of steroids to observation only did not find any significant difference between their study groups [30–34]. Accounting for their side effects, in the lack of clear effects on visual recovery, steroids should be used judiciously by clinicians. Moreover, a large percentage of TON patients have a concomitant head injury; the CRASH study tested the effectiveness of corticosteroids following acute head injury was terminated prematurely due to an increased mortality rate in patients treated with steroids [35].

## **3.1 Systemic steroids**

Surgical treatment for TON aims to reduce compression on the optic nerve exerted by edema, hematoma, or bony fragments. Currently, the main surgical approaches performed are medial transorbital external ethmoidectomy; transcranial surgery; and endoscopic transnasal surgery [36–38]. The transorbital ethmoidectomy and transcranial approach provide excellent surgical access to the optic canal, however, both are abandoned by many surgeons due to the high rate of complications and undesired cosmetic results. The endoscopic transnasal approach is more commonly used by surgeons. It provides adequate exposure for the medial bony wall of the optic canal through the sphenoid sinus with a less invasive procedure and more acceptable cosmetic results. However, it is a high-risk procedure due to the proximity of the internal carotid artery to the optic canal; and it should be done only by highly experienced surgeons in this kind of surgery. Several studies reporting the results of surgical decompression with or without steroids had been published in the literature with visual improvement rates ranging from 18–81% [39–46]. Since primary reports failed to show obvious benefits for surgical decompression over observation, efforts are still made by researchers to optimize the visual outcomes following surgery. Reasonably, the authors presented the following indications for surgical treatment [23, 42–47]: 1) history of traumatic head or face injury; 2) presence of hematoma or bony fragments compressing the optic verve; 3) poor response to initial medical therapy; 4) progressive visual loss not explained by other nontraumatic ocular pathology; 5) lack of evident damage to ocular tissue or intracranial optic nerve; 6) prolonger latency or reduction of amplitude in preoperative VEP scan. The optimal timing for surgery has been evaluated by several authors based on their own experiences. While some authors reported better visual outcomes in the early surgical intervention (<3 days) [48–50], others reported comparable visual improvement in the late surgical intervention (>7 days) [51]. Yu et al. compared immediate (within 3 days) to delayed (>3 days) optic canal decompression, and found that 73.5% of patients in the immediate surgical decompression group showed improved vision versus 46.9% in the delayed group [36]. Even though, the benefit of surgical decompression or the combination of surgical and medical treatment remains uncertain due to the lack of large comparative controlled studies. Moreover, several surgical complications, including CSF leak, infection, and bleeding, have been reported [37, 52–54]. Therefore, in the lack of clear evidence, the potential benefits and drawbacks of surgical treatment should be discussed in detail with the patient before surgery.

## **3.2 Surgical treatment**

In cases suspected of OCS, the examination must be performed as soon as possible, so as not to delay treatment. The conscious patient will complain about severe pain and vision loss. The patient will usually have marked eyelid swelling, proptosis, chemosis, and even subconjunctival hemorrhage. Severe ophthalmoplegia will be noted and even digital ocular palpation will demonstrate resistance to retropulsion and a firm globe indicating an elevated IOP. CT may be helpful in establishing the diagnosis in milder cases where there is uncertainty and vision remains intact, but when the clinical findings are suggestive and vision is markedly impaired, treatment should not be postponed until after imaging is performed. In cases of OCS urgent surgical decompression is the mainstay of treatment. A bedside, lateral canthotomy and cantholysis (LC/C) is the first-line approach for reducing intra-orbital pressure [55]. Bony orbital decompression can be considered an adjuvant procedure if an adequate response is not achieved after LC/C [56]. In these cases, reviewing orbital imaging is important to locate the hematoma or other causative pathology (air, abscess), and to plane the surgical approach (endonasal medial wall decompression, anterior orbitotomy via an eyelid crease incision, or transcranial approach) [14].

## **3.3 Erythropoietin**

In the last few years, erythropoietin was suggested as a potential treatment for TON due to its anti-inflammatory and antiapoptotic effects, based on studies of CNS trauma patients [57]. Primary studies reported better visual outcomes with EPO treatment [58, 59]. Recently, the TONTT, a phase 3, a large comparative study compared erythropoietin to steroids and observation in 100 TON patients [60]. All three study groups demonstrated significant visual improvement compared to the baseline BCVA. However, no significant difference was found between the study groups. Of note, color vision improvement was also observed in all three study groups even though it was significant only in the erythropoietin group.

### **3.4 Experimental treatments**

In the last two decades, research is ongoing to develop new therapies aiming to encourage neuroprotection and axonal regeneration. Stem cell transplantation is gaining more progress in the treatment of optic nerve damage due to their multidirectional differentiation. In a mice model, stem cells transplanted in the subretinal space differentiated into photoreceptor and retinal cells [61].

Recently, a prospective single-center prospective phase 1 study, investigated mesenchymal stem cell (MSC) transplantation in 20 patients with traumatic optic neuropathy. Optic canal decompression with mesenchymal stem cell implantation compared to optic canal decompression alone. Both groups showed significant improvements in vision compared with the baseline; however, there was no statistically significant difference between the study groups [62].

Investigations on other potential therapies, including anti-TNF, brain-derived neurotrophic factor (BDNF), and RNA, aiming to reduce retinal ganglion cell loss and encouraging axonal regeneration are in progress [63–65].

Currently, no standard of care therapy exists in addressing TON.

## **4. Prognosis**

Spontaneous visual recovery of about 40–60% has been reported in TON patients treated conservatively [9]. The final visual acuity following TON has a wide range

### *Traumatic Optic Neuropathy DOI: http://dx.doi.org/10.5772/intechopen.104731*

from 20/20 to NLP [28, 29]. The baseline visual acuity is the most important prognostic factor for recovery since it reflects the degree of damage to the optic nerve. Patients with better visual function are presumed to have more functioning retinal ganglion cells, while patients with no residual vision and poor visual acuity at a presentation associated have less functioning retinal ganglion cells. Hence, better visual acuity at presentation predicts a better final visual outcome, on the contrary, patients with no residual vision (NLP) have lower final visual outcomes.

According to some reports, patients who present with NLP are unlikely to improve at all [29, 66–68], while other reports indicated some rate of improvement even in a patient with no residual vision at presentation [66]. In patients with residual vision, those with lower visual acuity at presentation sometimes show more visual improvement rates [68–70]. Other negative prognostic factors presented by different authors include lack of improvement within the first 48 hours, optic canal fracture, absence of VEP responses, loss of consciousness, higher degrees of RAPD, age over 40 years, intra-sheath hematoma, and blood within the posterior ethmoidal cells [19, 71–73].

In cases of OCS, if treated within 2 hours, most patients will achieve a final visual acuity better than 20/40, though approximately 15% will be worse. Patients treated after 2 hours have poorer reported outcomes. In the case of delayed presentation, considering orbital decompression is still reasonable since there are reports of visual recovery even after delayed intervention and even with no decompression at all [74].

It is important to emphasize that recovery of vision after any kind of treatment modality mentioned, is not always immediate. There may be an ongoing improvement in VA for a few weeks post-intervention. Furthermore, most reports published provide a limited follow-up period and it is reasonable to deduce that long-term follow-up may show better outcomes. It should also be noted that even in cases of good VA acuity, some patients suffer from severe visual field defects.

## **Author details**

Ainat Klein\* and Wahbi Wahbi Department of Ophthalmology, Tel Aviv Suaraski Medical Center, Tel Aviv University, Tel Aviv, Israel

\*Address all correspondence to: kleinainat@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Steinsapir KD, Goldberg RA. Traumatic optic neuropathy. Survey of Ophthalmology. 1994;**38**:487-518

[2] Cockerham GC, Goodrich GL, Weichel LED, et al. Eye and visual function in traumatic brain injury. The Journal of Rehabilitation Research and Development. 2009;**46**(6):811-818

[3] Lee V, Ford RL, Xing W, Bunce C, Foot B. Surveillance of traumatic optic neuropathy in the UK. Eye (London, England). 2010;**24**(2):240-250

[4] Pirouzmand F. Epidemiological trends of traumatic optic nerve injuries in the largest Canadian adult trauma center. Journal of Craniofacial Surgery. 2012;**23**(2):516-520

[5] Jamal BT, Pfahler SM, Lane KA, et al. Ophthalmic injuries in patients with zygomaticomaxillary complex fractures requiring surgical repair. Journal of Oral and Maxillofacial Surgery. 2009;**67**:986-989

[6] Goldenberg-Cohen N, Miller NR, Repka MX. Traumatic optic neuropathy in children and adolescents. Journal of American Association for Pediatric Ophthalmology and Strabismus. 2004;**8**:20-27

[7] Gross CE, Dekock JR, Panje WR, Hershkowitz N, Newman J. Evidence for orbital deformation that may contribute to monocular blindness following minor frontal head trauma. Journal of Neurosurgery. 1981;**55**:963-966

[8] Crompton MR. Visual lesions in closed head injury. Brain. 1970;**93**:785-792

[9] Walsh FB, Hoyt WF. Clinical Neuro-Ophthalmology. 3rd ed. Vol. 3. Baltimore: Williams & Wilkins; 1969. p. 2380

[10] Thale A, Jungmann K, Paulsen F. Morphological studies of the optic canal. Orbit. 2002;**21**(2):131-137

[11] Foster BS, March GA, Lucarelli MJ, Samiy N, Lessell S. Optic nerve avulsion. Archives of Ophthalmology. 1997;**115**(5):623-630

[12] Smith DH, Meaney DF. Axonal damage in traumatic brain injury. The Neuroscientist. 2000;**6**(6):483-495

[13] Wang J, Hamm RJ, Povlishock JT. Traumatic axonal injury in the optic nerve: Evidence for axonal swelling, disconnection, dieback, and reorganization. Journal of Neurotrauma. 2011;**28**(7):1185-1198

[14] McCallum E, Keren S, Lapira M, Norris JH. Orbital compartment syndrome: An update with review of the literature. Clinical Ophthalmology. 2019;**13**:2189-2194

[15] Hargaden M, Goldberg SH, Cunningham D, Breton ME, Griffith JW, Lang CM. Optic neuropathy following simulation of orbital hemorrhage in the nonhuman primate. Ophthalmic Plastic and Reconstructive Surgery. 1996;**12**(4):264-272

[16] Levin LA, Beck RW, Joseph MP, Seiff S, Kraker R. The treatment of traumatic optic neuropathy — The international optic nerve trauma study. Ophthalmology. 1999;**106**:1268

[17] Lessell S. Indirect optic-nerve trauma. Archives of Ophthalmology. 1989;**107**:382-386

[18] Meyer S, Gibb T, Jurkovich GJ. Evaluation and significance of the pupillary light reflex in trauma patients. *Traumatic Optic Neuropathy DOI: http://dx.doi.org/10.5772/intechopen.104731*

Annals of Emergency Medicine. 1993;**22**(6):1052-1057

[19] Tabatabaei SA, Soleimani M, Alizadeh M, et al. Predictive value of visual evoked potentials, relative afferent pupillary defect, and orbital fractures in patients with traumatic optic neuropathy. Clinical Ophthalmology. 2011;**5**:1021-1026

[20] Kanamori A, Nakamura M, Yamada Y, Negi A. Longitudinal study of retinal nerve Fiber layer thickness and ganglion cell complex in traumatic optic neuropathy. Archives of Ophthalmology. 2012;**130**(8):1067-1069

[21] Guyon JJ, Brant-Zawadzki M, Seiff SR. CT demonstration of optic canal fractures. AJR. 1984;**143**:1031-1103

[22] Ibanez L, Navallas M, de Caceres IA, Martinez-Chamorro E, Borruel S. CT features of posttraumatic vision loss. AJR. American Journal of Roentgenology. 2021;**217**(2):469-479

[23] Manfredi SJ, Raji MR, Sprinkle PM, Weinstein GW, Minardi LM, Swanson TJ. Computerized tomographic scan findings in facial fractures associated with blindness. Plastic and Reconstructive Surgery. 1981;**68**(4):479-490

[24] Yang Q, Li Y, Zou Y, et al. Computerassisted three-dimensional reconstruction and spatial stereotaxis study of optic canal with multiplayer spiral computed tomographic. Neurosurgical Review. 2008;**22**:306-308 311

[25] Wang BH, Robertson BC, Girotto JA, et al. Traumatic optic neuropathy: A review of 61 patients. Plastic and Reconstructive Surgery. 2001;**107**(7):1655-1664

[26] Jang SY. Traumatic optic neuropathy. Korean Journal of Neurotrauma. 2018;**14**(1):1-5

[27] Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the second national acute spinal cord injury study. The New England Journal of Medicine. 1990;**322**(20):1405-1411

[28] Lai IL, Liao HT, Chen CT. Risk factors analysis for the outcome of indirect traumatic optic neuropathy with steroid pulse therapy. Annals of Plastic Surgery. 2016;**76**(Suppl 1):6

[29] Sitaula S, Dahal HN, Sharma AK. Clinical evaluation and treatment outcome of traumatic optic neuropathy in Nepal: A retrospective case series. Neuro-Ophthalmology. 2017;**42**(1):17-24

[30] Carta A, Ferrigno L, Leaci R, et al. Long-term outcome after conservative treatment of indirect traumatic optic neuropathy. European Journal of Ophthalmology. 2006;**16**:847-850

[31] Lee KF, Muhd Nor NI, Yaakub A, Wan Hitam W. Traumatic optic neuropathy: A review of 24 patients. International Journal of Ophthalmology. 2010;**3**:175-178

[32] Entezari M, Rajavi Z, Sedighi N, et al. High-dose intravenous methylprednisolone in recent traumatic optic neuropathy: A randomized double-masked placebocontrolled clinical trial. Graefe's Archive for Clinical and Experimental Ophthalmology. 2007;**245**:1267-1271

[33] Yu-Wai-Man P, Griffiths PG. Steroids for traumatic optic neuropathy. Cochrane Database of Systematic Reviews. 2013;**6**:CD006032

[34] Chaon BC, Lee MS. Is there treatment for traumatic optic neuropathy? Current Opinion in Ophthalmology. 2015;**26**(6):445-449 [35] CRASH Trial Collaborators. Final results of MRC CRASH, a rFandomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet. 2005;**365**(9475):1957-1959

[36] Yu B, Ma Y, Tu Y, Wu W. The outcome of endoscopic transethmosphenoid optic canal decompression for indirect traumatic optic neuropathy with no-lightperception. Journal of Ophthalmology. 2016;**2016**:6492858

[37] Yan W, Chen Y, Qian Z, et al. Incidence of optic canal fracture in the traumatic optic neuropathy and its effect on the visual outcome. The British Journal of Ophthalmology. 2017;**101**:261-267

[38] Chen HH, Lee MC, Tsai CH, et al. Surgical decompression or corticosteroid treatment of indirect traumatic optic neuropathy: A randomized controlled trial. Annals of Plastic Surgery. 2020;**84**:S80-S83

[39] Chen M, Jiang Y, Pang WH, et al. A 212 cases analysis of treatment for traumatic optic europathy by nasal endoscopic optic nerve decompression. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2017;**31**:1411-1414

[40] Gupta AK, Gupta AK, Gupta A, et al. Traumatic optic neuropathy in pediatric population: Early intervention or delayed intervention? International Journal of Pediatric Otorhinolaryngology. 2007;**71**:559-562

[41] Peng A, Li Y, Hu P, et al. Endoscopic optic nerve decompression for traumatic optic neuropathy in children. International Journal of Pediatric Otorhinolaryngology. 2011;**75**:992-998

[42] Sun J, Cai X, Zou W, et al. Outcome of endoscopic optic nerve decompression for traumatic optic neuropathy. The Annals of Otology, Rhinology, and Laryngology. 2021;**130**:56-59

[43] Wladis EJ, Aakalu VK, Sobel RK, et al. Interventions for indirect traumatic optic neuropathy: A report by the American Academy of ophthalmology. Ophthalmology. 2021;**128**(6):928-937

[44] Yang QT, Zhang GH, Liu X, Ye J, Li Y. The therapeutic efficacy of endoscopic optic nerve decompression and its effects on the prognoses of 96 cases of traumatic optic neuropathy. Journal of Trauma and Acute Care Surgery. 2012;**72**:1350-1355

[45] Oh H-J, Yeo D-G, Hwang S-C. Surgical treatment for traumatic optic neuropathy. Korean Journal of Neurotrauma. 2018;**14**(2):55-60

[46] Gupta D, Gadodia M. Transnasal endoscopic optic nerve decompression in post traumatic optic neuropathy. Indian Journal of Otolaryngology and Head & Neck Surgery. 2018;**70**:49-52

[47] Otani N, Wada K, Fujii K, Toyooka T, Kumagai K, Ueno H, et al. Usefulness of extradural optic nerve decompression via trans-superior orbital fissure approach for treatment of traumatic optic nerve injury: Surgical procedures and techniques from experience with 8 consecutive patients. World Neurosurgery. 2016;**90**:357-363

