Evaluation of Anterior Segment Parameters in Non-Ocular Pediatric Behçet’s Disease

Abstract

Objective

To investigate the ocular anterior segment parameters in pediatric Behçet’s disease (BD) without ocular involvement.

Methods

A retrospective study was conducted on 21 pediatric BD patients without ocular involvement and 24 age- and gender-matched healthy controls. Clinical and demographic characteristics of patients were recorded. Central corneal thickness (CCT), corneal endothelial cell density (CD), coefficient of variation (CV), hexagonal cell ratio (HEX), standard deviation (SD), and average cellular area (AVG), as evaluated by specular microscopy, were recorded. Minimum thickness (Thk_min), epithelial minimum and maximum thicknesses (Epi-Thkmin-_max), stromal Thk_min (Str-Thk_min), keratometric front and back maximum power (KFmax, KB_max), simulated keratometry —flat (Kflat), steep (Ksteep), and average (Kavg)—, and front and back elevation values (Elf, Elb) values measured with a corneal topography device were examined.

Results

Of the pediatric BD patients, 13 (61.9%) were girls, 8 (38.1%) were boys, and the mean age was 13.24±3.09 years. Of the healthy control patients, 14 (58.3%) were girls, 10 (41.7%) were boys, and the mean age was 13.29±2.96 years. No statistically significant differences were found in CCT, CD, CV, HEX, SD, and AVG values obtained by specular microscopy between pediatric BD patients without ocular involvement and healthy controls (p>0.05). In addition, no statistically significant differences were found between the Thkmin, Epi-Thkmin, Epi-Thkmax, Str-Thkmin, KFmax, KBmax, Kflat, Ksteep, Kavg, Elf, and Elb values in the corneal topography results of both groups (p>0.05).

Conclusions

No detectable changes in corneal parameters were observed in pediatric BD patients without ocular involvement. The anterior segment is an immune-privileged site.

INTRODUCTION

Behçet’s disease (BD), first described by Hulusi Behçet in 1937 with the triad of oral aphthae, genital ulcers, and uveitis, is an inflammatory disease with chronic relapses affecting various organ systems^{1, 2}. The pathophysiology of the disease involves an unknown cause activating the immune system and a vasculitis pattern observed in arteries and veins of all sizes^{2, 3}. BD is a disease that is frequently observed in the Silk Road basin but can be encountered in all regions of the world, generally affecting young adults (20 to 40 years of age)^{2, 3, 4, 5}. Pediatric BD, which is thought to account for approximately 15 to 20% of all BD cases, is a term used to describe the condition when the disease presents before the age of 16^{3, 4, 5, 6}.

It is stated that ocular involvement develops at rates ranging from 9% to 76% of pediatric Behçet’s patients^{7, 8, 9, 10, 11, 12, 13}. The most common ocular presentation of the disease is bilateral non-granulomatous panuveitis^{13, 14}. In patients under ten years of age, this presentation changes, and patients often present with anterior uveitis⁷. As a result of all these inflammatory conditions, a variety of alterations may be observed in the anterior segment, such as corneal endothelial changes, anterior and posterior synechiae, and cataracts^{15, 16}. Furthermore, studies have documented the presence of subclinical inflammation in eyes without clinical ocular involvement of BD^{17, 18}. Moreover, children may differ from adults in terms of disease duration, ocular tissue biomechanics, and immune system maturity, which could influence the susceptibility of the anterior segment to subclinical changes. This underscores the importance of studying pediatric patients, rather than extrapolating findings from adult cohorts.

The aim of our study was to investigate changes in ocular anterior segment parameters in pediatric BD patients without ocular involvement and to compare these parameters with those of control groups.

MATERIALS and METHODS

The files of 21 pediatric BD patients without ocular involvement who were referred to Ankara Etlik City Hospital Ophthalmology Uvea Unit between March and April 2024 and who had no signs of uveitis in their history or on examination, together with those of 24 age- and gender-matched healthy pediatric control patients who presented to the outpatient clinic for routine examination, were retrospectively reviewed. The study protocol was approved by the ethics committee of University of Health Sciences Türkiye, Ankara Etlik City Hospital with decision no.: AEŞH-BADEK-2024-459, date: 22.05.2024 and was conducted by the Helsinki Declaration.

