Neuro-Ophthalmic Injuries With Systemic Neurologic Injury or Traumatic Brain Injury in Operation Iraqi Freedom and Operation Enduring Freedom

Background: To analyze the final visual acuity (VA) of neuro-ophthalmologic injuries (NOI) in combat ocular trauma and to study the association of NOI with systemic neurologic injury (SNI) and traumatic brain injury (TBI). Methods: The Walter Reed Ocular Trauma Database was reviewed. Inclusion criteria were any US service member and Department of Defense civilians who suffered NOI, SNI, or TBI in Operation Iraqi Freedom or Operation Enduring Freedom. The primary outcome measure was the rate of poor final VA in patients with an NOI with secondary outcome measures the rate of SNI and TBI. in patients with NOI. Results: One hundred seventy-eight (20.00%) of 890 eyes had an NOI. Optic nerve injury was observed in 79 (44.38%) eyes, other cranial nerve injury in 68 (38.20%), Horner syndrome in 4 (2.25%), diplopia in 45 (25.28%), and ptosis in 13 (7.30%). In patients with NOI, 76 (42.69%) eyes had a final VA less than 20/200. In injured eyes (n = 359) of patients (n = 251) with TBI, 154 eyes (34.26%) had a final VA less than 20/200. In multivariate analysis, optic nerve injury (P < 0.001), unlike TBI (P = 0.47), was associated with final VA less than 20/200. SNI (n = 229) had a statistically significant association (odds ratio 29.8, 95% confidence interval 19.2-47.8, P < 0.001) with NOI. Optic nerve injury and cranial nerve injury were associated with TBI and SNI (all, P < 0.001). Conclusion: Optic nerve injury and cranial nerve injury are associated with TBI and SNI. Optic nerve injury, but not TBI or cranial nerve injury, is associated with a poor final VA.

Clinical Research: Epidemiology Meets Neuro-Ophthalmology Section Editors: Heather E. Moss, MD, PhD Stacy L. Pineles, MD Neuro-Ophthalmic Injuries With Systemic Neurologic Injury or Traumatic Brain Injury in Operation Iraqi Freedom and Operation Enduring Freedom Alexandria F. Jaksha, MD, Grant A. Justin, MD, Daniel I. Brooks, PhD, Cameron J. Elward, BS, Denise S. Ryan, MS, Eric D. Weichel, MD, Marcus H. Colyer, MD Background: To analyze the final visual acuity (VA) of neuroophthalmologic injuries (NOI) in combat ocular trauma and to study the association of NOI with systemic neurologic injury (SNI) and traumatic brain injury (TBI). Methods: The Walter Reed Ocular Trauma Database was reviewed. Inclusion criteria were any US service member and Department of Defense civilians who suffered NOI, SNI, or TBI in Operation Iraqi Freedom or Operation Enduring Freedom. The primary outcome measure was the rate of Baumholder Army Health Clinic (AFJ), Landstuhl Regional Medical Center, Landstuhl, Germany; Department of Ophthalmology (GAJ), Brooke Army Medical Center, San Antonio, Texas; Department of Surgery (GAJ, MHC), Uniformed Services University of the Health Sciences, Bethesda, Maryland; Department of Research Programs (DIB), Walter Reed National Military Medical Center, Bethesda, Maryland; School of Medicine (CJE), Uniformed Services University of the Health Science, Bethesda, Maryland; Warfighter Refractive Eye Surgery Program and Research Center (DSR), Fort Belvoir, Virginia; Retina Group of Washington DC (EDW), Greenbelt, Maryland; and Department of Ophthalmology (MHC), Walter Reed National Military Medical Center, Bethesda, Maryland. Supported by the Office of the Assistant Secretary of Defense for Health Affairs under the Broad Agency Announcement for Extramural Medical Research, BAA-16-R-BAA1 under Award No. W81XWH-17-2-0007. Abstract was presented at the American Academy of Ophthalmology Annual Meeting, October 30th, 2018, Chicago, IL. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the US Army Medical Department, the US Army Office of the Surgeon General, the Department of the Air Force, the Department of the Army, Department of Defense, the Uniformed Services University of the Health Sciences, or any other agency of the US Government. Address correspondence to Grant A. Justin, MD, Brooke Army Medical Center, 3551 Roger Brooke Drive, San Antonio, TX 78219; E-mail: [e-mail] 322 poor final VA in patients with an NOI with secondary outcome measures the rate of SNI and TBI. in patients with NOI. Results: One hundred seventy-eight (20.00%) of 890 eyes had an NOI. Optic nerve injury was observed in 79 (44.38%) eyes, other cranial nerve injury in 68 (38.20%), Horner