[48] Emanuelli E, Bignami M, Digilio E, Fusetti S, Volo T, Castelnuovo P. Posttraumatic optic neuropathy: Our surgical and medical protocol. European Archives of Oto-Rhino-Laryngology. 2015;**272**(11):3301-3309

[49] Wohlrab TM, Maas S, de Carpentier JP. Surgical decompression in traumatic optic neuropathy. Acta Ophthalmologica Scandinavica. 2002;**80**:287-293

*Traumatic Optic Neuropathy DOI: http://dx.doi.org/10.5772/intechopen.104731*

[50] Martinez-Perez R, Albonette-Felicio T, Hardesty DA, et al. Outcome of the surgical decompression for traumatic optic neuropathy: A systematic review and meta-analysis. Neurosurgical Review. Apr 2021;**44**(2):633-641

[51] Dhaliwal SS, Sowerby LJ, Rotenberg BW. Timing of endoscopic surgical decompression in traumatic optic neuropathy: A systematic review of the literature. International Forum of Allergy & Rhinology. 2016;**6**:661-667

[52] He Z, Li Q, Yuan J, et al. Evaluation of transcranial surgical decompression of the optic canal as a treatment option for traumatic optic neuropathy. Clinical Neurology and Neurosurgery. 2015;**134**:130-135

[53] Li H, Zhou B, Shi J, et al. Treatment of traumatic optic neuropathy: Our experience of endoscopic optic nerve decompression. The Journal of Laryngology and Otology. 2008;**122**:1325-1329

[54] Li HB, Shi JB, Cheng L, et al. Salvage optic nerve decompression for traumatic blindness under nasal endoscopy: Risk and benefit analysis. Clinical Otolaryngology. 2007;**32**:447-451

[55] Haubner F, Jägle H, Nunes DP, et al. Orbital compartment: Effects of emergent canthotomy and cantholysis. European Archives of Oto-Rhino-Laryngology. 2015;**272**(2):479-483

[56] Lee KYC, Tow S, Fong K-S. Visual recovery following emergent orbital decompression in traumatic retrobulbar haemorrhage. Annals of the Academy of Medicine, Singapore. 2006;**35**(11):831-832

[57] Ghezzi P, Brines M. Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death and Differentiation. 2004;**11**(Suppl 1):S37-S44

[58] Kashkouli MB, Pakdel F, Sanjari MS et al.) Erythropoietin: A novel treatment for traumatic optic neuropathy—A pilot study: Graefe's Archive for Clinical and Experimental Ophthalmology 2011;**249**(5):731-736

[59] Entezari M, Esmaeili M, Yaseri M. A pilot study of the effect of intravenous erythropoetin on improvement of visual function in patients with recent indirect traumatic optic neuropathy. Graefe's Archive for Clinical and Experimental Ophthalmology. 2014;**252**(8): 1309-1313

[60] Kashkouli MB, Yousefi S, Nojomi M, et al. Traumatic optic neuropathy treatment trial (TONTT): Open label, phase 3, multicenter, semi-experimental trial. Graefe's Archive for Clinical and Experimental Ophthalmology. 2018;**256**:209-218

[61] Feng X, Chen P, Zhao X, et al. Transplanted embryonic retinal stem cells have the potential to repair the injured retina in mice. BMC Ophthalmology. 2021;**21**:26

[62] Li J, Bai X, Guan X, Yuan H, Xu X. Treatment of Optic Canal decompression combined with umbilical cord mesenchymal stem (stromal) cells for indirect traumatic optic neuropathy: A phase 1 clinical trial. Ophthalmic Research. 2021;**64**(3):398-404

[63] Tse BC, Dvoriantchikova G, Tao W, et al. Tumor necrosis factor inhibition in the acute management of traumatic optic neuropathy. Investigative Ophthalmology & Visual Science. 2018;**59**:2905-2912

[64] Cui Q, So KF, Yip HK. Major biological effects of neurotrophic factors on retinal ganglion cells in mammals. Biological Signals and Receptors. 1998;**7**:220-226

[65] Park KK, Liu K, Hu Y, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science. 2008;**322**:963-966

[66] Yu B, Chen Y, Ma Y, Tu Y, Wu W. Outcome of endoscopic transethmosphenoid optic canal decompression for indirect traumatic optic neuropathy in children. BMC Ophthalmology. 2008;**18**(1):152

[67] Steinsapir KD. Treatment of traumatic optic neuropathy with highdose corticosteroid. Journal of Neuro-Ophthalmology. 2006;**26**:65-67

[68] Yang WG, Chen CT, Tsay PK, de Villa GH, Tsai YJ, Chen YR. Outcome for traumatic optic neuropathy- surgical versus nonsurgical treatment. Annals of Plastic Surgery. 2004;**52**(1):36-42

[69] Ma YJ, Yu B, Tu YH, et al. Prognostic factors of transethmosphenoid optic canal decompression for indirect traumatic optic neuropathy. International Journal of Ophthalmology. 2018;**11**:1222-1226

[70] Song Y, Li H, Ma Y, et al. Analysis of prognostic factors of endoscopic optic nerve decompression in traumatic blindness. Acta Oto-Laryngologica. 2013;**133**:1196-1200

[71] Holmes Mark D, Sires Bryan S. Flash visual evoked potentials predict visual outcome in traumatic optic neuropathy. Ophthalmic Plastic & Reconstructive Surgery. 2004;**20**(5):342-346

[72] Mohammed MA, Mossallam E, Allam IY. The role of the flash visual evoked potential in evaluating visual function in patients with indirect traumatic optic neuropathy. Clinical

Ophthalmology. 2021;**30**(15): 1349-1355

[73] Carta A, Ferrigno L, Salvo M, Bianchi-Marzoli S, Boschi A, Carta F. Visual prognosis after indirect traumatic optic neuropathy. Journal of Neurology, Neurosurgery, and Psychiatry. 2003;**74**:246-248

[74] Ujam A, Perry M. Emergency management for orbital compartment syndrome-is decompression mandatory? International Journal of Oral and Maxillofacial Surgery. 2016;**45**(11):1435-1437

## **Chapter 6**

## Traumatic Injury of the Carotid and Vertebral Arteries and their Neurointerventional Treatment

*Huachen Zhang, Hanrui Xu, Shikai Liang and Xianli Lv*

## **Abstract**

Traumatic injuries of the carotid and vertebral arteries include direct carotid-cavernous fistula, intracranial pseudoaneurysm and arterial dissection, which cause a series of symptoms and may be life threatening. Computed tomographic angiography is the most common modality for initial screening and diagnosis. The subsequent management of any identified vessel injury, however, is not clearly defined. With the development of neurointerventional materials and technology, endovascular therapy is playing an important role in treatment of these neurovascular injuries. Balloon, coil, liquid embolic materials, covered stent and flow diversion have been effectively used in clinical practice. This chapter reviews the epidemiology, injury mechanism, clinical manifestations, classification system, diagnostic imaging and endovascular treatment of traumatic neurovascular injuries.

**Keywords:** carotid artery, vertebral artery, neurointerventional treatment, trauma, vascular injury

## **1. Introduction**

Distribution of traumatic neurovascular injuries by location was 42% intracranial, 39% cervical, and 19% extracranial [1]. For the early recognition of lesions in different locations, imaging and clinical manifestations are the key to diagnosis. With regard to the treatment of these traumatic neurovascular diseases, the paradigm of treatment has shift from the destructive modality of carotid artery ligation or trapping to reconstructive modality of neurointerventional treatment. Endovascular treatment has been the first line treatment for traumatic injuries of the carotid and vertebral arteries including direct carotid-cavernous fistula, intracranial pseudoaneurysm and arterial dissection [1].

## **2. Traumatic carotid-cavernous fistula**

Traumatic carotid-cavernous fistula (TCCF) represents abnormal vascular communications in the skull base between the carotid artery system and the adjacent cavernous sinus [2]. TCCF is the most common type of CCF [3, 4]. Within the

#### **Figure 1.**

*A woman presented a traumatic CCF treated with detachable coils. A: Lateral view of the left internal carotid artery angiogram showing a direct CCF of Zipfel's type II with ophthalmic vein reflux (arrow). B: Lateral view of the left internal carotid artery angiogram showing complete obliteration of the CCF after coil embolization (arrow).*

cavernous sinus, the internal carotid artery (ICA) is bound by strong dural filaments and attachments, especially at its entrance and exit by its inferior and superior ascending segments [5]. Trauma can cause an intima-to-adventitia tearing in the ICA, leading to high-flow shunt between the cavernous sinus portion of the ICA and the cavernous sinus (**Figure 1**) [6]. TCCF also can be caused by iatrogenic injury from neurointerventional therapy, percutaneous treatment of trigeminal neuralgia, or transsphenoidal resection of pituitary tumor [6]. Endovascular recanalization of symptomatic chronic internal carotid artery occlusion (ICAOS) may cause CCF, because during the operation there may be severe ICA dissection with intimal inlet at the proximal end of ICA and adventitial outlet in ICA [6, 7]. In 1985, Barrow and his colleagues developed the classification system after extensive angiographic studies (**Table 1**) [8]. TCCF is of type A in Barrow's classification system. A recent grading system of dural arteriovenous fistulas (DAVFs) was proposed by Zipfel GJ from Washington University in 2009 covering CCFs (**Table 2**) [9]. The Zipfel's classification can stratify clinical status of cerebral and spinal DAVFs according to understanding of natural history in order to guide the appropriate evaluation and therapies of lesions [10].

The clinical manifestations of TCCF are mainly related to venous hypertension or venous rupture. The venous drainage from the cavernous sinus to the superior and inferior ophthalmic veins causes prominent ocular symptoms, such as progressive pulsatile exophthalmos, conjunctival congestion or edema, in 90% patients [5]. In up to 50% patients, visual loss may result from decreased ocular or retinal perfusion and


#### **Table 1.**

*The classification system of CCF introduced by Barrow and his colleagues [8].*

*Traumatic Injury of the Carotid and Vertebral Arteries and their Neurointerventional Treatment DOI: http://dx.doi.org/10.5772/intechopen.108588*


**Table 2.**

*The classification system of dural arteriovenous fistulas (DAVFs) introduced by Zipfel et al. in 2009 [9].*

papilledema because of venous stasis [11]. Cranial nerve dysfunction in III, IV, VI can cause diplopia [11]. Intracranial pulsatile tinnitus was obvious in patients with inferior petrosal sinus. The increased venous pressure caused by cortical venous drainage leads to venous rupture and bleeding.

## **3. Traumatic neurovascular Pseudoaneurysm**

Neurovascular pseudoaneurysm formation is the result of partial to complete disruption of the cerebral arterial wall, which ultimately leads to hematoma that is contained by the adventitia of the vessel wall or the perivascular soft tissues [12].

#### **Figure 2.**

*A 59-year-old woman presented decreased vision in both eyes. A: Axial MR imaging, T2-weighted, showing an invasive pituitary tumor involving bilateral internal carotid arteries (arrows). During transnasal endoscopic pituitary tumor resection, the left internal carotid artery was injured. After hemostasis by tamponade, cerebral angiography was performed for endovascular intervention. B: Frontal view of the left carotid artery angiogram showing a giant pseudoaneurysm of the cavernous segment of the internal carotid artery (arrow). C: Lateral view of the unsubtracted image showing the Willis covered stent was released (arrow). D: Lateral view of the left internal carotid artery angiogram showing complete obliteration of the giant pseudoaneurysm (arrow). E: the histological examination confirmed pituitary adenoma (H-E staining).*

Traumatic ICA pseudoaneurysms are rare, mostly occurring in the petrous bone segment and cavernous sinus segment, accounting for less than 1% of all aneurysms [13]. Traffic accidents, stab wounds and falling injuries cause 51%, 12% and 8% of traumatic aneurysms, respectively [14]. The risk factors related to pseudoaneurysm formation mainly include male patient, young age, skull base fracture, intracranial hemorrhage and high-energy injury mechanism [15, 16]. The pressure of arterial pulsation can form pulsatile hematoma, so pseudoaneurysm is easy to rupture. It is reported that most pseudoaneurysms will bleed again 3–7 days after injury, and the mortality rate is as high as 50% [17].

Pseudoaneurysms of carotid and vertebral arteries caused by iatrogenic arterial injury have also been reported. The injury of ICA during the operation of pituitary tumor and complex cervical hypervascular tumor can cause carotid pseudoaneurysm (**Figure 2**). Michael J. Alexander and his colleagues reported a case of acute petrous carotid pseudoaneurysm after myringotomy procedure [18]. Surgical treatment of craniocervical junction lesions may lead to the vertebral artery pseudoaneurysm.

Rupture of intracranial pseudoaneurysm will lead to subarachnoid hemorrhage, and the patient is characterized by severe headache, nausea, vomiting and meningeal irritation [19]. Giant hematoma can compress and damage adjacent nerves and blood vessels, resulting in ischemic symptoms of distal cerebral tissues. Moreover, pseudoaneurysm changes the blood flow, and easily forms thrombus in the aneurysm sac. When the thrombus falls off, it will cause the embolism of the distal artery leading to symptoms of stroke.

## **4. Traumatic arterial dissection**

Dissections of the carotid and vertebral arteries are due to laceration that occur in the intimal layer, which leads to blood under arterial pressure to enter the wall of the vessel and form an intramural hematoma [20]. The incidence of traumatic dissection of the carotid and vertebral arteries has been reported to be 0.08–0.4% of overall traumatic populations [21]. The most common sites of traumatic carotid and vertebral arterial dissections are 2–3 cm from the distal end of the bifurcations of the carotid artery and at C1–2 level, respectively [22]. Iatrogenic neurovascular dissection is a common complication, which is mainly attributed to damage of intimal layer caused by manipulation of guide wire and catheters [23].

Headaches are often the first symptom in adults [24]. Children usually present with symptoms of cerebral ischemia and most commonly hemiparesis [21, 25]. Because children's blood vessel is particularly vulnerable to stretching, and distorting forces. Trauma leads to a traumatic endothelial intimal lesion, followed by fibrin accumulation, leucocyte reaction, and the formation of thrombus to occlude the vascular lumen [26]. In patients presenting with sudden onset of unilateral Horner syndrome, the diagnosis of vertebral arterial dissection should be considered [27].

Early diagnosis of traumatic neurovascular dissection is necessary. Transcranial Doppler, computed tomography (CT), computed tomography angiography (CTA), and magnetic resonance imaging (MRI) can diagnose traumatic neurovascular diseases. Neurovascular dissection can be seen on T1 and T2 weighted images [28, 29]. According to a new study on the diagnosis of dissection, simultaneous non-contrast angiography and intraplaque hemorrhage (SNAP) sequence and T1-weighted volumetric isotropic turbo spin echo acquisition (T1-w VISTA) sequences in MRI can recognize intramural hematoma, intimal flap, and double lumen but SNAP images

*Traumatic Injury of the Carotid and Vertebral Arteries and their Neurointerventional Treatment DOI: http://dx.doi.org/10.5772/intechopen.108588*

had significantly higher intramural hematoma wall contrast than T1-w VISTA images. Therefore, SNAP sequence can early diagnose the neurovascular arterial dissection [29]. Cerebral angiography is not only a diagnostic tool, but also the basis of endovascular therapy of cerebrospinal vascular disorders.

## **5. Neurointerventional treatment**

#### **5.1 Traumatic carotid cavernous fistula**

With the development of endovascular neurosurgery, neurovascular therapy has become the main treatment of TCCFs [30–33]. In the 1960s and early 1970s, it is known that Serbinenko had developed a detachable, flow-directed balloon that was used to treat TCCF while preserving the carotid artery [33]. In China, detachable balloon was used to treat TCCF since the late of 1980s (**Figures 3** and **4**). Coil embolization may be considered in case of the small fistula (**Figure 1**). Temporary balloon or neurostent can be placed in the parent artery to prevent the coil from falling off and occluding the distal intracranial circulation [31]. But, balloon or coil embolization might cause cranial nerve palsy [32]. The detachable balloon or the application of the coil can occlude the fistula, which can maintain the patency of the ICA of the affected side in 70–90% cases (**Figure 5**) [33]. Transarterial embolization of TCCFs using detachable balloons or coils was considered to be a feasible, effective, and safe method for the treatment [34].

