Skeletal Expansion Via Craniofacial Distraction Osteogenesis Technique In Syndromic Craniosynostosis: Impact On Ophthalmic Parameters

doi:10.21203/rs.3.rs-3176222/v1

Background

This study aims to compare the changes in ophthalmic parameters among syndromic craniosynostosis patients who underwent craniofacial skeletal expansion procedures via distraction osteogenesis (DO).

Method

A retrospective study was conducted involving syndromic craniosynostosis patients who underwent surgical expansion via the DO technique from the year 2012 to March 2022. Changes in six parameters which consist of visual acuity, refractive error, optic disc health, intraocular pressure, degree of proptosis and orbital volume were measured objectively pre and post-surgery. For categorical parameters, the Chi-square cross-tab test was done. Paired sample T-test was used for normally distributed variables. Wilcoxon signed-rank test was used for non-normally distributed data.

Results

Visual impairment was present in 21.4% of eyes before surgery and increased to 28.5% post-surgery. Three patients had changes of refractive error post-surgery with one developed hypermetropia, another developed anisometropia and the last had improvement to no refractive error. Two patients had optic disc swelling which was resolved post-surgery. Intraocular pressure changes were inconsistent post-surgery. All patients achieved a significant reduction in the degree of proptosis post-surgery. Orbital volume calculation using computed tomography (CT) scans shows a significant increase in volume post-surgery for all patients.

Conclusion

Our study shows a significant increase in orbital volume post-surgery with a reduction in the degree of proptosis. Optic disc and nerve health improved after the surgery. Changes in terms of visual acuity, refractive error and IOP were inconsistent after the surgical intervention.

Craniosynostoses

Exophthalmos

Distraction osteogenesis

Orbit

Tomography

X ray Computed

Craniosynostosis is the early closure of one or more cranial sutures. The incidence of craniosynostosis is 1:2000 to 2500 live births worldwide and approximately 25% of patients with craniosynostosis are syndromic and involve more than one cranial suture fusion (1). Gene mutations such as Fibroblast Growth Factors Receptors (FGFR1, FGFR2, FGFR3); Twist Homologue (TWIST1) and Muscle Segment Homeobox (MSX) had been identified as common causative factors for craniosynostosis (2). These genes regulate cell growth, division, and maturation, as well as angiogenesis, wound healing, and embryonic development (2, 3). Common syndromes are Crouzon, Apert, Pfeiffer and Muenke. The characteristic features include skull and facial structural abnormalities with functional deficiency involving the intracranial region, vision, airway, oral and appearance (1).

Almost all patients with syndromic craniosynostosis (SC) have eye signs and symptoms (4). A combination of these symptoms can lead to visual loss. Patients with SC are recommended to have their eyes examined biannually until they reach 7 to 9 years old, then once a year (5). Papilledema is a warning sign of increased intracranial pressure (ICP) and could also be secondary to the narrowing of the optic canal (6). Worsening papilledema indicates increasing ICP and warrants (7).

Surgical intervention is the treatment of choice to correct acute symptoms among SC patients. Types of cranial expansion surgery include posterior vault expansion, frontal-orbital advancement and fronto-facial advancement surgery (8). It is an effective method to increase intracranial volume thus lowering the ICP and it also addresses midface deficiency to correct ophthalmic issues and restore nasopharyngeal airway passage (9). Cranial expansion surgery via distraction osteogenesis (DO) method had been reported to be superior in comparison to the conventional method. The technique can provide more mobility, achieving a superior amount of structural expansion with simultaneous soft tissue extension thus minimizing relapse, and limiting the potential frontal dead space post-surgery (10).

Even though multiple craniofacial studies are available, outcomes emphasizing ophthalmic issues among patients with SC are still lacking. The objective of this study is to compare the pre-and post-surgical changes of ophthalmic parameters in terms of visual acuity, refractive error, optic disc and nerve health, intraocular pressure, degree of proptosis, and orbital volume.

This retrospective study analyzed the records of all SC patients who underwent surgical expansion procedure via DO surgery between the year 2012 to March 2022 at Universiti Malaya Medical Centre. All information was obtained from the electronic medical records. All patients with syndromic craniosynostosis who underwent craniofacial surgery intervention via DO were included. All patients were required to have pre- and post-surgery CT scans. Patients that underwent conventional surgery correction, posterior vault expansion via DO and have acquired craniofacial deformity were excluded.

