Long-term Outcomes Following Surgery for Infantile Nystagmus Syndrome With Abnormal Head Positioning

Journal Pre-proof Long-term outcomes following surgery for infantile nystagmus syndrome with abnormal head positioning Yuxi Zheng, James J. Law, Derick G. Holt, David G. Morrison, Sean P. Donahue PII:

S0002-9394(19)30542-2

DOI:

https://doi.org/10.1016/j.ajo.2019.11.005

Reference:

AJOPHT 11131

To appear in:

American Journal of Ophthalmology

Received Date: 13 August 2019 Revised Date:

1 November 2019

Accepted Date: 4 November 2019

Please cite this article as: Zheng Y, Law JJ, Holt DG, Morrison DG, Donahue SP, Long-term outcomes following surgery for infantile nystagmus syndrome with abnormal head positioning, American Journal of Ophthalmology (2019), doi: https://doi.org/10.1016/j.ajo.2019.11.005. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.

Title: Long-term outcomes following surgery for infantile nystagmus syndrome with abnormal head positioning Short Title: Correction of head positioning in congenital nystagmus Authors: Yuxi Zheng 1, James J. Law 1, Derick G. Holt 2, David G. Morrison 1,3, Sean P. Donahue 1,3 1

Vanderbilt University School of Medicine, Nashville, TN, 37204, USA Vision Care Center, Fresno, CA, 97320, USA 3 Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN, 37204, USA 2

Corresponding author: Yuxi Zheng Office of Medical Student Affairs 2215 Garland Ave 201 Light Hall Nashville, TN 37232-0685 Telephone: (216) 889-7167 Fax: (774) 872-5048 [email protected]

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Introduction: Patients with infantile nystagmus syndrome (INS) often develop an abnormal head position where the amplitude of nystagmus is reduced to a minimum.1 Surgical management of abnormal head positioning (AHP) associated with INS has progressed since the first surgeries were proposed in the early 1950’s. Anderson postulated that there was a relative overaction of the muscles driving the slow phase of nystagmus and proposed a two-muscle surgery to recess these muscles2. Goto suggested an underaction of the muscles driving the fast phase of nystagmus and proposed a bilateral resection of the muscles driving the fast phase3. Kestenbaum independently proposed a four muscle surgery that combined both Anderson and Goto’s recessions and resections to move the globe in the direction of the head turn.4 Subsequent modifications of Kestenbaum’s numbers have been proposed, including Parks’ classic maximum, which described a resection and recession of a sum total of 13 per eye (5-6-7-8 rule).5 Parks suggested that this was the maximum surgery that could be done without risking rotational deficits. Since then, augmentations of increasing magnitude have been proposed, and others have shown success with 40% or 60% augmentations of Parks’ numbers, depending on the degree of the head positioning.6,7 Others have described modifications for head positioning that occurs in the pitch (chin up/chin down) and torsional (head tilt) position.8 We sought to report long-term efficacy of surgical treatment of compensatory head positioning in congenital nystagmus. We performed a retrospective, observational study of the long-term efficacy of surgical correction of AHP associated with nystagmus. Methods: A retrospective chart review was performed on 150 patients who eye muscle surgery for AHP associated with nystagmus at Vanderbilt Eye Institute between 1995-2018. This study was deemed IRB exempt by the Vanderbilt Institutional Review Board (IRB), and all data collection was in conformity with county, federal, or state laws, and was in adherence to the tenets of the Declaration of Helsinki. Head position, duction limitation, strabismus (if present), and visual acuity were evaluated at the preoperative visit, 1-3 weeks postoperatively, 2-5 months postoperatively, 2 years (±6 months), 5 years (±9 months), 10 years (±1 year) postoperatively, and at the last follow-up visit. Horizontal head position was approximated by the attending physician and recorded in degrees and subsequently categorized into minimal (≤10 degrees of straight), mild (1129 degrees), moderate (30-44 degrees), and severe (≥45 degrees). Vertical head posturing was approximated by observation and divided into 3 categories (instead of four) of minimal (1-15 degrees), moderate (16-30 degrees), and severe (31 degrees or more). We did not use a goniometer to measure head position as it was not standard practice at that time in our clinic. Postoperatively, a collapse of head positioning to minimal was considered a successful surgery. Ductions and versions were graded from -4 to + 4, with -2 to -1 considered a mild duction limitation, and -3 to -4 considered a

