Surgical Treatments to Improve Visual Acuity in Infantile Nystagmus Syndrome

Abstract

Purpose:

To review the literature on the efficacy of surgical procedures to improve visual acuity (VA) in patients with infantile nystagmus syndrome (INS).

Methods:

Literature searches were last conducted in January 2022 in the PubMed database for English-language studies with no date restrictions. The combined searches yielded 354 abstracts, of which 46 were reviewed in full text. Twenty-three of these were considered appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist.

Results:

One included study was a randomized trial; the remaining 22 were case series. The 23 studies included children and adults with INS and a variable proportion with anomalous head position (AHP), strabismus, and sensory diagnoses. The surgical interventions evaluated included large recessions, tenotomy and reattachment (TAR), myectomy with or without pulley fixation, and anterior extirpation of the 4 horizontal rectus muscles, as well as various procedures to correct an AHP in which VA was reported as a secondary outcome. The data were mixed, with improvements in binocular best-corrected visual acuity (BCVA) ranging from no improvement to 0.3 logarithm of the minimum angle of resolution (logMAR), or 3 lines. (Most studies were in the range of 0.05–0.2 logMAR.) Statistically significant improvement in VA was noted in 12 of 16 studies (75%) that performed statistical analyses, with no clear advantage of any single procedure. Complications and reoperations were lowest in patients who underwent TAR and highest in those who underwent myectomy or anterior extirpation.

Conclusions:

The best available evidence suggests that eye muscle surgery in patients with INS results in a modest improvement in VA.

Financial Disclosure(s):

Proprietary or commercial disclosure may be found after the references.

The American Academy of Ophthalmology (Academy) prepares Ophthalmic Technology Assessments to evaluate new and existing procedures, drugs, and diagnostic and screening tests. The goal of an Ophthalmic Technology Assessment is to systematically review the available research for clinical efficacy, effectiveness, and safety. After review by members of the Ophthalmic Technology Assessment Committee, other Academy committees, relevant subspecialty societies, and legal counsel, assessments are submitted to the Academy’s Board of Trustees for consideration as official Academy statements. The purpose of this assessment by the Ophthalmic Technology Assessment Committee Pediatric Ophthalmology/Strabismus Panel was to review the published literature on surgical procedures to improve visual acuity (VA) in patients with infantile nystagmus syndrome (INS).

Background

Infantile nystagmus syndrome is the most common form of nystagmus in children, with an estimated prevalence ranging from 1 in 821 to 1 in 6000 births.^1-3 It usually presents before 6 months of age and can be related to an underlying sensory disorder, such as ocular or oculocutaneous albinism, or be idiopathic (previously termed “congenital motor nystagmus”).^1-3 The waveform in INS may be pendular or jerk⁴ and uniquely exhibits exponentially increasing velocity during the slow phase.⁵ As in other forms of nystagmus, decreased foveation due to the rhythmic oscillations in INS leads to reduction in best-corrected visual acuity (BCVA). Some patients with INS have an eccentric null zone—a gaze position in which the nystagmus intensity is decreased and foveation is improved.⁵ Such patients may adopt an anomalous head position (AHP) to use the null zone (and maximize VA) for straight-ahead viewing. Additionally, strabismus may be present in up to 50% of children with INS.⁶

Treatment options for INS depend on the characteristics of the nystagmus and associated conditions. Generally, the goals of treatment are to improve VA by damping of nystagmus and correct any associated strabismus or AHP. Nonsurgical treatment options include optical correction, prisms, and medications. Contact lenses may provide better refractive correction than glasses, because they reduce optical aberrations and prismatic effect related to decentered use of spectacles in patients with an eccentric null zone.⁷ Additionally, contact lenses have been suggested to damp nystagmus by stimulating the ophthalmic branch of the trigeminal nerve, although this effect is controversial.^7,8 Base-out prisms may be used to stimulate convergence in patients with convergence damping of nystagmus.⁸ Various medications have also been reported to damp nystagmus in certain types of INS,^9-11 but they are used uncommonly because of limited evidence of benefit and potential side effects, especially in children. Botulinum toxin injection into horizontal rectus muscles may damp nystagmus, although this treatment generally requires repeated injections every few months.¹²

Surgery is the mainstay of treatment for patients with INS who have strabismus or AHP, and various procedures have been described to correct the AHP. For patients with a horizontal AHP, the most commonly performed surgeries are the Anderson procedure (recession of yoke horizontal rectus muscles)¹³ and the Kestenbaum procedure (also called the “Kestenbaum-Anderson” or “Anderson-Kestenbaum” procedure; this surgery involves recession and resection of all 4 horizontal rectus muscles).¹⁴ These procedures treat the AHP by shifting the null zone toward central gaze, which is accomplished by moving the eyes in the direction of the AHP. Procedures to treat a head tilt or vertical AHP similarly move the eyes in the direction of the AHP.¹⁵ In patients who have convergence damping of nystagmus without an AHP, the Cuppers artificial divergence procedure (bimedial rectus recessions) may improve BCVA.¹⁶ In patients with strabismus who undergo any of these procedures for INS, the surgical dose may be adjusted to correct ocular alignment simultaneously.