Two liquid embolic agents, n-butyl cyanoacrylate (nBCA) (Codman Neurovascular, Raynham, Massachusetts) and ethylene-vinyl alcohol copolymer (EVOH) (Onyx, ev3, Irvine, California) have become good choices. TCCF can be cured by transvenous catheterization of the cavernous sinus and embolization using Onyx assisted with transient balloon occlusion of the ICA at the fistula site. The Willis covered stent (Micro-Port, Shanghai, China) can protect the parent artery and

#### **Figure 3.** *Molds used by Prof. Zhongxue Wu for making detachabel latex balloons in the year of 1988.*

#### **Figure 4.**

*A 40-year-old man presented a traumatic CCF treated with detachable balloon in the year of 1988. A: Lateral view of internal carotid artery angiogram showing a direct CCF of Zipfel's type III with cortical veins reflux (arrow). B: Lateral view of internal carotid artery angiogram showing complete obliteration of the CCF after balloon embolization (arrow).*

#### **Figure 5.**

*A 27-year-old man presented a traumatic CCF treated with Willis covered stent. A: Lateral view of the right internal carotid artery angiogram, early arterial phase. B: Lateral view of the right internal carotid artery angiogram, late arterial phase. Showing a direct CCF of Zipfel's type III with pial veins reflux (arrow). C: Lateral view of the unsubtracted image showing the inflation of the balloon(arrow). D, lateral view of the unsubtracted image showing the Willis covered stent was released (arrow). E: Lateral view of the right internal carotid artery angiogram showing complete obliteration of the CCF after treatment (arrow).*

the mid- and long-term occlusion rate is reported to be 95.7% (**Figure 6**) [35]. Flow diversion is also an effective treatment. Its principle is that a flow diversion in the parent artery can reduce and disturb blood flow in the aneurismal sac causing blood stagnation and thrombosis [36].

## **5.2 Neurovascular Pseudoaneurysm**

Endovascular treatment for neurovascular pseudoaneurysm mainly includes liquid embolic agent, balloon or stent assisted coil embolization, Willis covered stent and

*Traumatic Injury of the Carotid and Vertebral Arteries and their Neurointerventional Treatment DOI: http://dx.doi.org/10.5772/intechopen.108588*

#### **Figure 6.**

*A 27-year-old woman presented a traumatic CCF treated with detachable balloon. A: Lateral view of the left internal carotid artery angiogram showing a direct CCF of Zipfel's type II with ophthalmic vein reflux. B: Lateral view of the left internal carotid artery angiogram showing complete obliteration of the CCF after detachable balloon embolization.*

flow diversion. The Onyx can be injected into the pseudoaneurysm cavity until the aneurysm cavity is completely closed [37]. Balloon or stent can assist coil embolization to prevent the coil from falling out. Willis covered stent can be a curative option and is placed in the parent artery to occlude the neck of pseudoaneurysm. When there are important arterial branches in the lesional area, the application of Willis covered stent may sacrifice the functional branches and cause symptoms of cerebral ischemia. Therefore, its use is limited to the area where no functional branches are found [38].

#### **5.3 Arterial dissection**

Coil occlusion of the parent artery is sufficient to prevent subsequent rupture of arterial dissection [39]. This procedure can be performed in the ICA with an open circle of Willis or a vertebral artery with adequate contralateral flow [40]. If the collateral circulation is insufficient, endovascular reconstruction therapy, such as covered stent or flow diversion, may be helpful to preserve the luminal patency and prevent further rupture of the arterial dissection [39].

## **6. Conclusion**

Traumatic injury of internal carotid and vertebral arteries mainly include TCCF, pseudoaneurysm and arterial dissection, which can cause pain, bleeding, edema, diplopia, visual impairment, and death. Cerebral angiography is the gold standard of diagnosis and endovascular treatment is the main method for traumatic neurovascular disease. This chapter helps to understand how endovascular treatments are slowly becoming the norm.

*Frontiers in Traumatic Brain Injury*

## **Author details**

Huachen Zhang1 , Hanrui Xu<sup>2</sup> , Shikai Liang1 and Xianli Lv1 \*

1 Department of Neurosurgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China

2 Department of Neurology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China

\*Address all correspondence to: lvxianli000@163.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Traumatic Injury of the Carotid and Vertebral Arteries and their Neurointerventional Treatment DOI: http://dx.doi.org/10.5772/intechopen.108588*

## **References**

[1] Harrigan MR, Hadley MN, Dhall SS, Walters BC, Aarabi B, Gelb DE, et al. Management of vertebral artery injuries following non-penetrating cervical trauma. Neurosurgery. 2013;**72**(Suppl 2):234-243. DOI: 10.1227/ NEU.0b013e31827765f5 PMID: 23417194

[2] Higashida RT, Halbach VV, Tsai FY, Norman D, Pribram HF, Mehringer CM, et al. Interventional neurovascular treatment of traumatic carotid and vertebral artery lesions: Results in 234 cases. AJR. American Journal of Roentgenology. 1989;**153**(3):577-582. DOI: 10.2214/ajr.153.3.577 PMID: 2763958

[3] Iorga ER, Costin D. Vascular emergencies in neuro-ophthalmology. Romanian Journal of Ophthalmology. 2020;**64**(4):323-332. DOI: 10.22336/ rjo.2020.54 PMID: 33367170; PMCID: PMC7739024

[4] Wang W, Li YD, Li MH, Tan HQ, Gu BX, Wang J, et al. Endovascular treatment of post-traumatic direct carotid-cavernous fistulas: A singlecenter experience. Journal of Clinical Neuroscience. 2011;**18**(1):24-28. DOI: 10.1016/j.jocn.2010.06.008 PMID: 20888773

[5] Fattahi TT, Brandt MT, Jenkins WS, Steinberg B. Traumatic carotid-cavernous fistula: Pathophysiology and treatment. The Journal of Craniofacial Surgery. 2003;**14**(2):240-246. DOI: 10.1097/00001665-200303000- 00020 PMID: 12621297

[6] Liu AF, Li C, Yu W, Lin LM, Qiu HC, Zhang YQ, et al. Dissection-related carotid-cavernous fistula (CCF) following surgical revascularization of chronic internal carotid artery occlusion: A new subtype of CCF and proposed

management. Chinese Neurosurgical Journal. 2020;**6**:2. DOI: 10.1186/s41016- 019-0180-9 PMID: 32922931; PMCID: PMC7398240

[7] Shih YT, Chen WH, Lee WL, Lee HT, Shen CC, Tsuei YS. Hybrid surgery for symptomatic chronic total occlusion of carotid artery: A technical note. Neurosurgery. 2013;**73**(1 Suppl Operative):E117-E123; discussion ons E123. DOI: 10.1227/ NEU.0b013e31827fca6c PMID: 23190641

[8] Barrow DL, Spector RH, Braun IF, Landman JA, Tindall SC, Tindall GT. Classification and treatment of spontaneous carotid-cavernous sinus fistulas. Journal of Neurosurgery. 1985;**62**(2):248-256. DOI: 10.3171/ jns.1985.62.2.0248 PMID: 3968564

[9] Zipfel GJ, Shah MN, Refai D, Dacey RG Jr, Derdeyn CP. Cranial dural arteriovenous fistulas: Modification of angiographic classification scales based on new natural history data. Neurosurgical Focus. 2009;**26**(5):E14. DOI: 10.3171/2009.2.FOCUS0928 PMID: 19408992

[10] Zhang H, Zhu K, Wang J, Lv X. The use of a new classification in endovascular treatment of dural arteriovenous fistulas. Neuroscience Informatics. 2022;**2**:100047. DOI: 10.1016/j.neuri.2022.100047

[11] Ringer AJ, Salud L, Tomsick TA. Carotid cavernous fistulas: Anatomy, classification, and treatment. Neurosurgery Clinics of North America. 2005;**16**(2):279-295, viii. DOI: 10.1016/j. nec.2004.08.004 PMID: 15694161

[12] Núñez DB Jr, Torres-León M, Múnera F. Vascular injuries of the neck and thoracic inlet: Helical CT-angiographic correlation. Radiographics. 2004;**24**(4):1087-1098; discussion 1099-100. DOI: 10.1148/ rg.244035035 PMID: 15256630

[13] Saito K, Baskaya MK, Shibuya M, Suzuki Y, Sugita K. False traumatic aneurysm of the dorsal wall of the supraclinoid internal carotid artery--case report. Neurologia Medico-Chirurgica (Tokyo). 1995;**35**(12):886-891. DOI: 10.2176/nmc.35.886 PMID: 8584086

[14] Luo CB, Teng MM, Yen DH, Chang FC, Lirng JF, Chang CY. Endovascular embolization of recurrent traumatic carotid-cavernous fistulas managed previously with detachable balloons. The Journal of Trauma. 2004;**56**(6):1214-1220. DOI: 10.1097/01. ta.0000131213.93205.57 PMID: 15211128

[15] Livshits IM, Berdinov BF, Musa G, Chmutin EG, Levov VA, Chmutin GK, et al. Traumatic intracranial aneurysms (TICA) in children: a description of two clinical cases of successful treatment and review of literature. Childs Nerve System. 24 Aug 2022. DOI: 10.1007/ s00381-022-05647-9. Epub ahead of print. PMID: 36002689

[16] Foreman PM, Harrigan MR. Blunt traumatic extracranial cerebrovascular injury and ischemic stroke. Cerebrovascular Diseases Extra. 2017;**7**(1):72-83. DOI: 10.1159/000455391 PMID: 28399527; PMCID: PMC5425764

[17] Dubey A, Sung WS, Chen YY, Amato D, Mujic A, Waites P, et al. Traumatic intracranial aneurysm: A brief review. Journal of Clinical Neuroscience. 2008;**15**(6):609-612. DOI: 10.1016/j. jocn.2007.11.006 PMID: 18395452

[18] Alexander MJ, Smith TP, Tucci DL. Treatment of an iatrogenic petrous carotid artery pseudoaneurysm with a

Symbiot covered stent: Technical case report. Neurosurgery. 2002;**50**(3):658- 662. DOI: 10.1097/00006123- 200203000-00047 PMID: 11841739

[19] Morton RP, Levitt MR, Emerson S, Ghodke BV, Hallam DK, Sekhar LN, et al. Natural history and Management of Blunt Traumatic Pseudoaneurysms of the internal carotid artery: The Harborview algorithm based off a 10-year experience. Annals of Surgery. 2016;**263**(4):821-826. DOI: 10.1097/SLA.0000000000001158 PMID: 25692360

[20] Kansagra AP, Balasetti V, Huang MC. Neurovascular trauma: Diagnosis and therapy. Handbook of Clinical Neurology. 2021;**176**:325-344. DOI: 10.1016/B978-0- 444-64034-5.00012-2 PMID: 33272402

[21] Mortazavi MM, Verma K, Tubbs RS, Harrigan M. Pediatric traumatic carotid, vertebral and cerebral artery dissections: A review. Child's Nervous System. 2011;**27**(12):2045-2056. DOI: 10.1007/ s00381-011-1409-x PMID: 21318614

[22] Kim SH, Kosnik E, Madden C, Rusin J, Wack D, Bartkowski H. Cerebellar infarction from a traumatic vertebral artery dissection in a child. Pediatric Neurosurgery. 1997;**27**(2):71-77. DOI: 10.1159/000121230 PMID: 9520078

[23] Ito H, Uchida M, Kawaguchi K, Hidaka G, Takasuna H, Goto T, et al. Delayed iatrogenic dissection caused by a carotid stent: A case report. NMC Case Report Journal. 2021;**8**(1):241-245. DOI: 10.2176/nmccrj.cr.2020-0258 PMID: 35079470; PMCID: PMC8769419

[24] Redekop GJ. Extracranial carotid and vertebral artery dissection: A review. The Canadian Journal of Neurological Sciences. 2008;**35**(2):146-152. DOI: 10.1017/ s0317167100008556 PMID: 18574926

[25] Wolfe SQ, Mueller-Kronast N, Aziz-Sultan MA, Zauner A,

*Traumatic Injury of the Carotid and Vertebral Arteries and their Neurointerventional Treatment DOI: http://dx.doi.org/10.5772/intechopen.108588*

Bhatia S. Extracranial carotid artery pseudoaneurysm presenting with embolic stroke in a pediatric patient. Case report. Journal of Neurosurgery. Pediatrics. 2008;**1**(3):240-243. DOI: 10.3171/PED/2008/1/3/240 PMID: 18352770

[26] Kieslich M, Fiedler A, Heller C, Kreuz W, Jacobi G. Minor head injury as cause and co-factor in the aetiology of stroke in childhood: A report of eight cases. Journal of Neurology, Neurosurgery, and Psychiatry. 2002;**73**(1):13-16. DOI: 10.1136/ jnnp.73.1.13 PMID: 12082038; PMCID: PMC1757298

[27] Debette S, Leys D. Cervical-artery dissections: Predisposing factors, diagnosis, and outcome. Lancet Neurology. 2009;**8**(7):668-678. DOI: 10.1016/S1474- 4422(09)70084-5 PMID: 19539238

[28] Steinke W, Rautenberg W, Schwartz A, Hennerici M. Noninvasive monitoring of internal carotid artery dissection. Stroke. 1994;**25**(5):998-1005. DOI: 10.1161/01. str.25.5.998 PMID: 7909394

[29] Xia S, Wang Y, Lv X, Chen C, Hui J, Wu X, Wang Z, Chen H, Ji J. The use of SNAP and T1-weighted VISTA in cervical artery dissection. Interventional Neuroradiology. 2 Mar 2022:15910199221082847. DOI: 10.1177/15910199221082847. Epub ahead of print. PMID: 35234066

[30] Lv XL, Li YX, Liu AH, Lv M, Jiang P, Zhang JB, et al. A complex cavernous sinus dural arteriovenous fistula secondary to covered stent placement for a traumatic carotid artery-cavernous sinus fistula: Case report. Journal of Neurosurgery. 2008;**108**(3):588-590. DOI: 10.3171/ JNS/2008/108/3/0588 PMID: 18312107

[31] Brenna CTA, Priola SM, Pasarikovski CR, Ku JC, Daigle P, Gill HS, et al. Surgical sparing and pairing endovascular interventions for carotidcavernous fistula: Case series and review of the literature. World Neurosurgery. 2020;**140**:18-25. DOI: 10.1016/j. wneu.2020.05.013 PMID: 32437988

[32] Lv X, Jiang C, Li Y, Wu Z. A promising adjuvant to detachable coils for cavernous packing: onyx. Interventional Neuroradiology. 2009;**15**(2):145-152. DOI: 10.1177/159101990901500202 PMID: 20465891; PMCID: PMC3299014

[33] Lv XL. Arteriovenous Malformations of the Brain. NY, USA: NOVA; 2020

[34] Lv X, Li Y, Yang X, Jiang C, Wu Z. Endovascular management of direct carotid-cavernous sinus fistulas. The Neuroradiology Journal. 2012;**25**(1):130- 134. DOI: 10.1177/197140091202500117 PMID: 24028886

[35] Wang YL, Ma J, Li YD, Ding PX, Han XW, Wu G. Application of the Willis covered stent for the management of posttraumatic carotid-cavernous fistulas: An initial clinical study. Neurology India. 2012;**60**(2):180-184. DOI: 10.4103/0028- 3886.96397 PMID: 22626700

[36] Byrne JV, Beltechi R, Yarnold JA, Birks J, Kamran M. Early experience in the treatment of intra-cranial aneurysms by endovascular flow diversion: A multicentre prospective study. PLoS One. 2010;**5**(9):e12492. DOI: 10.1371/journal. pone.0012492 PMID: 20824070; PMCID: PMC2932685

[37] Jadhav AP, Pryor JC, Nogueira RG. Onyx embolization for the endovascular treatment of infectious and traumatic aneurysms involving the cranial and cerebral vasculature. Journal of NeuroInterventional Surgery. 2013;**5**(6):562-565. DOI: 10.1136/ neurintsurg-2012-010460 PMID: 23132531

[38] Lv X, Jiang C, Li Y, Lv M, Zhang J, Wu Z. Intracranial pseudoaneurysms, fusiform aneurysms and carotidcavernous fistulas. Repair with percutaneous implantation of endovascular covered stents. Interventional Neuroradiology. 2008;**14**(4):435-440. DOI: 10.1177/ 159101990801400409 PMID: 20557743; PMCID: PMC3313811

[39] Nangarwal B, Bhaisora KS, Khatri D, Sharma A, Singh V, Maurya V, et al. An institutional experience and literature review on iatrogenic major vascular injury in neurosurgery: Proposal of a management algorithm. Neurology India. 2022;**70**(4):1580-1589. DOI: 10.4103/0028-3886.355143 PMID: 36076662

[40] Urasyanandana K, Songsang D, Aurboonyawat T, Chankaew E, Withayasuk P, Churojana A. Treatment outcomes in cerebral artery dissection and literature review. Interventional Neuroradiology. 2018;**24**(3):254-262. DOI: 10.1177/1591019918755692 PMID: 29433365; PMCID: PMC5967189

## **Chapter 7**

## Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal Injury

*Vinu V. Gopal, Rinku Raj Mullasseril and Goutam Chandra*

## **Abstract**

Even though head injury is a silent pandemic of the century producing immense social and economic impact, predictive models have not been established to develop strategies promoting the development of reliable diagnostic tools and effective therapeutics capable of improving the prognosis. Diffuse axonal injury (DAI) is a type of traumatic brain injury (TBI) that results from a blunt injury to the brain. Discovering biomarkers for DAI have been a matter of debate and research. A number of studies have reported biomarkers that are correlated with severity of TBI but no conclusive and reproducible clinical evidence regarding the same has been put forward till now. Additionally, many DAI biomarkers have limitations so that they cannot be generalized for universal applications. The properties of these biomarkers should be extensively researched along with the development of novel biomarkers to aid important clinical decisions for the benefit of the society. This chapter summarizes the existing biofluid-based biomarkers, critically examines their limitations and highlights the possibilities of a few novel biomolecules as prognostic biomarkers of DAI.

