Ocular Motor Nerve Palsy After Traumatic Brain Injury: A Claims Database Study

Traumatic brain injury (TBI) is one of the common causes of ocular motor nerve (oculomotor nerve [CN3], trochlear nerve [CN4], and abducens nerve [CN6]) palsies, but there has been no large study of ocular motor nerve palsy caused by TBI. This study aimed to investigate the characteristics of and differences in ocular motor nerve palsy after TBI, according to patient age and severity of TBI.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Ocular Motor Nerve Palsy After Traumatic Brain Injury: A Claims Database Study Hwan Heo, MD, PhD, Scott R. Lambert, MD Background: Traumatic brain injury (TBI) is one of the common causes of ocular motor nerve (oculomotor nerve [CN3], trochlear nerve [CN4], and abducens nerve [CN6]) palsies, but there has been no large study of ocular motor nerve palsy caused by TBI. This study aimed to investigate the characteristics of and differences in ocular motor nerve palsy after TBI, according to patient age and severity of TBI. Methods: This was a population-based retrospective cohort study that included patients who had ocular motor nerve palsy after TBI with $6 months of continuous enrollment using claims data from the IBM MarketScan Research Databases (2007–2016). We assessed sex, age at the first diagnosis of TBI, the severity of TBI, and the rates of strabismus procedures according to the age and severity of TBI. The rates of muscle transposition surgery and chemodenervation in CN3, CN4, and CN6 palsy were investigated. Results: A total of 2,606,600 patients with TBI met the inclusion criteria. Among them, 1,851 patients (0.071%) had ocular motor nerve palsy after TBI. The median age of the patients was 39 (Q1–Q3: 19–54) years, and 42.4% of the patients were female. The median continuous enrollment period after the first diagnosis of TBI was 22 (Q1– Q3: 12–38) months. Of the 1,350,843 children with TBI, 454 (0.026%) had ocular motor nerve palsy. Of the 1,255,757 adults with TBI, 1,397 (0.111%) had ocular motor nerve palsy. Among these 1,851 patients, CN4 palsy (697, 37.7%) occurred most frequently, and strabismus procedures were performed in 237 patients (12.8%). CN6 palsy developed most frequently in children. More children (16.5%) underwent strabismus surgeries than adults (11.6%) (P = 0.006). The proportion of CN4 palsy (52.3%) was higher while the proportion of CN3 palsy (15.5%) was Department of Ophthalmology (HH, SRL), Stanford University School of Medicine, Palo Alto, California; and Department of Ophthalmology (HH), Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea. Supported by National Institutes of Health Grants P30 EY026877 and Research to Prevent Blindness, Inc. The authors declare no conflict 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). Address correspondence to Scott R. Lambert, MD, Byers Eye Institute, 2452 Watson Ct, Palo Alto, CA 94303; E-mail: lambert7@ stanford.edu Heo and Lambert: J Neuro-Ophthalmol 2023; 43: 131-136 lower in patients with mild TBI than in patients with moderate-to-severe TBI (P , 0.001). Conclusions: CN4 palsy developed most frequently among patients of all ages, and only approximately 13% of the patients underwent strabismus procedures for ocular motor nerve palsy after TBI. The rate of development of ocular motor nerve palsy was approximately 4.3 times lower in children than adults, and children most frequently had CN6 palsy after TBI. Journal of Neuro-Ophthalmology 2023;43:131–136 doi: 10.1097/WNO.0000000000001635 © 2022 by North American Neuro-Ophthalmology Society T raumatic brain injury (TBI) is being increasingly recognized as a major cause of morbidity and mortality worldwide, with estimates of its incidence ranging from 106 to 790 per 100,000 people per year (1,2). Mild TBI frequently leads to disruptions in visual functioning, while moderate or severe TBI often causes structural lesions (3). TBI is one of the common causes of ocular motor nerve (oculomotor nerve [CN3], trochlear nerve [CN4], and abducens nerve [CN6]) palsies. Traumatic damage to the ocular motor nerve may be caused by stretching, tearing, contusion, or compression (4). Nevertheless, the frequency of ocular motor nerve palsy after TBI has not been previously studied in a large population. This study aimed to investigate the incidence of and differences in ocular motor nerve palsy after TBI according to patient age and