Six main parameters were collected which consisted of visual acuity; refractive error; optic disc and nerve health; intraocular pressure (IOP); degree of proptosis and orbital volume. Best-corrected visual acuity (BCVA) was measured using methods appropriate for age. Visual impairment (VI) by World Health Organization (WHO) was defined as vision worse than 6/12. Mild VI was defined as visual acuity worse than 6/12 to 6/18; moderate VI as visual acuity worse than 6/18 to 6/60; severe VI as visual acuity worse than 6/60 to 3/60 and blindness VI as visual acuity worse than 3/60. For pre-verbal infants, visual impairment was defined as the inability to fix and follow in the better eye (11).

Refractive error was assessed for each eye and the spherical equivalent was calculated. Myopia was defined as the spherical equivalent of 0.50 diopter and more. Hyperopia as + 2.00 diopter and more. Anisometropia was defined as a difference of at least 1 diopter of spherical equivalence between the two eyes. Significant astigmatism was defined as a cylinder value of 0.75 diopter. Regular astigmatism was defined as horizontal axis readings between 175◦ and 5◦ and vertical axis readings between 85◦ and 95◦. Oblique astigmatism was considered when the axis readings were beyond these figures (11).

Disc health status was assessed via fundoscopic examination using indirect binocular ophthalmoscopy. The presence of papilledema, optic disc color and disc margin data were noted. Most of our patients’ pre- and post-surgical IOP were assessed using ICARE (iCare TONOVET, Vantaa, Finland) which utilizes the rebound tonometry concept.

OsiriX MD (Pixmeo, Geneva, Switzerland) was used for image processing and analysis of the CT scans data. Pre- and post-op surgery CT scans was retrieved and formatted into Digital Imaging and Communication in Medicine (DICOM) format. The data sets were imported into a computed tomography-based three-dimensional reconstruction software. Manual region of interest (ROI) segmentation was done on a reconstructed Frankfurt plane. This can be done digitally with the OSirix software’s 3-Dimensional (3D) Multiplanar Reconstruction (MPR) tool.

A 3D volume-rendered image is produced and 3 defining points were labelled with 3D points as shown in Fig. 1A. The 3 points are bilateral porion and orbitale point. The axial slice containing all 3 points was identified on the 2-Dimensional (2D) image as shown in Fig. 1B. This axial plane will be the orientation of the image used for measurement and image analysis.

The degree of proptosis was measured on the CT scan axial view instead of the Hertel exophthalmometer as shown in Fig. 2. By adopting the method by Park et al., CT scans with a one mm slice thickness were used (12). The axial slice on the reconstructed Frankfurt’s plane with the most protruded eyeball was chosen. A horizontal line was drawn between the lateral orbital rims that cross the globe, known as the inter-zygomatic line. A perpendicular line was drawn forward from the horizontal line to the cornea’s most posterior surface. The forward line’s length was measured as the degree of proptosis (12).

Orbital volume calculation was done by adopting the method used by Shyu 2015 using OsiriX MD (Pixmeo, Geneva, Switzerland) software (13). A 3D surface-rendered image was constructed from the 2D data. A 3D point tool was used to outline the bony orbital rim. The marked points include the zygomatic-frontal processes at the lateral side, the anterior lacrimal crest at the inferior-medial orbital rim, the nasal process of the frontal bone at the superomedial side, and the supra- and infraorbital rims (13). Based on these landmarks, manual segmentation with the “closed polygon” ROI tool was used on the 2D axial view to determine the boundaries of the orbit. The landmarks identified on the 3D image can be identified on the 2D image slices as shown in Fig. 3.

A line connecting the lateral and medial orbital rim landmarks determined the anterior limit. The opening of the optic foramen into the orbit was chosen as the posterior limit. Sagittal-plane image was used to verify the most superior and inferior axial slices. The optic canal, soft tissue, and globe sections extending beyond the orbital rim were not included in the volume calculation. The compute ROI volume tool was used to automatically calculate the volume of the entire selected regions after finishing the ROIs on consecutive slices as shown in Fig. 4 (13).