There is no standard surgical treatment to improve BCVA in patients with INS, however. Most procedures aim to reduce nystagmus intensity by weakening the extraocular muscles. Because nystagmus in INS is typically horizontal, these procedures are usually performed on the 4 horizontal rectus muscles. Surgical options include large (retroequatorial) recessions,¹⁷ myectomy with or without pulley fixation,^18,19 and anterior extirpation.²⁰ Surgery on the rectus muscles to improve an AHP or strabismus has also been associated with improved VA.^21,22 Such effects are not simply due to shifting the null zone to central gaze, because improvement of VA in the null zone has been demonstrated.^23,24 On the basis of this observation, Dell’Osso et al²⁵ hypothesized that tenotomy and reattachment (TAR) of extraocular muscles would result in reduced nystagmus intensity; their group demonstrated improvement of visual behavior and oculography in an achiasmatic Belgian sheepdog that underwent this procedure. Hertle et al^26,27 later incorporated the TAR procedure in large series of patients with INS who underwent extraocular muscle surgery. Tenotomy and reattachment may reduce nystagmus intensity and thereby improve VA by altering proprioceptive feedback at the tendino-scleral interface (enthesis) of extraocular muscles.²⁸

To quantify improvements in the nystagmus waveform on nystagmography, Dell’Osso and Jacobs²⁹ developed the expanded nystagmus acuity function (NAFX), which is a measure of the potential acuity based on foveation. The NAFX and related functions are used as primary outcome measures in some studies of nystagmus surgery.^30,31 However, improvements in the nystagmus waveform do not always correlate with improvement in VA due to ocular comorbidities, such as albinism, that may reduce VA in patients with INS. Other potential benefits of nystagmus surgery that may be quantified by nystagmography, such as broadening of the high-acuity visual field,³² were not included in this assessment.

Question for Assessment

This assessment addresses the following question: What is the efficacy of surgical procedures to improve VA in patients with INS?

Description of Evidence

A literature search limited to English language studies was last conducted in January 2022 in the PubMed database. The following terms were used, along with publication and language filters: nystagmus, congenital[MeSH Terms] OR infantile nystagmus[Title/Abstract] OR infantile nystagmus syndrome[Title/Abstract] OR nystagmus congenital[Title/Abstract]) AND (surgery[Title/Abstract] OR recession[Title/Abstract] OR horizontal[Title/Abstract] OR tenotomy[Title/Abstract] OR myectomy[Title/Abstract] OR horizontal rectus muscles[Title/Abstract] OR horizontal recti[Title/Abstract] OR cupper[tiab] OR artificial divergence[tiab] OR anomalous[tiab] OR myectomy[tiab] OR Kestenbaum[tiab] OR Anderson[tiab] OR pulley[tiab] OR rectus muscles[tiab]) nystagmus, congenital/surgery[mh].

The searches yielded 354 articles. Forty-six abstracts met the inclusion criteria or had insufficient details in the abstract to determine study eligibility and were selected for full-text review. The inclusion criteria were as follows: (1) The primary objective of the study was to evaluate surgical treatment of INS; (2) the study reported BCVA in the null zone (or central acuity if no null zone was present) before and after surgery as an outcome measure; (3) follow-up duration was at least 1 month; and (4) at least 10 patients were included in the study. Although the panel recognized that 1 month of follow-up may not be indicative of the final outcome, it chose to include studies with shorter follow-up to evaluate both short-term and long-term effects of the procedures. Studies of procedures to treat an AHP if BCVA was only reported in central gaze or the position of gaze was not specified were excluded, because BCVA in central gaze would be expected to improve postoperatively in these cases due to shifting the null zone more centrally rather than damping of nystagmus. Data on nystagmography, complications, and reoperations as secondary outcomes were also collected.

Of the 46 articles identified for full-text review, 23 were excluded because they failed to meet the inclusion criteria, most commonly because the number of patients was less than 10 or BCVA was not assessed in the null zone. The panel methodologist (R.H.T.) assigned a level of evidence rating to the 23 articles deemed appropriate for inclusion using the Academy’s guidelines, which are based on the 2011 rating scale developed by the Oxford Centre for Evidence-Based Medicine.³³ Well-designed and well-conducted randomized controlled trials and systematic reviews are rated level I. Well-designed cohort studies and nonrandomized controlled cohort/follow-up trials are rated level II. Case series, case reports, and case-controlled studies, as well as reports based on inferences, are rated level III. One study, a randomized trial, was rated level II, and 22 studies were case series and rated level III.

Published Results

Nine of the 22 case series evaluated a single surgical procedure to improve VA in INS (large recessions, TAR, and myectomy with pulley fixation of all 4 horizontal rectus muscles).^{17,19,30,34-39} Five case series included patients who underwent surgical procedures primarily to correct an AHP.^{15,21,22,40,41} Eight case series evaluated 2 or more different surgical procedures for INS (in some cases, these procedures were designed to address strabismus or AHP).^{18,26,27,31,42-45} The level II randomized trial compared retro-equatorial recession (RER) and TAR of all 4 horizontal rectus muscles.⁴⁶

The study sizes ranged from 10 to 100 patients, and most studies included both children and adults, although 1 study included only children less than 2 years of age.⁴² Three studies included only patients with idiopathic INS (previously termed “congenital motor nystagmus”), and 2 studies exclusively focused on patients with albinism.^31,34 The remainder of the studies included a variable mix of patients with idiopathic and nonidiopathic INS. Although patients with and without an identifiable sensory condition are both categorized as INS in the current nomenclature, older studies used the terms “motor” and “sensory” nystagmus. In this assessment, data are presented with the nomenclature used by the study’s authors.

All studies except 2 included a variable proportion of participants with strabismus or AHP.^39,46 The remaining 2 studies included patients who underwent surgery solely to damp nystagmus and improve VA.

None of the studies included a control group of observation or conservative management without surgery. Therefore, it is unknown whether factors unrelated to the surgery may have impacted nystagmus intensity at postoperative visits (e.g., patients may be more relaxed at follow-up visits, which may improve measurements).