Demographic characteristics (age and gender), duration of BD, detailed anterior and posterior segment examination findings, best-corrected visual acuities (BCVA), intraocular pressures (IOP), spherical equivalents (SE) (spherical power +1/2 cylindrical power), corneal specular microscopy and corneal topography results were recorded from the patients’ files. A total of 45 patients were included in the study: the right eyes of 21 pediatric BD patients and the right eyes of 24 healthy pediatric patients.

Patients with less than 0.0 LogMAR; SE 2D or more; IOP outside the range of 11-21; any previous ocular disease or history of surgery; missing specular microscopy and corneal topography results in their files; active BD (e.g., active uveitis, oral or genital ulcers) at the time of examination or additional systemic disease other than BD; and those aged 18 years and older were excluded from the study.

Specular microscopy measurements were performed using a CEM-530 (NIDEK Co., Ltd, Japan). Values of Central corneal thickness (CCT), corneal endothelial cell density (CD, cells/mm²), coefficient of variation (CV), hexagonal cell ratio (HEX), standard deviation (SD), and average cellular area (AVG) from specular microscopy were recorded (Figure 1a).

Figure 1.

a) Specular microscopy measurement of a healthy patient; b) Corneal topography measurement of a healthy patient

CV: Coefficient of variation, CD: Corneal endothelial cell density, AVG: Average cellular area, HEX: Hexagonal cell ratio, Thkmin: Minimum thickness, Epi-Thkmin: Epithelial minimum thickness, Epi-Thkmax: Epithelial maximum thickness, Str-Thkmin: Stromal minimum thickness, KFmax: Keratometric front maximum power

Corneal topography measurements were performed with the Sirius (CSO, Florence, Italy) device, which uses the Placido ring and Scheimpflug camera systems. The following values were recorded: minimum thickness (Thkmin); epithelial minimum and maximum thicknesses (Epi-Thkmin-max); stromal minimum thickness (Str-Thkmin); keratometric front and back maximum power (KFmax, KBmax); simulated keratometry (SimK) flat (Kflat), steep (Ksteep), and average (Kavg); front elevation (Elf); and back elevation (Elb) (Figure 1b).

Statistical Analysis

The Statistical Package for the Social Sciences, version 23.0 (SPSS Inc., Chicago, IL, USA), was used for statistical analysis. Mean, SD, minimum, maximum, and median values were used to describe continuous data. Numerical and percentage values were used to describe nominal data. Yates’ chi-square test was used to compare independent nominal groups. The Mann-Whitney U test, a non-parametric test, was used to compare continuous data between independent groups.

A post-hoc power analysis was conducted for the primary corneal parameters (CCT, CV, Thkmin, and Ksteep) to evaluate the robustness of the negative findings. Based on the sample sizes (BD: n=21; control: n=24) and observed SDs, the calculated effect sizes were Cohen’s d ≈ 0.20, 0.06, 0.27, and 0.26, corresponding to achieved powers of approximately 15%, 3%, 9%, and 9% (α=0.05, two-sided). A p-value below 0.05 was considered statistically significant.

RESULTS

Among the pediatric BD patients without ocular involvement, 13 (61.9%) were girls and 8 (38.1%) were boys. The mean age of the patients was 13.24±3.09 years and the mean disease duration was 24.43±41.79 months. Of the healthy control patients, 14 (58.3%) were girls and 10 (41.7%) were boys. The mean age was 13.29±2.96 years. No statistically significant difference was found between the pediatric BD patients without ocular involvement and the healthy control group patients with respect to age and gender (p=1.0, Yates chi-square test; p=0.936, Mann-Whitney U test, respectively).

