Ocular changes in traumatic brain injury: A review

Abstract

Traumatic brain injury is represented by a penetrating or non-penetrating head injury, which causes disruption in the normal functioning of the brain. Traumatic brain injury has been an ardently debated topic of discussion due to its prevalence in media centric persons such as military personnel and athletes. Current assessments for traumatic brain injury have looked at vestibulo-ocular and vascular parameters to aid in diagnosis. Innovations in non-invasive ophthalmic imaging have allowed for the visualization of specific tissue structure/function relationships in a variety of ophthalmic and neurodegenerative diseases. As the eye and brain share significant embryological and physiological pathways, ocular imaging modalities may provide a novel and impactful tool in advancing assessment of traumatic brain injury. Herein, we examined the available literature and data on visual fields, mean retinal nerve fiber layer thickness, retinal ganglion cell layer thickness, and cerebral blood flow following traumatic brain injury. This review of published individual and population-based studies was performed in order to explore the feasibility and importance of considering ocular imaging biomarkers following traumatic brain injury.

Keywords

Neuroimaging trauma retina anatomy/biochemistry/physiology posterior segment complications of trauma

Introduction

Traumatic brain injury (TBI) is a disruption in normal brain function caused by a blunt injury such as a bump, blow, and jolt to the head and/or by a penetrating head injury.¹ It is estimated that over 10 million people suffer from a TBI each year worldwide. Approximately 1.7 million people sustain a TBI annually in the United States alone; nearly 80% of these patients are treated in the emergency department, 16% are treated as in-patients, and 3% result in death.² One group disproportionately affected by TBI is military personnel. Medical needs have changed in an era in which a majority of service members who sustain injury seek to return to duty. In addition, the military health system must be able to help patients stand down from duties when needed, recover as rapidly as possible, and return to full function. Following high-speed trauma, an evaluation for concomitant injuries is suggested in patients with TBI as the incidence of concomitant injuries may be as high as 78%, and these injuries can interfere with the rehabilitation and long-term outcome of the patient.³ TBI can be classified according to the severity based on the Glasgow Coma Scale, which uses eye response, verbal response, and motor response to describe a patient’s level of consciousness on a scale of 3–15. A Glasgow Coma Scale score of 13–15 indicates a mild brain injury, 9–12 suggests moderate brain injury, and 3–8 suggests a severe brain injury.^4–6

Visual complications following TBI, although not life threatening, affect functional vision and interfere with activities of daily living. Resultant damage and functional deficits can vary depending on two major factors: whether the injury was blast related or non-blast related and whether it was a penetrating or non-penetrating injury. Blast-related injuries have more than double chance of causing visual complications than non-blast-related injuries.⁷ In penetrating injuries, visual pathways and structures may be subject to physical damage such as lacerations due to fractured bone or foreign bodies. In non-penetrating injuries, also called closed-head injuries, damage to visual systems can occur due to displacement, stretching, and shearing forces.^8,9 Both mechanisms of injury are likely to result in visual deficits; many parts of the cortex involved in visual processing are located in areas vulnerable to TBI, and nearly 70% of sensory processing in the brain is related to vision.¹⁰ Recent innovations in ophthalmic imaging have allowed for the visualization of specific tissue structure/function relationships in a variety of ophthalmic and neurodegenerative diseases. As the eye and brain share significant embryological and physiological pathways, ocular imaging modalities may provide a novel and impactful tool in advancing assessment of TBI.

This review examines the current literature and data relating to ocular imaging modalities that track disturbances in ocular tissue and physiology following TBI. The main goal of this review is to explore the feasibility and importance of utilizing non-invasive ocular imaging biomarkers as tools to improve diagnostic and management options for clinicians treating persons suffering from TBI.

Materials and methods

Electronic databases utilized in the search strategy included all relevant journal articles from PubMed, Google Scholar, and Web of Science with publication dates up to February 2019. Journal article inclusion criteria were based on TBI, ocular disturbances, diagnostic approaches, repetitive brain injury, and blast injuries. The exclusionary criteria implemented included congenital brain injuries, pediatric patients, penetrating injuries, and assessments solely focusing on vestibular aspects of TBI. Keywords used in search strategy consisted of traumatic brain injury, repetitive brain injury, blast injuries, ocular factors, ocular vasculature, diagnostic modalities, imaging, optical coherence tomography (OCT), vision, and retina. Articles were also assessed for TBI diagnostic and predictors of outcome paradigms, in order to survey the current literature for up-to-date methodologies and approaches. Search parameters for the article publication date were configured to extract the most recent findings.