All studies reported a change in BCVA at distance in the null zone (or central gaze if there was no null zone). Most studies reported both binocular and monocular BCVA. The results of binocular BCVA testing are reported in this assessment because children with nystagmus frequently exhibit better VA when using both eyes because of latent components of nystagmus that may occur in some patients with INS.⁵ Only 1 study reported monocular BCVA exclusively.¹⁷ Several studies reported the individual BCVA values without calculating the average;^{19,34,35,38,44} in these cases, the mean BCVA preoperatively and postoperatively was calculated from the available data after conversion to logarithm of the minimum angle of resolution (logMAR). Eleven studies reported preoperative and postoperative nystagmography findings; amplitude and frequency were the most commonly reported parameters. Four articles used the NAFX or a related measure as a primary outcome.^26,30,31,42

All patients had at least 1 month of postoperative follow-up (range, 1 month to 6 years), and most studies reported VA at the end of follow-up. However, 3 studies tested BCVA at 6 to 12 weeks postoperatively to eliminate potential confounding by the normal improvement in VA with age in young children.^26,31,42

Review of Studies

Single Procedures to Improve Visual Acuity in Infantile Nystagmus Syndrome

Nine case series evaluated a single procedure to improve BCVA in INS: large, or retro-equatorial recessions (6 studies); TAR (2 studies); and myectomy with pulley fixation (1 study) of all 4 horizontal rectus muscles. The results of these studies are summarized in Table 1.

Table 1.

Summary of Level III Evidence of Single Procedures to Improve Visual Acuity in Infantile Nystagmus Syndrome

Study Year, First Author	No. of Patients	Mean Age in Years (Range)	Diagnoses (Motor vs. Sensory Nystagmus, Strabismus, Anomalous Head Position)	Procedure Details	Mean Improvement in Distance Binocular BCVA	Improvement in Nystagmography	Mean Follow-up Duration (Range)	Complications and Reoperations
Recession of 4 Horizontal Rectus Muscles
1991, Helveston17	10	18 (1.5–51)	6 (60%) motor/4 (40%) sensory 5 (50%) strabismus 5 (50%) AHP	MR and LR recessed 11.0–18.0 mm from limbus	1 line	N/A	9.8 (1–31) mos	None
1997, Davis34	12	20 (4–30)	12 (100%) albinism 3 (25%) strabismus 3 (30%) AHP	MR and LR recessed 10–14 mm bilaterally	0.13 log MAR*	N/A	13 (3–41) mos	3 (25%) reoperations for strabismus
2003, Alio35	42	24 (7–49)	38 (90%) motor/4 (10%) sensory 8 (19%) strabismus 7 (17%) AHP	Extended hangback recession of 14 mm (all 4 muscles)	0.08 log MAR* (P = 0.006)	N/A	2.5 (1–4) yrs	Induced strabismus requiring second procedure in 26%
2003, Kose36	12	16 (8–33)	8 (67%) motor/4 (33%) sensory 7 (58%) strabismus 3 (25%) AHP	Recession with scleral passes 8 mm posterior to insertion and loop suture 1–3 mm (all 4 muscles)	0.92 lines (P = 0.004)	Mean amplitude decreased from 11.9–3.5° (P = 0.002), frequency unchanged	15 (6–26) mos	None
2005, Bagheri37	20	15 (2–42)	4 (20%) motor/16 (80%) sensory 15 (75%) strabismus 7 (39%) AHP	MR recessed 12 mm, LR recessed 15 mm	0.11 logMAR (P = 0.02)	N/A	12 (1.5–56) mos	2 (13%) reoperations for residual esotropia
2006, Boyle38	18	32 (16–51)	18 (100%) motor 3 (17%) strabismus 0 AHP	MR recessed 8–10 mm, LR recessed 10–12 mm	0.04 logMAR* 50% 1 line improvement, 50% unchanged	N/A	3–14 mos	5 (28%) decreased stereopsis, 18 (100%) limitation in adduction, 16 (89%) limitation in abduction, 1 (6%) scleral perforation, 2 (11%) induced exotropia
Tenotomy and Reattachment of 4 Horizontal Rectus Muscles
2003, Hertle30	10	38 (19–55)	4 (40%) motor/6 (60%) sensory 50% PAN 7 (70%) strabismus 0 AHP	Standard	2.5 ETDRS letters	Mean increase in NAFX: 0.07 (1 Snellen line) non-PAN, 0.24 (2.5 lines) PAN	52 weeks	None
2016, Dubner39	15	15 (3–77)	9 (60%) INS, 6 (40%) acquired 0 strabismus 0 AHP	Standard	0.12 logMAR (P = 0.002)	N/A	8.6±4.9 mos	1 (7%) conjunctival cyst
Myectomy of 4 Horizontal Rectus Muscles with Pulley Fixation
2020, Lingua19	10	31 (18–42)	5 (50%) FH, 5 (50%) without FH (no FH) 6 (60%) strabismus 2 (20%) AHP	10-mm myectomy for MR; 17 mm for LR, with pulley fixation, and nasal transposition of a vertical rectus muscle	0.1 logMAR*	Amplitude decreased 54% (FH), 56% (no FH); frequency decreased 9% (FH), 51% (no FH)	6 mos	5 (50%) induced strabismus, 5 (50%) with loss of adduction

AHP = anomalous head position; BCVA = best-corrected visual acuity; FH = foveal hypoplasia; INS = infantile nystagmus syndrome; LR = lateral rectus; MR = medial rectus; N/A = not available; NAFX = expanded nystagmus acuity function; PAN = periodic alternating nystagmus.

^*Calculated from published results.

Retroequatorial Recessions of All 4 Horizontal Rectus Muscles.