No statistically significant difference was found between the CCT, CD, CV, HEX, SD, and AVG values ​​obtained by specular microscopy of pediatric BD patients without ocular involvement and healthy controls (p>0.05, Mann-Whitney U test) (for example, in pediatric BD patients CCT was 551.05±33.23 µm and CD was 3189.1±153.16 cell/mm², while in healthy controls CCT was 557.67±33.96 µm cell/mm² and CD was 3135.04±270.29 cell/mm²) (Table 1). No statistically significant correlation was found between disease duration in pediatric BD patients and CCT, CD, CV, HEX, SD, and AVG values (p>0.05, Spearman correlation test).

Table 1. Comparison of specular microscopy parameters in pediatric Behçet’s disease patients without ocular involvement and healthy controls.

Parameters	Non-ocular pediatric BD (n=21)	Healthy control (n=24)	p-value*
CCT (µm)	551.05±33.23 Median: 556 Min-max: 477-602	557.67±33.96 Median: 551.5 Min-max: 476-619	0.63
CD (cell/mm2)	3189.1±153.16 Median: 3145 Min-max: 2850-3440	3135.04±270.29 Median:3078.5 Min-max: 2699-3813	0.18
CV (%)	26.24±3.03 Median: 26 Min-max: 21-34	25.88±7.28 Median: 24 Min-max: 18-55	0.17
HEX (%)	66.76±5.09 Median: 68 Min-max: 53-74	69.79±4.43 Median: 70 Min-max: 62-79	0.06
SD (µm2)	77.9±11.34 Median: 77 Min-max: 58-103	75.17±12.69 Median: 73.5 Min-max: 55-98	0.35
AVG (µm2)	296.1±14.73 Median: 295 Min-max: 271-328	305.92±24.6 Median: 309 Min-max: 251-352	0.06

CCT: Central corneal thickness, CD: Corneal endothelial cell density, CV: Coefficient of variation, HEX: Hexagonal cell ratio, SD: Standard deviation, AVG: Average cellular area, *: Mann-Whitney U test.

No statistically significant difference was found between the Thkmin, Epi-Thkmin, Epi-Thkmax, Str-Thkmin, KFmax, KBmax, Kflat, Ksteep, Kavg, Elf and Elb values ​​evaluated as a result of corneal topography in pediatric BD patients without ocular involvement and healthy control groups (p>0.05 Mann-Whitney U test) (for example, in pediatric BD patients Thkmin was 536.95±32.41 µm and Ksteep was 44.22±1.71 D, while in healthy controls Thkmin was 545.75±32.9 µm and Ksteep was 43.84±1.18 D) (Table 2). No statistically significant correlation was found between disease duration in pediatric BD patients and the Thkmin, Epi-Thkmin, Epi-Thkmax, Str-Thkmin, KFmax, KBmax, Kflat, Ksteep, Kavg, Elf, and Elb values (p>0.05, Spearman correlation test).

Table 2. Comparison of corneal topography parameters in pediatric Behçet’s disease patients without ocular involvement and healthy controls.

