Introduction

Primary congenital glaucoma (PCG) is a rare disease caused by developmental malformations in the trabecular meshwork, the Schlemm’s canal and the anterior chamber angle. These malformations cause a blockage of the aqueous outflow system with subsequent increase of intraocular pressure (IOP) (Hoskins et al. 1984). The increased IOP results in stretching of the flexible infant eye, causing enlargement of the eye (buphthalmos) and clouding of the cornea. In time, the optic nerve can get irreversibly damaged. Visual development of children with PCG is hampered by the clouding of the cornea, refraction errors and optic nerve damage. Treatment of PCG is primarily surgical, and involves opening or bypassing the Schlemm’s canal (deLuise & Anderson 1983). Currently, diagnosis and management is largely driven by macroscopic observations (eye size and corneal clarity), whereas the underlying changes are at the microscopic level.

Ultrasound biomicroscopy (UBM) is a non-invasive technique used by ophthalmologists to evaluate the anterior segment of the eye. This technique was developed by Pavlin and Foster in the 1990s (Palvin et al. 1991). With UBM, deeper structures of the anterior segment can be imaged and measured, such as the iris, anterior chamber angle, scleral spur, ciliary body, Schlemm’s canal and the lens (Dada et al. 2007; Qureshi et al. 2019). UBM has been applied in adult glaucoma patients to study different types of glaucoma (Pavlin et al. 1992; Dada et al. 2007; Prata et al. 2013). UBM is performed in a supine position and can be performed in children.

The pathogenesis of PCG lies in the anterior segment. Severeness of the disease differs greatly amongst individuals. Some children have unilateral glaucoma that stabilizes after a single surgery, whereas others have bilateral disease and need multiple surgeries per eye to reduce the IOP. In vivo imaging of the anterior chamber in children with PCG could give more insight into the malformations and could be linked to the clinical picture. UBM might be an interesting tool to visualize, record and quantify the anterior segment malformations in PCG, to better understand the disease and to help clinical decisions.

In this review, we studied the literature on UBM of the anterior segment in PCG and made an overview of the morphological findings in these patients compared to controls.

Materials and Methods

A literature search through the PubMed database was performed on UBM, congenital glaucoma and anterior segment of the eye. The search term used stated: (Microscopy, Acoustic[MeSH] OR Microscopy, Acoustic*[tiab] OR Ultrasound biomicroscopy*[tiab]) AND (Hydrophthalmos[MeSH] OR Hydrophthalmos[tiab] OR Congenital glaucoma*[tiab] OR Pediatric glaucoma*[tiab] OR Buphthalmos[tiab] OR Childhood glaucoma*[tiab]) AND (Eye[MeSH] OR Anterior segment[MeSH] OR Eye*[tiab] OR Anterior segment*[tiab]). The search was performed in December 2020 by two researchers. Articles were included if the full-text was written in English. Other inclusion criteria were human studies with PCG patients (no animal or computer models), usage of UBM (no other types of imaging) and studies that characterized the anterior segment. Case reports were excluded. All included articles were critically appraised with the Joanna Briggs Institute critical appraisal checklist (Joanna Briggs Institute 2017). Based on these checklists, the methodological quality and risk of bias were assessed.

The following study and patient characteristics were collected: study design, number of eyes analysed, history of pressure-reducing surgery, sex, age, IOP, corneal diameter and ocular axial length. UBM measurements of various parameters of the anterior segment were collected. Figure 1 presents these parameters schematically. The parameters include: Trabecular iris angle (TIA): constructed of a line along the inner surface of the cornea and a line along on the opposite anterior iris surface and measured in degrees (Gupta et al. 2007; Hussein et al. 2014) or in μm (Shi et al. 2020); Trabecular meshwork thickness (TMT): measured at the anterior end point of the Schlemm’s canal (Shi et al. 2020); Iris thickness (IT): measured across a vertical line centrally from the iris root and the most probable location of the scleral spur, measured 500 μm (Shi et al. 2020) or 2 mm (Hussein et al. 2014 and Gupta et al. 2007) from the iris root; Ciliary process length (CPL): measured from the point of the most anterior tip of the ciliary body to the beginning of the zonules (Shi et al. 2020 end Gupta et al. 2007); Corneal thickness (CT): measured from the scleral spur to the outer surface of the corneal limbus (Shi et al. 2020) or from the centre inner surface of the corneal endothelium to the outer epithelial surface (Hussein et al. 2014); Schlemm’s canal (SC): Diameter of SC: defined as the distance between the most posterior and anterior part of the Schlemm’s canal directly adjacent to the TM (Tandon et al. 2017; Shi et al. 2020); Cross-sectional area (CSA) of SC: calculated using an automated area function in ImageJ (Shi et al. 2020) Anterior chamber depth (ACD): measured from the centre of the corneal endothelium to the anterior lens capsule (Hussein et al. 2014); Lens thickness (LT): measured from anterior to posterior lens capsule (Hussein et al. 2014 and Gupta et al. 2007); Zonular length (ZL): measured straight from the tip of the ciliary processes to the lens equator (Hussein et al. 2014 and Gupta et al. 2007); Posterior chamber depth (PCD): measured from the iris pigment epithelium to the first visible zonular fibre at a point just leaving the ciliary process or it was measured along a vertical line 1 mm central to the root of the iris (Hussein et al. 2014 and Gupta et al. 2007); Qualitative features: Other features of the anterior segment Detection of abnormal tissue membrane, rarefaction or stretching of the ciliary body, elongation of the ciliary process, abnormalities involving iris insertion level or Descemet’s membrane or Schwalbe’s line. High-frequency ultrasound biomicroscopy (UBM) image of the anterior segment showing an overview of the UBM parameters measured in primary congenital glaucoma and healthy eye. Upper figure: image of a primary congenital glaucoma (PCG) affected eye; lower figure: image of an unaffected healthy contralateral eye. ACD = anterior chamber depth, CPL = ciliary process length, CT = cornea thickness, IT = iris thickness, PCD = posterior chamber depth, SC = Schlem’s canal, SS = scleral spur, TIA = trabecular iris angle, TMT = trabecular meshwork thickness. Copyright: Picture adapted from Shi et al. (2020). According to open access copyright regulations of PLoS ONE. Results Inclusion of articles and critical appraisal