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severe duction limitation. Magnitude of strabismus (if present) was measured in prism diopters (PD) using SPCT and PACT. Strabismus was defined as a manifest deviation that exceeded 8 prism diopters. In a verbal child, binocular visual acuity was recorded using an age-appropriate optotype acuity and converted to LogMAR. When binocular vision was not recorded, the visual acuity of the better-seeing eye was converted to LogMar. In a preverbal child, the central-steady-maintained (CSM) method was used to evaluate visual acuity. For patients with horizontal preoperative head positioning, graded surgery was performed depending on the magnitude of baseline head positioning. A 50%-60% augmentation of Parks’ maximum was done if preoperative head positioning was severe. A 40% augmentation was done if the preoperative head positioning was moderate. Unlike in horizontal cases, surgical planning for vertical cases represented maximal dosages of recession-resection of vertical recti or weakening of both agonist muscles depending on the procedure. When strabismus co-existed with abnormal head posturing, surgery was performed on the fixating eye based upon the head position, but decreased in magnitude if the proposed surgery would worsen the strabismus.9 Wilcoxon signed rank tests were used to evaluate for changes in visual acuity over time. Results: 93 patients were male and 57 were female. Mean age at surgery was 8.1 years. Of the 150 patients, 31 had surgery for AHP in the pitch (chin up/down) position, and 119 had surgery for a horizontal AHP. Fifty-five patients underwent 50-60% augmentation, 19 underwent 40% augmentation, 5 underwent less than 40% augmentation; 37 patients had surgery modified for strabismus, and 3 underwent non-standard procedures. Of these, two were modified Anderson procedures and one was a Kestenbaum reoperation with unknown prior surgery. 57 patients has sensory abnormalities, 88 patients had idiopathic congenital nystagmus, and 5 had acquired forms of nystagmus. Of 150 patients, 132 patients presented for their 1-3 week follow-up, 107 patients presented for their 2-5 month follow-up, 57 patients presented for 2 year (±6 months) follow-up, 42 patients presented for 5 year (±9 months) follow-up, and 14 were seen 10 years (±1 year) post-operatively. Overall only 21% of patients required a second operation. Preoperative head positioning: Preoperatively, 93 (62%) had severe head positioning, 22 (15%) had moderate head positioning, 3 (2%) had mild head positioning. Given the retrospective nature of this study, 31 patients (21%) had a head positioning that was reported in direction but not quantified, and one patient did not have any reported baseline head position reported despite having surgery for a vertical head position.

