Association of Eyelid Disorders and Ocular Motility Disorders in Pediatric Age: an Epidemiologic Analysis. A Multicenter Retrospective Study.

Purpose: Aim of the study was to evaluate the prevalence and type of strabismus, ptosis and eyelid dynamic disorders features, to assess the prevalence of refractive errors, amblyopia and the association with ocular/systemic syndromes in a cohort of patients. Methods: Retrospective observational multicenter cohort study enrolling patients with coexisting ocular motility disorders, comitant and incomitant strabismus, ptosis and dynamic eyelid disorders who have never undergone surgery. Results: 137 out of 19.089 patients were enrolled, of which 97 with uniocular and 40 with binocular disease. Isolated congenital ptosis was observed in 84 patients. A polymalformative syndrome was present in almost one third of cases. There was a slight prevalence of esotropia; most patients were hypermetropic. In monocular disease, myopia affected prevalently older patients, who had worse ptosis margin reex distance and levator function, and signicantly higher astigmatism. Amblyopia occurred in 67.4% of the study sub-population. In monocular disease amblyopia was mild in 25.8%, moderate in 24.2% and severe in 11.3%. In binocular disease was mild in 25%, moderate in 41.7% and severe in 16.7%. Conclusions: All patients with coexisting eyelid and ocular motility disfunctions in pediatric age need ophthalmologic and systemic evaluation to accurately assess amblyopia, refractive errors and systemic/ocupollar disorders.

Shapiro-Wilk test to assess their distribution. Then, whether normally distributed, they were described as mean and standard deviation (SD), otherwise as median and interquartile range (IQR

General characteristics of the study cohort
During the 3-year study period 137 out of 19.089 patients (0.72%) afferent at the two Ophthalmological Pediatric Centers met the inclusion criteria.
In the same observation period, the total number of patients with eyelid static and dynamic disorders were 292 (1.52%) and the total number of isolated congenital ptosis was 84 (0.44%) Ninety-seven out of 137 patients had a monocular disease, affecting either right or left eye whereas in 40 cases the disease affected both eyes.

52.6% F), both overall and between groups.
Among systemic disorders the less prevalent were ocular syndromes and orbital diseases (6%), whilst in almost one third there was a polymalformative syndrome associated (28.5%). Types of strabismus were almost equally distributed, with a slight prevalence of esotropia (37.2%, n=51). In addition, most patients were hypermetropic (73.7%, n=101).
Patients with disease affecting both eyes were characterized by a signi cantly higher strabismus angle deviation for distance (p=0.039) and for near (p=0.023). As well, we observed a signi cantly higher prevalence of comitant strabismus deviation (p=0.021) and ptosis familiar history (p=0.008) among subjects with both eyes affected.
Levator function was indeed signi cantly lower in this subset of patients (median 8 vs 17; p<0.001). All characteristics of the study population are described in Table 1.
Each characteristic of interest in the two subgroups was further separately analysed.

Strabismus
Strabismus was classi ed as follows: esotropia, exotropia and vertical squint.
Patients with monocular disease assessment showed that ptosis onset occurs signi cantly later in those with vertical squint (median 6 moths vs.1 in exotropic and esotropic patients, p=0.010). An association instead emerged as for what concerns strabismus onset (p=0.083), which occurred much more lately in those with vertical squint.
As regards ptosis features, all patients with vertical squint had unilateral ptosis, with the congenital one much more prevalent (83.9% vs. 51.4% in esotropia and 75.9% in exotropia; p=0.010).
Looking at binocular disease a similar nding was observed as for vertical strabismus and an association with a younger age in patients with esotropia resulted (median 10 yrs. vs. 16 yrs in exotropia and 13 yrs in vertical squint; p=0.073). Finally, patients with esotropia have shown higher values of MRD (3 mm vs 1 mm in the other two categories; p=0.081). All data are described in Table 2.

Ptosis features
We thus analysed patients according to ptosis features, either unilateral or bilateral and, within these categories, congenital ptosis or eyelid asymmetry.
As regards patients with monocular disease, we observed that vertical strabismus was signi cantly higher among patients with unilateral congenital ptosis (p=0.011).
A signi cantly higher prevalence of esotropia occurred in patients with unilateral eyelid asymmetry (p=0.010). In the same subgroup MRD (median 4mm vs. 3mm; p<0.001) and levator function (median 18mm vs. 16mm; p<0.001) were signi cantly higher than among those with congenital ptosis.
Looking at patients with both eyes affected a similar nding was observed: the MRD (median 4mm vs. 1mm; p<0.001) and the LF (median 18mm vs. 8mm; p<0.001) were signi cantly higher in patients with bilateral eyelid asymmetry.
Conversely, astigmatism value was signi cantly lower in this subset of patients (median 0.75 vs. 2; p=0.026). An association instead emerged for a slightly higher refractive error in the group with eyelid asymmetry (p=0.060), and for a higher strabismus angle deviation for near, in the group with congenital ptosis (p=0.093). All data are reported in Table 3.

