Abstract
Traumatic brain injury (TBI) is one of the major cause of morbidity and mortality and it affects more than 1.7 million Americans each year. Depending on its location and severity, TBI leads to structural and functional damage in several parts of the brain such as cranial nerves, optic nerve tract or other circuitry involved in vision, and occipital lobe. As a result, the function associated with vision processing and perception are significantly affected and cause blurred vision, double vision, decreased peripheral vision and blindness. In this mini-review, we will focus the recent progress made to understand the pathology and underlying cellular/molecular mechanisms involved in the impairment of the integrity of visual systems following TBI.
Introduction
Traumatic brain injury (TBI) is one of the major causes of morbidity and mortality in the world and is multifactorial in nature (Feigin et al., 2013; Hyder et al., 2007; Rondina et al., 2005). Primary damage can happen by the mechanical forces at the moment of the injury but the secondary pathology results from the occurrence of multiple cellular, neurochemical and metabolic factors. Contact mechanisms of primary damage result either from an object striking the head or from contact between brain and skull, while acceleration/deceleration mechanisms of TBI result from an unrestricted head movement that leads to shear, tensile and compressive strains resulting in widespread damage to axons and blood vessels (Goodrich et al., 2007; Taber et al., 2006). TBI can be classified as focal, and diffuse (Harmon et al., 2013; Management of Concussion/m, 2009; Menon et al., 2010). The focal TBI results from the impact of the brain against the cranium which leads to contusions on the brain and subdural hemorrhage (Taber et al., 2006). The standard neuroimaging such as CT or MRI is usually employed to diagnose the focal injury (Chalela et al., 2007). On the other hand, the primary diffuse injury is an ongoing process consisting of hypoxic brain damage, brain swelling, vascular injury, and axonal injury which is the most common characteristic feature of diffusion injury (Taber et al., 2006). The most common locations for diffuse injury at the junction of gray matter-white matter, internal capsule, upper brainstem, and corpus callosum. MRI is reportedly more sensitive than CT in detecting the diffuse injury (Chalela et al., 2007; Lee and Newberg, 2005; Moreau et al., 2013). The severity of TBI depends on not only on the pre-injury condition but also secondary mechanisms such as cell death, inflammation, edema, neurogenesis impairment and axonal damage associated with TBI (Cernak and Noble-Haeusslein, 2010; Faden, 2002).
Despite the fact that TBI affects a significant part of the brain, vision impairment following TBI has not been well studied. Clinical studies suggest that TBI-patients have been suffering from various vision-related issues including photophobia, double vision, blurred vision, loss of vision, palsy, optic nerve abnormalities and visual processing problems (McCann and Seiff, 1994; Sarkies, 2004; Warner and Lessell, 1995; Warner and Eggenberger, 2010). A substantial number of studies are aimed to understand the alteration in the integrity of the visual system that can provide the critical information of vision related issues and helps screen and monitor the recovery of patients with TBI. Thus in this mini-review, we highlight the visual function deficits which are common in mild and moderate TBI along with molecular mechanisms associated with optic neuropathy and the vision deficits following TBI.
Traumatic optic neuropathy
Traumatic optic neuropathy can result from a direct and indirect injury (Levin, 2004; Sarkies, 2004; Steinsapir and Goldberg, 2011; Warner and Eggenberger, 2010). Direct injury results from the penetrating injury, however, the indirect injury results from the transmission of the forces from the distant site to the optic nerve which includes optic nerve head, intraorbital, intercanalicular, or intracranial portion. Both the direct and indirect traumatic event affects the optic nerve and causes functional impairment of vision (Steinsapir and Goldberg, 2011). Although, the optic nerve injury is the most common event after TBI but the diagnosis of optic nerve injuries in acutely injured patients are sometimes challenging for the clinicians. Using several imaging techniques and ophthalmoscopic studies the direct optic nerve injury can be classified in the following manner
Optic nerve avulsion: It is characterized by the absence of optic disc and a sign of hemorrhage and mostly occurs following several orbital trauma. More specifically, the optic nerve is damaged at the lamina crib rosa due to the rotation of the globe and results in an increase in intraocular pressure. This can be diagnosed by optical imaging and ultrasound imaging (Sawhney et al., 2003; Schumann et al., 2013; Ventura et al., 2014).
Optic nerve transection: It adversely affects sensitivity towards the light that can be evidenced by visual evoked potentials. This kind of damage results from midfacial trauma and orbital fracture (Levkovitch-Verbin, 2004; Magharious et al., 2011; Ventura et al., 2014).
Optic nerve sheath hemorrhage: It is identified as an expansion of nerve sheath with proptosis that ultimately leads to the hematoma. Detection of nerve sheath hemorrhage is challenging to clinicians (Budenz et al., 1994; Leeuw et al., 2015; Ventura et al., 2014).