the severity of TBI. METHODS Study Design and Data Source This population-based retrospective cohort study was performed using claims data from the IBM MarketScan Research Databases (2007–2016). The MarketScan Databases include more than 240 million patients insured by 350 unique health carriers. These databases include health insurance claims across the continuum of care (inpatient, 131 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution outpatient, outpatient pharmacy, and carve-out behavioral healthcare) and enrollment data from large employers and health plans across the United States. The data set includes the International Classification of Disease 9th and 10th revision (ICD-9-CM and ICD-10-CM, respectively) diagnosis codes and Current Procedural Terminology (CPT) version 4 procedure codes. Data access for this project was provided by the Stanford Center for Population Health Science Data Core, which is supported by the National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085) and internal Stanford funding. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH). The Stanford University School of Medicine Institutional Review Board determined that this study did not require IRB approval because all data were deidentified. Study Population Patients who were diagnosed with ocular motor nerve palsy (CN3, CN4, and CN6 palsy) after TBI (see Supplemental Digital Content, Table 1, http://links.lww.com/WNO/ A608) were enrolled in the study. We only included patients who had ICD codes for CN3, CN4, or CN6 palsy within 3 months after the diagnosis of TBI and had continuous enrollment for $6 months from the time of the first diagnosis of TBI. Patients who were diagnosed with CN3, CN4, or CN6 palsy, as well as patients who had CPT codes for strabismus surgeries (CPT codes: 67311, 67312, 67331, 67332, 67314, 67316, 67318, 67335, 67320, or 67345) before the first diagnosis of TBI were excluded. The following data were collected from the databases: date, sex, age at the first diagnosis of TBI, the period between the diagnosis of TBI and ocular motor nerve palsy, the period between the diagnosis of ocular motor nerve palsy and strabismus surgery in patients who had CPT codes for strabismus surgery, patients who had CPT codes for muscle transposition procedure (67320) or chemodenervation (67345), and continuous enrollment period after the first diagnosis of TBI. The severity of TBI was investigated based on the US Department of Defense Surveillance definition (see Supplemental Digital Content, Table 1, http://links.lww.com/WNO/A608) (5). Statistical Analysis The x 2 test was used to compare sex, severity of brain injury, the proportion of children, the proportion of ocular motor nerve palsies, and the number of patients who underwent strabismus surgery for ocular motor nerve palsy. The Mann–Whitney U test (children vs adults; mild brain injury vs moderate-to-severe brain injury) and Kruskal–Wallis H test (CN3 vs CN4 vs CN6 palsy) were used to compare age at the first diagnosis of TBI, the period between the diag132 nosis of TBI and ocular motor nerve palsy, the period between the diagnosis of ocular motor nerve palsy and strabismus surgery in patients with CPT codes for strabismus surgery, and continuous enrollment period after the first diagnosis of TBI. Statistical significance was set at P , 0.05. All statistical analyses were conducted using R software (version 4.0.0). RESULTS A total of 8,713,134,185 claims for 123,637,719 patients were analyzed using the MarketScan Databases (version 2.0); all the patients were aged 65 years or younger. A total of 2,606,600 patients with TBI met the inclusion criteria. Among them, 1,851 patients (0.071%) had ocular motor nerve palsy after TBI (Table 1). The median age of the patients was 39 (Q1– Q3: 19–54) years, and 42.4% of the patients were female. The median continuous enrollment period after the first diagnosis of TBI was 22 (Q1–Q3: 12–38) months. Among the 1,851 patients, the largest number of patients had CN4 palsy (697, 37.7%) and strabismus procedures were performed in 237 patients (12.8%) (Table 1). Of the 1,350,843 children with TBI, 454 (0.026%) had ocular motor nerve palsy. Of the 1,255,757 adults who had TBI, 1,397 (0.111%) had ocular motor nerve palsy. Table 2 summarizes the comparison of demographics and clinical characteristics between children and adults diagnosed with ocular motor nerve palsy after