is approximately 12–18 months of age, and in many European countries, surgery for IE is performed at the age of 2 or 3 years. There has been a call recently for surgery within 2 months of the onset of esotropia [36]. However, there have been no randomized studies with prospectively assigned early-surgery and late-surgery groups and an evaluation according to intention-to- treat. Elliot and Shafiq [37] concluded in their Cochrane review: “As there are no randomised controlled trials in the area at present, it has not been possible to resolve the controversies regarding … age of intervention in patients with IE. … There is clearly a need for good quality trials to be conducted in various areas of IE, in order to improve the evidence base for the management of this condition.”

Indeed, one cannot exclude the possibility that in the retrospective case-series studies, without a control group, an occasional child may have been operated that would have straightened to 60˝ stereopsis without surgery. Three such cases occurred in the first prospective study by Birch et al. [27] and two in the ELISSS.

Therefore, instead of providing the reader with a quick recipe on whether to operate early or late, it seems more appropriate to list and discuss the outcome measures that should be considered when contemplating early, very early, or late surgery in a specific child. The primary outcome measures are the following:

1.The binocular vision conserved or regained by early surgery.

2.The angle of strabismus after surgery and the longterm stability of alignment.

3.The number of operations to reach these goals or the chance of spontaneous reduction of the strabismus into a microstrabismus without surgery.

There are other outcome parameters that should be considered. For instance, the child’s psychological and motor development, and bonding between infant and parents may be improved by early surgery. These need evaluation within disciplines other than pediatric ophthalmology, however.

Endophthalmitis after strabismus surgery [38] occurs preferentially in first surgery in children under 6 years of age, but it is not yet clear whether its prevalence in young children di ers from that in very young children. Finally, general anesthesia may not be without risk in young children. As a case in point, in a recent population-based, retrospective birth cohort study, general anesthesia before the age of 4 years was significantly correlated with learning disability [39].

Summary for the Clinician

■IE may have many causes, ranging from motor to sensory. Whatever its cause, whether sensory or motor, the end state of untreated IE is characterized by lack of binocular vision. If its cause is motor, loss of binocular vision can, in principle, be limited by early surgery.

■Primary outcome measures of surgery are (1) binocular vision, (2) the angle and long-term stability of alignment, and (3) the number of operations or the chance of spontaneous reduction of the strabismus into microstrabismus without surgery.

11.2Outcome of Surgery in the ELISSS

11.2.1Reasons for the ELISSS

Early surgery may minimize further loss of the remaining binocular vision. The first prospective study of surgery for IE Birch et al. [27] reported 35% random dot stereopsis (disparity 400˝ or better) among 84 children operated at approximately 8.5 months. Sixty-three were aligned within 5.7°. The average number of operations was 1.5. Three were not operated and had full stereopsis.After this first prospective study of surgery for IE had been published, the need was felt in Europe for a large, prospective, controlled multicenter trial comparing early surgery for IE with late surgery.

11.2.2Summarized Methods of the ELISSS

In the ELISSS, all children with IE were included who first presented to one of the participating clinics. The ELISSS study committee considered randomization impossible, because it was anticipated that the parents would not cooperate: One first would have had to inform the parents of the possibility of surgery next week, only to postpone surgery for 2 years when the randomization procedure prescribed late surgery [40]. Instead, each of the participating clinics chose beforehand whether to operate all of their eligible patients in the recruitment period either early or late. Recruited children received an extensive baseline examination at 6–18 months of age, were assigned to early surgery (6–24 months) or late surgery (32–60 months), and were assessed at the age of 6 years. All children who first presented with convergent IE between 5 and 30° were included. However,

children with preor dysmaturity, nystagmus, nervous system deficit, retardation, dysmorphia or motility disorders other than upor downshoot in adduction, V- or A-pattern, or limitation of abduction were excluded.

11 Following recruitment, the angle of strabismus, refraction, degree of amblyopia, and limitation of abduction were assessed in an extensive baseline examination, based on a test–retest reliability study [41]. Orthoptic examinations, including angle and refraction, were repeated every 6 months. Cases with strongly established fixation preference and/or significant anisometropia underwent appropriate and e ective occlusion therapy to the point of near spontaneous alternation and central fixation of the worse eye. Reoperation was undertaken in cases with a residual esotropia of greater than 10°, or in case of overcorrection. Children were evaluated at the age of 6 years in the presence of independent observers. Endpoints were level of binocular vision, manifest angle of strabismus at distance fixation, remaining amblyopia, number of operations, vertical strabismus, angle at near, and influence of surgical technique.

