Ophthalmic Complications of Craniosynostosis and the Impact of Endoscopic Repair

Acknowledgment

None

Funding: Children’s Hospital Ophthalmology Foundation Chair Funds

Introduction

Craniosynostosis often affects the growth and development of the orbit resulting in morphologic changes of the orbital rim, the trajectory of the orbit, and internal volumetric proportions. ^, As such, there are a many ways that vision and ocular alignment are threatened. Ophthalmic abnormalities commonly associated with craniosynostosis include ptosis, exposure keratopathy, astigmatism, amblyopia, papilledema and optic atrophy, and strabismus both from primary abnormalities of extraocular muscle anatomy and their trajectory within the orbit, and secondary changes that can occur after fronto-orbital advancement (FOA). As such, regular ophthalmic evaluation is essential to prevent vision loss from these multitude of causes, many of which are treatable. Some centers have reported that 25% to 40% of syndromic craniosynostosis patients will have a best corrected visual acuity (BCVA) of 20/40 or worse in their better eye under various protocols of surveillance. In this chapter, we review the ophthalmic complications associated with craniosynostosis, what is known about their incidence and severity, and what we have learned when craniosynostosis is treated by endoscopic strip craniectomy (ESC) and orthosis rather than by FOA.

Ophthalmic Complications of Craniosynostosis

Refractive Errors and Amblyopia

Several studies have demonstrated that astigmatism is common. Mayer and colleagues have reported that 25% of healthy children between 1 and 48 months of age have at least 1 diopter (D) of astigmatism. Dobson and colleagues reported that the incidence of astigmatism (of at least 1 D) decreases from 50% in children 4.5 to 5.5 years of age to 12% in children 7 to 9 years of age. They concluded that “against-the-rule” astigmatism disappears by school age in most children. Craniosynostosis, whether syndromic or nonsyndromic, is frequently associated with higher degrees of oblique astigmatism, anisoastigmatism (significant difference in the amount of astigmatism in one eye compared to the other), and anisometropia (difference in refractive error comparing one eye to the other) which increase the risk of amblyopia. In a retrospective study evaluating patients with different forms of craniosynostosis, Hertle and colleagues reported that astigmatism was found in all patients with Crouzon syndrome (25 patients), 13 of 15 patients with Apert syndrome, and 9 of 18 patients with other forms of craniosynostosis. They noted that refractive errors are a significant cause of vision loss in this population for several reasons. Detection and adequate treatment may be limited if photophobia from exposure keratopathy limits the ability to perform an accurate refraction, and midface retrusion combined with relative exorbitism or proptosis creates technical challenges to wearing glasses or other forms of optical correction.

Nonsyndromic Craniosynostosis

Unilateral Coronal Synostosis (UCS)

Denis and colleagues evaluated 39 patients with UCS and reported anisoastigmatism of at least 1.5 D in 9 patients with equal frequency in the ipsilateral or contralateral eye. In contrast, Levy and colleagues reported that 54% (21 out of 39) of patients had at least 1 D of astigmatism, and of these patients, 76% had 1 D or greater astigmatism in the eye contralateral to the fused coronal suture. Only 7 out of 39 patients had spherical anisometropia. Amblyopia was found in 38% (15 of 39 patients), 80% of the time in the contralateral eye. Tarczy-Hornoch and colleagues found that 56% of 25 children with UCS had amblyogenic anisometropia, 79% on the side opposite to the synostosis. A similar observation was demonstrated by Macintosh and colleagues, who evaluated 52 patients with UCS and reported that 44% (25 patients) had greater than 1 D of anisometropia. One retrospective study of patients with UCS did not note an association of amblyopia with anisometropia. Ethnic differences have been reported by Tarczy-Hornoch and colleagues, who found a statistically significant difference in the prevalence of amblyogenic anisometropia among Hispanic UCS patients (72%) compared with non-Hispanic UCS patients (14%) ( P = .02).

The higher incidence of astigmatism in the eye contralateral to the fused suture in UCS has been explained by a downward displacement of the orbital roof which may place subtle pressure on the globe, altering corneal curvature. It is well-known that vascular malformations or masses in the eyelid produce secondary astigmatism by this mechanism (pressure on the globe). ^, Using 3-dimensional (3-D) computed tomography (CT) images to study a cohort of infants with UCS, Lo and colleagues demonstrated that the two eyes have different height-to-width ratios (orbital index).

