Introduction

Thyroid eye disease (TED) represents a prevalent type of orbital tissue inflammation associated with autoimmune disorders linked to thyroid dysfunction, which is characterized by a spectrum of metabolic and immunologic disturbances.^1,2 Because of their potent anti-inflammatory and immunosuppressive properties, systemic glucocorticoids have traditionally served as the first-line treatment for TED to mitigate inflammation. However, their use is fraught with a plethora of adverse effects, encompassing hyperglycemia, hypertension, metabolic disorders leading to the characteristic “moon face”, gastric ulcers, osteoporosis, and an increased susceptibility to infectious diseases.^3,4

To circumvent these adverse effects, local administration of glucocorticoids has been explored since Gebertt first reported this approach in 1961.^5,6 Localized delivery is accomplished through subconjunctival, and sub-Tenon injections. In contrast, retro-orbital-septal injection, introduced since Ebner’s report in 2004, offers an alternative method. This procedure, performed transcutaneously using a half-inch, 27-G needle, facilitates the precise delivery of medication into the lateral lower deep orbital fat, yielding promising results in the anti-inflammatory treatment of orbital tissue.⁷ Furthermore, Bagheri et al reported retro-orbital-septal injection of triamcinolone and dexamethasone into both the upper and lower quadrants of the orbital soft tissue.⁸ In this report, this approach was applied for patients with active TED who were resistant to or dependent on systemic steroids or faced complications related to systemic steroid use. The results demonstrated a significant reduction in orbital inflammation, including upper and lower eyelid retraction, ocular motility issues, and inflammatory markers such as the Clinical Activity Score (CAS) and NOSPECS classification. An intriguing aspect of the retro-orbital-septal delivery method is its capacity to produce a dramatic effect after only one or two injections.^7,8

Thus, this novel procedure may have advantages not only in local control of orbital inflammation but also in mitigating systemic adverse effects. However, no study to date has comprehensively evaluated the systemic effects of orbital corticosteroid injections, primarily because of the systemic absorption of the medication. The current report aims to address this gap by focusing on the efficacy and systemic effects of deep orbital injection of triamcinolone, with the intent of promoting and advancing this procedure. To achieve this goal, we conducted a prospective clinical investigation involving TED patients who underwent a single deep orbital injection of triamcinolone, followed by comprehensive ophthalmic and pharmacological assessments, including blood and urinary panels.

Patients and Methods

This prospective study enrolled Japanese individuals diagnosed with TED who underwent single, bilateral, deep orbital triamcinolone injections between January 2021 and March 2023. The study adhered to the principles outlined in the Declaration of Helsinki, with all patients providing signed informed consent. The Institutional Review Boards of the Oculofacial Clinic Group approved the study protocol, and the study was registered with the Ethical Committee of the Oculofacial Clinic Group (Approval Number: 2023072801).

The inclusion criteria consisted of a CAS of 3 or higher and localized inflammation affecting the extraocular muscles and upper eyelid retraction. The exclusion criteria included compressive optic neuropathy, severe TED (including dysthyroid optic neuropathy and corneal breakdown) necessitating intravenous methylprednisolone pulse therapy.

Injection Procedure

A total of 1 mL of triamcinolone acetonide (40 mg/mL) was administered posterior to the orbital septum using a 27-G, half-inch, disposable needle (0.30×12 mm, Dentronics, Tokyo, Japan) at four distinct sites, covering both the medial and lateral aspects of both the upper and lower eyelids (Figure 1).

Figure 1 Deep Orbital Injection of Triamcinolone Acetonide.

Assessment Metrics

Evaluation metrics included the CAS, margin-reflex distances (MRD1 and MRD2), intraocular pressure (IOP) measured via non-contact tonometry, hematological parameters (thyroid panel, comprehensive metabolic panel, and serum cortisol), urinary cortisol levels, and ocular motility assessed using the Hess area ratio (HAR%). The extent of proptosis was determined via magnetic resonance imaging (MRI), including measurements related to extraocular muscle sizes. All ophthalmic and systemic assessments were performed before injection and at 2 and 4 weeks post-injection.

