Etiology and Outcomes of Acquired Pediatric Sixth Nerve Palsies

Acquired sixth nerve (CN6) palsies in children may be benign or associated with an underlying neurologic condition. In children who presented with isolated (no associated neurologic or ophthalmic symptoms or signs) CN6 palsies, the rate of newly diagnosed neurologic disorders (such as tumors) is unclear. Moreover, the factors associated with spontaneous resolution and amblyopia in children with acquired CN6 palsies are unknown.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Etiology and Outcomes of Acquired Pediatric Sixth Nerve Palsies Melinda Y. Chang, MD, Mark S. Borchert, MD Background: Acquired sixth nerve (CN6) palsies in children may be benign or associated with an underlying neurologic condition. In children who presented with isolated (no associated neurologic or ophthalmic symptoms or signs) CN6 palsies, the rate of newly diagnosed neurologic disorders (such as tumors) is unclear. Moreover, the factors associated with spontaneous resolution and amblyopia in children with acquired CN6 palsies are unknown. Methods: We retrospectively reviewed the charts of all children younger than 18 years diagnosed with CN6 palsy at our institution from 2010 to 2020. We recorded ophthalmologic and neurologic history and examination findings, neuroimaging results, etiology of CN6 palsy, and outcomes including spontaneous resolution and amblyopia. We assessed etiologies of isolated and nonisolated CN6 palsies as well as frequency and factors associated with spontaneous resolution and amblyopia (in children #7 years). Results: One hundred seventy-two children met inclusion criteria. Twenty CN6 palsies (12%) were isolated at presentation. Most isolated cases were presumed postviral or postvaccination (50%) or idiopathic (30%), but 2 cases (10%) were associated with newly diagnosed tumors. Spontaneous resolution occurred in 59% of CN6 palsies at a median of 12.3 weeks and was associated with older age (P = 0.03) and nontumor etiology (P = 0.006). Amblyopia developed in 18% of children at risk, exclusively in those with anisometropia, pre-existing strabismus, or younger than 12 months. Conclusions: Our findings and chart reviews suggest that approximately 10% of isolated acquired pediatric CN6 palsies are associated with a newly diagnosed brain tumor. This risk must be discussed with parents when considering immediate vs delayed neuroimaging. In addition, infants The Vision Center at the Children’s Hospital Los Angeles (MYC, MSB), Los Angeles, California; and Roski Eye Center (MYC, MSB), University of Southern California, Los Angeles, California. Supported by Knights Templar Eye Foundation (M. Y. Chang), Children’s Eye Foundation of AAPOS (M. Y. Chang), and Research to Prevent Blindness (M. Y. Chang and M. S. Borchert). The authors report no conflicts of interest. Address correspondence to Melinda Y. Chang, MD, The Vision Center at the Children’s Hospital Los Angeles, 4650 Sunset Boulevard, Mailstop #88, Los Angeles, CA 90027; E-mail: Melinda.y.wu@ gmail.com e254 and children #7 years with secondary amblyogenic risk factors (anisometropia or pre-existing strabismus) require close follow-up to monitor and treat amblyopia. Journal of Neuro-Ophthalmology 2022;42:e254–e259 doi: 10.1097/WNO.0000000000001390 © 2021 by North American Neuro-Ophthalmology Society A cquired pediatric sixth nerve (CN6) palsies may be benign or the presenting sign of a serious neurologic disorder (1–9). The most concerning underlying etiology is a neoplasm, which is also the leading cause in most series, accounting for 19%–45% of cases (1,2,4–6). Because of the relatively high frequency of tumors causing pediatric CN6 palsies, some authors recommend neuroimaging in all cases (1). However, others cite a low rate of malignancy in isolated cases (no other ophthalmologic or neurologic symptoms or signs) and suggest initial close follow-up in these patients, with neuroimaging if new symptoms or signs develop or spontaneous resolution does not occur (2,10). The risk of delayed diagnosis of a neoplasm or other serious neurologic disorders must be weighed against the risk of anesthesia to acquire neuroimaging in a young or uncooperative child. As there are few data on the risk of an underlying neurologic condition (especially brain tumor) in isolated acquired pediatric CN6 palsies, we aimed to evaluate the neurologic diagnoses in a large series of children with isolated