Metopic Craniosynostosis

In a retrospective series of 91 individuals who had isolated metopic craniosynostosis, 20.9% (19 patients) had astigmatism, 5.5% (5 patients) had myopia, 5.5% (5 patients) had hyperopia, and 5.5% (5 patients) had anisometropia. A total of eight patients had amblyopia. Of these patients, amblyopia was caused by a combination of refractive error and strabismus in five patients and refractive error alone in three patients. Hypotelorism and upslanting of the lateral canthus is often associated with metopic synostosis.

Syndromic Craniosynostosis

In a retrospective series of 144 patients with syndromic craniosynostosis including Apert, Crouzon, Pfeiffer, and Saethre-Chotzen syndromes, Khan and colleagues reported that 39.8% of patients had BCVA of 20/40 or worse in the better seeing eye and 64.6% of patients had BCVA of 20/40 or worse in at least one of their eyes. Forty percent of patients had 1 D or greater of astigmatism in one of their eyes. Oblique astigmatism was present in at least one eye of 64% of these patients. The prevalence of astigmatism differed from one syndrome to another, with approximately 30% in Saethre-Chotzen syndrome patients, 43% in Crouzon syndrome patients, 45% in Pfeiffer syndrome patients, and 52% in Apert syndrome patients. The astigmatism may result, in part, from the downward slant of the superior orbital rim. Anisometropia of at least 1 D was found in 18% of patients compared to 3.5% of age-matched children without craniosynostosis. A review of 71 patients with Crouzon syndrome by Gray and colleagues demonstrated that 35% had vision loss in at least one eye and 9% had bilateral visual impairment. Amblyopia was a common cause of vision loss present in 21% of patients. Seventy-seven patients had significant ametropia. Fifty-seven percent had hyperopia of at least 2 D and 20% had myopia of at least 0.5 D. Consistent findings were reported by Tay and colleagues in a retrospective series of 55 patients with syndromic craniosynostosis (Apert, Crouzon, Pfeiffer, Saethre-Chotzen) or cranio-fronto-nasal dysplasia. Of these patients, 40% had visual impairment (35.5% bilateral and 9.1% unilateral), and amblyopia (16.7%) as well as ametropia (25%) were major risk factors. Forty percent of patients with syndromic craniosynostosis had astigmatism. There was a lower prevalence of hyperopia (18%) compared to that reported by Gray and colleagues (57%). ^,

Apert syndrome is mostly caused by fibroblast growth factor receptor gene 2 (FGFR 2) point mutations, either Ser252Trp or Pro253Arg. Patients with S252W mutation are far more likely to demonstrate significant astigmatism (82%) compared to those with P253R mutation (14%) ( P = .005). BCVA less than 20/40 in at least one eye was more prevalent in the S252W mutation group (60% compared with 12.5% in P253R mutation group) ( P < .05).

Several theories have been proposed to explain the high prevalence of astigmatism in syndromic craniosynostosis including exposure keratopathy with subsequent corneal distortion, ptosis especially in Saethre-Chotzen syndrome, and orbital dysmorphology and asymmetry.

Strabismus

Strabismus is a common oculomotor disorder in craniosynostosis, whether syndromic or nonsyndromic, with reported incidence ranging from 39% to 91% compared to an incidence of 2% to 3% in children under 6 years of age without craniosynostosis. In nonsyndromic single suture synostosis, it is most often found in patients with UCS. Several genetic mutations have been associated with craniosynostosis syndromes ^, and some of these mutations appear to increase the risk of strabismus in these sub-popuations. Strabismus is more common in Apert syndrome patients with S252W mutation (91%) compared with those with the P253R mutation (85%) and have a higher risk of superior rectus (SR) underaction ( P = .024) and are more frequently treated with strabismus surgery (64% compared with 14% in P253R mutation group) ( P = .039). The strabismus can be horizontal, vertical, or both, but the most common pattern is V-pattern strabismus characterized by horizontal, vertical, and torsional misalignment ( Fig. 7.1 ). A similar study reported that strabismus was more common in the S252W mutation group (47% compared with 39% in P253R mutation group); however, the difference was not statistically significant ( P = .546).

