Efficiency and Safety of Tocilizumab for the Treatment of Thyroid Eye Disease: A Systematic Review.

PURPOSE: To review existing literature concerning the effectiveness and safety of tocilizumab (TCZ) for managing thyroid eye disease. METHODS: A systematic search was conducted across the PubMed and Embase databases to identify studies on TCZ therapy, from inception to May 2023. The search included the keywords "Graves orbitopathy," "thyroid ophthalmopathy," "thyroid eye disease," "thyroid-associated orbitopathy," "thyroid-associated ophthalmopathy," "Graves ophthalmopathy," "endocrine ophthalmopathy," and "Tocilizumab." Only articles written in English, Spanish, or French were considered. RESULTS: Among the 1,013 articles initially screened, a total of 29 fulfilled the eligibility criteria and were selected. Most studies were case reports or case series, and only one randomized clinical trial was found. TCZ has been used mainly in glucocorticoid-resistant or relapsing cases, with a dosage ranging from 4 or 8 mg/kg every 4 weeks when intravenous or a weekly subcutaneous dose of 162 mg. Treatment duration is usually adjusted to the clinical response. TCZ is mostly effective in reducing inflammatory signs during the active phase of thyroid eye disease, with an improvement of at least 3 points in clinical activity score and an overall relapsing rate of 8.2%. Numerous studies have shown marked reductions in proptosis; although the only available randomized controlled trial reported a nonstatistically significant improvement 6 months after treatment, a recent meta-analysis indicated that TCZ seems to be the most effective treatment for reducing proptosis. No severe side effects related to intravenous or subcutaneous TCZ administration were reported. DISCUSSION: Despite these promising findings, randomized clinical trials to directly compare the efficacy and safety of TCZ and other currently available therapeutic options are needed.

Proof-of-concept and Randomized, Placebo-controlled Trials of an FcRn Inhibitor, Batoclimab, for Thyroid Eye Disease.

CONTEXT: Inhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye disease (TED). OBJECTIVE: We report the first clinical studies of an FcRn inhibitor, batoclimab, in TED. DESIGN: Proof-of-concept (POC) and randomized, double-blind placebo-controlled trials. SETTING: Multicenter. PARTICIPANTS: Patients with moderate-to-severe, active TED. INTERVENTION: In the POC trial, patients received weekly subcutaneous injections of batoclimab 680 mg for 2 weeks, followed by 340 mg for 4 weeks. In the double-blind trial, patients were randomized 2:2:1:2 to weekly batoclimab (680 mg, 340 mg, 255 mg) or placebo for 12 weeks. MAIN OUTCOME: Change from baseline in serum anti-TSH-R-Ab and total IgG (POC); 12-week proptosis response (randomized trial). RESULTS: The randomized trial was terminated because of an unanticipated increase in serum cholesterol; therefore, data from 65 of the planned 77 patients were analyzed. Both trials showed marked decreases in pathogenic anti-TSH-R-Ab and total IgG serum levels (P < .001) with batoclimab. In the randomized trial, there was no statistically significant difference with batoclimab vs placebo in proptosis response at 12 weeks, although significant differences were observed at several earlier timepoints. In addition, orbital muscle volume decreased (P < .03) at 12 weeks, whereas quality of life (appearance subscale) improved (P < .03) at 19 weeks in the 680-mg group. Batoclimab was generally well tolerated, with albumin reductions and increases in lipids that reversed upon discontinuation. CONCLUSIONS: These results provide insight into the efficacy and safety of batoclimab and support its further investigation as a potential therapy for TED.

Anterior versus posterior retractor reinsertion with a lateral tarsal strip for involutional entropion repair: A multicentric experience.

