Disease Modulation Versus Modification: A Call for Revised Outcome Metrics in the Treatment of Thyroid Eye Disease.

PURPOSE: This perspective introduces the concepts of disease-modulating and -modifying therapy for thyroid eye disease and offers novel metrics for therapeutic outcomes. METHODS: A focused literature review was performed. RESULTS: Modulators are treatments that suppress disease symptoms whereas modifiers alter the natural history of a disease. Though many drugs are capable of exhibiting both effects, consideration of a drug's primary effect is useful when considering therapeutic options. For thyroid eye disease, corticosteroids and teprotumumab are effective at modulating many signs and symptoms of the disease, particularly those related to soft tissue inflammation. Orbital radiotherapy and rituximab have demonstrated effectiveness at durably modifying the natural history of thyroid eye disease. CONCLUSIONS: Outcome metrics should reflect the unique therapeutic objectives associated with disease modulation and modification. This conceptual framework should guide treatment of thyroid eye disease.

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.

Long-term outcomes of fornix reconstruction and cicatricial entropion repair in ocular mucous membrane pemphigoid and drug-related secondary pemphigoid.

OBJECTIVE: To investigate the long-term outcomes of fornix reconstruction and cicatricial entropion repair in patients with ocular mucous membrane pemphigoid (MMP) and secondary MMP. METHODS: Retrospective chart review of patients with MMP undergoing either fornix reconstruction (with amniotic membrane or buccal mucosal graft) or Wies cicatricial entropion repair between January 1, 2000, and September 1, 2020. Patients had a positive mucosal biopsy and (or) clinical features of MMP or secondary MMP. The primary outcome was overall success of fornix reconstruction based on fornix depth maintenance at latest follow-up. Secondary outcomes included resolution of trichiasis, visual acuity, and improvement of subjective symptoms. RESULTS: Eight patients (10 eyes) with a diagnosis of MMP (3 males and 5 females; median age, 71 years) and 4 patients (4 eyes) with a diagnosis of secondary MMP (2 females and 2 male; median age, 87 years) were enrolled. Mean follow-up was 22.7 months (range, 0.3-87.5 months) for MMP patients and 15.4 months (range, 3.0-43.9 months) for secondary MMP patients. For MMP eyes, 30.0% underwent fornix reconstruction, 60.0% underwent entropion repair, and 10.0% received both. Re-formation of symblepharon and loss of fornix depth occurred in all MMP eyes at an average of 6.4 ± 7.0 months postoperatively, and trichiasis recurred in all patients at the last follow-up visit. In secondary MMP patients, 75.0% of the eyes showed recurrence of symblepharon, and 66.7% re-formed trichiasis. Both MMP and secondary MMP patients had short-term symptom improvements. CONCLUSIONS: Fornix reconstruction and cicatricial entropion repair in our cohort of MMP and secondary MMP patients resulted in short-term symptomatic improvement, but recurrence was seen, on average, at 6 months postoperatively.

Management of thyroid eye disease: a Consensus Statement by the American Thyroid Association and the European Thyroid Association.

Thyroid eye disease (TED) remains challenging for clinicians to evaluate and manage. Novel therapies have recently emerged, and their specific roles are still being determined. Most patients with TED develop eye manifestations while being treated for hyperthyroidism and under the care of endocrinologists. Endocrinologists, therefore, have a key role in diagnosis, initial management, and selection of patients who require referral to specialist care. Given that the need for guidance to endocrinologists charged with meeting the needs of patients with TED transcends national borders, and to maximize an international exchange of knowledge and practices, the American Thyroid Association and European Thyroid Association joined forces to produce this Consensus Statement.

Management of Thyroid Eye Disease: A Consensus Statement by the American Thyroid Association and the European Thyroid Association.

Thyroid eye disease (TED) remains challenging for clinicians to evaluate and manage. Novel therapies have recently emerged, and their specific roles are still being determined. Most patients with TED develop eye manifestations while being treated for hyperthyroidism and under the care of endocrinologists. Endocrinologists, therefore, have a key role in diagnosis, initial management, and selection of patients who require referral to specialist care. Given that the need for guidance to endocrinologists charged with meeting the needs of patients with TED transcends national borders, and to maximize an international exchange of knowledge and practices, the American Thyroid Association and European Thyroid Association joined forces to produce this consensus statement.