The literature search on PubMed initially yielded 28 hits. Twenty-two studies were excluded since they did not meet the inclusion criteria. No extra studies were found by screening the references of the remaining studies. The six remaining studies were all cross-sectional prospective studies. Shi et al. (2020), Tandon et al. (2017), Hussein et al. (2014) and Gupta et al. (2007) were case-control studies, whereas Shi et al. (2018) and Dietlein et al. (2000) made a comparison within all PCG patients included in the study.

Study and patient’s characteristics

The study and patient characteristics are summarized in Table 1. A total of 299 eyes were evaluated, including 221 eyes with PCG and 78 control eyes. Except for Gupta et al. (2007), all studies included both affected eyes in case of bilateral disease. Gupta et al. (2007), Shi et al. (2020) and Hussein et al. (2014) used the unaffected fellow eyes of unilateral glaucoma cases as control. Hussein et al. (2014) had an additional 15 eyes of 10 participants without intraocular disease as control. Tandon et al. (2017) included 19 eyes of 10 subjects without ocular history as a control.

Table 1. Study and patient characteristics. Shi et al. (2020) Tandon et al. (2017) Hussein et al. (2014) Gupta et al. (2007) Shi et al. (2018) Dietlein et al. (2000) Journal PLoS ONE J AAPOS Clin Ophthalmol J AAPOS Am J Ophthalmol Ophthalmol City, country Beijing, China USA Tanta, Egypt New Delhi, India Beijing, China Köln, Germany Group PCG Control PCG Control PCG Control PCG Control 1* 2* 3* PCG Number of eyes 51 11 17 19 25 15 45 28 14 13 22 34 Previous surgery 0 0 17 0 0 0 39 0 14 13 22 11 Male (%) 76.5 72.7 60.0 50.0 66.7 60.0 60.0 64.3 44.4 87.5 93.8 55.6 Mean age in months ± SD (range) 36 (3–96) 26 (5–79) 9.4 ± 11.80 (3d–36) 79.2 ± 79.8 (7w −204) 10.3 ± 3.59 (1–24) 14.5 ± 5.9 (2–24) 166 ± 38.4 (84–324) 169 ± 54 5 (3–40)† 36 (5–60)† 49.5 (11–60)† 63.9 (8.4–216) Mean IOP ± SD (range)a 33 (22–48)† 15 (12–20)† 51.4 ± 11.5 (34–72) n/p 25.9 ± 5.16 14.2 ± 3.2 n/p n/p 30 (22–44)† 33 (22–48)† 34 (24–46)† 19.6‡ (10–35) Mean CD ± SD (range) 13.0 (12–16)† 11.1 (11–12)† n/p n/p 13.1 ± 0.63 10.9 ± 0.60 13.3 ± 0.9 11.4 ± 1.2 13 (12–15)† 13.5 (12–14)† 13 (11–14)† n/a Mean AL ± SD (range) n/p n/p n/p n/p 23.1 ± 1.6 20.2 ± 0.8 26.1 ± 2.4 22.5 ± 2.5 n/p n/p n/p 25.4 (20–31.8) AL = axial length (given in millimetres), CD = corneal diameter (given in millimetres), IOP = intraocular pressure (given in mmHg)’, n/p data not present, PCG = primary congenital glaucoma, SD = standard deviation.