Ophthalmic Data Analysis

The CAS and systemic adverse effects were evaluated through standardized questionnaires. The MRD1 and MRD2 measurements were conducted in millimeters using ImageJ software (https://imagej.net/ij/index.html), with pupil diameter derived from non-contact tonometry data.

The extent of proptosis was assessed using MRI by measuring the distance between the corneal eminence and the connecting lines of the zygomatic bones in a horizontal section of a T1-weighted image.

The sizes of the inferior oblique, superior rectus, medial rectus, lateral rectus, and inferior rectus muscles were also assessed by MRI. The muscle size was determined at the point of greatest enlargement within the coronal section of the T1-weighted MRI image. Because of challenges in detecting the superior oblique muscle via MRI in most patients, this muscle was not investigated. Three-dimensional MRI reconstructions were generated using SYNAPSE VINCENT Ver. 5 software (Fujifilm Medical, Tokyo, Japan).

Ocular motility was quantified using the HAR% technique, which involves calculating the percentage ratio of the lengths of the vertical and horizontal sides on both the affected and healthy sides using the Hess chart. This method serves as an objective tool for assessing preoperative diplopia and orbital fracture severity.⁹ The HAR% measurement was employed to evaluate the effects of orbital steroid injection treatment.

Systemic Data Analysis

The thyroid panel assay comprised free triiodothyronine, free tetraiodothyronine, and thyroid-stimulating, thyrotropin receptor, thyroglobulin, and thyroid peroxidase antibodies. Comprehensive metabolic panel assessments included the white blood cell count, neutrophil count, and C-reactive protein, total bilirubin, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, creatinine, and glucose levels.

Statistical Analysis

Data analysis was conducted using SPSS Statistics Ver. 27 (IBM Corp., Armonk, NY, USA), with comparisons performed using the Wilcoxon signed-rank test.

Results

Ophthalmic Manifestations

The initial CAS (SD) averaged 4.22(1.29) and significantly decreased to 2.20(1.10) (P<0.001) at 4 weeks post-injection. The mean MRD1 measurement (SD) decreased from 4.25(1.67) mm to 3.53(1.55) mm (P<0.001) over the same period, while the MRD2 remained unchanged post-injection. We noted reductions in the maximum coronal area of the extraocular muscles, including the superior rectus (30.9%), inferior rectus (36.2%), medial rectus (21.1%), lateral rectus (26.9%), and inferior oblique (23.3%) (all P<0.001) (Figure 2). The mean HAR% (SD) was initially 94.42(4.45) % and increased to 98.94(6.26) % (P=0.014) after 4 weeks. No significant variations were observed in the IOP or the extent of proptosis (Table 1).

Table 1 Changes of Ophthalmic Parameters Before and 4 Weeks After a Single Deep Orbital Injection of 40 Mg of Triamcinolone Acetonide

Figure 2 Changes of cross-sectional area of extraocular muscles before and 4 weeks after a single deep orbital injection of 40 mg of triamcinolone acetonide. Abbreviations: IR, inferior rectus; SR, superior rectus; IO, inferior oblique; MR, medial rectus; and LR, lateral rectus muscles.

Systemic Manifestations

At 2 weeks after the injection, increases in white blood cell and neutrophil counts were observed (P=0.017, P=0.021), followed by subsequent decreases by week 4 (P=0.011, P=0.008). Importantly, no exacerbation of hepatic enzyme levels, glucose, or creatinine was observed (Table 2). Several indices within the thyroid panel were affected, with distinct decreases observed in free triiodothyronine (P<0.04), thyroid-stimulating antibody (P<0.02), thyrotropin receptor antibody (P<0.01), and thyroid peroxidase antibody, and the thyroglobulin antibody level gradually decreased within 4 weeks post-injection (Table 3). Serum and urinary cortisol levels temporarily decreased after 2 weeks (P<0.001, P<0.001) and then increased after 4 weeks compared with the 2-week levels (P=0.027, P=0.050). Adverse effects included menstrual irregularities (5/28,17.8%), internal hemorrhage (5/28, 17.8%), acne (2/28, 7.1%), insomnia (2/28, 7.1%), and leg cramps (1/28, 3.6%).