Data were analyzed with IBM Statistical Package for The Social Sciences (SPSS) Statistic for Windows, version 27.0 (IBM Corp, New York, USA). Descriptive data were expressed as mean standard deviation (SD) unless otherwise stated. For categorical parameters, the Chi-square cross-tab test was done. Paired sample T-test was used for normally distributed variables. Wilcoxon signed-rank test was used for non-normally distributed data. A value of P < 0.05 is considered statistically significant. The data collected were analyzed using an intention-to-treat basis.

(Insert Table 1)

Table 1 shows patients’ demographics, syndrome and outcome measures of visual acuity, refractive error, presence of papilledema and intraocular pressure in our study. All were diagnosed with syndromic craniosynostosis with 6 Crouzon syndrome (75.0%) and 2 Pfeiffer syndrome (25.0%). The mean age was 32 months old at the time of surgery.

Among the 8 patients, only 4 patients underwent genetic testing, 3 of which tested positive for the respective syndrome. All 3 positive genetic testing patients were diagnosed with Crouzon syndrome. The patient with Pfeiffer syndrome tested negative in the FGFR2 gene test.

Visual acuity measurement was available for 7 patients. Visual impairment was present in 3 eyes (21.4%) out of 14 eyes with visual acuity data before surgery. Post-surgery, VI was present in 4 eyes (28.5%) out of 14 eyes with visual acuity data.

Cycloplegic refraction data were available for 7 patients. Pre-surgery assessment of the 9 eyes shows that myopia was present in 4 eyes (44.4%), and 5 eyes (55.6%) shows no refractive error. Significant astigmatism was not present in all 4 patients pre-and post-surgery. Out of the 9 eyes with refractive data post-surgery, hypermetropia was present in 2 eyes (22.2%), 1 eye (11.1%) was myopic and 2 eyes (22.2%) show anisometropia with 4 eyes (44.5%) showing no refractive error. Significant astigmatism was not present in all 4 patients.

Optic disc assessment was available for 7 patients. 2 patients (28.6%) showed optic disc swelling with pallor disc in both eyes during the pre-surgery assessment. Post-surgery, there were no signs of optic disc swelling for all patients.

IOP values were available for 7 patients. The mean IOP of the right eye was 16.61 ± 3.44 mmHg pre-surgery and 19.57 ± 4.20 mmHg post-surgery. For the left eye, the mean IOP was 18.76 ± 6.41 mmHg pre-surgery and post-surgery was 19.86 ± 4.10 mmHg.

(Insert Table 2)

Table 2

Degree of proptosis and orbital volume at pre- and post-operative stage.
Patient	Degree Of Proptosis								Orbital Volume
	Right Eye				Left Eye				Right Eye				Left Eye
	Pre (mm)	Post (mm)	Diff (mm)	Diff (%)	Pre (mm)	Post (mm)	Diff (mm)	Diff (%)	Pre (cm³)	Post (cm³)	Volume Gain (cm³)	Volume Gain (%)	Pre (cm³)	Post (cm³)	Volume Gain (cm³)	Volume Gain (%)
1	23.1	13.7	-9.4	-41%	22.7	16.9	-5.8	-26%	7.45	19.56	12.10	162%	8.53	19.44	10.91	128%
2	26.2	24.6	-1.6	-6%	24.3	22.4	-1.9	-8%	12.71	12.70	-0.01	0%	12.87	12.98	0.11	1%
3	22.2	16.2	-6.0	-27%	22	16.0	-6	-27%	8.48	16.59	8.11	96%	8.01	12.89	4.87	61%
4	19.6	19.1	-0.5	-3%	21.7	19.8	-1.9	-9%	7.54	16.29	8.75	116%	8.18	16.83	8.65	106%
5	22.5	18.5	-4.0	-18%	21.9	19.3	-2.6	-12%	8.20	17.19	8.99	110%	6.81	12.84	6.03	88%
6	23.8	19.2	-4.6	-19%	24.2	19.4	-4.8	-20%	7.92	15.76	7.84	99%	7.68	15.59	7.91	103%
7	21.2	20.9	-0.3	-1%	19.2	20.6	1.4	+ 7%	6.53	8.42	1.89	29%	7.04	8.55	1.52	22%
8	21.4	12.5	-8.9	-42%	22.3	15.0	-7.3	-33%	8.36	18.40	10.042	120%	7.76	14.67	6.9	89%

