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.

Rundle's Curve: A Useful Construct That Does Not Fit All.

PURPOSE: The purpose of this study was to analyze Rundle's original data and subsequent articles on Graves orbitopathy (GO) natural history. METHODS: Rundle's texts were analyzed qualitatively and quantitatively. Serial measurements were plotted and fitted with different functions. Subsequent articles in the English literature on the natural history of GO were also analyzed. RESULTS: Different functions such as simple linear regressions, parabolic, saturating exponential growth, and exponential decay functions were well fitted for Rundle's data on measurements of proptosis and supraduction along time. The few quantitative data of the same variables post-Rundle were also well-fitted with various functions. CONCLUSION: Rundle described in his articles, from 1945 to 1957, 2 phases of ocular changes in GO: dynamic and static. However, he did not mention the pathophysiology of these phases nor used the terms inflammatory and cicatricial. Actually, most of his observations and the subsequent data in the literature on proptosis and supraduction did not obey the biphasic pattern of the so-called Rundle's curve.

Position of the anterior ethmoidal foramen and trauma to the cranial base during transconjunctival medial orbital decompression: a systematic literature review.

PURPOSE: To review the literature on the location of the anterior ethmoidal foramen (AEF) and trauma during transconjunctival medial wall decompression. METHODS: A comprehensive literature search was conducted using the PubMed, Embase, and Scopus databases, combining the terms "olfactory fossa" and "fovea ethmoidalis" with "trauma," "cerebrospinal fluid leak," "pneumocephalus," "orbital decompression," and "anterior ethmoidal artery" (AEA). All cases of cranial base trauma during medial orbital decompression and the anatomical studies on the location of the AEF and the course of the AEA were reviewed. RESULTS: Ninety-four articles were identified, of which 37 were related to the AEF, 41 reported the course of the AEA, and 16 to reported cases of cranial base trauma. Out of these cases, 10 were related to transconjunctival medial orbital decompression, affecting 11 patients. Most AEFs are situated at the frontoethmoidal suture, but up to 38.15% of AEFs are located above the suture on the frontal bone. Most AEFs are adjacent to the roof of the ethmoidal sinus. The distance of the AEF to the cranial base increases in the presence of supraorbital ethmoidal cells (SOEC). CONCLUSIONS: The position of the AEF is variable and should not be considered a safe landmark for all patients.

Orbital and paranasal sinuses changes after neonatal orbital exenteration for massive teratoma management.

A neonate at 13 days of age underwent a lid and conjunctiva-sparing orbital exenteration for a massive right orbital teratoma. To reduce the degree of orbital contraction, the entire temporalis muscle was rotated into the orbit along with a dermis-fat graft. Sequential postoperative orbital imaging showed that hyperostosis developed in the orbital apex at the age of two months. Despite a significant expansion of the fat graft, by the age of 4 years, hyperostosis had progressed to the anterior portion of the orbit associated with over-pneumatization of the paranasal sinuses. This case demonstrates that the bony changes in the orbit after neonatal exenteration are complex and involve the development of the paranasal sinuses.

The effect of rim-off deep lateral orbital decompression on the lateral rectus shape and oculomotor balance.

PURPOSE: The purpose of the study was to measure the effect of rim-off deep lateral decompression for Graves orbitopathy on the lateral rectus muscle path and oculomotor balance. METHODS: Retrospective analysis of the medical records and pre- and postoperative computed tomography scans of 34 orbits of 23 patients who underwent deep lateral decompression alone. The oculomotor balance of these 23 patients was measured with the alternate cover test and prisms before and after surgery. Bezier functions were used to measure the postoperative path of the lateral rectus in all decompressed orbits. RESULTS: Deep lateral decompression induced a curvilinear deformation of the lateral rectus. There was no significant correlation between the position of the point of maximum muscle displacement and the size of the residual lateral wall. The changes in the lateral rectus path had no adverse effects on the oculomotor balance of the patients. CONCLUSIONS: The location of the curvilinear deformation of the lateral rectus does not depend on the residual segment of the lateral wall. The changes of the lateral rectus path have no deleterious effect on the oculomotor balance.