Orbital hemorrhage: Typically this kind of damage is associated with proptosis and ophthalmoplegia and results in an increase in intraocular pressure (Brooks and Finkelstein, 1984; Krohel and Wright, 1979; Ventura et al., 2014).
Orbital emphysema: A hair-line fracture in the orbital wall causes an accumulation of air in the orbit that ultimately leads to proptosis and compression of the eye and nerve (Caesar et al., 2003; Gauguet et al., 2008; Ventura et al., 2014).
During the traumatic optic neuropathy from the indirect injury, the impact of head injury is transmitted to the optic nerve that may ultimately lead to blindness. In general, the injury on the forehead but not in the temporal region is responsible for blindness along with a loss of consciousness (Anderson et al., 1982; Atkins et al., 2008; Walsh, 1966). The histopathological analysis suggests that there was a significant hemorrhage in the optic nerve sheath and the nerve interstitium associated with shearing lesions and ischaemic necrosis of the intercanalicular and intracranial segments of the nerve (Crompton, 1970). The anterior indirect traumatic optic damage results from the separation of the optic nerve on the globe due to the rotation of the globe after trauma (Keane and Baloh, 1992). Impairment in the retinal blood circulation another critical factor that contributes to the optic neuropathy and is associated with axonal injury. The posterior indirect injury results in several vision defects including decreased color vision and field defects due to the either frontal or midfacial blow and can be diagnosed by fundoscopy along with the ophthalmic examination such as decreased acuity (Atkins et al., 2008). However, if the injury is severe, it can cause the loss of consciousness in 40–72% of patients (Blyth and Bazarian, 2010). Interestingly, the intracanalicular portion of the optic nerve is the most susceptible to posterior indirect optic damage which will be followed by shearing and ischemia that will cause vision loss as a long term effect (Atkins et al., 2008; Blyth and Bazarian, 2010). Moreover, a fracture within the canal is also considered as an indirect optic neuropathy and be diagnosed using CT imaging. The diagnosis of posterior optic neuropathy varies depending on how long after optic nerve injury patients are studied (Atkins et al., 2008; Blyth and Bazarian, 2010; Ventura et al., 2014).
Increased intracranial pressure (ICP) is associated with worse outcomes following TBI. Studies have confirmed that ICP is correlated with optic nerve sheath diameter (ONSD) on ultrasound (Blyth and Bazarian, 2010). Alteration in the ONSD is closely associated with mortality in patients with severe traumatic brain injury. The use of clinical markers to predict ICP is desirable as a first line measure to assist in decision making as to whether invasive monitoring is required. Correlations between ICP and ONSD using CT and Magnetic resonance imaging (MRI) have been observed in adult populations (Young et al., 2016). The ultrasonographic measurement of the ONSD is known to be an accurate monitor of elevated ICP (Blyth and Bazarian, 2010). However, it is yet unknown whether fluctuations in ICP result in direct changes in ONSD. In patients who have sustained a TBI, ultrasonography of the ONSD is an accurate, simple, and rapid measurement for detecting elevated ICP as well as immediate changes in ICP. Therefore, it might be a useful tool to monitor ICP, especially in conditions in which invasive ICP monitoring is not available, such as at trauma scenes (Maissan et al., 2015). Another interesting study using linear regression shows that ONSD was independently associated with increased ICP during initial hours. A total of 220 patients were included in the analysis. Overall, the cohort had a mean age of 35 years and 171 of 220 were male. The median admission GCS was 6 (Sekhon et al., 2014). The correlation between ONSD and mortality was further supported by another study where the enlargement of ONSD on initial CT scan has been found to be associated with increased mortality after severe TBI. This could offer the possibility to detect patients with raised ICP requiring urgent therapeutic interventions and/or invasive intracranial monitoring to guide the treatment. More specifically it is suggested that ONSD measured on the initial brain CT scan is independently associated with ICU mortality rate particularly when less than 7.3 mm which is the most common in severe TBI patients (Legrand et al., 2013).
Optic chiasm and related pathways
Severe head injury mostly results in traumatic chiasmal syndrome and the prevalence of this syndrome is about 3 in 326 patients. This syndrome is associated with a skull fracture and cranial neuropathy and causes deficits in pituitary and hypothalamus. Other associated injuries include carotid cavernous fistulae, traumatic carotid aneurysm, and meningitis associated with cerebrospinal fluid leakage. The loss of retinal ganglion cells and NFL layers following chiasmal syndrome can be monitored by Optical Coherence Tomography (OCT). On the other hand 9–14% of TBI patients showed the symptoms of the retro chiasmal syndrome. Basically, the occurrence of retro chiasmal defects increases with the severity of TBI may be due to an increased level of shearing (Domingo and de Villiers, 1993; Hassan et al., 2002; Van Stavern et al., 2001; Ventura et al., 2014).