Predictive Modeling of New-Onset Postoperative Diplopia Following Orbital Decompression for Thyroid Eye Disease.

PURPOSE: To identify risk factors for the development of new-onset, postoperative diplopia following orbital decompression surgery based on patient demographics, clinical exam characteristics, radiographic parameters, and surgical techniques. METHODS: We conducted a multi-center retrospective chart review of patients who underwent orbital decompression for thyroid eye disease (TED). Patient demographics, including age, gender, smoking history, preoperative exophthalmometry, clinical activity score (CAS), use of peribulbar and/or systemic steroids, and type of orbital decompression were reviewed. Postoperative diplopia was determined at a minimum of 3 months postoperatively and before any further surgeries. Cross-sectional area ratios of each extraocular muscle to orbit and total fat to orbit were calculated from coronal imaging in a standard fashion. All measurements were carried out using PACS imaging software. Multivariable logistic regression modeling was performed using Stata 14.2 (StataCorp, College Station, TX). RESULTS: A total of 331 patients without preoperative diplopia were identified. At 3 months postoperatively, 249 patients had no diplopia whereas 82 patients developed diplopia. The average postoperative follow-up was 22 months (range 3-156) months. Significant preoperative clinical risk factors for postoperative diplopia included older age at surgery, proptosis, use of peribulbar or systemic steroids, elevated clinical activity score, and presence of preoperative compressive optic neuropathy. Imaging findings of enlarged cross-sectional areas of each rectus muscle to the overall orbital area also conferred a significant risk of postoperative diplopia. Regarding surgical factors, postoperative diplopia was more common among those undergoing medial wall decompression, bilateral orbital surgery, and balanced decompression, whereas endoscopic medial wall decompression was found to be relatively protective. CONCLUSIONS: This study identifies risk factors associated with the development of diplopia following orbital decompression using multivariable data. This study demonstrates that several characteristics including age, clinical activity score, the cross-sectional muscle to orbit ratios, in addition to the type of orbital decompression surgery, are predictive factors for the development of new-onset postoperative diplopia.

Orbital Teratoma: Case Report and Management Review.

Orbital teratoma is a rare, vision-threatening, congenital neoplasm derived from all germ cell layers. The management of orbital teratoma is uncertain because of its rarity and variable severity. We present a case with complete tumor excision with preservation of vision and cosmesis. A 4-day-old female presented with progressive proptosis of the OD. She was born term following an uneventful pregnancy and delivery. MRI of the orbits showed a large right-sided mass centered within the intraconal space with heterogeneous signal intensity characteristics consistent with a teratoma. She underwent a right posterior orbitotomy. The tumor was wrapped around the optic nerve but was gradually separated from it and all other normal structures and delivered intact. Histology was compatible with an immature teratoma without evidence of malignancy. The patient is now 6 months old, visually attentive with no evidence of optic neuropathy, and has essentially normal appearance.

Surgical Technique to Retrieve a Migrated Lester Jones Lacrimal Tube.

PURPOSE: To describe a technique for retrieving an inferomedially migrated Jones lacrimal tube. METHODS: The distal end of the migrated Jones tube is visualized directly via the nose. The tip of an endoilluminator (23 Gauge Constellation Vision Systems) is bent to form a 45° to 60° angle using a mosquito forceps and inserted into the distal opening of the tube. The endoilluminator is used to push the tube upward toward the original medial canthal opening and limit downward displacement as the caruncular area is surgically explored. The light transilluminating the tube facilitates its visualization and retrieval in the caruncular area. A new tube may be threaded through the same passage, or if the ostium is traumatized, through a new passage. RESULTS: This technique is time-efficient and has proven to be safe and successful in subsequent patients. CONCLUSIONS: The described technique aids in retrieving an inferomedially migrated Jones tube with minimal trauma to the surrounding structures.