Monoclonal Antibodies for the Treatment of Graves Orbitopathy: Precision Medicine?

PURPOSE: To summarize the development, nomenclature, and rationale of the reported use of monoclonal antibodies (Mabs) in Graves Orbitopathy (GO) and to undertake a systematic review of the management of GO with Mabs. METHODS: The Pubmed and Embase databases and the Federal Brazilian searching site (Periódicos-CAPES) were screened. The authors searched all the keywords "monoclonal antibodies," "adalimumab," "belimumab," "infliximab," "rituximab," "teprotumumab," and "tocilizumab" combined with the terms "Graves Orbitopathy," "Graves eye disease" and "thyroid eye disease." All the articles published in English, French, and Spanish from 2000 to May 2022 were screened. Only publications with quantitative data on the activity of orbitopathy, proptosis, or both were included. RESULTS: Seventy-six articles of the 954 screened records met the inclusion criteria. Seven Mabs were described for treating GO. The three most reported Mabs were Rituximab, Tocilizumab, and Teprotumumab. Only eight randomized clinical trials compared the effect of these three Mabs and Belimumab with the effect of steroids or placebos. Adalimumab, Infliximab, and K1-70 only appeared in a few case series and case reports. Frequent mild-to-moderate and few major side effects occurred with the three most used Mabs. Relapse rates ranged from 7.4% for Tocilizumab to at least 29.4% for Teprotumumab. No randomized clinical trials compared Mabs head-to-head. CONCLUSION: Considering the lack of head-to-head comparisons between Mabs, the relapse rate, the possibility of severe collateral effects, and the cost of Mabs, it is not clear which Mab is the safest and most useful to treat GO.

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.

Margin rotation for tarsal buckling following ptosis surgery.

PURPOSE: To assess the clinical characteristics of tarsal buckling after ptosis correction and its management with margin rotation techniques. METHODS: Multicenter retrospective review of ten patients who developed upper eyelid entropion following ptosis correction. In all cases the tarsal deformity was corrected with margin rotational procedures with either a lid crease anterior approach or a traditional posterior approach. Data collection included patient demographics, type of ptosis surgery, and photographic documentation of the affected eyelids. RESULTS: Entropion occurred after a variety of different ptosis surgery techniques, including frontalis sling, levator advancement and supramaximal levator resection. A horizontal tarsal fold was detected in all eyelids, being in the upper third of the tarsus in 70% and in the central tarsus in 20% of the cases. Tarsal buckling was corrected in all cases with rotational surgery, with nine cases being operated through an anterior lid crease approach and 1, through the traditional posterior approach. The most reported complication was minimal residual ptosis. CONCLUSION: Tarsal buckling following ptosis surgery is associated with folds located in the upper part of the tarsus. Margin rotation techniques are effective in restoring the natural position of the eyelid margin in these cases.

Implications of the olfactory fossa anatomy in intracranial complications of inferomedial orbital decompression.

Two patients with thyroid eye disease underwent inferomedial orbital decompression complicated by a cerebrospinal fluid (CSF) leak. One of the cases developed a postoperative pneumocephalus resolved with conservative measures. In the second case, the CSF leak was managed intraoperatively. In both patients, a computed tomography (CT) scan revealed a pronounced slope of the lateral lamella of the cribriform plate, forming an obtuse angle with its lateral bony extension. When this anatomical disposition of the olfactory fossa (OF) is present, the course of the anterior ethmoidal artery (AEA) is usually embedded in the skull base, and its foramen should not be taken as the upper limit of the transconjunctival ethmoidectomy. The shape and relative height of the olfactory fossa and fovea ethmoidalis, and the course of the AEA should always be assessed before transconjunctival medial decompressions.

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.

Plasma cell IgG4 positivity in orbital biopsies of non-IgG4-related conditions.