PURPOSE: The aim was the comparison of two different approaches to re-insert the inferior eyelid retractors within addition to lateral tarsal strip at lower eyelid involutional entropion (LEIE) surgical correction. METHOD: This multicentric retrospective case series involved 233 consecutive patients (195 eyelids) who underwent LEIE repair. All the lids had a lateral tarsal strip (LTS) in addition to the reinsertion of retractors onto the tarsal plate via the anterior approach (group 1) or the posterior approach (group 2). The desired normal position of the eyelids at 6-month follow-up was considered 'surgical successes, while entropion recurrence and overcorrection (ectropion) were considered 'surgical failures'. RESULTS: One-hundred ninety-one (82%) surgeries were included in group 1 and 42 (18%) in group 2. The success rate was 92.1% (176 lids) in group 1 and 85.7% (36 lids) in group 2 (p = 0.188). The recurrence rate was statistically higher for group 2 (14.3%) than for group 1 (3.7%) (p = 0.016). Overcorrection only described in group 1 (3.1%). Both groups had a similar complication rate (p = 0.268), with trichiasis being the most frequent (14, 6%). Ten eyelids (47.6%) from the 21 overall failures were satisfactorily reoperated, and the remaining ones were treated conservatively. CONCLUSION: The anterior or posterior approach to reinsert lower eyelid retractors to tarsal plate in addition to LTS to correct LEIE can provide a similar outcome. However, the anterior approach achieves a slightly higher success rate with fewer recurrences but with a higher overcorrection rate.

Effect of Rim-Off Deep Lateral Orbital Decompression on Interpalpebral Fissure Shape.

PURPOSE: The purpose of this study is to compare the palpebral fissure shape after rim-off deep lateral decompression with and without restoration of the lateral orbital rim. METHODS: Retrospective cross-sectional quantitative analysis of the palpebral fissure images of 17 patients (25 eyes) who underwent rim-off deep lateral orbital decompression without repositioning of the rim (G1) and of 20 patients (34 eyes) operated with rim restoration. Quantification of palpebral fissure images included MRD 1 and MRD 2 , two lateral mid-pupil lid margin (MPD) distances, the width of the palpebral fissure, and the height and shape of the lateral canthus. RESULTS: Proptosis reduction did not differ significantly between G1 and G2. In both groups, decompression reduced the mean values of the MRD 1 and MRD 2 , the lateral height of the upper eyelid, and the height and angle of the lateral canthus. The palpebral fissure width and lateral height of the lateral lower eyelid were not affected. There was no significant difference between the mean changes of G1 and G2. Multivariate analysis showed that the lateral canthus decrease was correlated with changes in MRD 1 and MRD 2 . CONCLUSIONS: Small changes in palpebral fissure shape after deep lateral decompression are not dependent on the presence or absence of the lateral rim.

Childhood proliferative fasciitis of the orbit mimicking sarcoma: a case report.

Proliferative fasciitis (PF) is a benign fibroblastic reaction with histological and clinical characteristics that overlap with those of malignant soft tissue tumors; thus, it is referred to as a pseudosarcomatous reaction. It continues to be an important cause of diagnostic error and overtreatment. The childhood PF subtype has some distinct histological and immunohistochemical characteristics that make differential diagnosis with malignant tumors even harder, especially with sarcoma. These proliferations generally occur in the lower limbs, and the periorbital region is a rare location of appearance. Here, we describe a case of childhood subtype PF in a 16-year-old girl located in the periorbital area. To the best of our knowledge, this is the first reported case of childhood subtype PF in the periorbital area, and the third case if PF subtypes are not taken into account.

Bézier curves as a total approach to measure the upper lid contour: redefining clinical outcomes in palpebral surgery.

AIMS: To define and quantify the upper lid contour by adapting Bézier curves with a newly developed software in normal subjects, assessing their reliability. METHODS: Fifty eyes of 50 healthy patients with no ocular pathology were included in this study from October 2020 to November 2020. All measurements were performed on Bézier curves adjusted to the upper lid contour. An original software was used to measure the radial and vertical midpupil-to-lid margin distances (MPLD), temporal-to-nasal (T/N) ratios, contour peak location and grade of superposition (GS) and asymmetry (GA) indexes. We calculated differences in the variables measured regarding age, gender or the side of the eye being assessed. RESULTS: The mean Bézier curve showed an excellent level of inter-rater reliability (intraclass correlation coefficient of 0.99). The median GS index of each eyelid to the mean Bézier curve was 95.4%, 8.5 IQR, and the median GA index was 3%, 3.4 IQR. The mean contour peak location was -0.35 mm, SD 0.45. Overall, the mean central MPLD was 4.1 mm, SD 0.6. No significant differences were found between male and female patients in variables derived from Bézier curves. CONCLUSION: Bézier curves may become a very useful tool for the assessment of upper lid contour, contour peak and symmetry. GS and GA indexes, along with the T/N area ratio are potential outcomes for this purpose. All current variables can be obtained just from one single Bézier curve measurement. Our results offer an in-depth exhaustive description of these variables and their distribution in the normal population.