**Keywords:** diffuse axonal injury, biofluid, neuronal damage, prognosis, rehabilitation

## **1. Introduction**

Central nervous system (CNS) trauma including traumatic brain injury (TBI) is a major cause of long-term injury, disability and death among young adults worldwide [1, 2]. Around 1.6 million individuals suffer from TBI every year in India with 200,000 deaths [3]. In the USA, there were more than 223,000 TBI-related hospitalizations in 2018 and about 166 Americans died from TBI-related injury each day in 2019 [4]. These estimates do not include the many TBIs that are only treated in the emergency department, primary care, urgent care, or those that go untreated [5]. Since the affected individuals are disabled and out of work during the most productive period of their life, these devastating conditions have an enormous physical, mental and economic burden to the country.

TBI is a heterogeneous neurological condition, ranging from single or repetitive concussion /mild TBI to penetrating head injury, focal contusion, different forms of hematoma (subdural and epidural) and diffuse injury. Depending on the motor, verbal, and eye-opening responses of the affected individuals, the Glasgow coma scale (GCS) was designed to access the disability. The GCS measures the following three functions: Motor response (scores: 6-normal, 5-localized to pain, 4-withdraws to pain, 3-flexion response to pain, 2-extension response to pain, 1-no motor response), Verbal response (scores: 5-normal conversation, 4-oriented conversation, 3-words, but not coherent, 2-no words, only sounds, 1-none), and Eye-opening response (scores: 4-spontaneous, 3-to voice, 2-to pain, 1-none). Based on the GCS score, TBI is classified as mild, moderate, or severe. TBI patients with GCS of 13 to 15 are classified to be mild, which includes the majority of these patients. Patients with a GCS of 9 to 12 are considered to have a moderate TBI, while patients with a GCS below eight are classified as having a severe TBI [6].

The heterogeneous nature of TBI with respect to severity of the injury and comorbidities make patient outcome difficult to predict. While mild TBI or concussion may affect neural cells temporarily, severe TBI is associated with substantial axonal injury and physical damage to the brain, which can result in blood-brain barrier disruption and neuroinflammatory changes [7]. Moderate to severe TBI can usually be visible as structural abnormalities using radiological examinations such as computed tomography (CT) or magnetic resonance imaging (MRI). However, more subtle neural alterations characteristic of mild TBI are not easily detected by these imaging techniques.

Although TBI is an extremely complex condition, there have been many advances in recent years in relation to the diagnosis, monitoring and treatment of the affected patients. Shortcomings in our knowledge of the physiopathology of TBI and the development of reliable predictive models capable of offering an early orientation as to the patient outcome, will improve the diagnostic and therapeutic strategies on an individualized basis. Likewise, we need valid predictive models in severe TBI in order to define efficacy endpoints in the evaluation of new drugs or treatment strategies–since the usual primary endpoints (death and disability) are widely recognized as being inadequate and could explain the discouraging results obtained with certain promising drugs.

## **2. Pathogenesis of DAI**

Diffuse axonal injury (DAI) is a type of TBI that results from a blunt injury to the brain, which happens when the brain rapidly shifts inside the skull as an injury is occurring. It is one of the most common but devastating types of TBI. Neuronal injuries associated with DAI fall into two categories: (i) primary injury, which is directly caused by mechanical forces during the initial insult; and (ii) secondary injury, which is caused as a consequence of primary injury to further tissue and cellular damages.

### **2.1 Primary brain injuries**

Primary brain injuries refer to the sudden and profound injury to the brain that occurs at the time of the motor vehicle accident, gunshot wound, or accidental fall. The immediate impact of different mechanical insults to the brain can cause two types of primary TBI: focal and diffuse brain injuries. Focal TBI generally results from a blow to the head that produces cerebral contusions or hematomas. Epidural hematomas, subdural hematomas, and cerebral contusions are the results of focal

*Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*

brain injuries [8]. In contrast, diffuse lesions (also known as DAI) are seen more commonly in lesions that involve rapid acceleration, deceleration, or rotational forces. DAI accounts for about 70% of TBI cases. The sites that are most prone to DAI are the reticular formation, basal ganglia, superior cerebellar peduncles, limbic fornices, hypothalamus and corpus callosum [8]. Interestingly, both types of injuries may co-exist in patients who suffered from moderate to severe TBI [9].

Brain injuries may occur in one of two ways: closed brain TBI and penetrating TBI. Closed brain TBIs occur when there is a non-penetrating injury to the brain with no break in the skull. A closed brain injury is caused by a rapid forward or backward movement and shaking of the brain inside the bony skull that result in bruising and tearing of brain tissue and blood vessels. In contrast, Penetrating, or open head injuries occur when there is a break in the skull, caused by hitting with a sharp object such as a bullet. These injuries exhibit focal brain damage due to lacerations, compression and concussion forces with evidence of skull fracture and localized contusion (**Figure 1**) at the core of injury site, known as the 'coup' area [10, 11]. Compromised blood supply at the coup area due to epidural, subdural and intracerebral hemorrhages and hematomas might result in necrosis of neuronal and glial cells at confined layers of the brain. Secondary contusion may develop in brain tissues opposite to or surrounding the coup area due to secondary impact when the brain rebounds and strikes the skull [11].

#### **2.2 Secondary brain injuries**

Secondary brain injuries refer to the changes that evolve over a period of time after the primary brain injury. The biochemical, cellular and physiological events that occur during primary injury often progress into delayed and prolonged secondary damaging cascade of cellular, chemical, tissue, or blood vessel changes in the brain that contribute to further destruction of brain tissue. Secondary brain injuries can last from hours to days and even weeks and may be caused by impairment or local declines in cerebral blood flow resulting in local edema, hemorrhage, or increased intracranial pressure and even brain herniation. Other types of secondary injury due to TBI include hypercapnia, acidosis, meningitis and brain abscess [12]. Mechanistically, a number of factors contribute to these changes, which include excitotoxicity, loss of cerebral autoregulation, blood-brain barrier compromise, mitochondrial dysfunction, oxidative stress, lipid peroxidation, neuroinflammation, axon degeneration, impaired autophagy and apoptotic cell death (**Figure 1**) [10, 13].

The hallmark feature of DAI is extensive damage of axons predominantly in subcortical and deep white matter tissue, which leads to impairment of axonal transport and degradation of axonal cytoskeleton. The strong tensile forces generated during primary injury by rapid deceleration and acceleration of the brain due to multiple non-contact forces causing shearing and stretching injury in cerebral brain tissues damage neuronal axons, oligodendrocytes and blood vasculature, leading to brain edema and ischemic brain damage [14]. These axonal damages can persist for months after DAI.

The degree of axonal injury and neuronal degeneration determines the severity of TBI. While explosive blast TBI is a result of shock waves instead of inertial forces, it displays the characteristics of a typical DAI. Depending on the severity of the injury, patients may later develop cognitive deficits, behavioral changes and hemiparesis (**Figure 1**).

#### **Figure 1.**

*Schematic representation of the pathogenesis of TBI.* TBI *may be divided into* primary *injury and* secondary *injury. Primary* TBI *results from mechanical injury at the time of insult, while secondary injury is caused by the physiologic responses to the initial injury.* Primary *brain injury comprises the direct physical injury to the brain such as compression, deformation, displacement, stretching, shearing, tearing, and crushing of brain which results in damage to vasculature, neural, and glial tissues. Most of the neurological damage from TBI is due to the secondary injury which evolves over the ensuing hours and days after the initial injury or impact. The mechanisms by which TBI trigger neurodegeneration are areas of active research. Previous investigations found roles of excitotoxicity, loss of cerebral autoregulation, blood-brain barrier compromise, mitochondrial dysfunction, oxidative stress, lipid peroxidation, neuroinflammation, axon degeneration, impaired autophagy and apoptotic cell death in the development of neurodegeneration following brain injury. TBI produces both acute and chronic consequences that lead to permanent disabilities that increase long-term mortality and reduced life expectancy. The direct consequences of a single or repetitive TBI can result in various secondary pathological conditions, including seizures, sleep disorders, neurodegenerative diseases, neuroendocrine dysregulation, and psychiatric problems. Changes initiated by TBI can persist for weeks to months or even years after injury and significantly affect quality-of-life of the affected victims.*

## **3. Need for biofluid-based brain damage biomarkers**

While mild TBI or concussion may affect neural cells temporarily, severe TBI is associated with substantial axonal injury and physical damage to the brain, which can result in blood-brain barrier disruption and neuroinflammatory changes [7]. Although, moderate to extensive brain injury may be visible as structural abnormalities using CT scan or MRI, more subtle neural alterations characteristic of mild TBI are not easily detected by these imaging techniques. Moreover, changes due to DAI in the brain are often microscopic and may not be visualized on CT scan or MRI scans.

Mild TBI is highly prevalent in military populations, with many service members suffering from long-term symptoms [15]. It is also very common among road accident victims. The condition results from etiologies of neural contusion and axonal injury, which subsequently results in biochemical, metabolic, and cellular changes that may be responsible for some of the long-term problems observed in patients who develop post-concussion syndrome [16]. Moreover, moderate to severe TBI remains another important public health problem, due to the large percentage of unfavorable

## *Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*

outcomes involved such as death and disabling sequelae. The huge treatment costs, associated compensations, disability pensions and years of income from work lost in affected individuals are the major financially devastating turns in the affected families. Therefore, identifying critical markers of neural injury in biofluids of these patients would be crucial for predicting long-term functional outcome and for taking rehabilitation decisions. Encouragingly, significant scientific advances on the TBI biomarker research in the last decade have increased our understanding of the complex and heterogeneous pathophysiological processes associated with this condition. Emerging evidence from multiple research teams suggests that biofluid-based TBI biomarkers may have the potential to diagnose the presence of TBI of different severities, and to predict outcome.

## **4. Biomarkers for TBI/DAI**

A biomarker is defined as a quantifiable biological indicator specific for a given physiological or pathological condition. Based on clinical utility, biomarkers may be categorized as: 1) diagnostic biomarkers, which identify the presence or absence of TBI, 2) prognostic biomarkers, which inform the clinicians about expected outcomes in injured individuals, and 3) predictive biomarkers, which predict response to a specific intervention and can be used to monitor response to therapy. Identification of biological markers of TBI could offer a more precise indication of the extent and severity of TBI, independently of the prior biological substrate and of other circumstances that accompany severe TBI–thereby contributing to homogeneously define different patient categories and risk stratify the head injury. These can also serve to screen and identify patients who may expect an altered or complicated recovery or might develop neurobehavioral deficits during the latter part of their life. Such markers would facilitate


### **4.1 Which is an ideal biomarker?**

An ideal TBI/DAI biomarker should have

• high specificity and sensitivity for the brain tissue


The literature given below is a concise description of the principal investigational brain damage biomarkers with a description of the tissues in which they originate, the compartment from which samples were collected, their pathological serum concentrations, and the main prognostic features (**Table 1**).

#### **4.2 Tau protein**

Tau protein is an axonal cytoskeleton-stabilizing protein (**Figure 2**) of molecular weight of 30–50 kDa that provides structural elements of the cytoskeleton that are crucial for neuronal protein flow [46, 47]. There are 6 different tau protein isomers, which is phosphorylated at many sites by kinases such as casein kinase II, tau tubulin kinases, glycogen synthase kinase 3β, and cyclin dependent kinase 5 [48–50]. While these are present in a stable, unfolded and monomeric morphology in a healthy brain, tau proteins exist in hyperphosphorylated state in several neurodegenerative diseases including Alzheimer's disease (AD) [46, 51]. Interestingly, TBI has been indicated as a risk factor for later development of AD and other neurodegenerative conditions [52–56] .

Physical trauma causes activation of a number of proteases, which cause release of tau protein fragments in cleaved tau (c-tau) into the blood and CSF [57, 58]. Studies showed that the c-tau levels in CSF increase in the first 24 h after severe TBI [17, 59, 60]. Plasma phosphorylated tau (p-tau) and p-tau/t-tau ratios have been demonstrated to distinguish patients with acute and chronic TBI from healthy controls [18]. Smith and colleagues (1999) have shown deposition of p-tau following TBI [61]. C-tau in CSF is shown to be a predictor of clinical outcomes in severe TBI subjects [60, 62]. Moreover, elevated c-tau could be a chronic manifestation in DAI, since tau is localized to the axons [59]. However, the practical role of this molecule in DAI has not been fully established.

### **4.3 Amyloid-β (Aβ) protein**

Amyloid-β (Aβ) is a 4 kDa extracellular protein derived from amyloid precursor protein (APP), which is cleaved by secretase enzymes [63]. APP is a membrane *Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*


#### **Table 1.**

*Current and emerging DAI biomarkers.*

protein expressed in both CNS (APP 695) and peripheral organs and tissues (APP 751 and APP 770) [64]. APP with 695 amino acids is present as glycosylated receptors on cell surface and is hydrolysed by α-secretase followed by γ-secretase under normal conditions to produce soluble Aβ through non-amyloidogenic pathway [63, 65]. In amyloidogenic pathway, the mutations in APP and components of α-secretase, presinillin 1 (PSEN1) and presinillin 2 (PSEN2) leads to the cleavage by β amyloid cleaving enzyme-1 (BACE1) and γ-secretase to form insoluble Aβ, Aβ1–40 and Aβ1–42. This amyloidogenic cleavage leads to extracellular accumulation of Aβ plaques, a pathological hallmark in AD [20, 65, 66]. APP plays an important role in cell adhesion processes and thus high concentrations are found at neuronal synaptic junction. Certain type of caspase breaks it down into a series of products which accumulate in cell bodies and axons. There are discordant evidence on the use of this protein as biomarker of TBI. One study of 29 patients with severe TBI revealed low levels of this protein in CSF probably due to reabsorption of the protein in the form of amyloid plaques [21]. As a contradiction to the above, Emmerling et al. (2020) found increasing levels in CSF after trauma and suggested that this could be a result of secondary axonal damage or loss of integrity of the BBB [22]. These contradictory findings, have

#### **Figure 2.**

*Origin of biomarkers of DAI. In normal brain, NSE and UCH-L1 are localized in neuronal cytoplasm, while tau/c-tau are restricted mainly to axons and its terminals. Although tau is abundant in the neurons of the CNS, astrocytes express very low levels of this protein and it can be secreted into the brain interstitial fluid. APP is a type I transmembrane protein expressed in many cell types, including neurons. Aβ is derived from APP by enzymatic cleavage and is released to extracellular space. MBP is a constituent of neuronal myelin sheath, which is produced by oligodendrocytes. Spectrins (precursors of SBDPs), specifically βIV-spectrin is concentrated at axon initial segments and nodes of Ranvier. GFAP, CK-BB and S100B are normally present in astrocytes. DAI not only injures pre- and post-synaptic neurons but also damages their synapses, axons, myelin sheaths and neighboring astrocytes, oligodendrocytes, blood microvasculature and even the extracellular matrix network. Damages to specific cells and cellular components during DAI enable release of various molecules contained in those cells into the extracellular space. The released molecules, including those present in extracellular space like Aβ enter the damaged blood vessels and may be detected in the circulation.*

caused Aβ-protein to be regarded as a non-reproducible biomarker and its potential role remains unclear requiring further research.

#### **4.4 Myelin basic protein (MBP)**

MBP (molecular weight of 18.5 kDa), found in oligodendroglial cells, is a key structural component of the multi-layered myelin sheath covering nerve fibers. The *Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*

myelin sheath on neuronal axons serves as an insulator to increase the velocity of axonal impulse conduction. Due to the extended length of axonal fiber tracks, axons are particularly vulnerable to physical trauma to the brain. Thus, axonal injury is a common occurrence in both focal as well as diffuse brain trauma and can be found in TBI of all severities [14, 67]. As MBP maintains myelin structure by interacting with the lipids in the myelin membrane [68], axonal injury causes breakdown of the myelin sheath and release of MBP. This myelin-specific protein is also released into the bloodstream in cases of demyelinating diseases such as multiple sclerosis, or degradation by proteases, such as calpain [69, 70].