TBI. CN6 palsy was observed most frequently in children. More children (16.5%) underwent strabismus surgeries than adults (11.6%) (P = 0.006). Figure 1 shows that CN6 palsy was most frequent in patients aged 20 years or younger, while CN4 palsy was most frequent in patients aged 40 years and older. CN4 palsy (52.3%) was more frequent while CN3 palsy (15.5%) was less frequent in patients with mild TBI than in patients with moderate-to-severe TBI (P , 0.001). Only 17 patients (7.2%) with mild TBI underwent strabismus surgery (Table 3). Table 4 summarizes a comparison between patients with CN3, CN4, and CN6 palsy after TBI. The proportion of female patients was higher in CN3 palsy than in other palsies. Patients with CN6 palsy were the youngest (median age, 33 years); the proportion of children among patients with CN6 was the highest compared with the proportion of children with other palsies (30%). When compared with those with other palsies, patients with CN3 palsy had previous moderate-to-severe TBI while more patients with CN4 palsy had previous mild brain injury. There was no difference in strabismus surgery rates among patients with ocular motor nerve palsy. Among the patients who underwent strabismus procedures, muscle transposition was performed as the first strabismus procedure in 49.1% of the patients with CN3 palsy, while chemodenervation was performed in 21.0% of the patients with CN6. Heo and Lambert: J Neuro-Ophthalmol 2023; 43: 131-136 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographics and clinical characteristics of patients diagnosed with ocular movement nerve palsy after traumatic brain injury No. of Patients (%) or Median Value [Quartile 1; Quartile 3] (n = 1,851) Sex, n (%) Female Male Age at the first diagnosis of traumatic brain injury (yr) Brain injury severity, n (%) Mild Moderate to severe Ocular motor nerve palsy, n (%) Oculomotor nerve Trochlear nerve Abducens nerve Multiple nerve Strabismus surgery for ocular movement nerve palsy, n (%) None One or more surgeries The period between the diagnosis of traumatic brain injury and ocular motor nerve palsy (days) The period between the diagnosis of ocular motor nerve palsy and strabismus surgery (mo) Continuous enrollment period after traumatic brain injury (mo) 784 (42.4) 1,067 (57.6) 39 [19; 54] 239 (12.9) 1,612 (87.1) 443 697 676 35 (23.9) (37.7) (36.5) (1.9) 1,614 (87.2) 237 (12.8) 24 [6; 50] 7 [3; 13] 22 [12; 38] CONCLUSIONS We found that CN4 palsy was the most frequently occurring palsy in patients of all ages, and only 12.8% of the patients underwent strabismus procedures for ocular motor nerve palsy after TBI. In children with TBI, ocular motor nerve palsy developed approximately 4.3 times less often than in adults. However, more children underwent strabismus procedures than adults. CN6 was the most frequent form of palsy in children after TBI. CN4 was the most common form of palsy in patients with mild TBI. In a retrospective study of 4,278 cases of ocular motor nerve palsy, head trauma was the fourth leading cause of CN3 palsy, third leading cause of CN6 palsy, and second leading cause of CN4 palsy (6). Other studies have reported that head trauma is the most common cause of CN4 palsy (21% and 53%) (7,8). Our analysis of the claims data showed that CN4 palsy was the most frequent palsy after TBI in patients of all ages. CN4 is the smallest and longest of the ocular motor nerves. It is the only cranial nerve to emerge on the dorsal surface of the brainstem, and it is the only entirely crossed ocular motor nerve. The proximity of Heo and Lambert: J Neuro-Ophthalmol 2023; 43: 131-136 CN4 to the tentorial edge makes it susceptible to injury in cases of closed head trauma (8). The surgical rate of ocular motor nerve palsy after TBI has not yet been reported. Approximately 13 of 100 patients underwent strabismus procedures in our study. In a prospective multicenter study of acute traumatic CN6 palsy, the spontaneous recovery rate at 6 months after injury was 73% (9). Ocular motor nerve palsy occurred after mild TBI in approximately 13% of the patients. The incidence of CN4 palsy (52.3%) was significantly higher after mild TBI than after moderate-to-severe TBI (35.5%). In mild TBI without fracture, hematoma, or raised intracranial pressure, it has been suggested that the most likely mechanism of injury is the stretching of the nerve through acceleration in the midsagittal plane