Structural changes in the brain following TBI

TBI is an acquired brain injury encompassing a wide range of symptoms and disabilities. In the United States, TBI causes direct and indirect medical expenses that cost an estimated US$76 billion annually and is the primary cause of disability and death in young adults. The National Institute of Neurological Disorders and Stroke (NINDS), a branch of the National Institute of Health, funds research on the full range of severity of TBI. Their goals include funding research to better understand the mechanisms behind immediate and delayed effects of TBI on brain and its function, as well as developing new therapies to prevent or reverse brain damage.¹¹

TBI includes brain contusions caused by coup and contrecoup injuries due to impact of the brain within the skull.¹² More severe damage can be caused by external forces which may lead to subdural or epidural hemorrhage, subarachnoid hemorrhage, and shearing of nerve fibers. Repetitive trauma may cause concussion in the acute phase. More importantly, it can lead to chronic traumatic encephalopathy (CTE) with deposition of tau protein, which in turn may lead to neurodegeneration.¹³ The mechanisms of brain damage following blast injuries range from direct effects of the blast through shock waves in cerebrospinal fluid (CSF) and pressure effects to secondary effects from debris which may even cause penetrating wounds.¹⁴ The advancing shock wave within the tight configuration of the skull and meninges can cause brain swelling, cerebral vasospasm, and diffuse axonal injury (DAI).^15,16 Studies aim to better understand the lasting effects of a single head injury versus repetitive injuries to the brain, how repetitive TBI might lead to CTE, and how commonly these changes occur among adults.^11,17 McKee et al. in a postmortem study have examined the brain which had repeated mild TBI. They divided the pathology into four stages. In Stage 1, the gross appearance is normal, while the microscopic appearance shows perivascular tau protein and neurofibrillary and astrocytic tangles. Stage 2 and 3 show mild–moderate enlargement of ventricles on gross appearance. Microscopically, the presence of tau and neurofibrillary tangles increases as the severity increases. They are predominant in the frontal and temporal lobes and in the hippocampus. Cerebral atrophy begins in Stage 3, and in Stage 4, the atrophy is more pronounced with enlargement of the ventricles associated with reduction in the brain weight. Presence of widespread tau and neurofibrillary tangles is seen.¹⁸

The pathology in mild TBI following blast exposure has several similarities to that following repetitive TBI. Severe and moderate TBI caused by high pressure blast waves can cause cerebral edema, intracranial hemorrhage, and vasospasm, which may also be associated with a pseudoaneurysm.^15,19 In mild TBI, the patients exhibit neuropsychiatric symptoms, long-term cognitive disability, and other forms of post-traumatic stress disorder.^20,21 Postmortem examination reveals presence of tau protein as it is seen in CTE and other forms of neurodegenerative diseases. Immunohistochemistry reveals skip phenomenon and shows multifocal, neocortical, and subcortical neurofibrillary tangles and neuritic threads. These are found predominantly in the frontal lobe²¹ and also found in temporal lobes, thalamus, and hypothalamus.²² Utilizing non-invasive imaging for monitoring TBI and exploring biomarkers to be used for diagnoses are current topics of interest. With the recent awareness to explore CTE in ex–National Football League players, neurodegenerative conditions such as TBI and CTE have become a forefront for research.

Vascular changes in the brain following TBI

Trauma-induced vascular injury represents a currently underinvestigated area in TBI research. Devastating complications following TBI can be caused, in part, by various insults, including local perfusion reduction, micro-hemorrhages, and changes in oxygen metabolism, to cerebral vasculature.^23–25 For instance, Ponto et al.²⁶ using [¹⁵O] water positron-emission tomography imaging found that mean global cerebral blood flow (CBF) was significantly lower in veterans with a history of TBI, compared to veterans with no history of TBI. In addition, the CBF of the two veteran groups at rest and under increasing emotional stimuli was examined. Those with TBI had lower global CBF, but regional CBF without emotional stimulation was similar. Those without TBI exhibited a global CBF response to stress with an inverted parabolic response (resting < low stress > high stress), while those with TBI had a “flat” response to stress. The authors interpreted this as a possible indication of impaired vascular responsivity after TBI.²⁶ Another school of thought proposes that venous damage may play a significant role in vascular damage following TBI. This argument claims that rather than resulting in arterial ischemia, increased intracranial pressure leads to a reduction in blood flow via venous compression.²³ In addition to chronic vascular effects, neuroinflammatory-related changes after blast exposure are being considered as a potential mechanism of injury.¹⁹ Multiple studies have also identified accumulation of tau protein following blast injury.²⁷