MBP is found to be elevated in serum after severe TBI in children [23, 24] and after mild TBI in adults [24]. Even though, it takes around 1–2 days to appear in the serum after TBI, the peak levels of MBP can persist for up to 2 weeks and can be a specific indicator for future intracranial hemorrhage [71]. However, as per present literature there is contradicting evidence for its role in TBI/DAI [72–74]. There was no difference in initial levels of serum MBP in a pediatric population with mild TBI when compared with controls, but there was a significant difference in the peak MBP levels between patients and controls [72]. MBP is also expressed on the myelin of peripheral nerves and its transcripts are present in the bone marrow and immune system and therefore it is not specific to the CNS. Even though serum levels are correlated with patient severity and outcome [71, 75] it has limited sensitivity as a marker for predicting severity of TBI [76].

#### **4.5 Cerebral creatine kinase (CK) isoenzyme**

CK isoenzymes are of three types: CK-1 (also known as CK-BB) is predominantly expressed in brain, lung, thyroid and prostate glands, gastrointestinal tract, urinary bladder, uterus and placenta. CK-2 (CK-MB) and CK-3 (CK-MM) are expressed in cardiac and skeletal muscles [77]. Brain tissue-specific CK-1 (CK-BB), with a molecular weight of 40–53 kDa, is found in astrocytes [25, 26]. A peak in serum cerebral CK concentration is observed in the first few hours after severe TBI and then gradually decrease and the marker remains high for days [78–81]. In polytrauma, it remains persistently high without an initial dip [82, 83] . Its levels have been shown to rise significantly in CSF following hypoxic brain injury in cardiac arrest, which suggests that CK-BB release may be secondary to cerebral hypoperfusion due to systemic trauma [84]. The major limiting factor is that it has low sensitivity and specificity especially in cases of polytrauma [27, 85].

#### **4.6 Neuron-specific enolase (NSE)**

NSE, also known as γ -enolase or enolase 2, is a glycolytic enzyme with a molecular weight of 78 kDa and a half-life of 48 h. It exists as a homodimer (γ–γ) in mature neurons and neuroendocrine cells. The normal concentration of NSE in blood is <10 ng/ml. NSE elevations in blood compartment has been documented in severe as well as mild TBI [28–31, 86]. Experimental models of trauma have correlated serum NSE to the severity of damage in TBI [87]. Major limitation of using NSE as specific biomarker for TBI is that it is also abundantly expressed in red blood cells [88]. Moreover, increased levels of NSE was also recorded previously in the serum of patients following non-traumatic brain damage such as ischemic events, intracerebral hemorrhage, cardiopulmonary resuscitation, secondary cerebral hypoxia etc. [89]. Some studies had correlated the biomarker to the development of DAI, though its behavior has not been clearly established in prospective trials.

NSE was initially suggested to be a very promising TBI severity marker due to its specificity to neuronal tissue than of glial cells. However, the results published till date has been contradictory on its role in predicting prognosis of patients with severe TBI. Long half-life is a major limiting factor for its use in trauma setting. Also, extracranial origin of NSE was demonstrated in hemorrhagic shock, long bone fracture, hemolysis, heart surgery, ischemia–reperfusion injury and malignant lung tumors making it a poor marker for TBI [90–94].

## **4.7 Glial fibrillary acidic protein (GFAP)**

GFAP is a monomeric intermediate filament protein (molecular weight 52 kDa), present in the cytoskeleton of astrocytes in the brain. An increase in blood level of this biomarker suggests injury to the astrocytes and the BBB. Plasma concentrations >0.033 μg/l are regarded as pathological. Missler et al. (2002) were the first to propose the possible use of GFAP as an identifier of brain damage in serial serum measurements [95]. Later studies also confirmed that the serum concentration of this protein is not affected by extracranial injuries thus making it an effective biomarker for predicting poor outcome in the acute phase of severe TBI as well as for advocating the need for urgent neurosurgical procedures [41, 96]. GFAP (52 kDa) or its breakdown products (44–38 kDa) are released from injured brain tissue into biofluids such as CSF and enter the bloodstream after crossing the BBB with an early plasma peak (within 3 to 34 h) following brain injury [97, 98]. The blood levels then decrease gradually over the first week, starting from third day of injury.

Previous studies demonstrated that GFAP levels show an unfavorable outcome in patients with moderate or severe TBI [41, 96, 99, 100]. However, this may not be the case in patients with mild TBI due to the contamination from other sources [101–103]. However, Serum GFAP levels were also significantly higher in patients who died or had an unfavorable outcome [104]. Moreover, GFAP levels have correctly predicted neurological outcome at 6 months [35, 36, 104]. Furthermore, serum GFAP measured on day 1 of injury in pediatric TBI cases significantly correlated with functional outcomes at 6 months [105]. Thus, GFAP can be considered as an ideal biomarker of brain damage when combined with clinical variables though multicenter studies are needed for further validation.

### **4.8 S100-calcium binding protein B (S100B)**

S100B, the most widely studied brain damage biomarker, is a low molecular weight (11 kDa) calcium binding protein of astroglial origin [33]. The homodimeric beta-subtype of S100 proteins (S100B) is synthesized in astrocytes of the CNS and in Schwann cells of the peripheral nerves, where it regulates intracellular calcium levels [106–108]. S100B localizes to the nucleus and cytoplasm associating with endomembranes, the centrosomes, microtubules and type III intermediate filaments [109]. The protein is naturally secreted by astrocytes into the extracellular space. Low amounts of S100B can cross the BBB and enter the microvasculature. Elevated levels of S100B in the serum were observed in TBI patients as well as in patients suffering from neurodegenerative diseases [110]. The serum levels of the protein have been associated with clinical severity, radiological severity, and an unfavorable outcome [111–114] .

The biological function of this protein has not been fully established till date, though it is known to participate in neurogenesis, astrocytosis and axonal elongation. However, the molecule can also be produced and found outside the CNS, e.g., in kidney epithelial

#### *Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*

cells, ependymocytes, chondrocytes, adipocytes, melanocytes, Langerhans cells, dendritic cells, certain lymphocyte subpopulations, skeletal myofibers, myoblasts and muscle satellite cells [109]. Metabolism takes place in the kidneys, followed by excretion in urine, with an approximate half-life of 30–113 min, and is not affected by hemolytic phenomena [115]. Its role in urine level also needs further validated study. Since S100B can also be released from adipose tissue and cardiac/skeletal muscles, its levels are also elevated in orthopedic trauma without head injury [116]. Despite these confounders, S100B is actually a sensitive TBI biomarker for predicting CT abnormality and post-concussive syndrome development [117–119]. A number of previous studies have shown that S100B can actually differentiate between mild and severe TBI [120, 121].

The maximum serum concentration of S100B is reached 20 min after brain damage. The normal upper limit for this protein in relation to the detection of intracranial damage was defined as 0.1 μg/l based on a multicenter study in patients with mild TBI [122]. The measurement of S100B-protein can be influenced by patient age and gender in CSF samples but not in serum samples thus making it a practically feasible biomarker.

Some studies have determined its usefulness as a predictor of mortality, establishing orientative serum cut-off points for predicting a course leading to death or an unfavorable outcome [123–125]. On the other hand, S100B level has been correlated to the presence of secondary lesions, the extent of diffuse brain damage, and to modifications in intracranial pressure following different release patterns [126, 127]. S100B levels can also detect brain death development or mortality after severe TBI [128, 129]. Interestingly, serum levels of S100B > 0.7 ng/mL were reported to correlate with 100% mortality [130].

Another possible application of this protein refers to its time course according to the severity of the patient condition. A number of studies have documented persistently elevated serum levels in patients in those with poor GCS, while the plasma levels have been seen to decrease after 36 h among survivors [82, 131–133]. On the other hand, S100B protein has been suggested as a tool for monitoring management efficacy [134, 135], since it has been seen that the blood concentrations of the protein decrease after effective neurosurgical treatment thus making its role more relevant. A high level of S100B during the initial TBI can predict a poor outcome, especially if it is accompanied by a second increase in levels of serum S100B that occurs during the subacute phase [131, 136]. This second peak during the subacute phase may be due to secondary injury to the astroglial cells exhibiting excitotoxicity and neuroinflammation. In addition, elevation in serum levels of S100B and GFAP in TBI patients has been correlated with unfavorable neurological outcomes [137–139]. On the other hand, an initial lower level of S100B and the lack of second peak might suggest the occurrence of a mild TBI and a good functional recovery [140, 141].

A previous study demonstrated the sensitivity of S100B to predict significant intracranial pathology up to 100% but with specificity of only 28%.Moreover, in pediatric population (specifically for children under the age of 2 years), S100B is not a useful marker due to high normal levels in this group [32, 142]. Thus, S100B may be suggested to be used as an adjuvant marker in patients with TBI, but its diagnostic value is still controversial [76].

## **5. Limitations of the existing biomarkers**

Doctors in the acute hospital settings primarily rely on the patient's neurological examinations and radiologic imaging to characterize TBI/DAI diagnosis. Depending on the severity of the initial insult, different imaging modalities such as CT scan and MRI are used to obtain the necessary information for patient care and prognosis. However, CT scans, used for assessing cerebrovascular integrity or for determining gross anatomical changes induced to the brain, have low sensitivity to diffuse brain damage, and confers exposure to radiation [143]. In contrast, while MRI can provide information on the extent of diffuse injuries, yet its widespread application is restricted by prohibitive cost, limited availability of MRI in many hospitals, and practical difficulty of performing it in physiologically unstable TBI patients [143]. Thus, diagnostic and prognostic tools for risk stratification of TBI patients are very limited in the early stages after injury.

To fill this gap, research in the field of biofluid-based TBI biomarkers has increased exponentially over the last three decades [116]. Extensive research on fluid biomarkers have demonstrated that a number of brain-specific proteins, as illustrated above, have potential for acting as biomarkers of TBI. These biomolecules are released into the CSF and/or blood, after brain injury due to damage of neural cells [28, 144–146]. Additionally, neuroimmune activation might have the potential to be novel diagnostic and/or prognostic marker of TBI. A few of these molecules, like S100B have shown promise to be clinically used as biomarkers of TBI [145]. However, this has been disputed in recent studies [147] and till now, there are no rapid, definitive diagnostic blood tests for TBI.

Despite its high sensitivity and negative predictive value, S100B protein is not a specific marker of the CNS damage. Polytraumatized patients without TBI can present S100B protein elevations in blood, though the concentrations return to normal within 6 h after trauma. Patients with brain damage and associated extracranial injuries (hypotension, hypothermia, coagulopathy, inotropic drugs, sedatives, corticosteroids, etc.) can alter the early assessment of S100B protein. Therefore, early determination of this protein is to be avoided in patients with extracranial injuries associated with TBI making it's role dismal probably in trauma care even though the above features of an ideal biomarker are met.

## **5.1 Difficulty with interpretation**

CNS is very complex and can present a range of different lesions, which in turn can affect different target cells with variable degrees of severity. Brain damage markers must establish differentiations with respect to other alterations. Furthermore, the existence of the blood–brain barrier conditions the structural characteristics of these biomarkers, which must be able to cross the mentioned barrier in order to reach the bloodstream. Biomarkers are dynamic elements that experience changes in response to different inflammatory states, tissue necrosis etc. So serial measurements rather than isolated or point determinations are thus required.

### **5.2 Controversy**

As direct sampling of the damaged brain tissue is not practically feasible there is some controversy regarding the type of biological fluid that should be analyzed. CSF compartment is located closer to the damage site, but frequent collection of CSF samples is unethical. As a result, most biomarkers are studied in peripheral blood as the process is simple, accessible and reproducible. Thus, estimation of blood biomarkers will be the most appropriate option for performing simple and minimally invasive serial measurements. Still more easy will be to estimate biomarkers in fluids that serve as vehicles for their clearance, for example urine.

*Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*

## **6. Newly discovered biomarkers of interest.**

#### **6.1 Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1)**

UCH-L1 mainly resides in the cytoplasm of neuronal cell body representing approximately 5% of all the soluble brain proteins. It is implicated in the elimination of degraded and denatured proteins following oxidative phenomena [148]. Proteomics data first implicate UCH-L1 as promising TBI biomarker candidate [149, 150]. Later studies point to it as a promising brain damage biomarker, since there are data indicating that it can predict the presence of lesions on the CT scan, the need for neurosurgery, and the outcome of patients with TBI [151–153].

UCH-L1 can be detected in blood, with early increases in its serum concentration following brain injury [151]. The protein level in the blood is shown to be elevated both in mild and severe cases of TBI [100, 154]. Mondello et al. (2012) have obtained interesting results regarding its possible capacity to distinguish between focal and diffuse brain damage [155]. Additionally, it has been suggested that UCH-L1 together with GFAP form the foundation of a biomarker panel representing the two dominant cell types (neuron and astrocytes) in the brain [38]. Interestingly, serum levels of both of these proteins are elevated in professional breacher trainees who were exposed to repeated explosive discharges as well as athletes who experienced concussions [39, 40]. Further investigations are needed to evaluate the properties of this protein as a promising biomarker of DAI.

## **7. Spectrin degradation products (SBDPs)**

Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane forming a scaffold, which maintains plasma membrane integrity and cytoskeletal structure [156]. It is a heterodimeric protein, composed of two α and two β chains, and contains 106 contiguous amino acid sequence motifs called "spectrin repeats", which are essential to diverse cell functions such as cell adhesion, cell spreading, and the cell cycle [156].

Necrotic and apoptotic cell death during primary and secondary brain injury respectively, cause overactivation of cysteine proteases, such as calpain and caspase-3. These proteases cleave components of the axonal cytoskeleton [157] including spectrin resulting in generation of SBDPs with characteristic molecular weights [26, 158]. The presence of degradation products of spectrin has been described in the CNS in axons and presynaptic neuronal endings [23, 44, 159, 160]. However, SBDPs are not brain specific and its increased serum levels may reflect multiorgan damage in trauma [42, 161]. Moreover, accurate quantification of brain-derived SBDPs in blood is difficult since some proteins found in erythrocytes are similar to those found in the neuronal cytoskeleton [162], thus reducing the diagnostic value of SBDPs.

## **8. Neurofilament light chain (NfL)**

Neurofilaments, consisting of three chains, light (L), medium (M) and heavy (H), make up part of the axonal cytoskeleton. NfL is 68 kDa subunit of the neurofilaments located on the neuronal cytoplasm which is released in response to CNS neuronal damage due to neuroinflammation, neurodegeneration, and/or traumatic or vascular injury [163, 164]. Following axon damage, the influx of calcium alters the phosphorylation state of NfL and subsequent proteolysis. As a result, there is loss of cytoskeletal structure and NfL is released into both CSF and the bloodstream [165]. A number of investigational studies have underscored the role of NfL as biomarker of axon damage [45, 166, 167]. Serum NfL has been shown to distinguish patients with mild, moderate or severe TBI for months and even years after injury [168]. However, serum detection of NfH is considered a better biomarker candidate [169].

## **9. Conclusions**

Since all brain damage biomarkers have some limitation precluding their universal application in the management of severe TBI/DAI, they do not yet form part of routine clinical practice. Some markers, such as NSE and S100B protein, have shown good correlations to clinical severity, the extent of brain damage, response to treatment, and patient outcome. However, the limitations associated with the clinical yield of the molecule or invasiveness of the technique required to obtain the sample have not allowed their generalized use in this patient population.

On the other hand, further studies are needed to understand the role of these proteins in the physiology of the CNS and in the physiopathology of severe TBI/DAI, as well as to clarify the usefulness of those biomarkers that appear to be promising in this field. In this respect, mention must be made of nervous tissue-specific GFAP, as well as of other biomarkers that are currently the focus of interest, such as ubiquitin carboxyterminal hydrolase L1, the light neurofilaments and spectrin degradation products.

Since these molecules offer isolated information on some of the many elements implicated in the physiopathology of TBI/DAI, we believe that the best strategy is to analyze them in combination. Rather than seeking a biomarker exclusive for brain damage, this approach would allow us to define a panel of biomarkers which jointly – and considering the characteristics inherent to each of them–could offer information referred to severity, the potential benefits of management, and the evolutive course of patients following severe TBI. Only in this way can we hope to complement the traditional methods with a tool that is simple, non-invasive, reproducible and extraordinarily useful for addressing and managing severe TBI/DAI. Moreover, since TBI/DAI is quite complex heterogeneous conditions, it might be clinically justified to use multi-modal biomarkers to evaluate the status of full clinical endophenotypes by combining a panel of biofluid-based and physiologic biomarkers coupled with advanced neuroimaging that are appropriately obtained at multiple time points during the time course of TBI/DAI.

## **Conflicts of interest**

The authors declare that they have no conflicts of interest.

## **Financial support**

RRM is a senior research fellow of Indian Council of Medical Research (ICMR), Government of India. GC is supported by The Ramalingaswami fellowship from the Department of Biotechnology, and grants from the Department of Health Research and ICMR, Government of India.

*Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*

## **Author details**

Vinu V. Gopal1 \*, Rinku Raj Mullasseril<sup>2</sup> and Goutam Chandra<sup>2</sup> \*

1 Department of Neurosurgery, Government Medical College, Kottayam, Kerala, India

2 Center for Development and Aging Research, Inter-University Center for Biomedical Research and Super Specialty Hospital, Kottayam, Kerala, India

\*Address all correspondence to: vinu.acme5.kottayam@gmail.com; gchandra@iucbr.ac.in

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Werner C, Engelhard K. Pathophysiology of traumatic brain injury. British Journal of Anaesthesia. 2007;**99**:4-9. DOI: 10.1093/BJA/AEM131

[2] Hoffman SW, Harrison C. The interaction between psychological health and traumatic brain injury: A neuroscience perspective. The Clinical Neuropsychologist. 2009;**23**:1400-1415. DOI: 10.1080/13854040903369433

[3] Kalra S, Banderwal R, Arora K, Kumar S, Singh G, Chawla PA, et al. An update on pathophysiology and treatment of sports-mediated brain injury. Environmental Science and Pollution Research International. 2022;**29**:16786-16798. DOI: 10.1007/ S11356-021-18391-5

[4] Center for Disease Control. Injury Prevention and Control: Traumatic Brain Injury – Concussion. n.d. Available from: https://www.google.com/search?q=CDC %2C+2022.+Injury+Prevention+and+Co ntrol%3A+Traumatic+Brain+Injury+Cen ter+for+Disease+Control+(CDC)+and+ Prevention.&rlz=1C1YQLS\_enIN892IN8 92&oq=CDC%2C+2022.+Injury+Preven tion+and+Control%3A+Traumatic+Brai n+Injury+Center+f [Accessed: February 9, 2022]

[5] Bell JM, Breiding MJ, DePadilla L. CDC's efforts to improve traumatic brain injury surveillance. Journal of Safety Research. 2017;**62**:253-256. DOI: 10.1016/J.JSR.2017.04.002

[6] Mesfin FB, Gupta N, Shapshak AH, Taylor RS. Diffuse axonal injury. Encycl. Neurological Sciences. 2021:10-12. DOI: 10.1016/b0-12-226870-9/00726-7

[7] Wilson L, Stewart W, Dams-O'Connor K, Diaz-Arrastia R, Horton L, Menon DK, et al. The chronic and evolving neurological consequences of traumatic brain injury. Lancet Neurology. 2017;**16**:813-825. DOI: 10.1016/S1474-4422(17)30279-X

[8] Huffman JC, Brennan MM, Smith FA, Stern TA. 19 – Patients with neurologic conditions I. seizure disorders (including nonepileptic seizures), cerebrovascular disease, and traumatic brain injury. Massachusetts General Hospital Handbook of General Hospital Psychiatry, Elsevier. 2010:237-253. DOI: 10.1016/ B978-1-4377-1927-7.00019-4

[9] Skandsen T, Kvistad KA, Solheim O, Strand IH, Folvik M, Anne V. Prevalence and impact of diffuse axonal injury in patients with moderate and severe head injury: A cohort study of early magnetic resonance imaging findings and 1-year outcome: Clinical article. Journal of Neurosurgery. 2010;**113**:556-563. DOI: 10.3171/2009.9.JNS09626

[10] Ng SY, Lee AYW. Traumatic brain injuries: Pathophysiology and potential therapeutic targets. Frontiers in Cellular Neuroscience. 2019;**13**:528. DOI: 10.3389/ FNCEL.2019.00528

[11] Schmidt OI, Morganti-Kossmann MC, Heyde CE, Perez D, Yatsiv I, Shohami E, et al. Tumor necrosis factor-mediated inhibition of interleukin-18 in the brain: A clinical and experimental study in head-injured patients and in a murine model of closed head injury. Journal of Neuroinflammation. 2004;**1**:1-6. DOI: 10.1186/1742-2094-1-13

[12] Ganju A. Intensive care in neurosurgery. The Journal of Trauma and Acute Care Surgery. 2003;**54**:798. DOI: 10.1097/01.ta.0000058928.27063.6e *Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*

[13] Ray SK, Dixon CE, Banik NL. Molecular mechanisms in the pathogenesis of traumatic brain injury. Histology and Histopathology. 2002;**17**:1137-1152. DOI: 10.14670/ HH-17.1137

[14] Smith DH, Meaney DF, Shull WH. Diffuse axonal injury in head trauma. The Journal of Head Trauma Rehabilitation. 2003;**18**:307-316. DOI: 10.1097/00001199-200307000- 00003

[15] Philippi CL, Velez CS, Wade BSC, Drennon AM, Cooper DB, Kennedy JE, et al. Distinct patterns of resting-state connectivity in U.S. service members with mild traumatic brain injury versus posttraumatic stress disorder. Brain Imaging and Behavior. 2021;**15**:2616- 2626. DOI: 10.1007/S11682-021-00464-1

[16] Zhang J, Puvenna V, Janigro D. Biomarkers of traumatic brain injury and their relationship to pathology. In: Translational Research in Traumatic Brain Injury. Boca Raton (FL): CRC Press; 2016. pp. 263-276. DOI: 10.1201/ b18959-17

[17] Chatfield DA, Zemlan FP, Day DJ, Menon DK. Discordant temporal patterns of S100beta and cleaved tau protein elevation after head injury: A pilot study. British Journal of Neurosurgery. 2002;**16**:471-476. DOI: 10.1080/0268869021000030285

[18] Rubenstein R, Chang B, Yue JK, Chiu A, Winkler EA, Puccio AM, et al. Comparing plasma phospho tau, total tau, and phospho tau-total tau ratio as acute and chronic traumatic brain injury biomarkers. JAMA Neurology. 2017;**74**:1063-1072. DOI: 10.1001/ JAMANEUROL.2017.0655

[19] Liliang PC, Liang CL, Lu K, Wang KW, Weng HC, Hsieh CH, et al. Relationship between injury severity and serum tau protein levels in traumatic brain injured rats. Resuscitation. 2010;**81**:1205-1208. DOI: 10.1016/J. RESUSCITATION.2010.05.016

[20] Du X, Wang X, Geng M. Alzheimer's disease hypothesis and related therapies. Translational Neurodegeneration. 2018;**7**:1-7. DOI: 10.1186/s40035-018- 0107-y

[21] Franz G, Beer R, Kampfl A, Engelhardt K, Schmutzhard E, Ulmer H, et al. Amyloid beta 1-42 and tau in cerebrospinal fluid after severe traumatic brain injury. Neurology. 2003;**60**:1457-1461. DOI: 10.1212/01. WNL.0000063313.57292.00

[22] Emmerling MR, Morganti-Kossmann MC, Kossmann T, Stahel PF, Watson MD, Evans LM, et al. Traumatic brain injury elevates the Alzheimer's amyloid peptide Aβ42 in human CSF. A possible role for nerve cell injury. Annals of the New York Academy of Sciences. 2000;**903**:118-122. DOI: 10.1111/J.1749- 6632.2000.TB06357.X

[23] Ringger NC, O'Steen BE, Brabham JG, Silver X, Pineda J, Wang KKW, et al. A novel marker for traumatic brain injury: CSF alphaIIspectrin breakdown product levels. Journal of Neurotrauma. 2004;**21**:1443- 1456. DOI: 10.1089/NEU.2004.21.1443

[24] Zhang Z, Moghieb A, Wang KKW. Neuro-proteomics and neuro-systems biology in the quest of TBI biomarker discovery. In: Biomarkers of the Brain Injury and Neurological Disorders. Boca Raton (FL): CRC Press; 2014. pp. 21-59. DOI: 10.1201/b17644-7

[25] Thompson RJ, Kynoch PAM, Sarjant J. Immunohistochemical localization of creatine kinase-BB isoenzyme to astrocytes in human brain. Brain Research. 1980;**201**:423-426. DOI: 10.1016/0006-8993(80)91046-X

[26] Toman E, Harrisson S, Belli T. Biomarkers in traumatic brain injury: A review. Journal of the Royal Army Medical Corps. 2016;**162**:103-108. DOI: 10.1136/JRAMC-2015-000517

[27] Ingebrigtsen T, Romner B. Biochemical serum markers of traumatic brain injury. The Journal of Trauma. 2002;**52**:798-808. DOI: 10.1097/ 00005373-200204000-00038

[28] Buonora JE, Yarnell AM, Lazarus RC, Mousseau M, Latour LL, Rizoli SB, et al. Multivariate analysis of traumatic brain injury: Development of an assessment score. Frontiers in Neurology. 2015;**6**:68. DOI: 10.3389/FNEUR.2015.00068

[29] Böhmer AE, Oses JP, Schmidt AP, Perón CS, Krebs CL, Oppitz PP, et al. Neuron-specific enolase, S100B, and glial fibrillary acidic protein levels as outcome predictors in patients with severe traumatic brain injury. Neurosurgery. 2011;**68**:1624-1630. DOI: 10.1227/ NEU.0B013E318214A81F

[30] Stein DM, Kufera JA, Lindell A, Murdock KR, Menaker J, Bochicchio GV, et al. Association of CSF biomarkers and secondary insults following severe traumatic brain injury. Neurocritical Care. 2011;**14**:200-207. DOI: 10.1007/ S12028-010-9496-1

[31] Topolovec-Vranic J, Pollmann-Mudryj MA, Ouchterlony D, Klein D, Spence J, Romaschin A, et al. The value of serum biomarkers in prediction models of outcome after mild traumatic brain injury. The Journal of Trauma. 2011;**71**:S478-S486. DOI: 10.1097/ TA.0B013E318232FA70

[32] Berger RP, Dulani T, Adelson PD, Leventhal JM, Richichi R, Kochanek PM. Identification of inflicted traumatic brain injury in well-appearing infants using serum and cerebrospinal markers: A possible screening tool. Pediatrics. 2006;**117**:325-332. DOI: 10.1542/ PEDS.2005-0711

[33] Gonçalves CA, Concli Leite M, Nardin P. Biological and methodological features of the measurement of S100B, a putative marker of brain injury. Clinical Biochemistry. 2008;**41**:755-763. DOI: 10.1016/J. CLINBIOCHEM.2008.04.003

[34] Calcagnile O, Undén L, Undén J. Clinical validation of S100B use in management of mild head injury. BMC Emergency Medicine. 2012;**12**:1-6. DOI: 10.1186/1471-227X-12-13

[35] Czeiter E, Mondello S, Kovacs N, Sandor J, Gabrielli A, Schmid K, et al. Brain injury biomarkers may improve the predictive power of the IMPACT outcome calculator. Journal of Neurotrauma. 2012;**29**:1770. DOI: 10.1089/ NEU.2011.2127

[36] Mondello S, Kobeissy F, Vestri A, Hayes RL, Kochanek PM, Berger RP. Serum concentrations of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein after pediatric traumatic brain injury. Scientific Reports. 2016;**6**:1-8. DOI: 10.1038/SREP28203

[37] Davidoff MS, Middendorff R, Köfüncü E, Müller D, Ježek D, Holstein AF. Leydig cells of the human testis possess astrocyte and oligodendrocyte marker molecules. Acta Histochemica. 2002;**104**:39-49. DOI: 10.1078/0065-1281-00630

[38] Welch RD, Ayaz SI, Lewis LM, Unden J, Chen JY, Mika VH, et al. Ability of serum glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, and S100B to differentiate normal and

*Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*

abnormal head computed tomography findings in patients with suspected mild or moderate traumatic brain injury. Journal of Neurotrauma. 2016;**33**:203. DOI: 10.1089/NEU.2015.4149

[39] Tate CM, Wang KKW, Eonta S, Zhang Y, Carr W, Tortella FC, et al. Serum brain biomarker level, neurocognitive performance, and self-reported symptom changes in soldiers repeatedly exposed to low-level blast: A breacher pilot study. Journal of Neurotrauma. 2013;**30**:1620-1630. DOI: 10.1089/NEU.2012.2683

[40] Puvenna V, Brennan C, Shaw G, Yang C, Marchi N, Bazarian JJ, et al. Significance of ubiquitin carboxyterminal hydrolase L1 elevations in athletes after sub-concussive head hits. PLoS One. 2014;**9**:e96296. DOI: 10.1371/ JOURNAL.PONE.0096296

[41] Zoltewicz JS, Mondello S, Yang B, Newsom KJ, Kobeissy F, Yao C, et al. Biomarkers track damage after graded injury severity in a rat model of penetrating brain injury. Journal of Neurotrauma. 2013;**30**:1161-1169. DOI: 10.1089/NEU.2012.2762

[42] Yan X-X, Jeromin A. Spectrin breakdown products (SBDPs) as potential biomarkers for neurodegenerative diseases. Current Translational Geriatrics and Experimental Gerontology Reports. 2012;**1**:85-93. DOI: 10.1007/ s13670-012-0009-2

[43] Mondello S, Robicsek SA, Gabrielli A, Brophy GM, Papa L, Tepas J, et al. αII-Spectrin breakdown products (SBDPs): Diagnosis and outcome in severe traumatic brain injury patients. Journal of Neurotrauma. 2010;**27**:1203. DOI: 10.1089/NEU.2010.1278

[44] Pineda JA, Lewis SB, Valadka AB, Papa L, Hannay HJ, Heaton SC, et al.

Clinical significance of alphaII-spectrin breakdown products in cerebrospinal fluid after severe traumatic brain injury. Journal of Neurotrauma. 2007;**24**:354- 366. DOI: 10.1089/NEU.2006.003789

[45] Sass D, Guedes VA, Smith EG, Vorn R, Devoto C, Edwards KA, et al. Sex differences in behavioral symptoms and the levels of circulating GFAP, tau, and NfL in patients with traumatic brain injury. Frontiers in Pharmacology. 2021;**12**:3367. DOI: 10.3389/ FPHAR.2021.746491

[46] Khatoon S, Grundke-Iqbal I, Iqbal K. Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains. FEBS Letters. 1994;**351**:80-84. DOI: 10.1016/0014-5793(94)00829-9

[47] Mandelkow EM, Mandelkow E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harbor Perspectives in Medicine. 2012;**2**:1-25. DOI: 10.1101/ CSHPERSPECT.A006247

[48] Duan Y, Dong S, Gu F, Hu Y, Zhao Z. Advances in the pathogenesis of Alzheimer's disease: Focusing on tau-mediated neurodegeneration. Translational Neurodegeneration. 2012;**1**:24. DOI: 10.1186/2047- 9158-1-24

[49] Yang Z, Wang P, Morgan D, Lin D, Pan J, Lin F, et al. Temporal MRI characterization, neurobiochemical and neurobehavioral changes in a mouse repetitive concussive head injury model. Scientific Reports 2015;5(1):1-15. doi:10.1038/srep11178

[50] Rubenstein R, Chang B, Davies P, Wagner AK, Robertson CS, Wang KKW. A novel, ultrasensitive assay for tau: Potential for assessing traumatic brain

injury in tissues and biofluids. Journal of Neurotrauma. 2015;**32**:342. DOI: 10.1089/ NEU.2014.3548

[51] Mandelkow EM, Mandelkow E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harbor Perspectives in Biology. 2011;**3**:1-25. DOI: 10.1101/ cshperspect.a006247

[52] Iqbal K, Grundke-Iqbal I. Ubiquitination and abnormal phosphorylation of paired helical filaments in Alzheimer's disease. Molecular Neurobiology. 1991;**5**:399-410. DOI: 10.1007/BF02935561

[53] Moretti L, Cristofori I, Weaver SM, Chau A, Portelli JN, Grafman J. Cognitive decline in older adults with a history of traumatic brain injury. Lancet Neurology. 2012;**11**:1103-1112. DOI: 10.1016/ S1474-4422(12)70226-0

[54] Sivanandam TM, Thakur MK. Traumatic brain injury: A risk factor for Alzheimer's disease. Neuroscience and Biobehavioral Reviews. 2012;**36**:1376-1381. DOI: 10.1016/J. NEUBIOREV.2012.02.013

[55] Lee PC, Bordelon Y, Bronstein J, Ritz B. Traumatic brain injury, paraquat exposure, and their relationship to Parkinson disease. Neurology. 2012;**79**:2061-2066. DOI: 10.1212/ WNL.0B013E3182749F28

[56] Dams-O'Connor K, Gibbons LE, Bowen JD, McCurry SM, Larson EB, Crane PK. Risk for late-life re-injury, dementia and death among individuals with traumatic brain injury: A population-based study. Journal of Neurology, Neurosurgery, and Psychiatry. 2013;**84**:177-182. DOI: 10.1136/JNNP-2012-303938

[57] Hu W, Tung YC, Zhang Y, Liu F, Iqbal K. Involvement of activation of asparaginyl endopeptidase in tau

hyperphosphorylation in repetitive mild traumatic brain injury. Journal of Alzheimer's Disease. 2018;**64**:709. DOI: 10.3233/JAD-180177

[58] Marklund N, Vedung F, Lubberink M, Tegner Y, Johansson J, Blennow K, et al. Tau aggregation and increased neuroinflammation in athletes after sports-related concussions and in traumatic brain injury patients - a PET/MR study. NeuroImage: Clinical. 2021;**30**:102665. DOI: 10.1016/J. NICL.2021.102665