syndrome in 4 (2.25%), diplopia in 45 (25.28%), and ptosis in 13 (7.30%). In patients with NOI, 76 (42.69%) eyes had a final VA less than 20/200. In injured eyes (n = 359) of patients (n = 251) with TBI, 154 eyes (34.26%) had a final VA less than 20/200. In multivariate analysis, optic nerve injury (P , 0.001), unlike TBI (P = 0.47), was associated with final VA less than 20/200. SNI (n = 229) had a statistically significant association (odds ratio 29.8, 95% confidence interval 19.2-47.8, P , 0.001) with NOI. Optic nerve injury and cranial nerve injury were associated with TBI and SNI (all, P , 0.001). Conclusion: Optic nerve injury and cranial nerve injury are associated with TBI and SNI. Optic nerve injury, but not TBI or cranial nerve injury, is associated with a poor final VA. Journal of Neuro-Ophthalmology 2020;40:322-327 doi: 10.1097/WNO.0000000000000913 © 2020 by North American Neuro-Ophthalmology Society W ith the increased prevalence of improvised explosive device (IED) blast trauma and survival of combat injury in modern warfare, severe ocular injuries have increased (1-6). Previous studies have found that in populations of ocular injuries, approximately 5%-66% occur with neurologic injuries (3,7-17). These neurologic injuries frequently include neuro-ophthalmic injuries (NOI) and traumatic brain injury (TBI). The incidence of concomitant TBI and ocular injury has been investigated (3,18-21); however, these studies encompass populations that are difficult to compare due to their exclusion criteria. Few studies have covered rates of specific NOI and concomitant systemic neurologic injury (SNI). The objectives of this study were 3-fold: report on the incidence of NOI and associated SNI and TBI in combat Jaksha et al: J Neuro-Ophthalmol 2020; 40: 322-327 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology ocular trauma; analyze various NOI and their association with SNI and TBI; and assess the rate of poor final visual acuity (VA) less than 20/200 in NOI and complete a multivariate analysis to study whether NOI and TBI were risk factors for poor final visual outcome. METHODS This study was a retrospective compilation of data from US service members or Department of Defense (DoD) civilians injured in Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). Patients were evacuated between 2001 and 2011 from the respective theater of operations in Iraq or Afghanistan most often to Landstuhl Regional Medical Center (LRMC), Germany, and then on to the former Walter Reed Army Medical Center (WRAMC) in Washington, DC. Institutional Review Board approval was obtained from WRAMC, which developed the Walter Reed Ocular Trauma Database (WROTD). Further description of the data collection is outlined in previous studies (3,9). Data were collected on Microsoft Excel (Microsoft Corporation, Redmond, WA), housed on SPSS (IBM, New York), and then transferred to statistical software (STATA 14.0, College Station, TX) for data analysis. Inclusion criteria were patients who were either US service members or DoD civilians injured in OIF and/or OEF recorded in the WROTD who had an NOI as defined as an optic nerve injury, optic nerve avulsion, ptosis, diplopia, cranial nerve injury, and/or Horner syndrome. All NOI injuries, symptoms (diplopia), and diagnoses (optic nerve injury, other cranial nerve injury, Horner syndrome, and ptosis) were defined based off of review of patient records and what was diagnosed by the managing ophthalmologists. In addition, a separate database review was completed for patients with a TBI to assess both its association with NOI and effect on final VA. Exclusion criteria were injuries sustained outside of a combat-related injury or non-DoD civilian trauma. The primary outcome measure was the rate of poor final VA in patients with an NOI with secondary outcome measures being the rate of associated SNI and TBI. Using the Birmingham Eye Trauma Terminology (BETT) and converting Snellen acuities to vision grades, injuries were classified and analyzed (22). Grade 1 was equivalent to 20/40 or better, Grade 2 was 20/50 to 20/ 200, Grade 3 was 19/200 to 1/200, Grade 4 was hand motion or light perception, and Grade 5 was no light perception. The patients' ocular trauma scores (OTS) were calculated as described by Kuhn et al (23). When a patient was first conscious, providers assessed initial VA; however, because some of these wartime injuries were urgent