Parameters	Non-ocular pediatric BD (n=21)	Healthy control (n=24)	p-value*
Thkmin (µm)	536.95±32.41 Median: 543 Min-max: 466-588	545.75±32.9 Median: 541 Min-max: 463-604	0.55
Epi-Thkmin (µm)	47.95±2.64 Median: 48 Min-max: 44-56	47.21±3.79 Median: 48 Min-max: 38-53	0.91
Epi-Thkmax (µm)	58.33±3.98 Median: 58 Min-max: 50-69	57.33±4.69 Median: 57.5 Min-max: 48-70	0.25
Str-Thkmin (µm)	483.62±30.79 Median: 491 Min-max: 414-533	493.71±32.72 Median: 492.5 Min-max: 413-557	0.36
KFmax (D) (7.7 mm)	45.34±1.91 Median: 45.62 Min-max: 42.13-47.84	44.9±1.49 Median: 44.67 Min-max: 42.1-48.51	0.29
KBmax (D) (6.15 mm)	-6.88±0.76 Median: -6.61 Min-max: -9.33- (-6.16)	-6.90±0.74 Median: -6.61 Min-max: -9.15- (-6.17)	0.98
Kflat (D)	43.38±1.56 Median: 43.67 Min-max: 40.84-45.77	42.78±1.15 Median: 42.7 Min-max: 40.06-45.32	0.16
Ksteep (D)	44.22±1.71 Median: 44.54 Min-max: 41.27-46.86	43.84±1.18 Median: 43.74 Min-max: 41.91-46.71	0.31
Kavg (D)	43.82±1.6 Median: 43.97 Min-max: 41.09-46.31	43.3±1.14 Median: 43.33 Min-max: 40.96-46	0.18
Elf (µm)	1.87±1.35 Median: 1.63 Min-max: 0.45-6.64	2.16±2.15 Median: 1.19 Min-max: 0.27-7.95	0.66
Elb (µm)	4.01±3.33 Median: 2.8 Min-max: 0.33-11.27	4.19±4.56 Median: 2.48 Min-max: 0.21-16.81	0.60

Thkmin: Minimum thickness, Epi-Thkmin: Epithelial minimum thickness, Epi-Thkmax: Epithelial maximum thickness, Str-Thkmin: Stromal minimum thickness, KFmax: Keratometric front maximum power, KBmax: Keratometric back maximum power, Kflat: Flat keratometric power, Ksteep: Steep keratometric power, Kavg: Average keratometric power, Elf: Front elevation, Elb: Back elevation

*: Mann-Whitney U test

DISCUSSION

BD is a multisystem disorder characterized by chronic relapses. The involvement of immune components, such as immunoglobulins, immune complexes, acute-phase reactants, and the complement system, in the pathogenesis of this disease supports the view that the disease is autoimmune. In addition, abnormal neutrophil and endothelial cell activities are thought to play an important role in the pathogenesis of BD and may even be responsible for the development of many clinical conditions. Furthermore, it has been stated that tissue damage develops in BD with increased secretion of various cytokines^{3, 14, 19, 20}.

The resultant inflammatory conditions can lead to a variety of changes in the anterior segment^{15, 16}. The ocular involvement of pediatric BD is frequently characterised by the manifestation of anterior uveitis, but posterior segment manifestations such as retinitis, macular edema, vasculitis, and papillitis can also occur⁷. In addition, the authors reported that posterior segment changes may also occur in eyes without ocular involvement in pediatric BD¹⁷. Based on these ideas, we investigated anterior segment changes in pediatric BD patients without ocular involvement and compared these results with those of a control group. No studies on this subject have been reported in the literature.

Various changes can be observed in the corneal layers along with the developing ocular inflammation^{21, 22, 23, 24, 25}. In a study investigating corneal endothelial changes in patients with ocular BD who had at least a 3-month period of inactivity, the study reported that the mean CD and HEX values were statistically significantly lower than those in the control group, whereas the mean CV value was statistically significantly higher than in the control group. No statistically significant difference was found between the two groups in terms of CCT values. Consequently, the authors concluded that inflammation and oxidative stress products that develop as a result of ocular activation in BD affect the morphology and function of endothelial cells and that permanent endothelial cell morphological disorders may develop as a result, but they stated that these do not result in corneal decompensation²³.

A study examining corneal biomechanical parameters in active and inactive BD with ocular involvement reported that corneal resistance factor, intraocular pressure, and corneal thickness were statistically significantly higher in the active group than in the inactive BD and healthy control groups; this difference was not observed between the inactive BD and healthy control groups. As a result, the authors concluded that uveitis attacks did not cause permanent damage to corneal biomechanical changes²⁴. In another study comparing inactive BD patients with ocular involvement to a healthy control group, the BD group showed decreased corneal apex and thinnest-point thickness and increased anterior and posterior elevation and corneal astigmatism, and the authors suggested that these findings may have resulted from disruption of the proinflammatory–anti-inflammatory balance caused by recurrent uveitis attacks. In addition, it was stated that no statistically significant correlation was found between disease duration and anterior segment parameters in this study²⁵.