and nonisolated CN6 palsies to assess the risk of malignancy in both presentations. Furthermore, spontaneous recovery occurs in some children with acquired CN6 palsies, and previous studies have not identified factors that affect the rate of resolution other than underlying etiology (2,3). In addition, unlike adults with CN6 palsies, children are at risk of strabismic amblyopia. Only 1 previous study has evaluated amblyopia in children with CN6 palsies, and the factors associated with risk for amblyopia in children with acquired CN6 palsies are unknown (2). We conducted a 10-year retrospective study at our institution on etiology and outcomes of acquired pediatric CN6 palsies, with particular attention to 1) rates of Chang and Borchert: J Neuro-Ophthalmol 2022; 42: e254-e259 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution malignancies in isolated and nonisolated cases, 2) frequency and factors associated with spontaneous recovery, and 3) frequency and factors associated with amblyopia in children #7 years. METHODS This study was approved by the local institutional review board and adhered to the tenets of the Declaration of Helsinki and the US Health Insurance Portability and Accountability Act of 1996. The medical records of children examined at Children’s Hospital Los Angeles between January 1, 2010, and April 1, 2020, with a diagnosis of CN6 palsy were retrospectively reviewed. The electronic medical record was searched based on the International Classification of Disease (ICD)-9 and ICD-10 codes for abducens palsy (ICD-9 378.54 and ICD-10 H49.2). The records were reviewed to determine whether patients met criteria for diagnosis of CN6 palsy, which required limitation of abduction in 1 or both eyes, with esotropia greater in the direction of the palsied eye and/or esotropia worse at distance than near. Patients were excluded if they had congenital CN6 palsy, Duane syndrome, Moebius syndrome, were 18 years or older at diagnosis, did not meet criteria for CN6 palsy diagnosis, or were not examined by an ophthalmologist. Patients who initially presented to the emergency department were evaluated by both ophthalmology and neurology. Patients who were initially seen in outpatient setting were evaluated by the pediatric neuro-ophthalmology service. All patients underwent neuroimaging with MRI. The following data were extracted from the charts: demographics, birth and family history, medical history, ophthalmologic and neurologic history, results of ophthalmologic and neurologic examinations (including whether the CN6 palsy was complete and/or isolated), neuroimaging findings, etiology of CN6 palsy, treatments recommended, and outcomes including amblyopia and spontaneous resolution. A complete CN6 palsy was defined as inability to abduct past midline. Isolated CN6 palsies were diagnosed in patients with no additional neurologic or neuroophthalmologic signs or symptoms of an underlying neurologic condition, without a known history of malignancy. Etiology was determined based on neurologic and ophthalmic examination, neuroimaging, and other ancillary investigations as appropriate. Presumed postvaccination or postviral etiology was diagnosed in patients with a history of recent (less than 3 weeks before) vaccination or viral illness, negative workup including neuroimaging, and spontaneous resolution. Idiopathic etiology was diagnosed in patients with negative workup including neuroimaging and no history of recent viral illness or vaccination. Amblyopia was diagnosed in patients with greater than 2-line interocular difference in visual acuity or consistent fixation preference in nonverbal patients, with no other explanation Chang and Borchert: J Neuro-Ophthalmol 2022; 42: e254-e259 for amblyopia. In patients who also had anisometropia or pre-existing strabismus, amblyopia due to CN6 palsy was only diagnosed if patients initially had equal vision when they presented after the CN6 palsy. Spontaneous resolution was defined as no manifest strabismus at distance or near in primary, left, or right gaze positions without undergoing strabismus surgery. Data were collected in Microsoft Excel version 16.30 (Microsoft Corporation, Redmond, WA), and statistical analyses were conducted in GraphPad Prism version 8.4.3 (GraphPad Software, San Diego, CA). Demographics and etiology of pediatric CN6 palsies were assessed in all included patients. Motor outcomes were analyzed in the subset of patients who