Possible Mechanisms of Strabismus in Craniosynostosis

One or more of the following factors may explain the high incidence of strabismus in patients with craniosynostosis.

Absence or Dysgenesis of Extraocular Muscles

Several studies have documented absent or anomalous extraocular muscles in Apert, Crouzon, and Pfeiffer syndromes. In Apert syndrome, Bustos and Donahue reported a case of a 6-month-old patient with agenesis of inferior and superior oblique muscles in both eyes. Several authors have reported absent SR muscles. Helveston proposed that a combination of amblyopia and significant horizontal strabismus in a patient with congenital superior oblique (SO) palsy should raise the suspicion of an absent SO tendon. Pollard described 11 Apert syndrome patients with bilateral SO palsy and significant horizontal strabismus in primary and down gazes. Of these patients, five had no SO tendon in either eye and two had only a small fibrous muscle remnant at the anticipated location. The same finding has been described by Pinchoff and Sandall, who reported two patients (one patient had Apert syndrome, the other had Crouzon syndrome) both with absent SO tendons. Diamond and colleagues reported that 5 of 12 Crouzon patients undergoing strabismus surgery had abnormal extraocular muscles. Coats and colleagues evaluated 14 patients with craniosynostosis and noted bilateral anomalous SO tendon in 8 of these patients. Snir and colleagues reported a 29-year-old Crouzon syndrome patient who had bilateral agenesis of SR, inferior rectus (IR), SO, and inferior oblique (IO) muscles together with abnormal wide insertion of two horizontal muscles. Anomalous medial rectus (MR) and lateral rectus (LR) muscles insertions have been described by Caputo and Lingua in a Crouzon syndrome patient, whereas the MR was bifid, and twice the normal size. Both MR and LR muscles were inserted 2.5 mm posterior to the limbus. Coats and Ou described a Crouzon syndrome patient with bifid left MR insertion with two muscle bellies separated by 5 mm of sclera. Both bellies were inserted 9 mm from the limbus with a total width of 13.5 mm. Margolis and colleagues examined IO muscle from an Apert syndrome patient under light and electron microscope. They demonstrated morphological changes and structural alterations which may be responsible for ocular motility disturbances even with grossly normal looking muscle. Light microscopy disclosed enlarged hyalinized fibers with loss of myofibrillar organization. Under electron microscopy, fragmented swollen mitochondria with various nuclear abnormalities were seen. As FGFR2 has been demonstrated in human extraocular muscles, it is likely that FGFR2 mutation may be directly responsible for some of the extraocular muscle morphology reported. As most studies reporting absence of extraocular muscles predate modern high resolution orbital imaging, it is plausible that “absent” muscles may have been present, but thin and dysmorphic and potentially identifiable with higher resolution magnetic resonance imaging (MRI) sequences.

Excyclorotation of Recti Muscles

The most common form of strabismus in patients with craniosynostosis is V-pattern strabismus. Many factors may contribute to the pathogenesis of V-pattern strabismus. Excyclorotation of the rectus muscles is responsible in some cases. Excyclorotation is counter-clockwise rotation of the rectus muscles of the right eye and a clockwise rotation of the rectus muscles of the left eye ( Fig. 7.2 ). Using orbital CT imaging, Dagi and colleagues evaluated extraocular muscle excyclorotation near the orbital apex (posterior orbit) and near the muscle pulleys (anterior orbit) in patients with syndromic craniosynostosis (Apert, Crouzon, and Pfeiffer syndromes) and V-pattern strabismus. Patients classified with moderate-to-severe and severe (“see-saw”) V-pattern strabismus, demonstrated a significant correlation between the severity of V-pattern and the degree of rectus muscle excyclorotation at both the anterior and posterior orbital locations( Fig. 7.3 ). The degree of excyclorotation was significantly worse in patients with “see-saw” V-pattern strabismus (see Fig. 7.1 ) when compared with those with moderate to severe strabismus. This correlation was not identified in patients with mild-to-moderate V-pattern strabismus and is unlikely to be the cause in cases with milder V-pattern. Severe or see-saw V-pattern strabismus is more common in Apert syndrome patients than in those with Crouzon and Pfeiffer syndromes. This may result from the distinctive orbital anatomy characterizing each form of syndromic craniosynostosis. Apert syndrome typically results in lateral orbital wall protrusion and ethmoidal sinus ballooning not seen in patients with Crouzon or Pfeiffer syndromes. ^, ^, Weiss and colleagues demonstrated that excyclotorsion of rectus muscle pulleys changes their impact on alignment in a gaze-dependent manner, resulting in V-pattern exotropia in patients with Crouzon syndrome.