at the time of impact. Because of its thin structure, long intracranial course, and exit from the dorsal side of the brainstem, CN4 is susceptible to damage in mild head trauma (4). The mechanism of ocular motor nerve palsy after mild TBI is still unclear in most cases. The proposed mechanism involves stretching and distorting of the nerve fibers during the upward and downward movement of intracranial structures at the time of impact (4). Ocular motor nerve palsy is rare in children. In a larger pediatric series, congenital and trauma were the most common etiological factors, and 25% of the cases (9 of 36) were due to head trauma (10). In an institutionally based series, trauma was the most frequent cause of pediatric CN6 palsy, followed by neoplasia (11,12). Our results showed that ocular motor nerve palsy developed at a rate that was 4.3 times lower in children than in adults and that CN6 palsy was more frequent in children than in adults. CN6 is particularly vulnerable to trauma because of its long intracranial course. It may become injured because it crosses the apex of the petrous part of the temporal bone. As it passes from the brainstem and enters into the dura at the basilar process, it may get stretched by the downward and forward displacement of the brainstem. It may also become injured by fracture of the cranial floor, meningeal edema, or inflammation in the skull base (4). Because the apex of the petrous bone acts as a fulcrum, the abducens nerve is compressed, contused, and stretched at this point (13). TBI in children is different from TBI in adults. These differences can be attributed to age-related structural changes, the mechanism of injury based on the physical ability of the child, and difficulty in neurological evaluation of the pediatric population. There are biomechanical properties unique to pediatric brain injury because of a combination of higher plasticity and deformity, whereby external forces are absorbed in a different way compared with that in adults (14). Although it is assumed that these differences result in a lower rate of development of CN4 palsy and a more frequent occurrence of CN6 palsy in children than in adults, further investigation will be needed to determine the exact mechanism behind these observations. In our study, more children underwent strabismus procedures than 133 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Comparison of demographics and clinical characteristics between children and adults diagnosed with ocular motor nerve palsy after traumatic brain injury Children (0–18 Years) Adults (19–65 Years) (n = 454) (n = 1,397) Sex, n (%) Female Male Age at the first diagnosis of traumatic brain injury (yr)* Brain injury severity, n (%) Mild Moderate to severe Ocular motor nerve palsy, n (%) Oculomotor nerve Trochlear nerve Abducens nerve Strabismus surgery for ocular motor nerve palsy, n (%) None One or more surgeries The period between the diagnosis of traumatic brain injury and ocular motor nerve palsy (days)* The period between the diagnosis of ocular motor nerve palsy and the strabismus surgery (months)* Continuous enrollment period after traumatic brain injury (months)* P 185 (40.7) 269 (59.3) 12 [6; 16] 599 (42.9) 798 (57.1) 47 [33; 56] 0.425 64 (28.6) 390 (71.4) 175 (24.2) 1,222 (75.8) 91 (20.0) 149 (32.8) 203 (44.7)† 352 (25.2) 548 (39.2) 473 (33.9)† 379 (83.5) 75 (16.5) 21 [6; 49] 1,235 (88.4) 162 (11.6) 47 [33; 56] 0.549 5 [2; 12.5] 7 [4; 13.75] 0.02 26 [14; 44] 21 [12; 36] ,0.001 ,0.001 0.386 ,0.001 0.006 *Median value [quartile 1; quartile 3]. † Statistical significance by Bonferroni post hoc tests. adults. This could be interpreted in 2 ways: Fewer children recovered spontaneously or more aggressive and earlier treatment was performed on children. The clinical management of CN3 palsy is particularly challenging because 4 of the 6 extraocular muscles are involved (15). Other associated factors, such as the presence of ptosis, aberrant regeneration, poor Bell phenomenon, and lateral rectus contracture should be considered. We found that approximately half of the patients with CN3 palsy after TBI underwent muscle transposition surgery as the first strabismus procedure at a median time of 8 months after the diagnosis of traumatic CN3 palsy. A meta-analysis study concluded that patients with CN6 palsy when treated with botulinum toxin may FIG. 1. Number of patients with ocular motor nerve palsies by