TBI and the Neuro-Ophthalmologist: Afferent Symptoms and Signs

Traumatic brain injury (TBI) and concussion have received wide attention in the news due to its high incidence and the devastating short and long-term negative impact it can impart on affected patients and their families. It touches the lives of all ages and has been made a major funding priority for clinical and research investigation by granting agencies(1-3). The main causes of traumatic brain injury include motor vehicle accidents, falls, assault, sports trauma, and exposure to improvised explosive devices (IEDs) by military personnel. The epidemiology, pathology and medical management have been recently reviewed.

TBI AND THE NEURO-OPHTHALMOLOGIST: AFFERENT SYMPTOMS AND SIGNS Randy Kardon, MD, PhD University of Iowa Iowa City, IA LEARNING OBJECTIVES 1. List the abnormalities in the afferent visual system that have been reported with TBI and evidence for progressive neural degeneration in the visual system following TBI 2. Describe mechanisms of light sensitivity experienced after TBI 3. Describe brain areas showing loss of functional connectivity by resting fMRI after TBI CME QUESTIONS 1. To date, which of the following outcome measures has shown the most significant worsening in the years following mild TBI: A. Contrast sensitivity B. Pupil light reflex C. Retinal nerve fiber layer D. Retinal ganglion cell layer E. Automated perimetry global indices 2. Which of the following best defines the diagnosis of Chronic Traumatic Encephalopathy (CTE): A. Cognitive worsening over time B. Worsening depression over time culminating in suicidal ideation C. Progressive deterioration of CNS white matter by MRI diffusion tensor imaging (DTI) D. Progressive loss of white matter by MRI volume imaging E. Autopsy findings of a characteristic pattern of tau deposition in brain sulci 3. Which has been shown to be the most likely cause of photosensitivity in the setting of traumatic brain injury (TBI): A. Increase in retinal melanopsin with associated increase in the post-illumination pupil response B. Lowered rod and cone threshold response to light C. Increase in sensitivity of intra-retinal circuitry causing an increase in ganglion cell input of light signals to the brain D. Increase in sensitivity of visual cortex neurons E. Increase in sensitivity of recipient light responsive CNS neurons resulting in an exaggerated nociceptive grimace response KEYWORDS 1. 2. 3. 4. 5. Optical Coherence Tomography (OCT) Retinal Nerve Fiber Layer Light Reflexes Photosensitivity Higher Cortical Functions BACKGROUND Traumatic brain injury (TBI) and concussion have received wide attention in the news due to its high incidence and the devastating short and long-term negative impact it can impart on affected patients and their families. It touches the lives of all ages and has been made a major funding priority for clinical and 374 | North American Neuro-Ophthalmology Society research investigation by granting agencies(1-3). The main causes of traumatic brain injury include motor vehicle accidents, falls, assault, sports trauma, and exposure to improvised explosive devices (IEDs) by military personnel. The epidemiology, pathology and medical management have been recently reviewed (4). There has been a growing concern that repeated head impact injuries can lead to a Chronic Traumatic Encephalopathy (CTE), which is a diagnosis made at autopsy, revealing a characteristic pattern of brain atrophy with associated tau deposition in sulci of the brain, neurofibrillary tangles, and evidence of chronic inflammation (5-10). Prior to death (often from suicide) these patients often have a history of progressive dementia, disinhibition with emotional lability, depression and post-traumatic stress disorder (PTSD). Recently, there has been alarming evidence that CTE can occur years after even just one episode of TBI (11). Eye care and neurology providers are frequently called upon to evaluate visual symptoms in patients with a history of head trauma. Many of these patients have visual complaints such as light sensitivity, often associated with headaches and orbital pain (12), difficulty reading, and reduced performance of cognitivebased visual tasks in their daily activities such as driving, skilled sports, and playing video games (12,13). With the exception of obvious visual field defects caused by direct trauma to the visual pathways, most patients exhibit a normal eye exam, in spite of their visual complaints. There is a suspicion that higher order visual-cognitive functions have become impaired due to diffuse axonopathy causing deficits in connectivity between visual and cognitive areas of the brain, as revealed by functional MRI. The difficulty in identifying the source of visual complaints underscores the diagnostic and treatment dilemma facing healthcare providers, rehabilitation specialists, employers, teachers, athletic administrators and patients. Currently, our standard tests of visual function are relatively insensitive to detecting TBI-based effects on the visual system and response to treatment (14). More extensive neurobehavioral testing is often required