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Collapse of AHP Outcomes: Collapse of head positioning was defined as resolution of head positioning to within 10 degrees of straight for horizontal cases, and within 15 degrees of straight for vertical cases. At the 1-3 week follow-up (n=132), 126 patients (95%) had collapse of AHP. The success rate trended down during the 2-5 month (91%, n=107) and 2 year follow-ups (82%, n=57). However, at 5 and 10 years 93% (n=42) and 93% (n=14) of patients had successful collapse of head positioning respectively due to several patients having re-operation. Over and Undercorrection of AHP Outcomes: At 1-3 weeks, 5% of patients were overcorrected while none were undercorrected. Over and undercorrection rates peaked at 2 years post-operatively at 11% and 7% respectively. Ten years out, none were overcorrected and 7% were undercorrected. Six patients (4%) required reoperation for overcorrection (mean 2.7 years later) and 7 patients (5%) did for undercorrection (mean 3.9 years later). (Figure 1) Duction limitations: Significant duction limitations were noted in 9% of patients at the 2-5 month visit, in 10% of patients at the 2 year visit, in 5% of patients in the 5 year visit, and in no patients in the 10 year visit. Minor duction limitations were noted in 63% of patients at the 2-5 month visit, in 60% of patients at the 2 year visit, in 68% of patients in the 5 year visit, and in 60% of patients at the 10 year visit. Development of Strabismus: Overall a total of 6.7% of patients developed a new strabismus with an average magnitude of 18.7 PD. Only 5% of horizontal cases had an induced strabismus with an average magnitude of 10.3 PD. However, 13% of patients with pitch head positioning developed new strabismus with an average of 31.3 PD esodeviation. The majority of these patients had induced V pattern esotropia, resulting from vertical recession resection procedures. The overall reoperation rate due to new strabismus was 3.3%. Visual acuity (BV): Mean visual acuity is summarized in Table 1. Overall, there was no statistically significant change in visual acuity at 1-3 weeks, 2-5 months, 2 years, 5 years, and 10 years compared to preoperatively as calculated by the Wilcoxon signed rank test. Re-operation outcomes: Thirty-one patients (21%) required reoperation (mean 2.5 years) with highest rates when the original surgery was modified for preexisting strabismus (10 patients, 27%) or a pitch AHP (9 patients, 26%). Indications for reoperation included induced strabismus (6 cases, mean 3.5 years later), previous strabismus requiring reoperation(13 cases, mean 1.5 years later), overcorrection (6 cases, mean 2.7 years later), and undercorrection (7 cases, mean 3.9 years later). Three cases had both head positioning and strabismus as indications for reoperation. (Table 2). 79% of our patients required no further surgery. (Figure 2) A difference was found between reoperation rates between patients having idiopathic nystagmus compared to those with a known bilateral afferent pathway (sensory) defect (p=0.02 by Fischer-exact test).

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Discussion: The correction of head positioning in infantile nystagmus syndrome with eye muscle surgery has been reported frequently by many others (Table 3)6,7,10-14. Studies published by Calhoun & Harley in 19736, Nelson and colleagues in 19847, and Mitchell and colleagues in 198713 reported success of 40-60% augmentations with success rates ranging from 32% to 66% and average follow-up ranges from 13 to 54 months. Chang and colleagues10 also described a graded augmentation of a variation of Parks’ maximum with high success rates with a sample of 92 patients over a 33 month followup. These authors suggested that larger augmentations may be used for larger pre-op head positions with much smaller sample sizes or shorter length of follow-up than our study has. Our data support these conclusions with even higher success rates, possibly due to our increased proportion of 60% augmentations. Short-term, we observed a very high success rate of collapse of head positioning, with 95% of patients having resolution at the 1-3 week follow-up. Over time, the successful collapse of head positioning decreased to 82% by 2 years. Long-term follow-up of 5 and 10 years demonstrated success rates of 93% at both time points, with only 21% of patients requiring a second operation. Lee and colleagues in 200012 published higher success rates with lower dosages of surgery including classic Parks maximums, and 20-30% augmentation, with mean follow-up time of only 13 months. Our data suggest that undercorrection tends to present an average of almost 4 years post-operatively. Having only 13-month follow-up in the Lee report may have been too early to identify undercorrection of head positioning after their lower dosages of surgeries. Our surgical planning consists of the following algorithm. For patients with a horizontal face turn without strabismus, we use standard Kestenbaum with augmentation up to 60% depending on preoperative face-turn. Patients who have coexisting horizontal strabismus and face turn are best managed by first classifying into concordant and discordant groups. In cases of concordant strabismus, the dosage of surgery is decreased in the fellow eye. In cases of discordant strabismus, the dosage of surgery was decreased in the fixating eye (and a full 60% augmentation was performed in the non-fixating eye) in an attempt to balance between correction of the strabismus and correction of the AHP. Patients with pitch plane head position respond well when both elevators are weakened. In our cohort of patients, a small percentage developed new strabismus that was not seen prior with higher incidence in larger surgical augmentations. Most of these patients had surgery for a vertical (pitch plane) posturing, and only 3 patients with a horizontal face turn developed strabismus. We believe that this finding may be partially due to difficulty assessing strabismus when large baseline head positioning is present. Despite this, three patients with horizontal head turn without baseline strabismus developed new strabismus post-operatively that was severe enough for re-operation. It is likely that the v-pattern esotropia induced in patients with vertical recession-resections is due to the