11.2.3Summarized Results of the ELISSS

A total of 58 clinics in 13 countries recruited 532 children: 231 children at the age of 11.1 SD 3.7 months (baseline) for early surgery and 301 at the age of 10.9 SD 3.7 months for late surgery. An additional 442 patients screened for inclusion were excluded for various reasons, like prematurity (32), congenital nystagmus (49), or nervous system deficit (99). No di erences between groups were found in the baseline examination apart from a slightly larger angle in the early group [42]. Of 532 patients, 414 were evaluated at the age of 6 years in the presence of independent observers (82.7% of all forms were signed by the independent observer). Dropout rates were 26.0% in the early and 22.3% in the late group, but no di erences existed between dropouts and completers in the baseline examination, and clinics with many dropouts did not have better results. The final examinations were performed at the age of 6.8 SD 0.8 years, on average, in the early group and 6.8 SD 0.7 years in the late group. The interval between the last operation and the final examination was 4.4 SD 1.5 years in 157 children from the early group, and 2.3 SD 1.1 years in 187 children from the late group. The number of orthoptic examinations in the early group was 11.3 SD 5.2 per patient, including all children who later became dropouts; in the late group, it was 11.4 SD 4.6.

Fig. 11.1 Binocular vision at the age of 6 years after early or late surgery, stratified according to whether the children had been operated (black) or not (white) at the age of 6 years.Categories:(1) Bagolini negative, (2) Bagolini positive, (3) Housefly positive, (4) Titmus circles 200˝–140˝, (5) Titmus circles 100˝–40˝, (6) all figures of Lang Test or TNO 480˝ and 240˝, (7) TNO 120˝–15˝ (See Ref. [57])

11.2.4Binocular Vision at Age Six

At the age of 6 years, 51.2% of the early vs. 44.7% of the late group recognized Bagolini striated glasses, and 13.5% of the early vs. 3.9% (P = 0.001) of the late group recognized the Titmus Housefly; 3.0% of the early and 3.9% of the late group had stereopsis beyond Titmus Housefly (Fig. 11.1). Some children had been operated beyond the set time frame (6–18 and 32–60 months), but “as treated” analysis yielded the same result.

11.2.5Horizontal Angle of Strabismus at Age Six

At the age of 6 years, the manifest horizontal angle during fixation at distance was 2.15° SD 5.45° in the early group (N = 167) and 3.21° SD 6.29° in the late group (N = 231), wearing full refractive correction. Surprisingly, 35.1% of

Percentage for unoperated and operated patients

40

the early-surgery group and 34.8% of the late-surgery group were not aligned within 0–10°, despite the fact that the protocol prescribed to continue surgery until alignment within 0–10° had been reached. Many children had a small exotropia (especially in the early group), but in other cases, a large esotropia existed that had not been considered a priority by the parents in the period preceding the final examination. It was also surprising that the variation of the angle of strabismus at age 6 was equal to its variation at baseline at 11 months (Fig. 11.2). These findings underscore that surgery for IE is elective and, as clinicians, we primarily see patients while they are being treated by us until they are straight.

11.2.6Alignment is Associated with Binocular Vision

Children with at least Titmus Housefly stereopsis were better aligned (Fig. 11.3). Better alignment in case of better binocular vision has been found by Birch et al. [43] and Fu et al. [44]. In the study “Randomized comparison of bilateral recession vs. unilateral recession-resection for

IE” [45] among older children, 38.4% of the children had a positive Bagolini test postoperatively, although all children with any form of binocular vision preoperatively had been excluded. These children had significantly better ocular alignment, which may have been either a cause or a consequence of the gain of binocular vision.

Summary for the Clinician

■In the ELISSS, children with IE operated around the age of 20 months, achieved Bagolini striated glasses or Titmus Housefly stereopsis more frequently as compared to those operated around the age of 49 months.

■No di erence was found, however, for stereopsis beyond Titmus Housefly.

■Alignment was similar after early surgery, as compared to that after late surgery, but a large variation of the angle of strabismus was found at the age of 6 years in both groups.

■Children with stereopsis were aligned better,which may have been either a cause or a consequence of the gain of binocular vision.