In 1991, Helveston et al¹⁷ described large recessions of horizontal rectus muscles for 10 children and adults (mean age, 18 years) with INS with or without strabismus and AHP. Only 1 patient had no AHP or strabismus preoperatively and underwent recession of the medial rectus (MR) muscles 14.0 mm and lateral rectus (LR) muscles 18.0 mm posterior to the limbus. In the remaining patients, the amount of recession (range, 11.0–17.0 mm) was adjusted on the basis of the AHP and strabismus. Visual acuity was tested using the Snellen chart. Eight patients (80%) cooperated with preoperative and postoperative VA measurements; the 2 patients who could not be tested were 1.5 and 2.5 years of age. An average improvement of 1 line was noted on binocular BCVA (statistical significance not reported).

Subsequently, 5 articles^33-37 reported the results of retroequatorial horizontal rectus muscle recessions in case series ranging from 12 to 42 patients, including both children and adults who were diagnosed with sensory and motor nystagmus by the previous classification nomenclature. Binocular BCVA improvement ranged from 0.04 to 0.13 logMAR in these studies. This improvement was statistically significant (P < 0.02) in the 3 studies that performed statistical analyses. Minor variations in surgical technique were reported in each study, mainly related to the surgical dose.

Tenotomy and Reattachment of All 4 Horizontal Rectus Muscles.

Hertle et al³⁰ reported on a prospective case series of 10 adults (mean age, 37.5 years) who underwent TAR for INS. Five patients (50%) had albinism, and 5 patients (50%) had periodic alternating nystagmus (PAN). Binocular BCVA was assessed by a masked, certified technician using ETDRS charts, and examinations were performed 3 times in the 3-month period before surgery. Postoperative BCVA was tested at 52 weeks. On average, there was a gain of 2.5 ETDRS letters after surgery. The main outcome measure was the change in NAFX, which improved by 0.07 (1 Snellen line) in patients without PAN and 0.24 (2.5 Snellen lines) in patients with PAN (statistical significance not reported).

Dubner et al³⁹ conducted a prospective study of 15 children and adults (mean age, 15 years) with nystagmus who underwent TAR of all 4 horizontal rectus muscles. Unlike other studies in this assessment, the authors included both INS (60%) and acquired nystagmus (40%). The results were not reported separately for the 2 groups. Binocular BCVA was tested by one of the investigators (no masking reported) and improved a mean of 0.12 ± 0.18 logMAR, or approximately 1 line (P = 0.002), after surgery. Eye movement video recordings were performed in 14 patients (93%), and frequency was manually assessed. Postoperatively, the mean decrease in nystagmus frequency was 20.6 ± 34.2 beats/minute (P = 0.043).

Myectomy with Pulley Fixation of All 4 Horizontal Rectus Muscles.

Lingua and Gore¹⁹ reported a prospective case series of 10 adults (mean age, 31 years) who underwent myectomy of all 4 horizontal rectus muscles with pulley fixation. Initial results of the 4-muscle myectomy procedure, which removes attachments of all horizontal rectus muscles to the globe and intentionally limits ocular ductions, demonstrated high rates of postoperative exotropia.¹⁸ Horizontal strabismus after myectomy of all 4 rectus muscles is difficult to treat because of reduced surgical options.⁴⁷ Therefore, the authors added fixation of the muscle stump to the pulley in an attempt to maintain the orbital insertions of the rectus muscles and thereby improve postoperative ductions and alignment. All patients in this study had INS, and 5 (50%) had foveal hypoplasia (FH). During the procedure, a 10-mm myectomy of the MR muscles and 17-mm myectomy of the LR muscles were performed; the muscle stumps were sutured to the adjacent pulley tissue. Binocular BCVA was tested using Snellen optotypes (masking not reported) and converted to logMAR. Overall, the mean improvement in distance binocular BCVA was 0.1 logMAR (1 line). Improvement was greater (median, 0.15 logMAR) in patients without FH than in patients with FH (median, 0.05 logMAR), although statistical significance was not reported. Video nystagmography showed a decrease in amplitude in both FH (54%) and non-FH (56%) groups. Five patients (50%) required a second surgery for strabismus, and the authors concluded that pulley fixation did not reduce the risk of exotropia after myectomy.

Overall, large recessions, TAR, and myectomy with pulley fixation of all 4 horizontal rectus muscles conferred limited benefit on VA in patients with INS. Most studies reported postoperative VA improvements in the range of 0.1 logMAR, or 1 Snellen line.

Evidence of Visual Acuity Improvement in Procedures to Correct Anomalous Head Position in Infantile Nystagmus Syndrome

Table 2 summarizes evidence of binocular VA improvement in 5 case series of procedures in which the primary goal was to correct AHP in INS. In 1987, Taylor and Jesse²¹ described a series of 43 children and adults (mean age, 11 years) with congenital motor nystagmus who underwent procedures to correct a horizontal or vertical head position with or without strabismus. The patients were divided into 3 groups. Group 1 included patients with a horizontal AHP and no strabismus. Group 2 included patients with a horizontal AHP plus strabismus. In groups 1 and 2, the Anderson procedure was performed if nystagmus intensity was high, the Kestenbaum procedure was selected if the AHP was large, and the modified Anderson-Kestenbaum procedure (in which recessions were augmented) was chosen if both of these criteria were met. Group 3 included patients with a vertical AHP with or without strabismus; the surgical procedures were bilateral vertical rectus recession with bilateral oblique weakening. Binocular BCVA was assessed preoperatively “over several visits” to ensure stability of findings before surgery. A 7-line Snellen chart was used, and VA was checked in the AHP and primary gaze. The mean improvement in Snellen lines in the AHP after surgery ranged from 1 to 1.5 lines (statistical significance not reported).