had at least 6 months followup or evidence of spontaneous resolution before this. Amblyopia outcomes were assessed in children in the amblyogenic age range (7 years or younger) who had at least 6 months follow-up or spontaneous resolution. We excluded 1 patient from outcome analysis who underwent prophylactic patching because our goal was to evaluate outcomes in children without prophylactic amblyopia treatment. The Mann–Whitney test was used to compare continuous variables and the chi square test for categorical variables. The Fisher exact test was used if any category had a value of #5. Factors significant on univariate analysis were included in multivariate logistic regression models. P values less than 0.05 were considered significant. RESULTS One hundred seventy-two children met inclusion and exclusion criteria. The demographics, clinical characteristics, and etiologies of the CN6 palsies are presented in Table 1. The median age was 8.8 years, and 108 cases (63%) were unilateral. Tumor was the most frequent etiology (37%), followed by nontumor increased intracranial pressure (ICP, 19%), trauma (13%), inflammation (9%), infection (8%), presumed postviral or postvaccination (6%), idiopathic (4%), and others (4%). Etiologies in the ‟other” category included nonneoplastic mass lesions (2 brainstem cavernomas and 1 fibrous dysplasia), anoxic brain injury (1), and vincristine toxicity (2). Twenty cases (12%) were isolated with no accompanying neurologic or ophthalmologic symptoms or signs, including headache. The characteristics of isolated and nonisolated pediatric CN6 palsies are compared in Table 1. Children with isolated CN6 palsies were significantly younger (median age 4.7 vs 9.5 years, P = 0.0042). Isolated CN6 palsies were more commonly unilateral (90% vs 59%, P = 0.0065), with different etiologies than nonisolated cases (P , 0.0001). Of the 20 isolated cases, 10 (50%) were presumed postviral or postvaccination, 6 (30%) were idiopathic, 1 (5%) was traumatic, 1 (5%) was secondary to vincristine toxicity (‟other”), and 2 (10%) were related to e255 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographics, clinical characteristics, and etiology of sixth nerve (CN6) palsy in 172 children included in this study Median age (range) Male/female Unilateral Complete palsy Etiology Idiopathic Increased ICP (nontumor) Infection Inflammation Presumed postviral or postvaccination Trauma Tumor Others All Patients (n = 172) Isolated (n = 20) Not Isolated (n = 152) P Value 8.8 yr (1 mo–18 yr) 95 (55%)/77 (45%) 108 (63%) 48 (28%) 4.7 yr (7 mo–17 yr) 10 (50%)/10 (50%) 18 (90%) 6 (30%) 9.5 yr (1 mo–17 yr) 85 (56%)/67 (44%) 90 (59%) 42 (28%) 7 (4%) 33 (19%) 14 (8%) 16 (9%) 10 (6%) 6 (30%) 0 (0%) 0 (0%) 0 (0%) 10 (50%) 1 (0.66%) 33 (22%) 14 (9%) 16 (11%) 0 (0%) 0.0042* 0.62 0.0065* 0.82 ,0.0001* ,0.0001* 0.015* 0.38 0.22 ,0.0001* 22 (13%) 64 (37%) 6 (4%) 1 (5%) 2 (10%) 1 (5%) 21 (14%) 62 (41%) 5 (3%) 0.48 0.0065* 0.53 Cases with isolated (no associated neurologic or ophthalmologic signs or symptoms) and nonisolated presentation are analyzed separately and compared. *P , 0.05. ICP, intracranial pressure. newly diagnosed tumors (chordoma or schwannoma). On multivariate analysis, the only factor significantly associated with isolated presentation was etiology (idiopathic or postviral/postvaccination, P , 0.0001). Table 2 lists the systemic neurologic and neuroophthalmologic signs and symptoms in the 152 children with nonisolated CN6 palsies. The most common systemic neurologic symptoms were headache (38%), nausea and vomiting (22%), and gait instability or ataxia (20%) consistent with the 2 most common etiologies being tumor and nontumor increased ICP. The most frequent neuroophthalmologic signs associated with CN6 palsy were papilledema (22%) and other cranial nerve (CN) palsies, including CN7 (22%), CN4 (13%), and CN3 (5%). Optic atrophy was diagnosed in 9% of patients; in most cases, optic atrophy was considered secondary to previous papilledema, based on optic nerve appearance with gliosis and/or other signs of increased ICP on neuroimaging or lumbar puncture. Of the 172 patients included in this study, 95 (55%) met criteria for motor outcome analysis. Spontaneous resolution occurred in 56 patients (59%) at a median time of 12.3 weeks after the onset. Of the 39 patients without spontaneous resolution, 20 (51%) underwent strabismus TABLE 2. Systemic neurologic and neuro-ophthalmologic signs and symptoms