In a study in which anterior segment parameters in BD were examined in vivo by confocal microscopy, BDs were divided into two groups: ocularly involved (30 patients, 30 eyes) and non-ocularly involved (34 patients, 34 eyes), and were compared with a healthy control group (30 patients, 30 eyes). Patients in the ocular involvement group were reported to have been inactive for at least 3 months. As a result of this study, the BD group with ocular involvement exhibited the following: a decrease in mean endothelial density and subbasal nerve plexus compared to the non-ocular and control groups; polymegathism; an increase in the number of long nerve fibers; and nerve tortuosity. No difference was detected between the non-ocular BDs and the control group. The reason for these changes in the ocular BD group was interpreted as the effects of inflammation and oxidative stress²⁶.

Similar observations have been reported in pediatric patients with juvenile idiopathic arthritis-associated uveitis, another systemic disease that can cause anterior chamber inflammation, where corneal topography and endothelial morphology were also affected in eyes with ocular involvement, but not in those without ocular involvement²⁷. This comparison emphasizes that, in the absence of ocular involvement, subclinical anterior segment changes are unlikely in systemic inflammatory diseases.

We present, to our knowledge, the first study examining anterior segment parameters in pediatric BD. In our study, we did not find any statistically significant differences between parameters measured by specular microscopy (CCT, CD, CV) and those measured by topography devices (Thkmin, Epi-Thkmin, Epi-Thkmax) when comparing pediatric BD and healthy control groups.

An analysis of the existing literature shows that there is a greater focus on the changes of anterior segment parameters and their underlying causes in BD with ocular involvement. On the other hand, the reasons for the lack of such changes in BD without ocular involvement have rarely been investigated. The ocular system is one of the rare immune-privileged sites of the body, characterised by multiple barriers. The avascular nature of the cornea, in conjunction with the presence of various barriers within the intraocular region, such as the blood-aqueous and blood-retinal barriers, results in the immune-protected status of the ocular region^{28, 29}. It is hypothesized that the presence of immune barriers may have prevented systemic inflammatory attacks from affecting the ocular system and altering corneal parameters. Furthermore, the fact that ocular involvement was not observed may have been an important advantage in terms of less damage to these barriers and maintenance of the immune-protected area.

Study Limitations

There are some limitations to our study. Our study is single-center, and the number of patients is relatively small. This is an important limitation of our data in representing the general pediatric BD population. These results indicate that, while the current study was sufficiently powered to exclude large intergroup differences, subtle or moderate changes in anterior segment parameters may not have been detected. This limitation should be considered when interpreting the findings. In addition, we excluded patients with active systemic inflammation (e.g., oral or genital ulcers), thereby ensuring that our BD cohort consisted of patients in remission. This selection may bias the results toward finding no differences in corneal parameters compared to healthy controls, as subclinical changes might be less detectable in patients without active disease. Another important limitation is that our study included no pediatric BDs with ocular involvement (active or inactive). This prevented examination of how corneal parameters change in pediatric BDs with ocular inflammation during active versus inactive disease. In addition, heterogeneous results regarding corneal parameter changes reported in the literature precluded examination of the advantages and disadvantages associated with the pediatric age of the patient group. To clarify this uncertainty, larger multicenter studies that include pediatric BDs with ocular involvement are needed.

CONCLUSION

No detectable changes in corneal parameters were observed in this sample of pediatric BD patients without ocular involvement. The anterior segment is protected from systemic inflammation by the avascular nature of the cornea and the presence of ocular barriers.

Ethics

Ethics Committee Approval: The study protocol was approved in accordance with the ethics committee of University of Health Sciences Türkiye, Ankara Etlik City Hospital with decision no.: AEŞH-BADEK-2024-459, date: 22.05.2024 and was conducted by the Helsinki Declaration.

Informed Consent: Retrospective study.