age. 134 Heo and Lambert: J Neuro-Ophthalmol 2023; 43: 131-136 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Comparison of the demographics and clinical characteristics between patients with mild traumatic brain injury and moderate-to-severe traumatic brain injury Sex, n (%) Female Male The number of children (18 yr and older), n (%) Age at the first diagnosis of traumatic brain injury (yr)* Ocular motor nerve palsy, n (%) Oculomotor nerve Trochlear nerve Abducens nerve Strabismus surgery for ocular motor nerve palsy, n (%) None One or more surgery The period between the diagnosis of brain injury and ocular movement nerve palsy (d)* The period between the diagnosis of ocular motor nerve palsy and strabismus surgery (mo)* Continuous enrollment period after traumatic brain injury (mo)* Mild Brain Injury (n = 239) Moderate-to-Severe Brain Injury (n = 1,612) 112 (46.9) 127 (53.1) 64 (26.8) 41 [18; 53] 672 (41.7) 940 (58.3) 390 (24.2) 39 [19; 54] 37 (15.5)† 125 (52.3)† 76 (31.8) 406 (25.2)† 572 (35.5)† 600 (37.2) 222 (92.9) 17 (7.2)† 19 [5; 48] 1,392 (86.4) 220 (13.6) 25 [6; 51] 0.053 2 [0; 14] 7 [4; 13] 0.109 22 [11; 37.5] 22 [13; 38] 0.951 P 0.131 0.386 0.62 ,0.001 0.005 *Median value [quartile 1; quartile 3]. † Statistical significance by Bonferroni post hoc tests. have a similar or slightly increased chance of correct alignment of eyes in comparison with patients who received no treatment (16). Our results showed that approximately 20% of the patients with CN6 palsy after TBI underwent chemodenervation as the first strabismus procedure. This study has several limitations. First, it was conducted using claims data, which do not include the following clinical data: severity of the CN palsy, pupil involvement, angle of deviation, amount of cyclotorsion, presence of abnormal head posture, fixation preference, visual acuity, TABLE 4. Comparison of the demographics and clinical characteristics between patients with oculomotor nerve, trochlear nerve, and abducens nerve palsy after traumatic brain injury Oculomotor Nerve Trochlear Nerve Abducens Nerve Palsy (n = 443) Palsy (n = 697) Palsy (n = 676) Sex, n (%) Female Male Age at the first diagnosis of traumatic brain injury (yr)† The number of children (18 yrs and older), n (%) Brain injury severity, n (%) Mild Moderate to severe Strabismus surgery for ocular motor nerve palsy, n (%) None One or more surgeries Muscle transposition‡ Chemodenervation‡ The period between the diagnosis of traumatic brain injury and ocular motor nerve palsy (days)† The period between the diagnosis of ocular motor traumatic nerve palsy and strabismus surgery (months)† Continuous enrollment period after brain injury (months)† P ,0.001 223 (50.3)* 220 (49.7)* 41 [21; 53] 91 (20.5) 268 (38.5)* 429 (61.5)* 43 [21; 55] 149 (21.4) 277 (41.0) 399 (59.0) 33 [16; 52] 203 (30.0)* 37 (8.4)* 406 (91.6)* 125 (17.9)* 572 (82.1)* 76 (11.2) 600 (88.8) 386 (87.1) 57 (12.9) 28 (49.1) ,11§ 26 [6; 52] 622 (89.2) 75 (10.8) ,11§ ,11§ 26 [7; 54] 576 (85.2) 100 (14.8) 12 (12.0) 21 (21.0) 22 [6; 46] 0.082 8 [4; 15] 7 [2; 12] 6 [4; 12.3] 0.007 22 [13; 40] 23 [12; 38] 22 [13; 37] 0.867 ,0.001 ,0.001 ,0.001 0.002 *Statistical significance by Bonferroni post hoc tests. † Median value [quartile 1; quartile 3]. ‡ There is no patient who underwent muscle transposition and chemodenervation simultaneously. § Per Population Health Sciences Data Core policy to prevent deidentification, all cell sizes less than 11 are reported as ,11. Heo and Lambert: J Neuro-Ophthalmol 2023; 43: 131-136 135 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution the severity of TBI, and the factors that lead to the classification of TBI severity. Spontaneous recovery was not investigated. Furthermore, it was not possible to distinguish between unilateral and bilateral palsy in most patients because the ICD-9 codes do not include laterality. We could not investigate elderly patients older than 65 years because the MarketScan data set only includes patients aged 65 years or younger. Miscoding may have occurred when a provider submitted the wrong diagnosis or procedure code. In conclusion, based on medical claims data that reflect real-world practice, CN4 palsy was the most frequently occurring palsy in patients of all ages, and only approximately 13% of the patients underwent strabismus procedures for ocular motor nerve palsy after TBI. 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