Müllerotomy with anterior graded Müller muscle disinsertion for Graves upper eyelid retraction: validation of surgical outcomes using Bézier curves.

PURPOSE: To assess with Bézier curves the outcomes of Müllerotomy with anterior graded Müller muscle disinsertion for the treatment of Graves upper eyelid retraction (UER). METHODS: Eighty-six eyelids of 52 inactive GO patients operated from November 2018 to June 2021 were included in this study. All measurements were performed on Bézier curves adjusted to the upper lid contour with a previously validated algorithm. Lid contour was classified regarding grade of superposition (GS) as excellent (GS > 90%), good (GS 85-90%) or poor (< 85%). Surgical success was defined as complete or partial if postoperative grade of asymmetry was < 10% with an excellent or good lid contour, respectively. RESULTS: The mean age was 51 ± 10.4 years with a range from 31 to 78 years and a mean follow-up of 14.4 ± 7.4 months. There was a significant improvement of median GS (p < 0.0001) from preoperative (74.3%; 10.7 IQR) to postoperative values (91.7%; 6.3 IQR). A normalization of postoperative contour peak (- 0.69; 1.27 SD) and MPLD90 (4.2 mm; 0.8 SD) was noticed (p < 0.0001). Postoperative lid contour was excellent in 62 (72%), good in 16 (19%) and poor in 8 eyelids (9%). Surgical success was achieved in 42 patients (81%), from which 34 (81%) were complete. Reintervention was required in 14 eyelids (16%). CONCLUSIONS: Measuring surgical outcomes with Bézier curves allows an automated, complete and objective assessment, giving more consistency to our data compared to previous reports. Müllerotomy with graded Müller muscle disinsertion is a safe and effective procedure for Graves UER, offering predictable results.

Postoperative drift and dose-response of strabismus surgery in thyroid eye disease: predicting desired outcomes with intraoperative adjustable sutures.

OBJECTIVE: To report outcomes of strabismus surgery in thyroid eye disease using intraoperative bow-knot adjustable sutures under topical anaesthesia and calculate prediction models for surgical correction and postoperative drift depending on surgical dose-response. METHODS: We retrospectively reviewed patients operated on from 2016 to 2021. A satisfactory outcome was defined as no diplopia with maintenance of vertical (<5 PD) and horizontal (<10 PD) stable alignment at primary gaze. Subjective diplopia corrected with prisms within successful motor alignment was defined as a fair result. Otherwise, the result was considered to be poor. RESULTS: A total of 73 patients were included (60 females, 82%). Mean preoperative horizontal and vertical deviations were 26.9 PD (19.1 SD), and 11.8 PD (7.6 SD), respectively. Mean horizontal drift was -3.2 PD (5.2 SD), whereas mean vertical drift was -3.4 PD (3.3 SD). A linear regression established a dose-response of 2.37 PD/mm for each medial rectus recession (p < 0.0001; r2 = 0.777) and 3.75 PD/mm for unilateral inferior rectus recession (p < 0.0001; r2 = 0.922). Final success rate was satisfactory in 62 patients (85%), fair in 7 patients (10%), and poor in 4 patients (5%). CONCLUSIONS: Muscle recession with intraoperative adjustable sutures is effective for the treatment of thyroid eye disease strabismus. Predictable dose-responses could be achieved with a drift toward overcorrection. Undercorrection proportional to the planned surgical dose should be the immediate postoperative target of choice. Other variables such as orbital decompression and concurrent vertical and horizontal surgery do not correlate with dose-response and postoperative drift. However, further studies are necessary to validate our findings.