to elucidate specific cognitive deficiencies which require visual input. Various tests of vision have also been proposed as subclinical indicators for monitoring acute and chronic effects of TBI in order to make decisions about return to sports, return to work or return to military duty. These include visual acuity, contrast sensitivity (15,16), saccadic eye movement tasks (17,18), quantification of fixation instability, convergence deficiency (19), pupil light reflex abnormalities (20-23) corneal blink reflex evoked by air puff (24), and evoked potentials from the retina and visual cortex (25,26). Many sensory and neurologic functions are acutely affected immediately following head trauma, but there is no evidence yet as to whether the acute changes measured are predictive of chronic deficits (17). Acute sensory biomarkers of traumatic brain injury and return to baseline A great deal of investigation has gone into identifying acute biomarkers that can be detected following head injury. The main motivation has been to use some quantifiable measure for identifying an index of severity of CNS dysfunction after acute head trauma and for monitoring recovery. Potential indicators of acute head trauma, that are easily accessible have included a battery of brief neurocognitive tests, measures of balance performance, hearing, eye movements (including tests of saccades, pursuit, convergence), contrast sensitivity, pupil light reflex and serum biomarkers such as neurofilament light. The following tests of afferent visual function have been found to be acutely affected after head trauma: • the pupil light reflex • the mechanical (CO2 puff) corneal blink reflex • contrast sensitivity and visual acuity • evoked potentials from the eye Indeed, there are a number of indicators that reflect an acute change in afferent ocular functional status after head trauma when compared to baseline pre-TBI measurements in the same subject or to a normal, matched cohort. However, the sensitivity and specificity of these tests are limited by the overlap in test 2021 Annual Meeting Syllabus | 375 results with normal cohorts and repeat measurement variability which render them suboptimal. None have emerged as clear predictors of permanent dysfunction, since most acute changes of these indicators resolve over a relatively short period of time. There is a critical need to relate acute changes in function to chronic effects of trauma resulting in progressive neurodegeneration over time. This is no easy task because such a study would require baseline testing and then repeat testing immediately after head impacts, followed by long term follow up in a susceptible population such as individuals in contact sports or military personnel pre and post training with follow up after active duty with exposure to blast or head trauma. At present, acute changes, which are mostly reversible, have yet to provide predictive value for long-term deficits. Chronic sensory biomarkers of traumatic brain injury and neuro-degeneration over time Through a grant from the DOD and VA administered through the Chronic Effects of Neurotrauma Consortium (CENC) my colleagues and I at the Minneapolis VA, Palo Alto VA and Iowa City VA performed a longitudinal study of 69 veterans with mild TBI and 70 age-matched control veterans examined every 3-6 months with the following testing: visual acuity, contrast sensitivity, pupil light reflex, optical coherence tomography (OCT) of the retinal layers, neurocognition, MRI and functional MRI (at rest with eyes closed). Subjects were tested over a period ranging from 18 months to 5 years to determine any evidence of progressive neurodegenerative changes over the study period. The purpose of this longitudinal study was to discover whether structural and functional measures of the visual pathway revealed evidence for longterm progressive worsening over time in veterans with a history of one or multiple episodes of head trauma from concussion or blast injury. Locations within the afferent sensory pathway that potentially can be affected by traumatic brain injury • Photoreceptors – commotio retinae • Retinal ganglion cells – OCT thinning of ganglion cell complex after mild TBI • Visual radiations • Visual cortex • Cortical neural networks – reduced connectivity between visual cortex and cognitive areas of the brain such as pre-frontal cortex revealed by fMRI • Trigeminal neural networks (12) – leading to photosensitivity and post-traumatic headache (similar to migraine) Optical coherence tomography (OCT) is recognized as a non-invasive imaging technology utilized quantify the layers of the retina with high resolution at the micron level with high precision and repeat measurement reproducibility. The relationship between OCT measures of retinal layer thinning and degree of CNS neurodegeneration has been well-established in disorders such as Alzheimer Disease, Parkinson Disease, and multiple sclerosis (MS). OCT has been used to detect neurodegeneration in preclinical models of TBI (27-29) and in a few human studies (30,31), but longitudinal studies have been lacking. Our recently completed longitudinal study, funded