A common sequela of TBI is traumatic cerebral vascular injury (TCVI). TCVI is likely partially responsible for the functional deficits and chronic disability seen due to TBI.²⁸ In addition, specific vascular damage, including decreased CBF and prominent vasospasm, has been documented following blast exposure TBI. These changes are also accompanied by a breakdown of the blood-brain barrier and subsequent increased vascular permeability.¹⁹ The decrease in CBF following a TBI has been described as having a triphasic pattern. The first phase is hypoperfusion, which occurs during the first 24 h following TBI. Next, hyperemia occurs in post-injury days 1–3. Finally, vasospasm occurs in post-injury days 4–14. Low CBF has been linked to poorer outcomes following a TBI, and therefore, it is important to understand the mechanisms that maintain adequate CBF in TBI patients.²⁹ Chronically, magnetic resonance imaging (MRI) studies on rats and histopathologic examination following TBI have revealed evidence for reduced blood flow throughout the injured and contralateral hemisphere. Chronic reductions in blood flow can evolve slowly and may exacerbate deficits that were initiated by the acute injury. In addition, reduced blood flow can aggravate inflammatory and excitotoxic changes.³⁰ Bailey et al.³¹ showed reduced cerebral autoregulation and reduced cerebrovascular reactivity to changes in CO₂ in boxers who suffered chronic TBI. This provides evidence for impaired cerebral hemodynamic function in boxers following repetitive, subconcussive head trauma. Reduced cerebral vascular autoregulation can explain why chronic TBI manifests as a progressive disease that persists beyond a person’s athletic career.³¹ How this reduction in CBF will affect the retinal blood flow in the long term has not yet been adequately studied. Due to their shared embryological origin and shared physiology, biomarkers of both cerebral and retinal blood flow were found to be simultaneously disturbed in glaucomatous optic neuropathy.³² This, together with the data above, suggests possible merit to utilizing non-invasive ocular imaging modalities to assess significance in TBI management.

Ocular manifestations following TBI

Advances in explosive devices causing increased fragmentation have led to a rise in risk of ocular trauma following TBI to almost 50 times, relative to its total body surface area.³³ A retrospective study by Weichel et al.³⁴ (n = 152) sought to determine the impact of TBI on veterans with combative ocular trauma. The authors found that closed-globe injuries were more likely to be associated with concomitant brain injury, rather than open globes.³⁴ Patients report a wide range of visual symptoms, including decrease in visual acuity, visual field defects, difficulty with coordinated eye movements, and higher order deficits involving visual perception and visuospatial function, following a blast-induced TBI.^35,36 Retinal injuries ranged from intraretinal hemorrhages, retinal detachment, and choroidal rupture.¹⁰ Reported rates of post-chiasmal field defects detected by manual techniques in patients with TBI have ranged from 3.2% to 39%.^9,10,37–39 Patients treated as in-patients reported more visual field defects than those treated as outpatients, and these visual field defects were more common in blast injuries compared to non-blast injuries.¹⁰ One of the significant field defects observed is homonymous hemianopia. In their study of 61 military personnel exposed to blast injury, Lemke et al.⁴⁰ found that 15% of their participants had hemianopic or quadrantanopic visual field defects and 36% had abnormal global visual field indices.