Table 2.

Summary of Level III Evidence of Binocular Visual Acuity Improvement from Procedures to Correct Anomalous Head Position in Infantile Nystagmus Syndrome

Study Year, First Author	No. of Patients	Mean Age in Years (Range)	Diagnoses (Motor vs. Sensory Nystagmus, Strabismus, Anomalous Head Position)	Procedures	Mean Improvement in Distance Binocular BCVA in Null Position	Improvement in Nystagmography in Null Position	Mean Follow-up Duration (Range)	Complications and Reoperations
1987, Taylor21	43	11 (4–35)	43 (100%) motor, 19 (44%) strabismus, 38 (88%) horizontal AHP, 5 (12%) vertical AHP	Group 1: horizontal AHP without strabismus (49%): Anderson and/or Kestenbaum Group 2: horizontal AHP with strabismus (40%): Anderson and/or Kestenbaum Group 3: vertical AHP (12%): vertical rectus recession and oblique weakening	Group 1: 1.25–1.5 lines Group 2: 1–1.25 lines Group 3: 1.5 lines	N/A	26 (3–72) mos	None
2006, Gupta40	12	11 (6–22)	12 (100%) motor 0 strabismus 12 (100%) horizontal AHP	Augmented Anderson procedure (MR recess 9 mm, LR recess 12 mm)	2 ETDRS letters (P = 0.2)	No change in intensity (P = 0.08)	3 mos	8 (67%) mild limitation of ductions
2011, Hertle15	24	9.5 (2.5–38)	18 (75%) sensory, 14 (58%) horizontal strabismus, 24 (100%) vertical AHP	Bilateral vertical rectus recession + oblique weakening + horizontal rectus, TAR or recession for strabismus	0.2 logMAR (P = 0.003)	Foveation time increased by 62.1 ms (P < 0.002)	14 (6–38) mos	1 (4%) reoperation for vertical strabismus, 24 (100%) mild limitation in vertical ductions, 1 (4%) conjunctival cyst
2011, Kumar22	28	11 (3.5–23)	8 (29%) sensory (albinism), 3 (11%) strabismus, 28 (100%) horizontal AHP	1. Anderson-Kestenbaum 2. Modified Anderson 3. Anderson + TAR	0.09 logMAR (P = 0.002), no difference between surgical groups	N/A	1 mo	None
2019, Graf41	29 recruited 24 reported	7 (4–44)	12 (41%) sensory, 0 strabismus, 29 (100%) horizontal AHP	High-dose Anderson (13-mm recessions)	0.037 logMAR (P = 0.06)	N/A	15 mos	3 (13%) reoperations for residual AHP or strabismus

AHP = anomalous head position; BCVA = best-corrected visual acuity; LR = lateral rectus; MR = medial rectus; N/A = not available; TAR = tenotomy and reattachment.

In a study limited to patients with vertical AHP, Hertle et al¹⁵ prospectively evaluated 24 children and adults (mean age, 9.5 years) with INS who underwent surgery. The surgical procedures were vertical rectus recessions, oblique weakening, and horizontal rectus recession or TAR to damp nystagmus and treat associated horizontal strabismus. Binocular BCVA was tested in the null zone using ETDRS and single crowded HOTV letters, following the Pediatric Eye Disease Investigator Group Amblyopia Treatment Study protocols. At 6 to 8 weeks postoperatively, binocular BCVA improved by 0.2 logMAR (P = 0.003). Eye movement recordings demonstrated a significant increase in foveation time (P < 0.002).

In contrast, 2 studies of augmented Anderson procedures (recession of yoke horizontal muscles) in children and adults with INS and horizontal AHP reported no significant improvement in binocular BCVA in the null zone postoperatively.^22,39 In 1 study,³⁹ electronystagmography was performed, and there was no difference in the intensity of nystagmus in the null position before and after surgery (P = 0.08).³⁹ However, the horizontal AHP did improve postoperatively.

Finally, Kumar et al²² reported a nonrandomized prospective case series of children and adults with INS and horizontal AHP who underwent Kestenbaum-Anderson, modified Anderson, or Anderson procedures with TAR. Overall, binocular BCVA improved by 0.09 logMAR, or nearly 1 line (P = 0.002), but there was no significant difference among the 3 groups.

In summary, it was found that procedures to improve AHP in patients with INS may result in marginal improvement in BCVA in the null zone. Studies reported VA gains ranging from 2 ETDRS letters to 0.2 logMAR. Although in some cases statistically significant, the clinical significance of this improvement is debatable.

Evidence Comparing Visual Acuity Improvement across Multiple Procedures in Infantile Nystagmus Syndrome

A summary of the evidence from studies comparing or including multiple procedures to improve VA in INS is included in Table 3.

Table 3.

Summary of Evidence from Studies Comparing Multiple Procedures to Improve Visual Acuity in Infantile Nystagmus Syndrome^*