Inclusion of PCG affected eyes varied between 17 and 51 eyes per study. Intraocular pressure-reducing surgery was performed in 116 eyes. All studies had a higher percentage of male PCG patients. Shi et al. (2018) did not divide patients in study and control groups, but in three types of trabeculodysgenesis (severe, moderate, mild) based on UBM examination. Age ranged from 1 day to 27 years. Age differed between the studies. Table 1 also outlines the average IOP, corneal diameter and axial length. All IOP measurements are before surgery, except for Dietlein et al. (2000).

Outcomes on UBM imaging of anterior segment in PCG

Since there is no standardization of UBM in imaging the anterior segment in PCG, the outcome measures differed between the studies. Shi et al. (2020), Tandon et al. (2017), Hussein et al. (2014) and Gupta et al. (2007) had comparable study approaches in which anterior segment parameters were measured and described with UBM. Their results are outlined in Tables 2 and 3. Shi et al. (2018) and Dietlein et al. (2000) had different study approaches and are separately discussed. In Table 4, we outline the UBM characteristics and settings.

Table 2. Quantitative outcomes of UBM measurements. Shi et al. (2020) Tandon et al. (2017) Hussein et al. (2014) Gupta et al. (2007) PCG Control P PCG Control PCG Control P PCG Control P TIA (μm) 64.52 ± 15.28 48.02 ± 15.62 0.002 x x 58.470 ± 5.57 51.040 ± 6.90 0.002 38 0 ± 10 220 ± 8.5 0.004 TMT (µm) 111.52 ± 40.79 95.37 ± 25.72 0.072 x x x x x x x x IT (µm) 188.10 ± 40.62 235.25 ± 65.34 0.002 x x 320 ± 40 330 ± 60 0.394 370 ± 100 500 ± 90 0.026 CPL (µm) 1498.88 ± 300.02 1278.37 ± 130.28 0.018 x x x x x x x x Corneal limbus thick-ness (µm) 702.73 ± 100.37 771.62 ± 78.59 0.030 x x x x x x x x SC meridional diameter (µm) 257.70 ± 66.70 335.09 ± 104.76 0.009 x x x x x x x x Largest CSA of SC (µm2) 3363.91 ± 1082.98 5130.66 ± 1231.90 <0.001 x x x x x x x x Diameter of SC (µm) x x x 64.9 ± 10.9 142 ± 33.2 x x x x x x CCT (µm) x x x x x 700 ± 190 540 ± 30 0.012 x x x ACD (mm) x x x x x 3.55 ± 0.32 2.69 ± 0.45 0.001 x x x Lens thickness (mm) x x x x x 3.32 ± 0.18 3.44 ± 0.39 0.206 2.9 ± 0.3 3.8 ± 0.4 0.02 Zonular length (mm) x x x x x 1.02 ± 0.15 0.77 ± 0.16 0.001 01.49 ± 0.4 0.8 ± 0.2 0.000 PCD (µm) x x x x x 330 ± 60 560 ± 90 0.001 780 ± 200 200 ± 400 0.03 CB thickness (mm) x x x x x x x x 0.8 ± 0.3 1.1 ± 0.25 0.03 ACD = anterior chamber depth, CB = ciliary body, CCT = central corneal thickness, CPL = ciliary process length, CSA = cross-sectional area, IT = iris thickness, P = p-value, PCD = posterior chamber depth, PCG = primary congenital glaucoma, SC = Schlemm’s canal, TIA = trabecular iris angle, TMT = trabecular meshwork thickness, UBM = ultrasound biomicroscopy. Table 3. Qualitative outcomes of UBM measurements. Shi et al. (2020) Tandon et al. (2017) Hussein et al. (2014) Gupta et al. (2007) SC Observation (%) 73.1 50 n/p n/p Abnormal tissue membrane (%) 27.5 n/p 12 91 Abnormal iris configuration (%) n/p n/p 100 n/p Abnormal insertion of iris or ciliary process (%) n/p Reported without % 56 17 Elongated CB or ciliary process (%) n/p n/p Reported without % 22 CB = ciliary body, SC = Schlemm’s canal, UBM = ultrasound biomicroscopy. Table 4. UBM characteristics and settings. Position Anaesthesia Type UBM Meridians Transducer frequency (MHz) Additional settings Shi et al. (2020) and Shi et al. (2018) Supine General iUltrasound imaging system 3, 6, 9 and 12 o’clock 80 Axial resolution 25 µm, lateral resolution 50 µm, electron resolution 10 µm; tissue penetration depth 2 mm, scan rate 7 frames/second; imaging window size 4.5 × 4.5 mm; at least 20 ultrasound images for each position Tandon et al. (2017) Supine, upright General, topical iUltrasound imaging system 3, 6, 9 and 12 o’clock 80 Lateral resolution of 50 um and axial resolution of 25 um Gupta et al. (2007) Supine Topical UBM P-40 Vertical, horizontal 50 Hussein et al. (2014) Supine