VIP/VPAC Axis Expression in Immune-Mediated Inflammatory Disorders: Associated miRNA Signatures.

Few studies have considered immune-mediated inflammatory disorders (IMID) together, which is necessary to adequately understand them given they share common mechanisms. Our goal was to investigate the expression of vasoactive intestinal peptide (VIP) and its receptors VPAC1 and VPAC2 in selected IMID, analyze the effect of biological therapies on them, and identify miRNA signatures associated with their expression. Serum VIP levels and mRNA of VPAC and miRNA expression in peripheral blood mononuclear cells were analyzed from 52 patients with psoriasis, rheumatoid arthritis, Graves' disease, or spondyloarthritis and from 38 healthy subjects. IMID patients showed higher levels of VIP and increased expression of VPAC2 compared to controls (p < 0.0001 and p < 0.0192, respectively). Receiver operating characteristic curve analysis showed that the levels of VIP or VPAC2 expression were adequate discriminators capable of identifying IMID. Treatment of IMID patients with anti-TNFα and anti-IL12/23 significantly affected serum VIP levels. We identified miRNA signatures associated with levels of serum VIP and VPAC2 expression, which correlated with IMID diagnosis of the patients. The results indicate that the expression of VIP/VPAC2 is able of identify IMIDs and open up a line of research based on the association between the VIP/VPAC axis and miRNA signatures in immune-mediated diseases.

Primary periocular squamous cell carcinoma in central Spain: Factors related to recurrence.

PURPOSE: To describe the characteristics and recurrence rates of primary periocular squamous cell carcinoma (SCC) in Spain. METHODS: This retrospective study investigates the characteristics of primary periocular SCC at two tertiary centers in Spain from 2000 to 2020. Data were collected on demographics, skin phenotype, location, clinical and histological diagnosis, the commitment of surgical margins, recurrence, and risk factors. Multivariate analysis and risk factors were used to investigate recurrence rates, considering p < 0.05 as statistically significant. RESULTS: Over the 20-year studied period, 107 patients with primary periocular SCC were assessed. The mean age of SCC was 76.8 ± 12.8 years, 55 (50.9%) were females, and 105 (98.1%) had Fitzpatrick skin phenotype type II or III. SCC lesions affected less than 1/3 of the eyelid (56/52.3% cases), mainly the lower lid (42/39.3% lesions). Sixty (56.1%) cases were SCC differentiated, 76 (71%) had clear margins. Clinical diagnosis of SCC corroborated with histological in 84 (78.5%) cases and orbital involvement occurred in 18 (16.8%) cases. Recurrence was observed in 13 (12.1%) cases, occurring more in large tumors and undifferentiated subtype (53.8%), with committed margins (69.2%) (p = 0.001), being the commitment of margins a significant predictor for recurrence, although thickness was an independent predictor. CONCLUSION: Periocular SCC in Spain showed a similar pattern as in the world. The risk of recurrence is increased in undifferentiated and large periocular SCC, partially removed with committed margins.

Orbital myopericytoma: an unusual tumor in an unusual location.

A 71-year-old male with a 4-month history of bulging, tearing, and redness in the right eye presented with vision loss, proptosis, conjunctival hyperemia, and chemosis. Magnetic resonance imaging showed a right intraconal solid mass with extraconal extension, hyper-intense in T2 sequences with heterogeneous contrast enhancement. Complete excision of the mass was performed through a lateral orbitotomy. Histological analysis revealed a neoplasm with high vessel density, solid growth of oval cells, a concentric proliferation of the wall of small vessels, and a weak and patchy positivity for smooth muscle actin. These findings were consistent with the diagnosis of myopericytoma. After surgery, visual acuity improved in the affected eye and after 18 months of follow-up there have been no signs of recurrence.

Upper Eyelid Contour Changes After Orbital Decompression in Graves Orbitopathy.