Primary Nasocutaneous Fistulae in Granulomatosis With Polyangiitis: A Case Series and Literature Review.

PURPOSE: To report the presentation, investigation, management, and outcomes of primary nasocutaneous fistulae in granulomatosis with polyangiitis and review the literature of this complication. METHODS: Retrospective series of 5 patients with granulomatosis with polyangiitis and nasocutaneous fistulae and the medical and surgical management strategies employed. RESULTS: Two cases presented with fistulae as the primary symptom of their systemic disease. Systemic management of granulomatosis with polyangiitis is a primary concern and two cases had inadequate control at presentation such that surgical intervention was deferred. Of the other 3 cases, 2 were closed using a median forehead flap and the other with an orbicularis advancement flap. An endonasal approach was attempted in 1 case but was unsuccessful due to the friable nature of the nasal mucosal tissue. CONCLUSIONS: Nasocutaneous fistulae should alert the clinician to underlying granulomatosis with polyangiitis, which may be a presentation of this condition. Systemic management of disease is often a barrier to surgical management. Myocutaneous flaps may be the most reliable management option to achieve closure.

Differences in 7th and 8th edition American Joint Committee on Cancer staging for periocular sebaceous carcinoma.

OBJECTIVE: To examine the clinicopathological features of periocular sebaceous carcinoma and describe the differences in T category between the seventh and eighth editions of the American Joint Committee on Cancer (AJCC) staging system for eyelid carcinoma in a Canadian population. METHODS: This study is a single-centre retrospective review of consecutive patients diagnosed with periocular sebaceous carcinoma at Vancouver General Hospital over a 24-year period. Medical records and pathological slides were reviewed. Clinicopathological features, management, and outcomes were recorded. Each carcinoma was staged as per both the seventh and eighth editions AJCC staging system for eyelid carcinoma. RESULTS: Forty-five patients (25 women, 20 men) were identified with a median age of 74 years (range 42-91 years). Tumour size was with a median of 4 mm (range 1-30 mm) and a mean of 6.7 mm. Using the seventh edition, patients were assigned the following T categories: Tis = 10, T1 = 9, T2 = 11, T3 = 8, T4 = 0. Under the eighth edition, 18 of 45 patients (40%) were restaged, with the majority of these (15 patients, 33%) being downstaged. The eighth edition categories were as follows: Tis = 10, T1 = 22, T2 = 3, T3 = 0, T4 = 3. Three patients developed disease recurrence, 2 of whom (staged T2c and T4b) died of disease. CONCLUSIONS: There were substantial differences in the seventh and eighth editions of AJCC for the staging of periocular sebaceous carcinoma. Our series had small tumours at presentation with infrequent recurrences or metastases. We found a high number of patients with in-situ-only disease.

Perioperative Prophylactic Antibiotics in 1,250 Orbital Surgeries.

PURPOSE: Intravenous antibiotic prophylaxis is used for many clean-contaminated surgeries or clean surgeries with an implant, but its value for clean orbital surgery has not been determined. This study investigated infection risks and adverse effects related to antibiotics in patients undergoing orbital surgery. METHODS: A prospective, nonrandomized comparative case series of all patients undergoing orbital surgery with participating surgeons between October 1, 2013, and March 1, 2015. Types of surgery, antibiotic regimens, corticosteroid use, antibiotic side effects, and surgical site infections (SSIs) were entered into an electronic database and subsequently analyzed. Cases in which patients received postoperative oral antibiotics were analyzed separately. RESULTS: Of 1,250 consecutive orbital surgeries, 1,225 met inclusion criteria. A total of 1208 patients were included in the primary analysis: 603 received no antibiotic prophylaxis (group A), and 605 received a single dose of intravenous antibiotic (group B). Five patients (0.42%) developed an SSI, 3 in group A and 2 in group B. The difference in SSI rates was not statistically significant between the 2 groups (p = 0.66). Antibiotic prophylaxis, alloplastic implants, paranasal sinus entry, and corticosteroid use were not associated with differences in SSI rates. All SSIs resolved on a single course of oral antibiotics; an implant was removed in 1 case. There were no complications associated with a single dose of intravenous prophylaxis. However, 12% of 17 patients (group C) who received 1 week of oral postoperative prophylactic antibiotics developed antibiotic-related complications (diarrhea, renal injury), yielding a number needed to harm of 8.5. CONCLUSIONS: In this large series, antibiotic prophylaxis does not appear to have reduced the already low incidence of SSI following orbital surgery. Given the detriments of systemic antibiotics, the rarity of infections related to orbital surgery, and the efficacy of treating such infections should they occur, patients undergoing orbital surgery should be educated to the early symptoms of postoperative infection and followed closely, but do not routinely require perioperative antibiotics.