Table 2 shows the changes in the degree of proptosis and orbital volume pre-and post-surgery. The mean degree of proptosis of the right eye pre-surgery was 23.02 ± 2.18 mm and 18.55 ± 3.33 mm post-surgery. The mean degree of proptosis pre-surgery for the left eye was 23.18 ± 2.98 mm and 17.90 ± 3.52 mm post-surgery. One case had increased proptosis by 1.4mm (+ 7%). There is a significant reduction in the degree of proptosis for both eyes, right eye (p = 0.010) and left eye (p = 0.002).

The mean orbital cavity volume of the right eye was 8.40 ± 1.85 cm³ pre-surgery and 15.61 ± 3.54 cm³ post-surgery. The mean orbital cavity volume for the left orbit was 8.36 ± 1.91cm³ pre-surgery and 14.22 ± 3.24cm³ post-surgery. The mean increment post-surgery was 7.22cm³ for the right orbit volume and 5.86cm³ for the left orbit. All orbit showed a significant increase in orbital volume post-surgery. (Right orbit (p = 0.002) and left orbit (p = 0.003).

The prevalence of visual impairment among patients in this study was 21.4% before surgical intervention. This prevalence is lower in comparison to visual impairment of preschool-going age (25%) and much higher in the school-going age (1.4%) normal population of Malaysia (14, 15). In comparison to other similar craniosynostosis studies, Khan et al found that 64.6% of patients had visual acuity less than 6/12 while Tay et al found that 44.6% of patients had visual impairment (16, 17). Rafique et al. reported a higher prevalence of visual impairment which is at 32.1% in all craniosynostosis but one-third of the visual impaired patients were non-syndromic patients (11). Pre and postoperative visual acuity findings can be inconclusive and misleading as visual acuity of children develops with time (18).

Refractive error especially anisometropia is the leading cause of amblyopia. Amblyopia is the most common cause of decreased visual acuity in children with craniosynostosis (19). Due to the high prevalence of refractive error in this population, visual rehabilitation with glasses is critical to preventing amblyopia. However, most of these children have flat nasal bridge and proptosis, making fitting of glasses difficult thus resulting in lower compliance (11). In an examination of 141 syndromic craniosynostosis cases, Khan et al discovered a 40% prevalence of astigmatism larger than 1 diopter (D) and an 18% prevalence of anisometropia, compared to a 3.5% prevalence in the general population.(16) Another review by Tay et al. reported a similar 40% prevalence of astigmatism and 16% prevalence of anisometropia (17). However, no significant astigmatism was detected among the patients in our study. This could be due to the young age of most of our patients during the initial and immediate post-operative assessment. The development of the eyeball is most rapid in the first 2 years of life thus refractive error is not consistent at this time (20).

Prevention of optic neuropathy and addressing progressive papilledema were the major ophthalmological indicators for early surgical intervention. Optic neuropathy is the second most common ophthalmological complication after amblyopia which causes loss of vision (21). Even though papilledema is an indicator of increased ICP, some studies showed that not all cases with increased ICP have papilledema thus warranting other associated signs to be explored. Liasis et al. reported 50% of patients had papilledema in the presence of increased ICP (18). Severe obstructive apnea can also lead to an increase in ICP, and subsequently papilledema and optic neuropathy. Sharma et al. found that a previous episode of papilledema can predict the likelihood of a recurrence, particularly during the period of maximum brain growth, which lasts until the age of 6 (22). This is in line with a study by Lenroot et al. on brain development in children and adolescents whereby the brain achieved 95% of the maximum size by the age of 6 (23).