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strengthening of the adducting force of the inferior rectus muscles in downgaze by resection and weakening of adducting force of the superior recti in upgaze. The induction of strabismus after modified Kestenbaum surgery has not been previously described. Visual acuity in our cohort of patient remained unchanged with some variability between time-points possibly accounted for by the variability of patients returning to clinic. Any measured change in visual acuity as a result of this surgery is of at best a minimal nature. We did not determine any of the other previously described outcome metrics of visual function, such as NAFX, null zone position, or nystagmus amplitude. Our study has several limitations, including its retrospective nature. Fewer patients attended follow-up later, and the group of patients returning over longer periods of time may not be representative of the entire cohort of patients. While we do have long-term follow-up on many patients, it is difficult to assess if the long-term success rate is representative of the original 150 patients. It may be inflated, because any poor outcomes that presented at follow-up usually underwent reoperation. Conversely, the success rate may be artificially low, because patients may be more likely to return when there is a poor outcome. The estimation of head position rather than precise measurement with goniometer is another limitation. In fact, in 31 patients the estimated amount of head positioning was unable to be determined by retrospective review. In summary, strabismus surgery for the head positioning associated with INS produces excellent outcomes with good collapse of AHP for at least 10 years post-operatively.

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Acknowledgements/Disclosure: Funding/Support: This research was supported by an unrestricted grant from Research to Prevent Blindness, Inc. Lions Eye Research Foundation. b. Financial Disclosures: The disclosure statement for the manuscript should comprise ALL FINANCIAL DISCLOSURES IN MEDICINE BY EVERY AUTHOR whether or not you judge them to be related to the submitted manuscript. This includes all personal fees such as income from honoraria, consulting, lectures, speakers' bureaus, expert testimony, commercial employment, stock or equity interests, or intellectual property rights (royalties, patents, licenses, copyright) as well as miscellaneous support Yuxi Zheng: No financial disclosures. Derick G. Holt: No financial disclosures James J. Law: No financial Disclosures. David G. Morrison: No financial Disclosures Sean P. Donahue: No Financial Disclosures

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References 1. Richards MD, Wong A. Infantile nystagmus syndrome: clinical characteristics, current theories of pathogenesis, diagnosis, and management. Can J Ophthalmol. 2015;50(6):400-408. 2. Anderson JR. Causes and treatment of congenital eccentric nystagmus. Br J Ophthalmol. 1953;37(5):267-281. 3. Goto N. A study of optic nystagmus by the electrooculogram. Acta Societatis Ophthalmologica Japonica. 1954;58:851-851. 4. Kestenbaum A. [New operation for nystagmus]. Bull Soc Ophtalmol Fr. 1953;6:599-602. 5. Parks MM. Symposium: nystagmus. Congenital nystagmus surgery. Am Orthopt J. 1973;23:35-39. 6. Calhoun JH, Harley RD. Surgery for abnormal head position in congenital nystagmus. Trans Am Ophthalmol Soc. 1973;71:70-87. 7. Nelson LB, Ervin-Mulvey LD, Calhoun JH, Harley RD, Keisler MS. Surgical management for abnormal head position in nystagmus: the augmented modified Kestenbaum procedure. Br J Ophthalmol. 1984;68(11):796-800. 8. Lee J. Surgical management of nystagmus. J R Soc Med. 2002;95(5):238-241. 9. Zheng Y, Holt DG, Law JJ, Morrison DG, Donahue SP. Management of strabismus associated with infantile nystagmus syndrome: A novel classification to assist in surgical planning. Am J Ophthalmol. 2019. 10. Chang YH, Chang JH, Han SH, Lee JB. Outcome study of two standard and graduated augmented modified Kestenbaum surgery protocols for abnormal head postures in infantile nystagmus. Binocul Vis Strabismus Q. 2007;22(4):235241. 11. Graf M, Droutsas K, Kaufmann H. [Congenital nystagmus: indication, results and dosage of Kestenbaum surgery in 34 patients]. Klin Monbl Augenheilkd. 2000;217(6):334-339. 12. Lee IS, Lee JB, Kim HS, Lew H, Han SH. Modified Kestenbaum surgery for correction of abnormal head posture in infantile nystagmus: outcome in 63 patients with graded augmentaton. Binocul Vis Strabismus Q. 2000;15(1):53-58. 13. Mitchell PR, Wheeler MB, Parks MM. Kestenbaum surgical procedure for torticollis secondary to congenital nystagmus. J Pediatr Ophthalmol Strabismus. 1987;24(2):87-93. 14. Scott WE, Kraft SP. Surgical treatment of compensatory head position in congenital nystagmus. J Pediatr Ophthalmol Strabismus. 1984;21(3):85-95.