PURPOSE: To evaluate the effect of orbital decompression on the upper eyelid contour. METHODS: A paired cross-sectional analysis of the upper eyelid contour was performed for 103 eyes of 66 patients who underwent orbital decompression. A control group of 26 normal subjects was also included. The eyelid contour of all participants were measured with Bézier lines adjusted to the eyelid contour and 9 midpupil eyelid margin (MPD) distances from a horizontal line bisecting the pupil. One central, corresponding to the margin reflex distance (MRD 1), and 8 equally distributed medially and laterally at 20% of the interval between the lines. Patients were classified as with flare if the height of the most lateral MPD relative to the MRD 1 was above the upper limit of the controls. RESULTS: Preoperatively 63 of the 103 contours were classified as flare + (F+). After decompression MRD1 showed a mean decrease of 0.4 mm and the location of the contour shifted 0.8 mm medially. These changes were not correlated with proptosis reduction. Orbital decompression decreased the lateral curvature of the contours especially for the F+ lids. In 40% of the F+ eyelids the flare sign disappeared after decompression. CONCLUSIONS: Orbital decompression affects the lateral eyelid contour and diminishes the amount of lateral eyelid retraction surgery necessary to correct the flare sign. In 40% of the patients, the eyelid contour is normalized with proptosis reduction only.

The addition of a conjunctival flap to a posterior lamella auricular cartilage graft: A technique to avoid corneal complications.

PURPOSE: To present the benefits of the addition of a conjunctival flap when correcting lower eyelid retraction using an auricular cartilage graft. METHODS: An auricular cartilage graft was obtained either from the concha o the scaphoid fossa. When preparing the receiving bed, the conjunctival incision was made 2 mm below the inferior margin of the lower eyelid tarsus, therefore, a conjunctival flap arising from the inferior border of the tarsus was obtained. The cartilage graft was placed in the lower eyelid. The inferior border of the graft was sutured to the retractors and conjunctiva using absorbable sutures. The superior border was sutured to the inferior tarsus, so that de conjunctival flap covered the superior portion of the graft. RESULTS: Fourteen patients underwent the surgical technique. No corneal complications were observed in the early or late postoperative period. Donor site complications were not encountered. CONCLUSIONS: The confection of a conjunctival flap that lines the superior portion of an auricular cartilage graft in the lower eyelid provides protection against corneal postoperative complications until the graft is epithelized.

Lid Flare Measurement with Lateral Midpupil Distances.

PURPOSE: To assess the sensitivity and specificity of lateral midpupil lid distances for the detection of upper lid lateral flare. METHODS: Lateral lid flare was determined by unanimous agreement among six experienced oculoplastic surgeons in the grading of photographs obtained for patients with Graves orbitopathy (GO). Bézier lines were employed to extract the upper eyelid contours of the patients and a control group of age and sex matched subjects. Custom software was employed to determine 5 lateral midpupil eyelid distances. The sensitivity and specificity of each measurement in detecting lateral flare were estimated from receiver operating characteristic curves. The non-parametric Kruskal-Wallis one-way analysis of variance (ANOVA) with Dunn's posthoc test was used to compare the median values of the contour parameters between groups. RESULTS: The degree of agreement between judges evaluated with the Fleiss' Kappa test was relatively high (K = 0.69, z = 16.6, p < .0001). The raters classified 12 lids with lateral lid flare (LLF) and 7 without LLF in patients with GO. There was no agreement on the presence or absence of LLF in 11 lids. In all eyes, lateral midpupil lid distances diminished from the center of the eyelid towards the lateral canthus. Receiver operating characteristic analysis for the midpupil distances revealed that the fourth distance from the center demonstrated high sensitivity and specificity in detecting flare. At this location (2.5 mm medial to the lateral canthus) a midpupil distance equal to or greater than 60% of the margin reflex distance (MRD1) indicated the presence of flare. CONCLUSIONS: - A single measurement of a lateral midpupil eyelid distance 2.5 mm medial to the lateral canthus is a sensitive and specific measurement for the diagnosis of the LLF.

Treatment of Graves' ophthalmopathy. / Tratamiento de la oftalmopatía de Graves.