and/or severe cases, VA often could not be tested until after initial surgeries and many times not until after they had arrived at WRAMC. For the entire data set (n = 890), 57 patients were intubated, and 44 eyes were missing data for initial Jaksha et al: J Neuro-Ophthalmol 2020; 40: 322-327 VA. Per protocol, providers tested VA in the immediate postinjury period (as possible), 20-50 days after injury, 150-200 days after injury, and finally at the last documented VA date. Realistically, in many cases, only initial and final VAs were obtained. Because of the limitations of documentation, intermediate VAs were not analyzed, but the eyes without intermediate VAs were not excluded from the data set. Statistical Analysis Univariate analysis was completed using the Fisher exact test for categorical variables and the Wilcoxon rank-sum test with continuity correction for continuous variables. Odds ratios (ORs) and 95% confidence intervals (CIs) given for categorical variables were also computed through the Fisher method. Multivariate analysis was completed using binomial logistic regression; significance was assessed using the Type 3 likelihood ratio test as implemented in the "car" package (24). Univariate and multivariate analyses discarded cases with missing information and analyzed records in which none of the variables tested in that analysis had missing values; proportions and incidence rates counted the total number of positive incidences over the total number of eyes in the set. Alpha was set at 0.05 for all analyses. RESULTS Neuro-ophthalmic Injuries A total of 178 (20.00%) of 890 eyes in the WROTD had an NOI as described in Table 1. Patient demographic information, mechanism of injury, and eye protection use were compiled (Table 1). A list of previously reported rates of NOI was completed (See Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A386) (3,8,10,17,19,21,25-37). Initial and final VA scores and OTS were recorded in Table 2. Systemic Neurology Injuries Analyses were completed to review associated systemic neurologic injuries to NOI as demonstrated by Table 3. Of all subjects in the WROTD with SNI (n = 229), there was a statistically significant relationship (OR 29.8, 95% CI 19.2-47.8, P , 0.001) with neuro-ophthalmic injury. Traumatic Brain Injury A separate subanalysis of all subjects in the WROTD with a TBI (n = 251 patients, 359 eye injuries) was completed: 79 eyes were noted with an afferent pupillary defect, 47 eyes had a reported optic nerve injury, 17 patients experienced diplopia, 3 eyes were associated with a Horner syndrome, and 45 eyes were associated with a cranial nerve injury. Associations between specific NOI injuries and TBI were studied (Table 3). In addition, a separate analysis of the initial and final VA and OTS for patients with TBI injuries is presented in Table 4. 323 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology TABLE 1. Neuro-ophthalmic injury incidence by type (n = 178) Neuro-ophthalmic Injuries and Signs Afferent pupillary defect Diplopia Other cranial nerve injury Horner syndrome Optic nerve avulsion Optic nerve injury Ptosis Demographics Unilateral injuries Bilateral injuries Average age (yrs) Injured in Iraq Injured in Afghanistan Mechanism Improvised explosive device Gunshot wound Motor vehicle accident Rocket propelled grenade Other Mine Mortar Helicopter crash Eye protection Adherent Nonadherent Undocumented Incidence 76 45 68 4 13 79 13 94 84 27.8 159 19 93 27 19 18 9 4 4 2 (42.70%) (25.28%) (38.20%) (2.25%) (7.30%) (44.38%) (7.30%) (52.81%) (47.19%) (range 19-48) (89.33%) (10.67%) (52.25%) (15.17%) (10.27%) (10.11%) (5.06%) (2.25%) (2.25%) (1.12%) 48 (26.97%) 34 (19.10%) 96 (53.93%) Risk of Poor Visual Acuity A multivariate analysis was completed to compare risk factors for poor final VA less than 20/200. For this analysis, retinal detachment, globe rupture, and perforating injury were included as they are components of the OTS. Optic nerve injury was selected instead of a relative afferent pupillary defect (fourth component of the OTS), as at times the afferent pupillary defect that was recorded in the WROTD may have been completed by a nonophthalmologist. Endophthalmitis, the last component of the OTS, was not included as it was very rare in the WROTD. Phthisis was selected because it was a common cause of blindness in this cohort. Cranial nerve injury was selected because of its common association