by the VA and DOD through the Chronic Effects of Neurotrauma Consortium (CEMC) aimed to identify evidence of neurodegeneration through longitudinal evaluation of structural and functional changes in the visual and central nervous system in veterans with a history of mild TBI. Mild TBI has been the main focus of preclinical and clinical studies because it is the most prevalent form of TBI in both the civilian (e.g. sports, motor vehicle and work-related head injuries) and military populations (e.g. blast injury and related concussions from improvised explosive devices). The results of this study showed that progressive thinning of the retinal nerve fiber layer (RNFL) but not ganglion cell layer, occurred significantly more in mild TBI compared to matched control veterans (JAMA Network Open, in press). Some functional measures such as contrast sensitivity also showed lesser deterioration over time. Volume of occipital cortex also decreased over an 18-month measurement period, even years after mild TBI. Functional MRI also showed disconnections between visual cortex and prefrontal 376 | North American Neuro-Ophthalmology Society cortex in veterans with a history of mild TBI (32). This is the first longitudinal study of subjects with mild TBI showing evidence for chronic neurodegeneration years after initial head trauma. Neuro-inflammation and the immune system’s role in chronic effects of TBI on afferent sensory neurons While traumatic brain injury (TBI) has long been considered a static event, TBI is better classified as a chronic disease process1. Those with a history of TBI, including mild TBI (mTBI), are at greater risk for neurodegenerative diseases, such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Chronic Traumatic Encephalopathy (CTE). It is suspected that mTBI may initiate a process of persistent neuroinflammation and long-term gray and white matter atrophy leading to progressive neural degeneration over time. Several large studies have shown an association between a history of TBI and an increased risk of AD and PD (33), even in individuals with no known cognitive impairments after TBI. These findings raise the important question about the long-term consequences of mTBI, culminating in Chronic Traumatic Encephalopathy (CTE), even in the absence of dysfunction following acute injury or after seemingly complete recovery of function after an acute head injury. Surprisingly, a recent study of rugby players found that CTE could eventually occur even after a single head injury (11). Serum biomarkers may predate, by many years, the development of cognitive and functional deficits (34-36). Longitudinal studies can provide critical information on the temporal arc between the earliest biomarker changes after acute TBI and the subsequent cognitive and functional deficits impacting independence and quality of life. Based on autopsy studies from the Boston Brain Bank at the Boston University and VA under the direction of Dr. Ann McKee, there is significant evidence for a neuroinflammatory process in the brains from patients diagnosed at autopsy with CTE (7,37), which could account for the chronic progressive nature of the neurodegeneration that occurs years after head trauma. Recently, in preclinical models of blast injury in rodents, our research group at the Iowa City VA Center for the Prevention and Treatment of Visual Loss has demonstrated an immunologic response that occurs following TBI that can be passively transferred from blood of animals receiving blast injury to naïve animals not receiving blast injury, resulting in loss of retinal ganglion cells. Through recent funding from the VA the details of the immunologic response to blast injury are being investigated. This line of research may be very important in understanding the immune mechanisms and its potential therapeutic modulation in preventing chronic neurodegeneration after TBI. Similar passive transfer of an immune response has also been demonstrated in glaucoma and multiple sclerosis. SUMMARY Acute traumatic brain injury has been demonstrated to have immediate effects on the afferent visual system, which are short lasting. However, recently there has been evidence for progressive neurodegeneration in the visual system of veterans over time, many years after TBI, based on OCT of the RNFL and MRI of visual cortex, that is greater than seen in a matched aging cohort without TBI. Pathology of brains after TBI has shown evidence of neural degeneration with tau deposition that is thought to spread through a prion-like process and is also accompanied by evidence of chronic neuroinflammation. CME ANSWERS 1. C 2. E 3. E REFERENCES 1. Houston MN, O'Donovan KJ, Trump JR, Brodeur RM, McGinty GT, Wickiser JK, D'Lauro CJ, Jackson JC, Svoboda SJ, Susmarski AJ, Broglio SP, McAllister TW, McCrea MA, Pasquina P, Cameron KL. Progress and Future Directions of the NCAA-DoD Concussion Assessment, Research, and Education (CARE) 2021 Annual Meeting Syllabus | 377 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Consortium and Mind Matters Challenge at the US Service Academies. 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