The IgG4-related disease (IgG4-RD) is a systemic condition defined as a fibro-inflammatory disorder, characterized by the occurrence of tumor-like lesions in multiple organs including the eye adnexa. The main diagnostic criterion is based on histopathological findings, especially on the IgG4+/IgG+ plasma cell ratio. In this article, we reviewed the literature of non-IgG4-RD orbital conditions with IgG4 positivity. There were 20 reports of inflammatory non-IgG4-RD orbital lesions and 14 reports of orbital lymphoid proliferations with significant IgG4 positivity. The role of plasma cells IgG4 in the pathogenesis of non-IgG4-RD is not clear. Considering the large spectrum of diseases caused by a variety of different etiopathogenic mechanisms, we think that the common denominator of IgG4+ in these conditions might be related to the peculiar properties of down regulation of immune response of the IgG4 and not to a specific link to IgG4-RD.

Congenital Opticmeningoceles.

Congenital optic nerve cystic-like malformations associated with normally developed globes are extremely rare. We describe 3 children who presented since birth with proptosis, and eye motility limitation. MRI showed in all cases that the intraorbital segment of the optic nerves was malformed with large cystic-like lesions in the intraconal segment of the orbit. In all cases, biopsies of the wall of the lesions were positive for glial fibrillary acidic protein. Since this protein is a neurobiomarker that exists only in astrocytes in the central nervous system, nonmyelinating Schwann cells of peripheral nerves, and enteric glial cells, we believe that these lesions represent true opticmeningoceles.

Frontalis Linkage Without Intraoperative Eyelid Elevation for the Management of Myopathic Ptosis.

PURPOSE: To report the effect of frontalis linkage without intraoperative eyelid elevation for the management of myopathic ptosis. METHODS: Retrospective analysis of 21 (42 eyelids) myopathic patients with bilateral ptosis who were operated between 1999 and 2017. All patients had orbicularis weakness and poor or absent Bell's phenomenon. Surgery consisted of using an autogenous fascia sling to link the tarsal plate to the frontalis muscle without any degree of intraoperative eyelid elevation. The main outcome measures were margin reflex distance, brow height and degree of brow excursion and degree of lagophthalmos, and exposure keratitis. RESULTS: After surgery, there were significant changes (p <0.0001) in both margin reflex distance and brow position. Mean margin reflex distance increased to 1.4 mm ± 1.34 DP and with full frontalis contraction, it reached 3.0 mm ± 1.73 DP, while mean brow position decreased 1.6 mm ± 1.59 SD, p < 0.0001. Postoperative lagophthalmos was not detected in 31 (74%) eyes. In the remaining 11 eyes (26%), lagophthalmos ranged from 1.2 to 5.2 mm (mean = 1.7 mm ± 0.74 DP). Mild inferior superficial keratitis was detected in 14 eyes (33.3%) of 7 patients only 3 of which had lagophthalmos. One patient needed additional surgery to correct unilateral eyelid retraction. Overall, 81.81% of the patients were pleased with the procedure. CONCLUSIONS: Myopathic ptosis can be alleviated with a minimal amount of lagophthalmos by just linking the tarsal plate to the frontalis muscle without lifting the eyelid margin intraoperatively.

Systemic Diffuse Large B-Cell Lymphoma Presenting as Bilateral Orbital Vasculopathy.

The authors report a case of a 58-year-old man with bilateral proptosis and signs of orbital inflammation without any associated systemic findings. MRI showed diffuse orbital infiltration. An intraconal orbital biopsy revealed polyclonal lymphoplasmacytic infiltration and non-necrotizing lymphoid small-vessel vasculopathy. The orbital symptoms resolved following a 2-week course of oral prednisone. Three months later, the patient experienced abdominal pain and weight loss. Ultrasonographic investigation showed hepatosplenomegaly, a retroperitoneal mass, and inguinal lymphadenopathy. A lymph node biopsy revealed a diffuse large B-cell lymphoma. The patient underwent chemotherapy but died 6 months later with metastatic disease. This case suggests that diffuse orbital inflammation with nonspecific vasculitis may be an early paraneoplastic finding associated with diffuse large B-cell lymphoma.