Study Year, First Author	Level of Evidence	Study Design	No. of Patients	Mean Age (Range)	Diagnoses (Motor vs. Sensory Nystagmus, Strabismus, AHP)	Procedures	Mean Improvement in Distance Binocular BCVA in Null Position	Improvement in Nystagmography in Null Position	Mean Follow-up Duration (Range)	Complications and Reoperations
2004, Hertle31	3	Case series	15	16 (2.5–43) yrs	15 (100%) oculocutaneous albinism, 15 (100%) strabismus, 9 (60%) AHP	Strabismus or AHP (80%): 4 horizontal muscle recession and resection Nystagmus only (20%): 4 horizontal muscle TAR	0.1 logMAR (P = 0.000001) No difference among surgical groups	NAFX improved by 0.19 (P = 0.00006)	16.5 mos	1 (7%) reoperation due to consecutive strabismus
2006, Hertle27	3	Case series	75	16.5 (2.5–61) yrs	33 (44%) motor/42 (56%) sensory, 51 (68%) strabismus, 36 (48%) AHP	Strabismus or AHP (83%): 4 horizontal muscle recession, resection, transposition Nystagmus only (17%): 4 horizontal muscle TAR	0.2 logMAR (P = 0.001) No difference among surgical groups	Null zone width increased by 16° (P < 0.001)	18 mos	None
2009, Hertle42	3	Case series	19	18 (5–29) mos	4 (21%) motor/15 (79%) sensory, 13 (68%) strabismus, 11 (58%) AHP	Strabismus or AHP (84%): 4 horizontal muscle recession, resection, transposition Nystagmus only (16%): 4 horizontal muscle TAR	1.3 logMAR (P = 0.003)	Nystagmus optimal foveation fraction improved from 0.16–0.34 (P = 0.0002)	17 (9–22) mos	None
2010, Hertle26	3	Case series	100	14 (1.5–59) yrs	32 (32%) motor/68 (68%) sensory, 71 (71%) strabismus, 62 (62%) horizontal or vertical AHP	9 procedures involving horizontal or vertical rectus muscle recession, resection, tenotomy, or transposition ± oblique muscle weakening	0.23 logMAR (P < 0.05) No significant difference among surgical groups	Automated NAFX increased from 0.273–0.462 (P = 0.0002)	11 (9–23) mos	12 (12%) reoperation for recurrent strabismus or new/recurrent AHP
2021, Hertle45	3	Case series	75	36 (18–72 yrs)	~80% sensory	9 procedures involving horizontal or vertical rectus muscle recession, resection, tenotomy, or transposition ± oblique muscle weakening	0.14 logMAR (P < 0.01)	Best NAFX values improved by 18.5%–24% (P < 0.01)	14 (13–78) mos	12% reoperation for recurrent strabismus or new/ recurrent AHP
2012, ElKamshoushy43	3	Case series	21	15 (7–25) yrs	17 (81%) motor/4 (19%) sensory (albinism), 4 (19%) strabismus, 8 (38%) AHP	No AHP (62%): 4 horizontal muscle recession AHP (38%): Kestenbaum-Anderson	No AHP: 0.07 logMAR (P = 0.009) AHP: 0.05 logMAR (P = 0.11) No difference between groups	N/A	4 mos	None
2013, Akbari44	3	Case series	14	27 (18–44) yrs	9 (64%) motor/5 (36%) sensory (albinism) 8 (43%) strabismus 0 AHP	Strabismus (43%): 2 horizontal muscle recession, 2 horizontal muscle TAR No strabismus (57%): 4 horizontal muscle TAR	Strabismus: 0.03 logMAR† (not significant) No strabismus: 0.06 logMAR (P = 0.07)	Strabismus: amplitude decreased 25% (P = 0.06) No strabismus: amplitude decreased 33% (P = 0.002)	7 (3–15.5) mos	None
2016, Lingua18	3	Case series	39	16 (1.5–61) yrs	20 (51%) motor/19 (49%) sensory 24 (62%) strabismus, 7 (18%) AHP	SAEP, 51% MWR, 49%	SAEP: 1.7 lines MWR: 1.5 lines	Mean amplitude decrease SAEP: 75% MWR: 60%	SAEP: 14 (6–26) mos MWR: 6 (1–12) mos	Reoperations: SAEP 5 (25%) MWR 4 (21%) Limitation of ductions: SAEP −1.7 MWR −0.5 Orbital hemorrhage: SAEP 1 (5%)
2016, Singh46	2	Randomized trial	10	Minimum age 5 yrs	Unknown if motor or sensory 0 strabismus 0 AHP	RER of 4 horizontal rectus muscles (50%) TAR of 4 horizontal rectus muscles (50%)	RER: 0.1 logMAR (P = 0.32) TAR: 0 logMAR (P = 1)	Mean decrease in amplitude RER: OD 0.1° (P = 0.05), OS 0.07° (P = 0.07) TAR: OD 0.01° (P = 0.10), OS 0.06° (P = 0.08)	6 mos	None

AHP = anomalous head positions; BCVA = best-corrected visual acuity; MWR = myectomy without reattachment; NAFX = expanded nystagmus acuity function; OD = right eye; OS = left eye; RER = retroequatorial recession; SAEP = Sinskey anterior extirpation procedure; TAR = tenotomy and reattachment.

^*AHPs are horizontal unless otherwise specified.

^†Calculated from published results.

Studies Conducted by Hertle et al.

Hertle et al published 5 case series^{26,27,31,42,45} of patients with INS who underwent several different procedures to damp nystagmus or improve strabismus and AHP. It is unclear if some patients were included in more than 1 publication; however, there was overlap in ages and diagnoses in some reports. There may also be overlap in patients from the 2 previously discussed studies by the same group.^15,30

In 2006, Hertle and Yang²⁷ reported on a prospective series of 75 children and adults (mean age, 16.5 years) with INS who underwent 4 horizontal rectus muscle surgery. There were 4 groups of patients: (1) strabismus only; (2) AHP only; (3) both strabismus and AHP; and (4) no strabismus or AHP. Patients in groups 1 to 3 underwent 4 horizontal muscle recession and resection procedures to correct strabismus or AHP. Patients in group 4 underwent TAR of 4 horizontal rectus muscles. Binocular BCVA in the null zone was assessed by a masked examiner using ETDRS or single surrounded HOTV letters at 1, 2, and 3 weeks before surgery and 6 to 8 weeks after surgery. Mean logMAR improved from 0.6 to 0.4 (P = 0.001). Although there was no difference among the 4 surgical groups, there was an effect of age, with patients younger than 8 years experiencing significantly more improvement than older patients (P = 0.01). Eye movement recordings were also performed and demonstrated a significant increase in null zone width after surgery (P < 0.001), with no differences among the 4 surgical groups.