in 152 children with nonisolated acquired sixth nerve palsies Systemic Neurologic Signs and Symptoms Headache Nausea and vomiting Gait instability or ataxia Altered mental status Upper and/or lower extremity weakness Dizziness Seizures Fever Bulbar symptoms* Increasing head circumference Decreased hearing Urinary retention or incontinence Numbness and tingling Neck or back pain Neuro-Ophthalmologic Signs and Symptoms 58 33 30 20 16 10 8 8 6 3 3 3 2 2 (38%) (22%) (20%) (13%) (11%) (7%) (5%) (5%) (4%) (2%) (2%) (2%) (1%) (1%) Papilledema CN7 palsy CN4 palsy Optic atrophy CN3 palsy Dorsal midbrain syndrome Nystagmus Internuclear ophthalmoplegia Visual field defect Gaze palsy Skew deviation CNV1 hypesthesia — — 33 (22%) 33 (22%) 20 (13%) 13 (9%) 8 (5%) 7 (5%) 5 (3%) 4 (3%) 4 (3%) 3 (3%) 1 (0.7%) 1 (0.7%) — — *Bulbar signs and symptoms included dysphagia, vocal cord paralysis, slurred speech, and drooling. CN, cranial nerve. e256 Chang and Borchert: J Neuro-Ophthalmol 2022; 42: e254-e259 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Demographics, clinical characteristics, and etiologies of sixth nerve palsies in 95 children who were followed until spontaneous resolution or at least 6 months Median age (range) Male/female Unilateral Complete palsy Pre-existing strabismus Amblyopia Etiology Idiopathic Increased ICP (nontumor) Infection Inflammation Presumed postviral or postvaccination Trauma Tumor Others Spontaneous Resolution (n = 56) No Spontaneous Resolution (n = 39) 11.3 yr (1 mo–17 yr) 30 (54%)/26 (46%) 37 (67%) 12 (23%) 0 (5%) 1 (1.8%) 7.5 yr (1 mo–17 yr) 20 (51%)/19 (49%) 26 (67%) 10 (26%) 2 (5%) 7 (18%) 3 (5%) 17 (30%) 7 (13%) 8 (14%) 4 (7%) 5 (9%) 12 (21%) 0 (0%) 1 (2.5%) 7 (18%) 1 (2.5%) 2 (5%) 0 (0%) 5 (13%) 20 (51%) 3 (8%) P Value 0.03* 0.83 .0.99 0.81 0.17 0.0071* 0.006* 0.64 0.19 0.14 0.19 0.14 0.52 0.002* 0.064 Characteristics of CN6 palsies that spontaneously resolved are compared with those that did not. *P , 0.05. CN, cranial nerve; ICP, intracranial pressure. surgery. Table 3 shows the demographics, clinical characteristics, and etiology of patients who experienced spontaneous resolution compared with those who did not. Children with spontaneous resolution were significantly older (median age 11.3 vs 7.5 years, P = 0.03) and are more likely to have nontumor etiology (P = 0.006). Lack of spontaneous resolution was significantly associated with amblyopia (P = 0.0071). On multivariate regression, older age (P = 0.0079) and nontumor etiology (P = 0.0003) remained significant predictors of spontaneous resolution. Amblyopia outcomes were assessed in 45 children aged 7 years or younger with adequate follow-up (followed until resolution or at least 6 months). Eight children (18%) had amblyopia at diagnosis or developed amblyopia during follow-up. The demographics, clinical characteristics, and etiologies of children who did and did not develop amblyopia are shown in Table 4. Younger age was the most significant predictor of amblyopia (median age 5 vs 43 months, P = 0.0003). In addition, anisometropia was more common in children who developed amblyopia (38% vs TABLE 4. Demographics, clinical characteristics, and etiologies of sixth nerve palsies in 45 children at risk for amblyopia (7 years or younger) who were followed until spontaneous resolution or at least 6 months Median age (range) Male/female Unilateral Complete palsy Pre-existing strabismus Anisometropia Etiology Idiopathic Increased ICP (nontumor) Infection Inflammation Presumed postviral or postvaccination Trauma Tumor Others Amblyopia (n = 8) No Amblyopia (n = 37) P Value 5 mo (1–34 mo) 7 (78%)/2 (22%) 5 (63%) 5 (63%) 1 (13%) 3 (38%) 43 mo (1–94 mo) 17 (46%)/20 (54%) 28 (76%) 11 (30%) 0 (0%) 1 (3%) 0 (0%) 5 (63%) 0 (0%) 0 (0%) 0 (0%) 2 (25%) 1 (13%) 0 (0%) 2 (5%) 6 (16%) 4 (11%) 5 (14%) 4 (11%) 2 (5%) 13 (35%) 1 (3%) 0.0003* 0.14 0.66 0.11 0.18 0.01* 0.07 .0.99 0.01* .0.99 0.57 .0.99 0.14 0.40 .0.99 Children who developed amblyopia are compared with children who did not. *P , 0.05. ICP, intracranial pressure. Chang and Borchert: J Neuro-Ophthalmol 2022; 42: e254-e259 e257 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 3%, P = 0.01). On multivariate regression, only younger age remained a significant predictor of amblyopia (P = 0.04). Of the 8 children with amblyopia, 3 had anisometropia, 1 had pre-existing strabismus, and the other 4 were younger than 12 months at the onset of CN6 palsy. CONCLUSIONS Our study