Ocular complications following repeated head trauma as seen in contact sports, like boxing and football, can vary from asymptomatic lesions to severe vision-threatening complications like retinal detachment. Structures frequently affected included the iris, lens, angle of the anterior chamber, retina, and optic nerve.^41,42 Wedrich et al.⁴³ in their study of 25 asymptomatic active boxers found that 76% had pathologic ocular structural findings which were attributed to contusion trauma. Twenty-eight percent of boxers with anterior segment lesions had lesions of the posterior segment also. Peripheral retinal scars were the most common abnormality seen (60%). Other posterior segment abnormalities included posterior vitreous detachment (12%) and retinal tears or holes (24%). Significant correlations were found between the total number of bouts and total number of losses and retinal tears.^43–45

Retina in TBI

The retina is the tissue that hosts ganglion cells responsible for receiving and delivering visual stimuli to the brain. In terms of TBI, inflammation due to microglial proliferation following blast injuries can lead to visual impairments in military personnel.⁴⁶ Studies on rodents in both repetitive brain injury and blast injury have shown a decrease in the optic nerve diameter and a thinning of the retinal nerve fiber layer (RNFL) following TBI.^47,48 Research using blast-induced animal models (mice) showed an increased activation of inflammatory markers, glial fibrillary acidic protein, and loss of retinal ganglion cells (RGCs).⁴⁶ An in vitro study utilizing adipose-derived stem cells, pre-stimulated with inflammatory cytokines, mitigated visual dysfunction following blast injuries via reduced expression of inflammatory cytokines.⁴⁶

In a study observing 16 Olympic boxers over a period of 18 months, researchers noted that the macula and RNFL of the boxers showed thinning on OCT, compared to healthy sedentary controls.⁴⁹ In patients with acquired post-geniculate visual pathway lesions, a reduction of the circumpapillary RNFL thickness corresponding to hemianopic visual field loss was detected using spectral domain optical coherence tomography (SD-OCT).⁵⁰ In addition, this change was more evident at 24 months than at the initial visit. This further change suggests that retrograde trans-synaptic degeneration (RTSD) is at least partially responsible for RNFL thinning following TBI.⁵⁰ This phenomenon has also been observed in the degeneration of RGCs following damage to structures in the posterior visual pathway.⁵¹ RTSD was previously thought to be seen in congenital lesions only,^52–54 but it has since been demonstrated in acquired lesions as well, such as the posterior visual pathway lesions.^55–58 Evidence of RGC damage may not always be found initially, especially if the lesion is small.⁵⁶ The trans-synaptic neuronal degeneration may cascade over time, increasing permanent disability over a period of time after the initial central nervous system damage. Although the limits to this cascade are not known, recent findings suggest that when trans-synaptic degeneration occurs in a retrograde direction, this process does not extend over more than one synapsing neuron.⁵⁹ In a study on patients affected by multiple sclerosis, it is noted that RTSD stops at the inner nuclear layer, a neuronal network capable of plasticity. However, this was not seen in the primary visual cortex, rendering the structure vulnerable to anterograde trans-synaptic degeneration.⁵⁹

When imaging the retina to detect damage following TBI, it is important to evaluate which area of the retina will yield the most consistent and accurate results. Segmentation of retinal layers has allowed the study of functional areas in greater detail. The macula has the highest density of RGCs and, therefore, may be the optimal location to detect early damage of RGCs. In addition, optic disk edema may obscure axonal loss at the optic nerve head, making the macula an even better candidate for RGC analysis.⁶⁰ This is supported by studies that have demonstrated that patients with optic tract lesions and optic chiasm compression have macular RGC thinning.^61,62 Atrophy of the RGC layer serves as a good predictor of poor visual function and can correlate topographically with the visual field deficits present. For instance, in patients with glaucoma or chiasmal tumors, RGC layer atrophy has been demonstrated to correlate with permanent visual field loss.^63,64 Because the eye and brain share embryological tissue origins and in some diseases share aspects of pathophysiology, we propose that RGC damage following TBI may cause parallel changes in the visual fields.

Following TBI, damage to retrogeniculate areas subserving vision can lead to defects in the visual field, including scatter field defects,⁶⁵ homonymous hemianopia, or homonymous quadrantanopia.⁴⁶ This can lead to impairment of reading skills (hemianopic dyslexia) and limitations of daily activities such as driving, which can have a significant impact on an individual’s socioeconomic status and quality of life.⁵⁶ Trans-synaptic degeneration of the visual pathway has been demonstrated in both an anterograde pattern and a retrograde pattern in neurodegenerative diseases such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and glaucoma.^66–70 Vien et al.⁷¹ discussed a clinical case study of a patient with RTSD demonstrated by progressive thinning of the RNFL following TBI. The patient was 2 months removed from a motorcycle accident causing severe TBI. Using an SD-OCT taken 10 months before the trauma and serial SD-OCTs following trauma, RNFL thinning was detected as early as 2 months after trauma. The authors asserted that the rate of regression of the RNFL was fastest in the initial 2 months after trauma and slowed down in the ensuing 4–5 months.⁷¹ Further studies are needed to understand the mechanisms involved in the sequence of events following TBI and their respective effects on visual function.