In 2010, Hertle et al²⁶ reported a larger prospective case series of 100 children and adults (mean age, 14 years) who underwent eye muscle surgery for INS. The patients underwent 1 of 9 procedures designed to damp nystagmus and address horizontal, vertical, or torsional head posture and strabismus. Recessions, resections, TAR, and transpositions of horizontal or vertical rectus muscles were included, in addition to oblique weakening procedures. This study also included patients with convergence damping of nystagmus who underwent the artificial divergence procedure in addition to TAR of the LR muscles. Binocular BCVA in the preferred head position was tested using Teller acuity cards in preverbal children, with the cards held vertically to more clearly visualize the direction of preferential looking in children with horizontal nystagmus. In older individuals, the ETDRS or single crowded HOTV (Pediatric Eye Disease Investigator Group Amblyopia Treatment Study protocol) letters were used. Two independent examiners assessed VA within hours of each other both 1 week preoperatively and 6 to 8 weeks postoperatively. Mean binocular BCVA in the null zone improved from 0.68 to 0.45 logMAR (P < 0.05). There was no significant difference among surgical groups. In this study, eye movement recordings were analyzed using the Automated Nystagmus Acuity Function instead of the NAFX to account for head and body movements in infants and young children. The mean Automated Nystagmus Acuity Function improved significantly after surgery (P = 0.0002), with no difference among the 9 surgical groups.

In 2021, similar findings were reported by Hertle et al⁴⁵ in a case series of 75 adults with INS who underwent eye muscle surgery to damp nystagmus and treat strabismus or AHP if indicated. The authors chose 1 of the 9 procedures described above based on the patient’s preoperative characteristics. Mean binocular BCVA in the null zone improved significantly from 0.55 to 0.41 logMAR (P < 0.01). The NAFX also improved significantly after surgery (P < 0.01).

The same group also published 2 smaller case series focused on specific patient populations: individuals with oculocutaneous albinism³¹ and infants less than 2 years of age.⁴¹ As in the larger studies, a combination of rectus muscle recession, resection, and TAR were used to treat strabismus or AHP and damp nystagmus. Binocular BCVA was assessed using the same age-appropriate techniques described in the larger studies. In both groups, binocular BCVA in the null position improved significantly, with the greatest improvement in the infants (0.3 logMAR, P = 0.003). Nystagmography also demonstrated significantly improved foveation time in both groups.

Studies by Other Authors.

Two small prospective case series evaluated multiple procedures involving all 4 horizontal rectus muscles in children and adults with INS.^42,43 The procedures included 4 horizontal rectus muscle TAR or recession, the Kestenbaum-Anderson procedure, and 2 horizontal muscle recession plus 2 horizontal muscle TAR, depending on the presence or absence of strabismus and horizontal AHP. There was no statistically significant improvement in binocular BCVA postoperatively for any of the surgical groups, except for a minimal (<1 line) improvement in patients who underwent 4 horizontal muscle recession (0.07 logMAR, P = 0.009).

In 2016, Lingua et al¹⁸ reported a case series of 39 children and adults (mean age, 16 years) with nystagmus who underwent the Sinskey anterior extirpation procedure (SAEP) or myectomy without reattachment (MWR) to damp nystagmus. The authors did not specify whether the study was limited to patients with INS, and procedure choice was not randomized. Supplemental procedures (nasal transposition of a vertical rectus or superior oblique muscle, or inferior oblique weakening) were performed to treat pre-existing or limit induced strabismus. Binocular BCVA at distance was reported preoperatively and postoperatively, but quantitative VA testing was not performed in 7 patients (18%). The mean improvement in binocular BCVA was similar between groups (1.7 and 1.5 lines in the SAEP and MWR groups, respectively; no statistical analysis performed). The authors noted that greater improvements were seen in children less than 10 years of age with no ocular pathology. On videonystagmography, the mean decrease in nystagmus amplitude was 75% and 60% in the SAEP and MWR groups, respectively.

Finally, Singh et al⁴⁶ conducted the only randomized trial included in this assessment. The study was rated level II because of methodological limitations, including its small sample size (total 10 patients). There was no power calculation to guide recruitment. Patients with INS without strabismus or AHP were randomized to undergo RER (MR 9 mm, LR 12 mm) or TAR of 4 horizontal rectus muscles. Binocular BCVA was assessed using ETDRS and Snellen charts, but examiner masking was not reported. There was no significant improvement in binocular BCVA in the patients who underwent RER (mean improvement 0.1 logMAR, P = 0.32) or TAR (0 logMAR change, P = 1). Contrast sensitivity and stereopsis did improve for both groups (P < 0.04). On nystagmography, mean amplitude decreased in both groups, but frequency did not change.

Overall, comparative studies of procedures to improve VA in INS (mainly involving horizontal muscle recession, resection, or TAR) did not demonstrate superiority of any single procedure. Cohort studies of patients undergoing a combination of rectus muscle recession, resection, TAR, or transposition by a single group reported VA gains ranging from 0.1 to 0.3 logMAR, or 1 to 3 Snellen lines.^{26,27,31,42,45} A single study comparing the SAEP and MWR found that postoperative VA improved by 1.5 to 1.7 lines.¹⁸ However, reoperations were more frequent after extirpation and myectomy procedures because of induced strabismus (see “Reoperations”).