confirms previous reports that acquired CN6 palsies in children, in contrast to adults, are frequently associated with serious underlying neurologic conditions (1–5). Similar to previous studies, tumors, nontumor increased ICP, and trauma were the most common etiologies (1–5). Only 10% of cases were found to have no underlying neurologic diagnosis (idiopathic, presumed postviral, or postvaccination). In our study, 20 pediatric acquired CN6 palsies were isolated (no associated neurologic or ophthalmic signs or symptoms), and the majority (80%) of these were either idiopathic or presumed secondary to recent viral illness or vaccination. Of the remaining 4 cases, 1 had a history of trauma and 1 was secondary to vincristine treatment of Wilms tumor. Only 2 patients had newly diagnosed tumors (1 low-grade clival chordoma vs schwannoma that has not progressed over 1 year of follow-up and 1 parasellar schwannoma). To the best of our knowledge, ours is the largest case series to date of isolated pediatric CN6 palsies. Previous studies have similarly found low rates of new malignant tumors in children with isolated CN6 palsies (Table 5). Newly diagnosed malignant tumors were reported by Kodsi and Younge (4) (1 medulloblastoma), Lee et al (1) (1 medulloblastoma), and Dotan et al (6) (3 brainstem gliomas). Not included in this table (because isolated CN6 palsies were not analyzed separately) is a study by Park et al (11) in which 13 of 57 children (23%) with isolated third, fourth, or sixth nerve palsies had an underlying neoplasm. However, headache was not considered as a neurologic symptom in that study. Among the 4 studies (including ours) that reported the total number of isolated pediatric CN6 palsies (1,2,6), the rate of a newly diagnosed malignant tumor was 10% if we consider our case of clival chordoma vs schwannoma to be malignant. Therefore, the prevalence of malignancy in cases of isolated pediatric CN6 palsies is low, and of those found, it is unlikely that delayed diagnosis would have affected the treatment outcomes. Parents should be advised of this and given the option to defer imaging at the time of diagnosis. However, neuroimaging is mandatory if new neurologic or ophthalmologic symptoms develop or spontaneous resolution does not occur. Regarding outcomes, we found that 59% of patients experienced spontaneous resolution and recovery was more likely in older children and those with nontumor etiology. Few previous reports have evaluated outcomes of pediatric CN6 palsies. Aroichane and Repka found that only 25% of children aged 7 years or younger with CN6 palsies had spontaneous recovery (2) consistent with our finding that older age is associated with a better prognosis. The authors additionally noted that tumors had the lowest recovery rate, similar to our study. Other investigators have also found higher rates of spontaneous resolution in nontumor etiologies (3,12). It is unclear why older age was predictive of better recovery independent of etiology on multivariate analysis. We speculate that because older children have more established binocularity, they may have better control of a residual esodeviation after CN6 palsy, resulting in a final deviation that is esophoric rather than esotropic. The median time to spontaneous recovery in our study was 12.3 weeks, which is also similar to previous reports (3). Therefore, we agree with previous recommendations that the maximum time that a nonresolving acquired pediatric CN6 palsy should be observed without neuroimaging is 3 months (2). We separately analyzed amblyopia outcomes in children at risk (7 years or younger). The rate of amblyopia was TABLE 5. Comparison of the current study to previous studies of children with isolated (no associated neurologic or ophthalmologic symptoms or signs) sixth nerve (CN6) palsies and their underlying etiologies Etiology of Isolated CN6 Palsies Kodsi and Younge (4) Aroichane and Repka (2) Lee et al (1) Holmes et al (8) Merino et al (9) Dotan et al (6) Current study Total # Pediatric CN6 Palsies # Isolated CN6 Palsies Brain Tumor (Newly Diagnosed and Malignant) Trauma 88 NR 3 (1) 64 5 75 12 15 16 172 7 NR NR 16 20 Congenital Idiopathic or Benign Recurrent Postviral or Postvaccination Others NR NR NR NR NR 0 NR NR NR NR NR 1 (1) 0 0 5 (3) 2 (1)* 2 NR NR 1 1 1 NR NR 1 0 3 NR NR 5 6 0 NR NR 3 10 0 NR NR 1 1 *Based on imaging characteristics and longitudinal follow-up, 1 tumor was either a low-grade clival