Ocular motor neuropathies
One of the other reported injuries is oculomotor nerve injury and it ranges from 3–11% of TBI patients. During this injury, cranial nerve III is mostly affected compared to cranial nerve IV and VI although GCS scores are not so higher. Clinical studies suggest that cranial nerve III injury shows the discontinuation of the nerve from its exit from the midbrain. Other studies have shown that traumatic edema or hemorrhage causes hemination which leads to compression of cranial nerve III or the nerve can be contused over the skull base. Cranial nerve IV injury has been observed in 3–13% of TBI patients. Interestingly, cranial nerve IV is the thinnest one and being affected due to the impact of the contusions and hematomas resulted due to an impact on the midbrain. It was also observed that injuries related to cranial nerve VI are shown to 4–6% of TBI patients. However, cranial nerve VI injury is generally associated with a flexion-extension injury which results from the vertical movement of the brain following trauma. An elevated intracranial pressure due to edema or hemorrhage results in delayed abducens injury which also affect cranial nerve VI injury (Chen et al., 2005; Coello et al., 2010; Dhaliwal et al., 2006; Kim and Chang, 2013; Ventura et al., 2014).
Axonal injury following TBI
Much of the morbidity after TBI is associated with TAI (Traumatic Axonal Injury). Although most TAI studies focus on corpus callosum white matter, the visual system has received increased interest. Persistent RGC survival was also consistent with the finding of reorganization in the proximal axonal segments after TAI, wherein microglia remained inactive. In contrast, activated microglia/macrophages closely enveloped the distal disconnected, degenerating axonal segments after injury (Wang et al., 2013). However, the question is that whether TAI within the injured brain is related with specific anterograde and retrograde consequences following TBI. It was observed that delayed axonal swelling was consistent with the disconnection. But there are some differences between the proximal and distal swelling. It was shown that the proximal swellings showing regression and reorganization, while the distal swellings persisted, although showing signs of impending degeneration. Collectively, the results of this study within the injured optic nerve provide a great insight into the evolving pathobiology associated with TAI (Wang et al., 2011).
TBI-related vision defects can be associated with psychological, motor or developmental symptoms which can complicate accurate diagnosis and treatment. Recent studies suggest that an alteration in axonal structures is well correlated with posttraumatic phases following TBI. Maxwell et al hypothesized that spreading depression results in depolarization of central glia, disrupt axonal ionic homeostasis, injure axonal mitochondria and allow the onset of axonal degeneration throughout an increasing volume of brain tissue; and contribute toward post-traumatic continued loss of white matter (Maxwell, 2013). Moreover, there is increasing evidence in the experimental and clinical TBI literature that loss of central myelinated nerve fibers continues over the chronic post-traumatic phase after injury. Myelin dislocations occur within internodal myelin of larger axons after TBI. The myelin dislocations contain elevated levels of free calcium. The volume of myelin dislocations increase with greater survival and are associated with disruption of the axonal cytoskeleton leading to secondary axotomy. Calpains, a family of Ca2+-dependent proteases, have been implicated in this pathologic cascade. It was shown that overexpression of the endogenous calpain inhibitor calpastatin in optic nerve axons partially preserved axonal transport after stretch injury. These results provide direct evidence that axonal calpains play a causal role in transport disruption after in vivo stretch injury (Ma et al., 2012).
There are known limitations of conventional computed tomography and MRI in detecting neural injury in patients with mild TBI. Diffusion tensor imaging (DTI) provides a method to further assess cerebral injury in this patient population, who showed visual field defects after mild TBI (Jang and Seo, 2015). The DTI was also used to determine if central axonal injury is associated with vestibulopathy and ocular convergences. Studies in patients suggest that posttraumatic vestibulopathy contributes significantly to axonal injury. Thus DTI evaluation of vestibular structures may provide a diagnostic imaging tool in patients and may serve as a biomarker to aid the prognosis (Alhilali et al., 2014). Recently, Red/near-infrared irradiation therapy (R/NIR-IT) delivered by laser or light-emitting diode (LED) has improved functional outcomes in a range of CNS injuries. However, this technique was not useful in clinical settings because of its two critical drawbacks 1) it can not provide discrete information regarding the degree of penetration and 2) it lacks optimal treatment parameters for different CNS injury. Thus, further optimization in delivery devices, wavelength, intensity, and duration of R/NIR-IT is required to reconsider the laser therapy for different CNS injury types (Giacci et al., 2014).