Table 2 Changes of Serum Laboratory Data Before and 4 Weeks After a Single Deep Orbital Injection of 40 Mg of Triamcinolone Acetonide

Table 3 Changes of Thyroid Panel and Cortisol Level Before and 4 Weeks After a Single Deep Orbital Injection of 40 Mg of Triamcinolone Acetonide

Discussion

The present study introduces a promising therapeutic approach for TED management through a single deep orbital injection of 40 mg of triamcinolone acetonide. This intervention significantly improved the inflammatory activity of TED, including upper eyelid retraction and extraocular muscle swelling, while exhibiting minimal adverse ocular and systemic effects.

Deep orbital injection, as an emerging technique, allows for the direct administration of steroids to the posterior aspect of the orbital globe, bypassing the orbital septum.^7,8,10–12 Our results align with previous reports, demonstrating that the injection of triamcinolone has a substantial anti-inflammatory effect on the extraocular muscles and levator muscles of the upper eyelids. This study includes differences in the studied populations (East Asian vs Caucasian) and variations in methodology (frequency, injection area, and steroid agents) compared with previous reports; nevertheless, our study substantiates the concept that a single orbital corticosteroid injection can attenuate TED activity.¹³

One concern associated with local administration of steroid agents around the eye is the potential adverse effect on IOP. Previous research has explored the mechanisms underlying corticosteroid-induced ocular hypertension, which is often linked to changes in gene expression in the trabecular meshwork.¹⁴ The absence of elevated IOP in our study could be attributed to corticosteroid administration in the posterior segment, potentially minimizing direct effects on the endothelium of Schlemm’s canal. Deep orbital injection delivers corticosteroids closer to the inflamed orbital tissue and farther from Schlemm’s canal, resulting in less of an increase in IOP (0%–16.7%)^7,8,11,12,15 than that produced with pre-aponeurotic or sub-Tenon injection (4%–31%).^16–20 However, the deep orbital injection technique must be approached with caution because of reported complications such as globe perforation, vessel occlusion, and toxic neuropathy, although our study did not encounter such issues.^7,8

In addition to its ophthalmic effects, we vigilantly monitored potential systemic effects of orbital corticosteroid injections. While intravenous methylprednisolone pulse therapy has been associated with acute and severe liver damage and metabolic disorders,^21–25 our study observed minimal hepatic, glycemic, and renal impacts by a single local injection. However, serum and urinary cortisol levels displayed temporary decreases, suggesting a mild depression in endogenous cortisol production. Ebner et al also reported blood and urinary cortisol levels after multiple orbital injections, with only urinary cortisol showing a difference between week 0 and week 10 after injection.⁷ Our study provides a more detailed understanding of the influence of a single injection, indicating that cortisol can be systemically absorbed for up to 2 weeks, with levels tending to rebound to normal within 4 weeks, particularly in blood. This finding suggests that monthly local injections can limit systemic adverse effects. Moreover, Alkawas et al compared the clinical effects of multiple deep orbital injections with oral steroid administration and concluded that orbital injection is effective and safe in mitigating the systemic adverse effects of steroids, further supporting the safety and efficacy of deep orbital injection.¹²

An additional contribution of our study compared with previous reports is the decrease in antibodies related to TED activity, signifying the suppression of systemic autoimmune responses by local injection.^26–34 This finding suggests that the orbital steroid agents may be absorbed into the bloodstream to some extent, implying that local injection can impact TED activity not only locally but also systemically. In other words, the systemic impact is limited, indicating that adverse systemic effects resulting from local injection are within an acceptable range.

Several limitations warrant consideration. Our study focused on a single initial administration, lacking data on multiple administrations in clinical settings and long-term follow-up. Consequently, the effects and side effects of multiple injections remain unexplored. Future research should also investigate dose-dependent side effects and conduct comparative analyses of various steroid injection administration methods to provide a comprehensive understanding of their safety and efficacy.

Conclusions

In summary, our study robustly demonstrates the favorable effects of a single deep orbital corticosteroid administration for TED treatment without inducing substantial local or systemic adverse effects. Improvements in local and systemic assessments, TED-related antibody levels, and orbital muscle dimensions underscore the effectiveness of this intervention in modulating TED activity. While our study has limitations, including a limited patient cohort and a lack of iterative treatments, comprehensive validation will necessitate an expanded and iteratively treated patient series in the future.