Graves' ophthalmopathy is an inflammatory disease with primary involvement of the extraocular muscles and the orbit. It encompasses the most common extra-thyroid manifestation in patients with Graves-Basedow disease. The underlying cause is molecular mimicry with the TSH receptor in ocular fibroblasts, leading to an immuno-mediated pathogenesis. Glucocorticoids at high doses are the cornerstone in moderate-severe cases. However, some patients are corticorresistant or intolerant. In recent years, therapeutic novelties have been described in terms of the dosage of the immunosuppressive treatments used, as well as the emergence of biological therapy in this field. The objective of this review is to update the treatment of Graves' ophthalmopathy, as well as to present alternative options in patients resistant or intolerant to glucocorticoids.

Oscillopsia After Isolated Lateral Wall Decompression Versus Balanced or 3-Wall Decompression.

PURPOSE: To assess the incidence of postoperative masticatory oscillopsia after orbital decompression, comparing results between isolated lateral wall and balanced or 3-wall orbital decompression. METHODS: An observational retrospective study was performed, involving 161 consecutive patients who underwent orbital decompression between 2008 and 2018. Patients' clinical data were registered, and archives were revised for data compilation. Patients were divided into 2 groups according to the type of surgery: "lateral" group included patients who underwent isolated lateral wall decompression and "lateral plus" group involved patients with balanced or 3-wall decompression. Exclusion criteria were secondary decompressions, those not including lateral wall and asymmetrical surgeries, so analysis was performed among 131 remaining patients. Oscillopsia was self-reported and was registered as present or not. Diplopia was evaluated according to Paridaens grading system. RESULTS: Statistical analysis among the 131 patients with lateral wall decompression (isolated or in combination) was performed. Seven patients referred oscillopsia, 5 among "lateral" group, while 2 reported oscillopsia on "lateral plus" group (p = 0.001). The authors found no differences on new-onset or worsening of diplopia between groups (p = 1). CONCLUSIONS: Oscillopsia was significantly higher after isolated lateral wall decompression than after balanced or 3-wall decompression, while no differences were found between groups according to diplopia status. Transmission of temporal muscle contraction to the orbit seems to be the cause of the oscillopsia. The authors postulate that the absence of orbital floor or medial wall may act as a dampener for the temporalis muscle contractions, allowing the orbital contents to be expanded through them, and avoiding oscillopsia.

Nerve Sheath Myxoma Involving the Medial Rectus Muscle: A Case Report.

A 63-year-old man reported a 2-year history of painless OS proptosis. The first MRI, performed in the institution of origin, resulted in a diagnosis of hemangioma versus orbital pseudotumor. Examination revealed proptosis and mild chemosis. Ancillary tests were normal, and oral prednisone was initiated without remarkable changes. Later, an incisional biopsy identified the lesion as an intramuscular myxoma of the left rectus, and a new MRI was ordered. It described a fusiform thickening of the medial rectus with and exophytic growth below the inferior rectus and upward toward the superior oblique. Due to the localization of the lesion, a combined transcaruncular and swinging eyelid approach with a lateral orbitotomy was performed. Histopathological examination revealed a proliferation of stromal origin composed of myxoid matrix with fusocellular and stellate-shaped cells. Cells were S-100, CD34, and CD56 positive and negative for epithelial membrane antigen, CD68, CD10, actin, and desmin. Results were consistent with a left medial rectus nerve sheath myxoma.

Frontalis Suspension Using Autologous Fascia Lata in Children Under 3 Years Old.

PURPOSE: To analyze functional results and complications of the use of autologous fascia lata in frontalis suspension in children under 3 years old and to confirm its technical viability. METHODS: A retrospective review of 8 patients (12 eyes) who underwent frontalis suspension using autologous fascia lata sling. RESULTS: Twelve eyes of 8 patients were analyzed, with an average age of 1.8 ± 0.6 years. Preoperatively, the mean margin-to-reflex distance 1 was -0.17 ± 0.577 mm. Postoperatively the mean margin-to-reflex distance 1 was 2.66 ± 0.492 mm without any graft donor site or corneal complications. No recurrence was recorded in the follow-up period (mean follow-up period 28.5 ± 32.33 months). CONCLUSIONS: Autologous fascia lata is an eligible material in frontalis suspension in children under 3 years old, despite the traditional oculoplastic dogma that advises against.