Retinal oximetry is a non-invasive ocular imaging technique that provides assessment of oxygen content and extraction of major retinal blood vessels. Retinal oximetry may be useful in understanding how TBI affects retinal oxygen delivery and utilization. Specifically, this technique provides insight into oxygen utilization in the retina, and therefore retinal metabolism, by determining the amount of oxyhemoglobin (HbO₂) versus deoxyhemoglobin (Hb) in retinal vessels.⁷² Following TBI, the alteration in the microcirculation is multifactorial. For example, it has been reported that damaged and edematous tissue can compress extrinsic microvasculature, causing smooth muscle contraction of resistance arterioles and induction of intravascular thrombosis.⁷³ Hemoglobin, which is released as a consequence of post-traumatic subarachnoid hemorrhage, may also play a role in trauma-induced microvascular disturbance.⁷³

Retinal photographic oximetry has shown to be useful in identifying reduced oxygen arterio-venous (A/V) ratios in other neurogenerative diseases such as glaucoma. For instance, Olafsdottir et al.⁷⁴ found that in neurodegenerative conditions like glaucoma, greater visual field defects were associated with increased retinal venous oxygen saturation and decreased A/V difference, presumably implying poorer oxygen extraction from the retinal arterioles.

The effect of TBI on the anatomy and vascular structure of the retina has so far been an underinvestigated area. The results of this review yielded one study that examined retinal microvasculature changes in patients with mild TBI.⁷⁵ The study quantitatively assessed retinal vascular parameters including vessel caliber, fractal dimensions, tortuosity, and bifurcation in patients with mild TBI at a preliminary visit and 6-month follow-up. The findings suggested that arteriolar and venous tortuosity was significantly increased after mild TBI. Even after adjustment for age in an analysis of a covariance model, the findings remained consistent. Recent advances in imaging modalities, such as SD-OCT, SD-OCT angiography (SD-OCTA), Heidelberg retinal flowmeter (HRF), and retinal oximetry, allow non-invasive imaging and quantification of retinal thickness, retinal vessel density, blood flow, and oxygen saturation. SD-OCTA provides high-resolution three-dimensional (3D) images of the blood flow and vessel density in the superficial and deep retinal plexus of the retina. This novel non-invasive imaging technique may provide insight into neural pathologies with vascular components, such as TBI.

Conclusion

There is a lack of prospective data on TBI and related changes to ocular structure and function. With both established and newly emerging non-invasive ocular imaging modalities, the potential to elucidate novel biomarkers in TBI may be realized. The ocular manifestations following TBI are potentially numerous, involving anatomic, physiologic, and neural dysfunction in both the anterior and posterior segments of the eye. This review focused on ocular and vascular parameters in TBI and their potential usefulness in TBI diagnosis and prognosis. Several studies have demonstrated changes in CBF following TBI,^23,28,76 but its effect on retinal blood flow has never been thoroughly studied. Similarly, there have been no studies on humans measuring the changes in the oxygen saturation in the retinal vessels following TBI. In theory, using modalities, such as SD-OCT, SD-OCTA, retinal flowmetry, and retinal oximetry, may provide a novel, safe, non-invasive, approach to quantify changes in retinal thickness, retinal blood flow, and oxygen saturation after TBI. If proven, these biomarkers will provide new research horizons for developing improved screening and prognostic evaluations in TBI patients.

Footnotes

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Alon Harris would like to disclose that he receives remuneration from Shire, CIPLA, and AdOM for serving as a consultant. Dr Harris also holds an ownership interest in AdOM, Nano Retina, and Oxymap. All relationships listed above are pursuant to Indiana University’s policy on outside activities. The contribution of the author Alice C. Verticchio Vercellin was supported by Fondazione Roma and by the Italian Ministry of Health.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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