Retropositioning of Trochlea

In patients with UCS, the ipsilateral orbit has a characteristic “harlequin deformity” ( Figs. 7.4–7.6 ) which results in elevation and posterior displacement of the trochlea of the SO. This desagittalization of the trochlea increases SO laxity, thereby decreasing the muscle’s ability to incyclotort and infraduct the eye. Retropositioning of the trochlea can also occur during FOA. During FOA, the trochlea is separated from its anatomical insertion and then passively replaced, sometimes in a desagittalized position. Regardless of the cause of SO underaction, there is secondary overaction of its opponent muscle, the inferior oblique (IO). Asymmetry between SO and IO action often results in V-pattern strabismus and, sometimes, secondary ocular torticollis. ^,

Other Theories

It has been proposed that anatomic orbital changes may result in enhanced contact between IO and the undersurface of the globe. Such changes may result in overaction of the IO and underaction of the SO with resultant V-pattern. ^, Denis and colleagues proposed that fronto-zygomatic displacement of the lateral orbit in these cases increases the tension on both IR and IO muscles resulting in overaction of these muscles and V-pattern strabismus. Late migration of surgical screws into orbit may result in vision loss or induced strabismus ( Fig. 7.7 ).

Patterns and Management of Strabismus in Craniosynostosis

V-pattern strabismus, the most common form of strabismus in craniosynostosis, is a horizontal deviation with an increase in the angle of strabismus in up gaze compared to down gaze of at least 15 prism diopters (PD). Normal ocular alignment is essential for the development of binocular single vision and stereopsis. A common associated finding in this population is ocular torticollis (head tilt to enable binocular fusion) often exacerbated by non-ocular torticollis ( Fig. 7.8 ). Normalization of ductions and versions by strabismus surgery will reduce torticollis if it is ocular in nature, but the results may prove disappointing if the child has lost binocularity due to amblyopia and suppression. Strabismus surgery to improve ocular alignment in such cases may minimally reduce torticollis. Strabismus surgery in the population of patients with craniosynostosis, especially syndromic, is much more challenging than in the general population. Techniques described include IO weakening procedures, SO tucking, adjustment for seemingly absent extraocular muscles by transposition of others, and relocation of excyclorotated muscles and aberrant insertions ( Fig. 7.9 ). ^, ^, ^, The best timing for strabismus surgery depends on a several factors including age, presence or absence of binocular potential, and other impending surgery. An approach to reducing the V-pattern includes consideration of the gaze of maximum misalignment (Knapp classification), presence of see-saw pattern (see Fig. 7.1 ), the presence or absence of binocular fusion or fusional potential, anomalous anatomy or position of extraocular muscles, angulation of the orbital bones possibly resulting in extraocular muscles excyclorotation, and orbital asymmetry. Preoperative orbital imaging to evaluate the relative degree of excyclorotation, and position of the recti and the trajectory of the SO, can provide important information for surgical planning. High-resolution MRI is most useful for visualizing extraocular muscle detail and CT for orbital changes. 3-D ultrasound can provide additional information. Although imaging provides accurate information on extraocular muscle location and trajectory, nothing substitutes for insights gained by intraoperative exaggerated traction testing of the SO and IO, forced ductions of the rectus muscles, and intraoperative view of the quality and trajectory of the extraocular muscles.

Papilledema and Optic Neuropathy

Craniosynostosis affects skull growth which may result in intracranial hypertension. Increased intracranial pressure (ICP) may result from abnormalities within the intracranial venous system as well. A hallmark of elevated ICP is the development of papilledema ( Figs. 7.10 and 7.11 ) which sometimes is accompanied by new intraocular myelin migration ( Fig. 7.12 ). Chronic papilledema and elevation in ICP result in optic atrophy and permanent vision loss ensues ( Fig. 7.13 ).