[59] Zemlan FP, Rosenberg WS, Luebbe PA, Campbell TA, Dean GE, Weiner NE, et al. Quantification of axonal damage in traumatic brain injury: Affinity purification and characterization of cerebrospinal fluid tau proteins. Journal of Neurochemistry. 1999;**72**:741-750. DOI: 10.1046/J.1471-4159.1999.0720741.X

[60] Zemlan FP, Jauch EC, Mulchahey JJ, Gabbita SP, Rosenberg WS, Speciale SG, et al. C-tau biomarker of neuronal damage in severe brain injured patients: Association with elevated intracranial pressure and clinical outcome. Brain Research. 2002;**947**:131-139. DOI: 10.1016/S0006-8993(02)02920-7

[61] Smith DH, Chen XH, Nonaka M, Trojanowski JQ, Lee VMY, Saatman KE, et al. Accumulation of amyloid beta and tau and the formation of neurofilament inclusions following diffuse brain injury in the pig. Journal of Neuropathology and Experimental Neurology. 1999;**58**:982- 992. DOI: 10.1097/00005072- 199909000-00008

[62] Pandey S, Singh K, Sharma V, Pandey D, Jha RP, Rai SK, et al. A prospective pilot study on serum cleaved tau protein as a neurological marker in severe traumatic brain injury. British Journal of Neurosurgery. *Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*

2017;**31**:356-363. DOI: 10.1080/02688697. 2017.1297378

[63] Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet (London, England). 2011;**377**:1019-1031. DOI: 10.1016/S0140-6736(10)61349-9

[64] Wang J, Gu BJ, Masters CL, Wang YJ. A systemic view of Alzheimer disease - insights from amyloid-β metabolism beyond the brain. Nature Reviews. Neurology. 2017;**13**:612-623. DOI: 10.1038/nrneurol.2017.111

[65] Liu PP, Xie Y, Meng XY, Kang JS. History and progress of hypotheses and clinical trials for Alzheimer's disease. Signal Transduction and Targeted Therapy. 2019;**4**(1):1-22. DOI: 10.1038/ s41392-019-0063-8

[66] Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer's disease. Lancet (London, England). 2016;**388**:505-517. DOI: 10.1016/ S0140-6736(15)01124-1

[67] Xu J, Rasmussen IA, Lagopoulos J, Haberg A. Diffuse axonal injury in severe traumatic brain injury visualized using high-resolution diffusion tensor imaging. Journal of Neurotrauma. 2007;**24**:753- 765. DOI: 10.1089/NEU.2006.0208

[68] Deber CM, Reynolds SJ. Central nervous system myelin: Structure, function, and pathology. Clinical Biochemistry. 1991;**24**:113-134. DOI: 10.1016/0009-9120(91)90421-A

[69] Ming CL, Akle V, Zheng W, Kitlen J, O'Steen B, Larner SF, et al. Extensive degradation of myelin basic protein isoforms by calpain following traumatic brain injury. Journal of Neurochemistry. 2006;**98**:700-712. DOI: 10.1111/J.1471-4159.2006.03882.X [70] Ottens AK, Golden EC, Bustamante L, Hayes RL, Denslow ND, Wang KKW. Proteolysis of multiple myelin basic protein isoforms after neurotrauma: Characterization by mass spectrometry. Journal of Neurochemistry. 2008;**104**:1404-1414. DOI: 10.1111/J.1471-4159.2007.05086.X

[71] Thomas DGT, Palfreyman JW, Ratcliffe JG. Serum-myelin-basicprotein assay in diagnosis and prognosis of patients with head injury. Lancet (London, England). 1978;**1**:113-115. DOI: 10.1016/S0140-6736(78)90415-4

[72] Berger RP, Adelson PD, Pierce MC, Dulani T, Cassidy LD, Kochanek PM. Serum neuron-specific enolase, S100B, and myelin basic protein concentrations after inflicted and noninflicted traumatic brain injury in children. Journal of Neurosurgery. 2005;**103**:61-68. DOI: 10.3171/PED.2005.103.1.0061

[73] Beers SR, Berger RP, Adelson PD. Neurocognitive outcome and serum biomarkers in inflicted versus noninflicted traumatic brain injury in young children. Journal of Neurotrauma. 2007;**24**:97-105. DOI: 10.1089/ NEU.2006.0055

[74] Giacoppo S, Bramanti P, Barresi M, Celi D, Cuzzola VF, Palella E, et al. Predictive biomarkers of recovery in traumatic brain injury. Neurocritical Care. 2012;**16**:470-477. DOI: 10.1007/ S12028-012-9707-Z

[75] Yamazaki Y, Ohtaka H, Morii S, Kitahara T, Ohwada T, Yada K. Diagnostic significance of serum neuron-specific enolase and myelin basic protein assay in patients with acute head injury. Surgical Neurology. 1995;**43**:381-383. DOI: 10.1007/978-4-431-68231-8\_86

[76] Mehta T, Fayyaz M, Giler GE, Kaur H, Raikwar SP, Kempuraj D, et al. Current trends in biomarkers for traumatic brain injury. Open Access Journal of Neurology & Neurosurgery. 2020;**12**:86

[77] Wallimann T, Hemmer W. Creatine kinase in non-muscle tissues and cells. Molecular and Cellular Biochemistry. 1994;**133-134**:193-220. DOI: 10.1007/ BF01267955

[78] Rabow L, Hedman G. CKBBisoenzymes as a sign of cerebral injury. Acta Neurochirurgica. Supplementum (Wien). 1979;**28**:108-112. DOI: 10.1007/978-3-7091-4088-8\_24

[79] Kaste M, Hernesniemi J, Somer H, Hillbom M, Konttinen A. Creatine kinase isoenzymes in acute brain injury. Journal of Neurosurgery. 1981;**55**:511-515. DOI: 10.3171/JNS.1981.55.4.0511

[80] Rabow L, DeSalles AAF, Becker DP, Yang M, Kontos HA, Ward JD, et al. CSF brain creatine kinase levels and lactic acidosis in severe head injury. Journal of Neurosurgery. 1986;**65**:625-629. DOI: 10.3171/JNS.1986.65.5.0625

[81] Skogseid IM, Nordby HK, Urdal P, Paus E, Lilleaas F. Increased serum creatine kinase BB and neuron specific enolase following head injury indicates brain damage. Acta Neurochirurgica. 1992;**115**:106-111. DOI: 10.1007/BF01406367

[82] Mussack T, Kirchhoff C, Buhmann S, Biberthaler P, Ladurner R, Gippner-Steppert C, et al. Significance of Elecsys S100 immunoassay for real-time assessment of traumatic brain damage in multiple trauma patients. Clinical Chemistry and Laboratory Medicine. 2006;**44**:1140-1145. DOI: 10.1515/ CCLM.2006.190

[83] Stopfkuchen H, Schranz D, Salzmann G, Jüngst BK, Wiss M, Schwarz M. The diagnostic value of CK-MB isoenzyme determinations in children with head injury and polytrauma. Monatsschrift für Kinderheilkunde. 1984;**132**:594-599

[84] Kärkelä J, Bock E, Kaukinen S. CSF and serum brain-specific creatine kinase isoenzyme (CK-BB), neuron-specific enolase (NSE) and neural cell adhesion molecule (NCAM) as prognostic markers for hypoxic brain injury after cardiac arrest in man. Journal of the Neurological Sciences. 1993;**116**:100-109. DOI: 10.1016/0022-510X(93)90095-G

[85] Morris MC, Bercz A, Niziolek GM, Kassam F, Veile R, Friend LA, et al. UCH-L1 is a poor serum biomarker of murine traumatic brain injury after polytrauma. The Journal of Surgical Research. 2019;**244**:63-68. DOI: 10.1016/J. JSS.2019.06.023

[86] Berger RP, Pierce MC, Wisniewski SR, Adelson PD, Clark RSB, Ruppel RA, et al. Neuron-specific enolase and S100B in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatrics. 2002;**109**:E31. DOI: 10.1542/ PEDS.109.2.E31

[87] Liu M, Zhang C, Liu W, Luo P, Zhang L, Wang Y, et al. A novel rat model of blast-induced traumatic brain injury simulating different damage degree: Implications for morphological, neurological, and biomarker changes. Frontiers in Cellular Neuroscience. 2015;**9**:168. DOI: 10.3389/ FNCEL.2015.00168

[88] Verfaillie CJ, Delanghe JR. Hemolysis correction factor in the measurement of serum neuron-specific enolase. Clinical Chemistry and Laboratory Medicine. 2010;**48**:891-892. DOI: 10.1515/ CCLM.2010.159

*Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*

[89] Pfeifer R, Börner A, Krack A, Sigusch HH, Surber R, Figulla HR. Outcome after cardiac arrest: Predictive values and limitations of the neuroproteins neuron-specific enolase and protein S-100 and the Glasgow coma scale. Resuscitation. 2005;**65**:49-55. DOI: 10.1016/J. RESUSCITATION.2004.10.011

[90] Pelinka LE, Jafarmadar M, Redl H, Bahrami S. Neuron-specific-enolase is increased in plasma after hemorrhagic shock and after bilateral femur fracture without traumatic brain injury in the rat. Shock. 2004;**22**:88-91. DOI: 10.1097/01. SHK.0000130157.34382.3F

[91] Wolf H, Krall C, Pajenda G, Leitgeb J, Bukaty AJ, Hajdu S, et al. Alterations of the biomarker S-100B and NSE in patients with acute vertebral spine fractures. The Spine Journal. 2014;**14**:2918-2922. DOI: 10.1016/j. spinee.2014.04.027

[92] Kok WF, Koerts J, Tucha O, Scheeren TWL, Absalom AR. Neuronal damage biomarkers in the identification of patients at risk of long-term postoperative cognitive dysfunction after cardiac surgery. Anaesthesia. 2017;**72**:359-369. DOI: 10.1111/ ANAE.13712

[93] Yuan X, Wang J, Wang D, Yang S, Yu N, Guo F. NSE, S100B and MMP9 expression following reperfusion after carotid artery stenting. Current Neurovascular Research. 2019;**16**:129-134. DOI: 10.2174/ 1567202616666190321123515

[94] Zhang X, Ma S, Chen Y, Yin Y, Bai W, Tan J, et al. The isocitrate dehydrogenase 1 is a potential prognostic indicator for non-small cell lung cancer patients. The International Journal of Biological Markers. 2021;**36**:27-35. DOI: 10.1177/17246008211052571

[95] Missler U, Orlowski N, Nötzold A, Dibbelt L, Steinmeier E, Wiesmann M. Early elevation of S-100B protein in blood after cardiac surgery is not a predictor of ischemic cerebral injury. Clinica Chimica Acta. 2002;**321**:29-33. DOI: 10.1016/ S0009-8981(02)00061-X

[96] Okonkwo DO, Yue JK, Puccio AM, Panczykowski DM, Inoue T, McMahon PJ, et al. GFAP-BDP as an acute diagnostic marker in traumatic brain injury: Results from the prospective transforming research and clinical knowledge in traumatic brain injury study. Journal of Neurotrauma. 2013;**30**:1490-1497. DOI: 10.1089/ NEU.2013.2883

[97] Yang Z, Wang KKW. Glial fibrillary acidic protein: From intermediate filament assembly and gliosis to neurobiomarker. Trends in Neurosciences. 2015;**38**:364-374. DOI: 10.1016/J.TINS.2015.04.003

[98] Adrian H, Mårten K, Salla N, Lasse V. Biomarkers of traumatic brain injury: Temporal changes in body fluids. ENeuro. 2016;**3**:ENEURO.0294-16.2016. DOI: 10.1523/ENEURO.0294-16.2016

[99] Nylén K, Öst M, Csajbok LZ, Nilsson I, Blennow K, Nellgård B, et al. Increased serum-GFAP in patients with severe traumatic brain injury is related to outcome. Journal of the Neurological Sciences. 2006;**240**:85-91. DOI: 10.1016/J. JNS.2005.09.007

[100] Diaz-Arrastia R, Wang KKW, Papa L, Sorani MD, Yue JK, Puccio AM, et al. Acute biomarkers of traumatic brain injury: Relationship between plasma levels of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein. Journal of Neurotrauma. 2014;**31**:19-25. DOI: 10.1089/ NEU.2013.3040

[101] Hainfellner JA, Voigtländer T, Ströbel T, Mazal PR, Maddalena AS, Aguzzi A, et al. Fibroblasts can express glial fibrillary acidic protein (GFAP) in vivo. Journal of Neuropathology and Experimental Neurology. 2001;**60**:449- 461. DOI: 10.1093/JNEN/60.5.449

[102] Posti JP, Hossain I, Takala RSK, Liedes H, Newcombe V, Outtrim J, et al. Glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 are not specific biomarkers for mild CT-negative traumatic brain injury. Journal of Neurotrauma. 2017;**34**:1427- 1438. DOI: 10.1089/NEU.2016.4442

[103] Shemilt M, Boutin A, Lauzier F, Zarychanski R, Moore L, McIntyre LA, et al. Prognostic value of glial fibrillary acidic protein in patients with moderate and severe traumatic brain injury: A systematic review and meta-analysis. Critical Care Medicine. 2019;**47**:e522-e529. DOI: 10.1097/ CCM.0000000000003728

[104] Lei J, Gao G, Feng J, Jin Y, Wang C, Mao Q, et al. Glial fibrillary acidic protein as a biomarker in severe traumatic brain injury patients: A prospective cohort study. Critical Care. 2015;**19**:1- 12. DOI: 10.1186/S13054-015-1081-8/ TABLES/3

[105] Fraser DD, Close TE, Rose KL, Ward R, Mehl M, Farrell C, et al. Severe traumatic brain injury in children elevates glial fibrillary acidic protein in cerebrospinal fluid and serum. Pediatric Critical Care Medicine. 2011;**12**:319-324. DOI: 10.1097/PCC.0B013E3181E8B32D

[106] Olsson B, Zetterberg H, Hampel H, Blennow K. Biomarker-based dissection of neurodegenerative diseases. Progress in Neurobiology. 2011;**95**:520-534. DOI: 10.1016/J.PNEUROBIO.2011.04.006

[107] Persson L, Hårdemark HG, Gustafsson J, Rundström G,

Mendel-Hartvig I, Esscher T, et al. S-100 protein and neuron-specific enolase in cerebrospinal fluid and serum: Markers of cell damage in human central nervous system. Stroke. 1987;**18**:911-918. DOI: 10.1161/01.STR.18.5.911

[108] Xiong H, Liang WL, Wu XR. Pathophysiological alterations in cultured astrocytes exposed to hypoxia/ reoxygenation. Sheng Li Ke Xue Jin Zhan. 2000;**31**:217-221

[109] Donato R, Sorci G, Riuzzi F, Arcuri C, Bianchi R, Brozzi F, et al. S100B's double life: Intracellular regulator and extracellular signal. Biochimica et Biophysica Acta. 2009;**1793**:1008-1022. DOI: 10.1016/J.BBAMCR.2008.11.009

[110] Michetti F, D'Ambrosi N, Toesca A, Puglisi MA, Serrano A, Marchese E, et al. The S100B story: From biomarker to active factor in neural injury. Journal of Neurochemistry. 2019;**148**:168-187. DOI: 10.1111/JNC.14574

[111] Einav S, Shoshan Y, Ovadia H, Matot I, Hersch M, Itshayek E. Early postoperative serum S100β levels predict ongoing brain damage after meningioma surgery: A prospective observational study. Critical Care. 2006;**10**:1-10. DOI: 10.1186/CC5058/FIGURES/4

[112] Anczykowski G, Kaczmarek J, Jankowski R, Guzniczak P. The reference level of serum S-100B protein for poor prognosis in patients with intracranial extracerebral hematoma. EJIFCC. 2011;**22**:66

[113] Grevfors N, Lindblad C, Nelson DW, Svensson M, Thelin EP, Rubenson WR. Delayed neurosurgical intervention in traumatic brain injury patients referred from primary hospitals is not associated with an unfavorable outcome. Frontiers in

*Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*

Neurology. 2021;**11**:1799. DOI: 10.3389/ FNEUR.2020.610192

[114] Chen YH, Cheng ZY, Shao LH, Shentu HS, Fu B. Macrophage migration inhibitory factor as a serum prognostic marker in patients with aneurysmal subarachnoid hemorrhage. Clinica Chimica Acta. 2017;**473**:60-64. DOI: 10.1016/J.CCA.2017.08.018

[115] Jönsson H, Johnsson P, Höglund P, Alling C, Blomquist S. Elimination of S100B and renal function after cardiac surgery. Journal of Cardiothoracic and Vascular Anesthesia. 2000;**14**:698-701. DOI: 10.1053/JCAN.2000.18444

[116] Papa L, Silvestri S, Brophy GM, Giordano P, Falk JL, Braga CF, et al. GFAP out-performs S100β in detecting traumatic intracranial lesions on computed tomography in trauma patients with mild traumatic brain injury and those with extracranial lesions. Journal of Neurotrauma. 2014;**31**:1815-1822. DOI: 10.1089/NEU.2013.3245