chordoma or schwannoma. CN, cranial nerve; NR, not reported. e258 Chang and Borchert: J Neuro-Ophthalmol 2022; 42: e254-e259 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 18%, which is lower than reported by the only comparable study. Aroichane and Repka found that 12 of 55 patients (22%) had amblyopia at diagnosis and 8 (14%) developed amblyopia during follow-up, leading to a total amblyopia rate of 36% (2). The reasons for the discrepancy between our study and theirs are unknown. We found that factors significantly associated with amblyopia included younger age, nontumor increased ICP (mainly hydrocephalus), and anisometropia. Patient ages in our studies were similar (median 2.83 years in our subgroup of children at risk for amblyopia compared with the mean age of 3.3 years in the Aroichane and Repka study). The rates of nontumor increased ICP or hydrocephalus were also similar (24% in our study and 23% in the Aroichane and Repka study). It is possible that their study included higher rates of children with anisometropia because this was not reported or that other unidentified factors account for the difference. Among the 8 children who developed amblyopia in this study, 3 had anisometropia and 1 had congenital esotropia with a V-pattern before developing CN6 palsy. The remaining 4 children were younger than 12 months when CN6 palsy was diagnosed. Therefore, in children who have an acquired CN6 palsy and an additional amblyogenic risk factor or younger than 12 months at diagnosis, we recommend particularly vigilant follow-up to ensure timely diagnosis and management of amblyopia. The limitations of our study include retrospective analysis and inconsistent follow-up. We evaluated outcomes only in children who were followed until spontaneous resolution or at least 6 months, and we cannot rule out the possibility that patients who were lost to follow-up before 6 months differed in a systematic way from the patients included in this study. Furthermore, it is possible that some patients in the persistent CN6 palsy group experienced spontaneous resolution after completing their last follow-up (minimum 6 months), although we judge this to be unlikely because the median length of follow-up in the nonresolved group was 25 months and previous studies reported that spontaneous recovery, if it occurs, happens by 3–4 months after the onset of CN6 palsy (3). Moreover, we could not analyze changes in the angle of strabismus over time and whether this affected outcomes because many of our patients underwent initial evaluation in the emergency department and the deviation was not measured with prisms. Finally, our cohort includes children who presented to an urban tertiary care children’s hospital, and the etiologies represented may differ from patients seen in other settings. In conclusion, based on our series and literature review, approximately 10% of children with an isolated acquired CN6 palsy have a newly diagnosed brain tumor. In deciding whether to undergo immediate neuroimaging (vs initial Chang and Borchert: J Neuro-Ophthalmol 2022; 42: e254-e259 observation with subsequent neuroimaging if new neurologic or ophthalmic symptoms/signs develop or spontaneous resolution does not occur) in a child with an isolated acquired CN6 palsy, parents must weigh the risk of delayed diagnosis of a malignancy against the risk of general anesthesia in a young, uncooperative patient. In our patients, spontaneous resolution occurred in approximately 50% of cases at a median time of 12 weeks; thus, 3 months is the maximum time that observation is recommended for a nonresolving acquired pediatric CN6 palsy. In addition, although we advise careful assessment for amblyopia in all children aged 7 years or younger who develop CN6 palsy, we suggest especially close follow-up in infants and children with secondary amblyogenic risk factors. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. Y. Chang and M. S. Borchert; b. Acquisition of data: M. Y. Chang and M. S. Borchert; c. Analysis and interpretation of data: M. Y. Chang and M. S. Borchert. Category 2: a. Drafting the manuscript: M. Y. Chang and M. S. Borchert; b. Revising it for intellectual content: M. Y. Chang and M. S. Borchert. Category 3: a. Final approval of the completed manuscript: M. Y. Chang and M. S. Borchert. REFERENCES 1. Lee MS, Galetta SL, Volpe NJ, Liu GT. Sixth nerve palsies in children. 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