with TBI and SNI. Finally, TBI and SNI were included. Optic nerve injury, retinal detachment, phthisis, globe rupture, and penetrating injury were all significant risk factors (all P , 0.001) for final VA less than 20/200. Cranial nerve injury (P = 0.6) and TBI (P = 0.47) were equivocal, and SNI was noted to have a negative correlation with poor visual outcome (P = 0.007). DISCUSSION Neuro-ophthalmic trauma occurs commonly in combat injuries because of a variety of mechanisms of injury and along various components of the visual pathway. Blast 324 injuries from IEDs have led to a higher rate of TBI and NOI than in civilian trauma. Animal studies have demonstrated blast injuries cause NOI along the entire visual pathway, not isolated to a particular region (38-41). At the cellular level, blast injuries cause hypertrophy of astrocytes, physical destruction of the neuron cytoskeleton, ionic imbalances, and ultimately cell death (42). Our analysis demonstrated an NOI rate of 20.00% in 890 combat injured eyes. Previous rates of NOI in ocular trauma have a wide range (5%-66%) with wartime trauma generally having a higher rate (3,7-17). Combat injuries place patients at increased risk of multisystem trauma and high-energy injuries. NOI may be more prevalent in these injury patterns because of the less localized injury. However, in our study of patients injured in combat, we found the rate of NOI in ocular trauma closer to the distribution of civilian than previously reported combat rates. There is a wealth of literature in civilian ocular trauma that discusses the rates of specific NOI in ocular injuries. Optic nerve injury represents approximately 20% of all ocular trauma (3,7), while cranial nerve injury among all ocular trauma has been noted at 6% (3). However, it can be difficult to compare civilian studies with our study as they often focus on different sets of NOI signs or represent highly specified subsections of the population. In addition, the mechanism of injury often involves a higher velocity object in military trauma with the introduction and use of IEDs. One study (26) noted 2% of civilian ocular traumas were open globe injuries, 0.5% were optic nerve injuries, and the most common cause of ocular injury was superficial foreign bodies (33%). In the WROTD, 37.98% of eyes had open globe injuries, 8.88% had optic nerve injuries, and 33.03% of total eyes had orbital fractures. These data suggest that the rates of optic nerve injuries and open globe injuries were more prevalent in OIF and OEF in ocular traumas, compared with civilian settings, and this can likely be attributed to high velocity mechanism of injury in IED blasts in the combat environment. Differentiating between diffuse TBI-dependent visual impairment and a specific NOI pathway injury visual impairment can be difficult. A study of civilian trauma demonstrated 11% of TBI patient suffered a concurrent Zone 3 injury or approximately 5 mm posterior to the limbus (43). A study by Brahm et al (44) found that combat injured inpatients and outpatients with TBI had VA loss of 20/200 or less of 13% and 1.6%, respectively. Previous research indicates 39%-66% of wartime patients with mild-severe TBI have some form of ocular injury (9,45). Civilian trauma studies similarly revealed 30%-40% TBI patients suffer an ocular injury (46,47). More specifically, the rates of optic nerve injuries in patients with TBI have been reported at rates of 0.1%-22% (18,48,49). In our study, we found that approximately 35% of patients with a TBI had a final VA less than 20/200. Although optic nerve injuries (P , 0.001) have been found to be a risk Jaksha et al: J Neuro-Ophthalmol 2020; 40: 322-327 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology TABLE 2. Ocular trauma score (OTS) and VA in neuro-ophthalmic injuries (n = 178) OTS Category (Raw Score) No. of Eyes, % 5 (91-100) 4 (81-90) 3 (66-80) 2 (45-65) 1 (0-44) Adnexal Neurologic Unknown 16 9 23 40 23 17 34 16 Initial VA Grade No. of Eyes, % Grade 1 ($20/40) Grade 2 (20/200-20/50) Grade 3 (1/200-19/200) Grade 4 (LP/HM) Grade 5 (NLP) Unknown 62 18 12 31 39 16 (34.84) (10.11) (6.74) (17.42) (21.91) (8.99) Final VA Grade (8.99) (5.06) (12.92) (22.47) (12.92) (9.55) (19.10) (8.99) No. of Eyes, % Grade 1 ($20/40) Grade 2 (20/200-20/50) Grade 3 (1/200-19/200) Grade 4 (LP/HM) Grade 5 (NLP) Unknown 73 12 12 19 45 17 Change in Visual Acuity (41.10) (6.74) (6.74) (10.67) (25.28) (9.55) No. of