Reoperations

Most reoperations were performed for residual, consecutive, or induced strabismus. The rate of reoperations in patients who underwent large recessions of horizontal rectus muscles ranged from 0% to 25%.^17,34-38 There were no reoperations on eye muscles in patients who underwent only TAR.^30,39 One patient who underwent TAR required postoperative removal of a conjunctival cyst.³⁹ In patients who underwent procedures to correct AHP, the indication for reoperation was strabismus or residual AHP; the reoperation rate was 0% to 12%.^{15,21,22,40,41} In studies that combined patients who underwent rectus muscle recession, resection, TAR, and transposition to damp nystagmus and improve strabismus and AHP, the rate of reoperation also ranged from 0% to 12%.^{26,27,31,42,45} The reoperation rates for patients who underwent the SAEP, MWR, and myectomy with pulley fixation were 25%, 21%, and 50%, respectively.^18,19

Complications

Postoperative limitation of ductions was highly variable. Among studies of large recessions of 4 horizontal rectus muscles, the reported rate of duction limitation ranged from 0% to 100%.^36,38 The discrepancy is likely related to the degree of limitation considered significant by the authors, and possibly by differences in surgical technique and dose. Among patients who underwent procedures to improve AHP, most reported mild limitation in the direction opposite the preoperative face turn.²¹ Lingua et al¹⁸ reported an average duction limitation of only 1.7 (on a 4-level scale) in patients who underwent SAER and 0.5 in MWR. However, in the series of patients who underwent myectomy with pulley fixation, the authors reported that only 50% of patients had preserved adduction.¹⁹

Most studies did not report sensory outcomes, but 1 study of patients who underwent large horizontal rectus muscle recessions reported loss of stereopsis in 28% of patients.³⁸ However, Singh et al⁴⁶ found improved stereopsis and Akbari et al⁴⁴ reported no change in stereopsis in patients who underwent large horizontal rectus recessions. Studies of patients who underwent procedures to correct AHP reported no change^15,40 or mild improvement in binocularity.²² There was no loss of stereopsis in patients who underwent SAEP or MWR.¹⁸ In patients who underwent myectomy with pulley fixation, 2 patients lost stereopsis and 2 patients gained stereopsis.¹⁹ The 2 patients who gained stereopsis both had a 1-line improvement in binocular BCVA.

Other complications were in 2 patients who developed conjunctival cysts^15,39 and 1 patient who had intraoperative scleral perforation during 4 horizontal muscle recession.³⁸ Additionally, 1 patient who underwent SAEP had an intraorbital hemorrhage.¹⁸

Conclusions

Overall, the level II and III evidence reviewed in this assessment suggests that the improvement of binocular BCVA after surgery in patients with INS is modest. The majority of studies reported BCVA improvement between 0.05 and 0.2 logMAR. Although this improvement was statistically significant in 75% of studies that performed statistical analyses, the clinical significance of this improvement is marginal for most patients.

There was no clear difference among the various procedures included in this assessment on VA outcomes. Moreover, the reoperation and complication rates were similar among large horizontal rectus recessions and various procedures (recessions, resections, and transpositions) to treat AHP or strabismus in patients with INS. Complications may be lower with TAR and higher with myectomy and anterior extirpation.

Level II and III evidence also suggests that eye muscle surgery improves the nystagmus waveform in INS, as evidenced by increased foveation time and improvement on the NAFX and related measures.^{15,26,30,31,42,45} However, damping of nystagmus does not always correlate with improvement in BCVA.⁴⁴

A limitation of our study is that the minimum follow-up time of 1 month may not be indicative of the final outcome. However, among the studies with less than 6 months of follow-up, the results were consistent with the conclusions above.^22,40,43

Future Research

Because all of the studies in this assessment were rated level II or III, further research is necessary to determine the optimal procedure to damp nystagmus in patients with INS with or without an AHP or strabismus. In addition to the need for rigorous study design, such as a randomized controlled trial with a sufficient sample size based on a power calculation, other considerations include consistent patient characteristics and a standardized method of VA testing. Ideally, patients included in such studies would have no preoperative strabismus or AHP, because this would necessitate individual adjustments of the surgical dose and may confound results. Visual acuity should be tested binocularly using standard optotypes in older children and adults. In nonverbal children with INS, additional research is necessary to validate methods of VA testing, such as Teller acuity using vertically oriented cards. Testing should be performed by a masked examiner with repeated measurements because of variability in VA that may occur in patients with INS. In addition to VA testing, which is inherently subjective because it depends on patient response, objective nystagmography should be included as a secondary outcome measure. An initial prospective, randomized, masked study comparing surgical treatment with conservative management may be necessary to establish the benefit (if any) of surgery before comparative studies of surgical procedures are performed. A nonsurgical comparison group is important because of the potential for placebo effects related to participation in a clinical trial.

Because the improvement in VA appears to be modest with all currently described surgeries for INS, future research should also explore new surgical techniques and alternative interventions. Optical therapy, prisms, and medications have all been used to damp nystagmus.^7-10,12 Studies to compare these various treatment options individually or in combination may lead to important insights on the management of INS.

Abbreviations and Acronyms:

AHP

anomalous head position

BCVA

best-corrected visual acuity

FH

foveal hypoplasia

INS

infantile nystagmus syndrome

logMAR

logarithm of the minimum angle of resolution

LR

lateral rectus

MR

medial rectus

MWR

myectomy without reattachment

NAFX expanded

nystagmus acuity function

PAN

periodic alternating nystagmus

RER

retroequatorial recession

SAEP

Sinskey anterior extirpation procedure

TAR

tenotomy and reattachment

VA

visual acuity