Intraocular pressure changes among SC patients were not usually reported. In our study, even though our study shows an increase of mean intraocular pressure post-surgery, 7 eyes out of 12 eyes showed a reduction in IOP value. Patients with globe expansion and corneal clouding as a result of increased IOP may experience a loss of vision (24). There are only a few reports on the existence of elevated IOP in patients with SC. Alshamrani et al. reported a case of a 10-year-old patient with Crouzon syndrome who had closed angles and anterior segment dysgenesis as a secondary cause of congenital glaucoma (25). Schultz et al. reported a similar case of a 4-year-old patient that suffered significant visual impairment due to anterior segment dysgenesis, optic nerve hypoplasia, exposure keratopathy, and elevated IOP in the absence of increased ICP (24).

All patients in our study presented with a certain degree of proptosis. Forte et al. reported that proptosis is often present with both features of exophthalmos and exorbitism and found that the globe soft tissue volume is bigger when compared to the normal population (26). Soft tissue globe volume in unoperated patients with Crouzon and Pfeiffer syndrome was considerably greater than in controls up to the age of 5 (27). However, a recent study by Lu et al. reported that the globe soft tissue volume is in the normal range in patients with Crouzon syndrome in comparison to the control group (28). Multiple studies had shown that proptosis in SC was caused by the abnormal orbital cavity volume with a relatively normal orbital soft tissue content (27, 29, 30). Measurement of proptosis using CT shows high intra-observer reliability and reproducibility. There is no significant difference between the measurement of CT and Hertel but the study shows a slightly higher value from measurement done from CT scan. However, the distinctions between the two approaches should not be applied interchangeably because they can lead to clinical interpretation mistakes (31).

Forte et al. reported bony orbital volume of patients with Apert was smaller by 21% and Crouzon by 23% in comparison to the normal population (26). Lu et al. also reported a reduction of the orbital volume by 16 to 24% among their patients with Crouzon in comparison to the control group (28). Post-surgically, Way et al. reported of structural expansion ranged from 41–127% post-monobloc DO and the increment was greatest in very young patients but decreased consistently with age (27). The increment reported in our study was much higher in comparison to many other studies with an approximation of 22–162%. Bender et al. study showed increase orbital cavity volume post-surgically and found that there was no association between exorbitism and orbital rim movements, as well as no correlation between volume enlargement and orbital rim movements (30). This contradicts the findings of Nout et al., who found a substantial association between orbital volume gain and anterior infraorbital rim displacement in Le Fort III advancement (32). Patients who have early cranial vault expansion may be able to postpone development plateauing until they are 10 to 14 years old, and surgery may not be required at all. On the other hand, early fronto-facial advancement surgery in babies or during a dynamic time of orbital growth is likely to observe the need for secondary surgery, maybe driven by FGFR2 drive to Crouzonoid skeletal prematurity (27). Given the growth potential of intra-orbital content, an overcorrection should be considered during the distraction of the midface segment to accommodate for the growth.

There are a few limitations to this study. Given this being a retrospective study, missing data was one of the major setbacks in obtaining complete data. Additionally, the time frame of assessment parameters for each patient was not standardized during pre-and post-surgery. A long-term prospective study with comprehensive pre-and post-surgery systematic assessment along with a fixed follow-up interval is recommended.

In conclusion, surgical expansion via craniofacial DO technique significantly increases the orbital cavity volume and reduces the degree of proptosis among SC patients. Changes in terms of visual acuity, refractive error and IOP were inconsistent after surgical intervention.

Ethics approval and consent to participate

Ethical approval was obtained from the Medical Research Ethics Committee of the Universiti Malaya Medical Centre, Kuala Lumpur, Malaysia. (Approval Number- DF OS2022/0083 (P)).

Consent for publication

Not applicable

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Competing interests

The authors declare no competing interests.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Authors’ contribution

LCK involved in the conceptualization of the study, analyzed and interpreted the patient data and also writing of the manuscript draft. FH and NI were involved in conceptualization of the study along with major review and editing of the manuscript. MKH was involved with review and editing of the manuscript. All authors read and approved the final manuscript.

Acknowledgement

Not applicable

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No competing interests reported.

Skeletal Expansion Via Craniofacial Distraction Osteogenesis Technique In Syndromic Craniosynostosis: Impact On Ophthalmic Parameters

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Abstract

Background

Method

Results

Conclusion

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Background

Materials and Method

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Discussion

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