Eyes, % Improved Worsened No change Unknown Initially intubated 53 14 84 18 9 (34.54) (4.74) (40.67) (11.14) (8.91) HM, hand motion; LP, light perception; NLP, no light perception; VA, visual acuity. factor for final VA less than 20/200, in our study, TBI itself was not (P = 0.47). However, TBI was more likely to occur with OTS Category 1 or 2 injuries (OR 1.55, 95% CI 1.1- 2.18, P = 0.01). From our review of the literature, there is a paucity of analyses studying the relationship of systemic neurologic injuries and NOI. We found that patients who had systemic neurologic injuries had a very strong relationship (OR 29.8, 95% CI 19.2-47.8, P , 0.001) with NOI. Direct optic nerve injuries and cranial nerve injuries (P , 0.001) but not diplopia, ptosis, Horner, or optic nerve avulsion were associated with an SNI. However, the latter injuries had very low observed rates in our study, and this may contribute to their lack of significance. In addition, although counterintuitive, a negative correlation was found between SNI and poor visual outcome (P = 0.007) in the multivariate model. This is likely due to the strength of association between the other variables in this model and poor visual outcome. Further research into this observation is required. These data demonstrate the importance of having patients with an NOI be evaluated by the neurology service for associated systemic neurologic injuries. There were multiple limitations to this study. Wartime injuries are urgent, and in severe cases, the initial VA could not be tested until after surgery or late in the patient's care. This made calculating OCT and predicted VA outcomes troublesome for certain patients. In addition, relatively poor longitudinal patient data tracking from the point of injury to WRAMC, where some patients were rapidly transferred from WRAMC to other hospitals, made long-term TABLE 3. Systemic neurologic injury and traumatic brain injury and associated specific neuro-ophthalmic injury Systemic Neurologic Injury Injury Optic nerve injury Optic nerve avulsion Ptosis Cranial nerve injury Horner TBI OR 95% CI P Injury OR 95% CI P 3.42 1.56 0.99 4.05 0.56 2.08-5.65 0.40-5.46 0.22-3.58 2.38-7.00 0.01-5.72 ,0.001 0.54 1 ,0.001 0.7 Optic nerve injury Optic nerve avulsion Ptosis Cranial nerve injury Horner 2.4 1.3 1.02 2.98 1.78 1.45-3.98 0.35-4.48 0.28-3.58 1.74-5.22 0.2-21.5 ,0.001 0.78 1 ,0.001 0.66 CI, confidence interval; OR, odds ratio; TBI, traumatic brain injury. Jaksha et al: J Neuro-Ophthalmol 2020; 40: 322-327 325 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology TABLE 4. Ocular trauma score (OTS) and visual acuity in traumatic brain injury (n = 359 eyes) OTS Category (Raw Score) No. of Eyes, % 5 (91-100) 4 (81-90) 3 (66-80) 2 (45-65) 1 (0-44) Adnexal Neurologic Unknown Initial VA Grade Grade 1 ($20/40) Grade 2 (20/200-20/50) Grade 3 (1/200-19/200) Grade 4 (LP/HM) Grade 5 (NLP) Unknown 56 28 56 59 43 27 34 56 No. of Eyes, % 111 38 27 59 68 56 (30.92) (10.58) (7.52) (16.43) (18.94) (15.60) Final VA Grade Grade 1 ($20/40) Grade 2 (20/200-20/50) Grade 3 (1/200-19/200) Grade 4 (LP/HM) Grade 5 (NLP) Unknown (15.60) (7.80) (15.60) (16.43) (11.98) (7.52) (9.47) (15.60) No. of Eyes, % 182 26 15 27 81 28 (50.70) (7.24) (4.18) (7.52) (22.56) (7.8) HM, hand motion; LP, light perception; NLP, no light perception; VA, visual acuity. outcomes difficult to assess. Patients with neuro-ophthalmic injuries unrecognized at the point of injury, minimal enough to not be evacuated from theater, or severe enough that they resulted in death before arriving to Walter Reed Army Medical Center were not captured in this study. Finally, systemic neurologic injuries, TBI, ptosis, and diplopia were loosely defined in our study, and further specific analysis examining peripheral vs central neurologic injuries is needed. In conclusion, this article raises interesting associations between NOI and SNI and TBI. NOI occurs commonly in combat eye injuries (20%) and is very strongly associated with SNI and TBI. Cranial nerve injuries and optic nerve injuries are associated with SNI and TBI (all, P , 0.001). Direct optic nerve injury, but not TBI or cranial nerve injury, was a risk factor for a poor final VA less than 20/ 200. Future wartime ophthalmic databases should include better characterization of NOI and its correlation with TBI and SNI. 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