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Figure Captions: Figure 1: Kaplan-Meier survival curve for overall reoperation rates Figure 2: Rate of overcorrection and undercorrection of head positioning over time post-operatively. Black triangles represent reoperation times of individual patients with indication of overcorrection. The black arrow represents mean time to reoperation (2.7 years). Grey circles represent reoperation times of individual patients with indication of undercorrection. The grey arrow represents mean time to reoperation (3.9 years). n=132 at 1-3 wk, n=107 at 2-5 mo, n=57 at 2 yr, n=42 at 5 yr, n=14 at 10 yr.

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Table 1: Summary of mean visual acuity in LogMAR and Snellen equivalent. Visual Acuity (Logmar) Visual Acuity (Snellen equivalent) Pre-operative 0.412 20/52 1-3 weeks 0.461 20/58 2-5 months 0.371 20/47 2 years 0.439 20/55 5 years 0.409 20/51 10 years 0.475 20/59

Table 2: Summary of reoperation cases and indications. Overcorrection and undercorrection refer to head positioning only. Pre-existing strabismus refers to reoperation for strabismus when it existed at baseline. Induced strabismus refers to strabismus not present at pre-operative visit. Original surgery modification

Mean time to reoperation

Number of cases, percentage

Details (# - indication)

40% Augmentation

3.8 years

4 (21%)

3 – Overcorrection 1 – Induced strabismus

60% Augmentation

2.9 years

8 (15%)

2 – Preexisting strabismus 2 – Induced strabismus 1 – Overcorrection 1 – Undercorrection 1 – Induced vertical head positioning 1 – Both overcorrection and induced strabismus

Strabismus Modification

1.6 years

10 (27%)

6 – Preexisting strabismus 2 – Undercorrection 1 – Overcorrection and strabismus 1 – Undercorrection and strabismus

Pitch Head Positioning

2.6 years

9 (29%)

3 – Preexisting strabismus 3 – Undercorrection 2 – Induced strabismus 1 – Induced horizontal head positioning

Table 3: Review of outcomes of modified Kestenbaum procedure for horizontal AHP in INS Authors

Type of surgery

Calhoun & Harley (1973)6

Classic maximum, Classic plus 1, 40% augmentation 40% augmentation, 60% augmentation Classic maximum, 10-40% augmentation, Coexisting strabismus Classic maximum, Classic plus 1, 6.5-8-9-10 augmentation, 40%-60% augmentation Classic maximum, 20%-30% augmentation Dose effect 1.5° per mm Classic maximum, 6-7-6-7 Classic maximum, 20-60% augmentation, Strabismus modification

Nelson et al (1984)7 Scott & Kraft (1984)14 Mitchell et al (1987)13 Lee (2000)12 Graf (2000)11 Chang (2007)10 Zheng (2019)

Sample Mean size Follow -up 19 13 mo

% corrected AHP within 10° 32%

15

33 mo

66%

32

30 mo

63%

38

54 mo

50%

63

13 mo

89%

31 92

-33mo

65% 88%

119

46mo

83%