[117] Metting Z, Wilczak N, Rodiger LA, Schaaf JM, Van Der Naalt J. GFAP and S100B in the acute phase of mild traumatic brain injury. Neurology. 2012;**78**:1428-1433. DOI: 10.1212/ WNL.0B013E318253D5C7

[118] Barbosa RR, Jawa R, Watters JM, Knight JC, Kerwin AJ, Winston ES, et al. Evaluation and management of mild traumatic brain injury: An eastern Association for the Surgery of trauma practice management guideline. Journal of Trauma and Acute Care Surgery. 2012;**73**:S307-S314. DOI: 10.1097/ TA.0B013E3182701885

[119] Zongo D, Ribéreau-Gayon R, Masson F, Laborey M, Contrand B, Salmi LR, et al. S100-B protein as a screening tool for the early assessment of minor head injury. Annals

of Emergency Medicine. 2012;**59**:209-218. DOI: 10.1016/J. ANNEMERGMED.2011.07.027

[120] Rothoerl RD, Woertgen C, Holzschuh M, Metz C, Brawanski A. S-100 serum levels after minor and major head injury. The Journal of Trauma. 1998;**45**:765-767. DOI: 10.1097/00005373- 199810000-00025

[121] Herrmann M, Curio N, Jost S, Wunderlich MT, Synowitz H, Wallesch CW. Protein S-100B and neuron specific enolase as early neurobiochemical markers of the severity of traumatic brain injury. Restorative Neurology and Neuroscience. 1999;**14**:109-114

[122] Biberthaler P, Musaelyan K, Krieg S, Meyer B, Stimmer H, Zapf J, et al. Evaluation of acute glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 plasma levels in traumatic brain injury patients with and without intracranial lesions. Neurotrauma Reports. 2021;**2**:617. DOI: 10.1089/ NEUR.2021.0048

[123] Da Rocha AB, Schneider RF, De Freitas GR, André C, Grivicich I, Zanoni C, et al. Role of serum S100B as a predictive marker of fatal outcome following isolated severe head injury or multitrauma in males. Clinical Chemistry and Laboratory Medicine. 2006;**44**:1234- 1242. DOI: 10.1515/CCLM.2006.218

[124] Rodríguez-Rodríguez A, Egea-Guerrero JJ, León-Justel A, Gordillo-Escobar E, Revuelto-Rey J, Vilches-Arenas Á, et al. Role of S100B protein in urine and serum as an early predictor of mortality after severe traumatic brain injury in adults. Clinica Chimica Acta. 2012;**414**:228-233. DOI: 10.1016/J.CCA.2012.09.025

[125] Gradisek P, Osredkar J, Korsic M, Kremzar B. Multiple indicators model of long-term mortality in traumatic brain injury. Brain Injury. 2012;**26**:1472-1481. DOI: 10.3109/02699052.2012.694567

[126] Raheja A, Sinha S, Samson N, Bhoi S, Subramanian A, Sharma P, et al. Serum biomarkers as predictors of long-term outcome in severe traumatic brain injury: Analysis from a randomized placebo-controlled phase II clinical trial. Journal of Neurosurgery. 2016;**125**:631- 641. DOI: 10.3171/2015.6.JNS15674

[127] Thelin EP, Frostell A, Mulder J, Mitsios N, Damberg P, Aski SN, et al. Lesion size is exacerbated in hypoxic rats whereas hypoxia-inducible factor-1 alpha and vascular endothelial growth factor increase in injured normoxic rats: A prospective cohort study of secondary hypoxia in focal traumatic brain injury. Frontiers in Neurology. 2016;**7**:23. DOI: 10.3389/FNEUR.2016.00023

[128] Rainey T, Lesko M, Sacho R, Lecky F, Childs C. Predicting outcome after severe traumatic brain injury using the serum S100B biomarker: Results using a single (24h) time-point. Resuscitation. 2009;**80**:341-345. DOI: 10.1016/J. RESUSCITATION.2008.11.021

[129] Egea-Guerrero JJ, Murillo-Cabezas F, Gordillo-Escobar E, Rodríguez-Rodríguez A, Enamorado-Enamorado J, Revuelto-Rey J, et al. S100B protein may detect brain death development after severe traumatic brain injury. Journal of Neurotrauma. 2013;**30**:1762. DOI: 10.1089/NEU.2012.2606

[130] Kellermann I, Kleindienst A, Hore N, Buchfelder M, Brandner S. Early CSF and serum S100B concentrations for outcome prediction in traumatic brain injury and subarachnoid hemorrhage. Clinical Neurology and Neurosurgery. 2016;**145**:79-83. DOI: 10.1016/J. CLINEURO.2016.04.005

[131] Thelin EP, Johannesson L, Nelson D, Bellander BM. S100B is an important outcome predictor in traumatic brain injury. Journal of Neurotrauma. 2013;**30**:519-528. DOI: 10.1089/ NEU.2012.2553

[132] Park SH, Hwang SK. Prognostic value of serum levels of S100 calcium-binding protein B, neuronspecific enolase, and interleukin-6 in pediatric patients with traumatic brain injury. World Neurosurgery. 2018;**118**:e534-e542. DOI: 10.1016/J. WNEU.2018.06.234

[133] Yin W, Weng S, Lai S, Nie H. GCS score combined with CT score and serum S100B protein level can evaluate severity and early prognosis of acute traumatic brain injury. Nan Fang Yi Ke Da Xue Xue Bao. 2021;**41**:543-548. DOI: 10.12122/J. ISSN.1673-4254.2021.04.09

[134] Korfias S, Stranjalis G, Boviatsis E, Psachoulia C, Jullien G, Gregson B, et al. Serum S-100B protein monitoring in patients with severe traumatic brain injury. Intensive Care Medicine. 2007;**33**:255-260. DOI: 10.1007/ S00134-006-0463-4

[135] Taheri A, Emami M, Asadipour E, Kasirzadeh S, Rouini MR, Najafi A, et al. A randomized controlled trial on the efficacy, safety, and pharmacokinetics of metformin in severe traumatic brain injury. Journal of Neurology. 2019;**266**:1988-1997. DOI: 10.1007/ S00415-019-09366-1

[136] Thelin EP, Nelson DW, Bellander BM. Secondary peaks of S100B in serum relate to subsequent radiological pathology in traumatic brain injury. Neurocritical Care. 2014;**20**:217-229. DOI: 10.1007/S12028-013-9916-0

[137] Di Battista AP, Buonora JE, Rhind SG, Hutchison MG, Baker AJ, *Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*

Rizoli SB, et al. Blood biomarkers in moderate-to-severe traumatic brain injury: Potential utility of a multi-marker approach in characterizing outcome. Frontiers in Neurology. 2015;**6**:110. DOI: 10.3389/FNEUR.2015.00110

[138] Lee JY, Lee CY, Kim HR, Lee CH, Kim HW, Kim JH. A role of serum-based neuronal and glial markers as potential predictors for distinguishing severity and related outcomes in traumatic brain injury. Journal of Korean Neurosurgical Association. 2015;**58**:93-100. DOI: 10.3340/JKNS.2015.58.2.93

[139] Thelin EP, Nelson DW, Bellander BM. A review of the clinical utility of serum S100B protein levels in the assessment of traumatic brain injury. Acta Neurochirurgica. 2017;**159**:209-225. DOI: 10.1007/S00701-016-3046-3

[140] Bloomfield SM, McKinney J, Smith L, Brisman J. Reliability of S100B in predicting severity of central nervous system injury. Neurocritical Care. 2007;**6**:121-138. DOI: 10.1007/ S12028-007-0008-X

[141] Pham N, Fazio V, Cucullo L, Teng Q, Biberthaler P, Bazarian JJ, et al. Extracranial sources of S100B do not affect serum levels. PLoS One. 2010;**5**:e12691. DOI: 10.1371/JOURNAL. PONE.0012691

[142] Piazza O, Storti MP, Cotena S, Stoppa F, Perrotta D, Esposito G, et al. S100B is not a reliable prognostic index in paediatric TBI. Pediatric Neurosurgery. 2007;**43**:258-264. DOI: 10.1159/000103304

[143] Papa L, Edwards D, Ramia M. Exploring serum biomarkers for mild traumatic brain injury. In: Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press; 2015. pp. 301-308. DOI: 10.1201/b18126

[144] Blennow K, Zetterberg H. The past and the future of Alzheimer's disease fluid biomarkers. Journal of Alzheimer's Disease. 2018;**62**:1125-1140. DOI: 10.3233/JAD-170773

[145] Li J, Yu C, Sun Y, Li Y. Serum ubiquitin C-terminal hydrolase L1 as a biomarker for traumatic brain injury: A systematic review and metaanalysis. The American Journal of Emergency Medicine. 2015;**33**:1191-1196. DOI: 10.1016/J.AJEM.2015.05.023

[146] Janigro D, Bailey DM, Lehmann S, Badaut J, O'Flynn R, Hirtz C, et al. Peripheral blood and salivary biomarkers of blood-brain barrier permeability and neuronal damage: Clinical and applied concepts. Frontiers in Neurology. 2021;**11**:577312. DOI: 10.3389/FNEUR.2020.577312

[147] Rogatzki MJ, Morgan JE, Baker JS, Knox A, Serrador JM. Protein S100B and brain lipid-binding protein concentrations in the serum of recently concussed rugby players. Journal of Neurotrauma. 2021;**38**:2247-2254. DOI: 10.1089/NEU.2021.0004

[148] Larsen CN, Price JS, Wilkinson KD. Substrate binding and catalysis by ubiquitin C-terminal hydrolases: Identification of two active site residues. Biochemistry. 1996;**35**: 6735-6744. DOI: 10.1021/BI960099F

[149] Kobeissy FH, Ottens AK, Zhang Z, Liu MC, Denslow ND, Dave JR, et al. Novel differential neuroproteomics analysis of traumatic brain injury in rats. Molecular & Cellular Proteomics. 2006;**5**:1887-1898. DOI: 10.1074/MCP. M600157-MCP200

[150] Liu MC, Akinyi L, Scharf D, Mo J, Larner SF, Muller U, et al. Ubiquitin

C-terminal hydrolase-L1 as a biomarker for ischemic and traumatic brain injury in rats. The European Journal of Neuroscience. 2010;**31**:722-732. DOI: 10.1111/J.1460-9568.2010.07097.X

[151] Papa L, Brophy GM, Welch RD, Lewis LM, Braga CF, Tan CN, et al. Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury. JAMA Neurology. 2016;**73**:551-560. DOI: 10.1001/ JAMANEUROL.2016.0039

[152] Bazarian JJ, Biberthaler P, Welch RD, Lewis LM, Barzo P, Bogner-Flatz V, et al. Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): A multicentre observational study. Lancet Neurology. 2018;**17**:782-789. DOI: 10.1016/ S1474-4422(18)30231-X

[153] Richard M, Lagares A, Bondanese V, De La Cruz J, Mejan O, Pavlov V, et al. Study protocol for investigating the performance of an automated blood test measuring GFAP and UCH-L1 in a prospective observational cohort of patients with mild traumatic brain injury: European BRAINI study. BMJ Open. 2021;**11**:e043635. DOI: 10.1136/ BMJOPEN-2020-043635

[154] Papa L, Akinyi L, Liu MC, Pineda JA, Tepas JJ, Oli MW, et al. Ubiquitin C-terminal hydrolase is a novel biomarker in humans for severe traumatic brain injury. Critical Care Medicine. 2010;**38**:138-144. DOI: 10.1097/CCM.0B013E3181B788AB

[155] Mondello S, Linnet A, Buki A, Robicsek S, Gabrielli A, Tepas J, et al. Clinical utility of serum levels of ubiquitin C-terminal hydrolase as a biomarker for severe traumatic brain injury. Neurosurgery. 2012;**70**:666-675. DOI: 10.1227/neu.0b013e318236a809

[156] Zhang R, Zhang CY, Zhao Q, Li DH. Spectrin: Structure, function and disease. Science China. Life Sciences. 2013;**56**:1076-1085. DOI: 10.1007/ S11427-013-4575-0

[157] Wang KKW, Posmantur R, Nath R, McGinnist K, Whitton M, Talanian RV, et al. Simultaneous degradation of alphaII- and betaII-spectrin by caspase 3 (CPP32) in apoptotic cells. The Journal of Biological Chemistry. 1998;**273**:22490- 22497. DOI: 10.1074/JBC.273.35.22490

[158] Pike BR, Zhao X, Newcomb JK, Posmantur RM, Wang KKW, Hayes RL. Regional calpain and caspase-3 proteolysis of alphaspectrin after traumatic brain injury. Neuroreport. 1998;**9**:2437-2442. DOI: 10.1097/00001756-199808030- 00002

[159] Pineda JA, Wang KKW, Hayes RL. Biomarkers of proteolytic damage following traumatic brain injury. Brain Pathology. 2004;**14**:202-209. DOI: 10.1111/J.1750-3639.2004. TB00054.X

[160] Farkas O, Polgár B, Szekeres-Barthó J, Dóczi T, Povlishock JT, Büki A. Spectrin breakdown products in the cerebrospinal fluid in severe head injury--preliminary observations. Acta Neurochirurgica. 2005;**147**:855-860. DOI: 10.1007/S00701-005-0559-6

[161] Svetlov SI, Larner SF, Kirk DR, Atkinson J, Hayes RL, Wang KKW. Biomarkers of blast-induced neurotrauma: Profiling molecular and cellular mechanisms of blast brain injury. Journal of Neurotrauma. 2009;**26**:913. DOI: 10.1089/NEU.2008.0609

[162] Li J, Li XY, Feng DF, Pan DC. Biomarkers associated with diffuse traumatic axonal injury: Exploring pathogenesis, early diagnosis, and

*Recent Advances in the Development of Biofluid-Based Prognostic Biomarkers of Diffuse Axonal… DOI: http://dx.doi.org/10.5772/intechopen.104933*

prognosis. The Journal of Trauma. 2010;**69**:1610-1618. DOI: 10.1097/ TA.0B013E3181F5A9ED

[163] Zetterberg H. Neurofilament light: A dynamic cross-disease fluid biomarker for neurodegeneration. Neuron. 2016;**91**:1-3. DOI: 10.1016/J. NEURON.2016.06.030

[164] Gaetani L, Blennow K, Calabresi P, Di Filippo M, Parnetti L, Zetterberg H. Neurofilament light chain as a biomarker in neurological disorders. Journal of Neurology, Neurosurgery, and Psychiatry. 2019;**90**:870-881. DOI: 10.1136/JNNP-2018-320106

[165] Van Geel WJA, Rosengren LE, Verbeek MM. An enzyme immunoassay to quantify neurofilament light chain in cerebrospinal fluid. Journal of Immunological Methods. 2005;**296**:179- 185. DOI: 10.1016/J.JIM.2004.11.015

[166] Laverse E, Guo T, Zimmerman K, Foiani MS, Velani B, Morrow P, et al. Plasma glial fibrillary acidic protein and neurofilament light chain, but not tau, are biomarkers of sports-related mild traumatic brain injury. Brain Communications. 2020;**2**:fcaa137. DOI: 10.1093/BRAINCOMMS/FCAA137

[167] Shahim P, Politis A, van der Merwe A, Moore B, Ekanayake V, Lippa SM, et al. Time course and diagnostic utility of NfL, tau, GFAP, and UCH-L1 in subacute and chronic TBI. Neurology. 2020;**95**:e623-e636. DOI: 10.1212/ WNL.0000000000009985

[168] Shahim P, Politis A, van der Merwe A, Moore B, Chou YY, Pham DL, et al. Neurofilament light as a biomarker in traumatic brain injury. Neurology. 2020;**95**:e610-e622. DOI: 10.1212/ WNL.0000000000009983

[169] Anderson KJ, Scheff SW, Miller KM, Roberts KN, Gilmer LK, Yang C, et al.

The phosphorylated axonal form of the neurofilament subunit NF-H (pNF-H) as a blood biomarker of traumatic brain injury. Journal of Neurotrauma. 2008;**25**:1079-1085. DOI: 10.1089/ NEU.2007.0488

## *Edited by Xianli Lv, Yi Guo and Gengsheng Mao*

Traumatic brain injury (TBI) has the highest incidence of all common neurological dysfunctions and is a risk factor for a variety of neurological diseases. TBI is a major public health burden and the care of TBI patients is difficult. This book provides a comprehensive overview of TBI, addressing progress and needs in research as well as challenges in treatment. Chapters address such topics as emergency room airway management in TBI, craniocerebral injury in pediatric patients, traumatic optic neuropathy, and more.

Published in London, UK © 2022 IntechOpen © wenht / iStock

Frontiers In Traumatic Brain Injury

Frontiers In

Traumatic Brain Injury

*Edited by Xianli Lv, Yi Guo and Gengsheng Mao*