Refractive errors
Refractive error was classi ed as myopic, hypermetropic and anisometropic.
In patients with monocular disease, older patients were signi cantly more myopic (median 14.5 years vs. 10 hypermetric and 11 anysometric, p=0.005). Moreover, refractive error was signi cantly lower in myopic subjects, even though such result is affected by the small sample size of anisometropic patients.

Diseases Categories
For what concerns categories, we run all the categories grouped through the isolated one, in order to minimize the bias due to small sample sizes of the single subgroups.
Among patients with binocular disease, indeed, patients of the isolated category had a signi cantly higher prevalence of strabismus familiar history (50% vs. 5.6%, p=0.043). There was also an association with higher MRD in this subgroup (median 3mm vs. 1mm, p=0.064). All data are reported in Table 5.

Amblyopia
Sixty-two patients with monocular disease were assessed for the visual acuity vs. 24 with binocular disease. Fifty-one uncooperative patients (37.2%) were not assessed. Amblyopia was reported in 58 out of 86 patients (67.4%).

Discussion
Over a 3-year study period, this multicenter study analyzed 137 out of 19.089 patients (0.72%) afferent at the two Ophthalmological Pediatric Centers. The overall prevalence of isolated congenital ptosis was 0.44% (84 out of 19089 patients), of whom 27 (32.1%) were associated with ocular motility disorders. The reported prevalence of strabismus associated with congenital ptosis ranges from 18-36%, [1,2,3,4] which is a much higher prevalence than in the general population [11].
In about one third of cases there was a accompanying diagnosis of polymalformative syndrome. The binocular type shows a signi cantly higher prevalence of ptosis familiar history, comitant strabismus, signi cant higher strabismus angle deviation and lower levator function values.
Regarding strabismus type (esotropia, exotropia, vertical squint), congenital unilateral ptosis was prevalent in patients with vertical squint. Some Authors suggested that strabismus could be secondary to a disruption of binocularity by the ptotic eyelid [12].
On the other hand, as for congenital ptosis associated with vertical strabismus it would be reasonable to suppose that a prenatal insult or maldevelopment of the third cranial nerve could play an important role [13,14]. Moreover, according to known literature, refractive error value was signi cantly higher in patients with esotropia [15].
As for ptosis features, we observed a signi cantly higher prevalence of esotropia and mild ptosis, as well as a good levator function in patients with unilateral and bilateral eyelid asymmetry. These data are mainly related to the clinical features of Type I Duane Retraction Syndrome [16].
With regard to refractive error features, older patients with monocular disease were signi cantly more myopic, and had a signi cantly worse ptosis MRD and LF, as well as higher astigmatism value. Several authors reported more severe refractive errors in moderate or severe ptosis. Zeng et al. reported a higher frequency of hyperopia and a lower axial length -corneal radius (AL/CR) ratio in case of severe ptosis, suggesting a delay in the growth of the eye [17]. Huo L et al. instead deemed that long-standing congenital ptosis might produce myopia [18]. The refractive modi cations were also related to a mechanic effect of ptotic eyelid on ocular surface that reshapes the corneal surface [19, , 20]. Our data con rm a mechanical and deprivational effect of moderate and severe eyelid ptosis, which can lead to refractive changes.
The monocular isolated association, as compared with the other categories, is signi cantly associated with polymalformative syndromes (37.8% vs. 13%, p=0.026) and more often shows an incomitant strabismus deviation.
Amblyopia occurred in the 67.4% of the assessed subpopulation. In monocular disease the 25.8% was diagnosed as mild, the 24.2% as moderate and 11.3% as severe (vs. the 25%, 41.7% and 16.7% in those with binocular disease). Amblyopia estimated prevalence in the general population ranges from the 2.5-5.6% [21,22]. The reported prevalence of amblyopia in patients with ptosis and ptosis and strabismus is 7-8 times higher, and it is associated to a higher prevalence of refractive errors and to a not alternating strabismus [11,[23][24][25]].

Conclusions
To the best of our knowledge, this is the rst study investigating the relation of eyelids and ocular motility disorders. Eyelid static and dynamic disorders and ocular motility disorders are often related. These patients thus need a careful ophthalmologic and systemic evaluation due the high prevalence of amblyopia, refractive errors and systemic/ocular associated disorders.

Declarations Data Availability
The datasets generated and/or analysed during the current study are not publicly available due the common policy of our institution, but are available from the corresponding author on reasonable request.    * Others: congenital cranial dysinnervation disorders, Genetic, CNS disorders/neurological diseases, Ocular syndromes/orbital diseases. ** Amblyopia was analysed on the subgroup of patients for which information was available. *** Qualitative variables are expressed as absolute and percentage frequency quantitative data as median and interquartile range (IQR). Signi cant data are in bold, suggestive p-values in italic.