The loss of Retinal Ganglion Cells (RGC) following TBI
The ongoing loss of white and gray matter from the injured brain is common during the chronic phase and this can be monitored by MRI in humans. Loss of myelinated fibers continued throughout the experimental period upto 12 weeks in guinea pig stretch-injury optic nerve model of TBI. There were hypertrophy and proliferation of glial cells within the surrounding neuropil (Mohammed Sulaiman et al., 2011; Sofroniew and Vinters, 2010). The most rapid loss was of the largest fibers; loss of intermediate-sized fibers continued, but the numbers of the smallest fibers increased from 3 weeks onward. An interesting study was done where much of intact and pyknotic retinal ganglion cells was compared with the loss of white and gray matter. It was observed that a relatively low-grade loss of RGCs occurred throughout the experiment, with about 60% remaining at 12 weeks’ survival. Moreover, quantitative evidence shows that after traumatic axonal injury (TAI) there is a continuing loss of nerve fibers and their cell bodies from a CNS tract over a 3-month post-traumatic interval (Mohammed Sulaiman et al., 2011).
Transsynaptic retrograde degeneration (TRD) can occur as soon as 2 months after severe TBI with damage posterior to the lateral geniculate nucleus. Progressive RNFL loss can be tracked with SD-OCT, and the rate of thinning may slowly stabilize over time. Visual field defects can improve months after the trauma but may not correspond to the progressive RNFL loss detected by SD-OCT (Vien et al., 2016). A recent study has shown that TAI does not induce retinal ganglion cell (RGC) death which was monitored by a quantification of immunoreactivity of Brn3a, an RGC marker. It was also demonstrated that there is no RGC loss, which is further confirmed by the electron microscopic analysis where RGC viability remains unaltered. Persistent RGC survival was also consistent with the finding of reorganization in the proximal axonal segments after TAI, wherein microglia/macrophages remained inactive. In contrast, activated microglia/macrophages are associated with the distal disconnected, degenerating axonal segments after injury (Wang et al., 2013). Collectively, these data provide novel insight into the pathology associated with TAI wherein axonal degeneration functions with microglia activation and RGC survival in a concerted manner (Wang et al., 2013). However, optic nerve crush injury leads to the death of RGCs, both as a direct result of the primary injury and via secondary degeneration induced by neurotoxins secreted by dying RGCs. Studies have shown that, if optic nerve crush is preceded by an unrelated injury to another part of the central nervous system, for example, the spinal cord, the ensuing T cell-mediated protective autoimmunity results in a significant increase in RGC survival.
This data suggests that brain injury sustained a certain time before optic nerve injury has a protective effect on RGC survival, but this neuroprotective effect appears to be unrelated to retinal BDNF (Ben Simon et al., 2006). Previously, Kruppel-like factor 4 (KLF4) has been reported to negatively regulate axon regeneration of injured RGCs through inhibition of JAK-STAT3 signaling and blocking KLF4 may be a potential therapeutic strategy for the treatment of TBI (Cui et al., 2016). Recently, a novel neuroprotective compound P7C3-S243 has shown to prevent in vivo functional deficits in the visual system via preventing the loss of RGC (Dutca et al., 2014), although the mechanism has not been elucidated yet.
Conclusion
TBI-related vision defects can be associated with psychological, motor or developmental symptoms which can complicate accurate diagnosis and treatment. The method to measure ONSD using CT scan, however, needs further confirmation about the specificity of the technique. Moreover, the link between ONSD enlargement on an initial CT scan and raised intracranial pressure also needs to be confirmed by further studies (Masquere et al., 2013). Previously, it was shown that repeated mild TBI produced more acute neuron death and glial reactivity than a single TBI along with persistent behavioral dysfunction and chronic pathological changes within the visual system but the symptoms are not associated with lengthening the inter-injury interval (Bolton Hall et al., 2016). More studies are needed to understand in depth how repeated TBI affects the structural and functional integrity of visual systems. As a part of the cellular mechanism, it was shown that optic neuropathy, axonal injury and the loss of RGC contributes significantly to the vision impairment following TBI (Figure 1). The molecular mechanisms associated with these cellular changes have not been well studied. However, the Brn3a and BDNF have been shown to contribute for loss of RGC and an activation of calpain has been associated with axonal injury following TBI. Of course more studies are needed to understand these molecular mechanisms in detail. In addition, the PERG testing serves as a noninvasive test in the living organism to identify early damage to the visual system, which may reflect corresponding damage in the brain that is not otherwise detectable by noninvasive means. This provides the basis for developing an earlier diagnostic test to identify patients at risk for developing chronic visual system damage after TBI, particularly at an earlier stage.
Figure 1.
A schematic representation on how TBI leads to vision impairment.
Acknowledgments
N.S is supported by funding from NIH (RO1EY025622 and RO1NS094516).
Footnotes
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