An In Vitro Model Assessing the Penetration of Hyaluronidase through Optic Nerve Dura for Management of Hyaluronic Acid Facial Filler Embolism.

BACKGROUND: Blindness from ophthalmic or central retinal artery embolism is one of the most devastating complications of cosmetic filler facial injections. A proposed therapy to mitigate visual loss is prompt retrobulbar injection of hyaluronidase into the retrobulbar space. Despite Zhu et al. showing a lack of evidence and very limited published literature for reversing visual loss with this intervention, it is still widely accepted as a treatment for filler-related emboli. The purpose of this study was to evaluate the penetration of hyaluronidase through optic nerve dura using an in vitro model. METHODS: At study conclusion, five 1-cm-long segments of fresh optic nerve were obtained and injected with highly crosslinked hyaluronic acid filler, then ligated on both ends in a watertight fashion. The sections were immersed in three concentrations of hyaluronidase solution for 24 hours. Histopathologic examination of the specimen was performed to assess the presence of filler. RESULTS: The optic nerve sections were 1.1 cm (range, 0.8 to 1.2 cm). Three were immersed in 20 ml of 1500 IU/ml hyaluronidase solution and two were immersed in saline as control. After 24 hours, there was a persistence of hyaluronic acid within the optic nerves. CONCLUSIONS: There is a lack of evidence for penetration of optic nerve sheath by hyaluronidase. This raises question about the effectiveness of retrobulbar injection of hyaluronidase in reversing filler-related blindness. Further studies are needed before this can be adopted as the treatment of choice. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Primary replacement for the management of exposed orbital implant.

Purpose: We present a series of primary orbital implant replacement for cases of implant exposure to describe our experience of this one-staged surgical approach. Methods: This study reports on a one-stage technique which involved the removal of the exposed implant or dermis fat graft (DFG) and insertion of a secondary (replacement) in the same procedure, with a variety of materials, including autologous tissue. Re-exposure in a socket where a DFG was placed was defined as a new defect in the newly epithelialized conjunctiva or dehiscence of the dermis-conjunctiva junction. All cases of primary replacement for the management of exposed orbital implant, porous and non-porous, were included, even when there were clinical signs suggestive of infection. The primary outcome was the rate of re-exposure, requiring additional surgical procedures. Infection following primary replacement was a secondary outcome. Results: Seventy-eight patients had primary replacement for the management of an exposed orbital implant. 6.4% had re-exposure at a mean follow-up of 49.7 months (9.1% for ball implants and 4.5% for DFG). The rate of exposure was higher in those with prior signs of infection than those without (8% vs. 3.6%). Re-exposure occurred in 4.5% of cases with DFG implantation, 4.3% of cases with non-porous implants and in 20% of cases with porous implants. Conclusion: Primary replacement for management of exposed orbital implant, porous and non-porous, has a high rate of successful outcome even in cases with presumed or confirmed infection.

Grading Severity and Activity in Thyroid Eye Disease.

PURPOSE: Thyroid eye disease (TED) is an autoimmune disorder causing inflammation, expansion, and fibrosis of orbital fat, muscle, and lacrimal gland. This article reviews the different methods of grading severity and activity of TED and focuses on the VISA Classification for disease evaluation and planning management. METHODS: Accurate evaluation of the clinical features of TED is essential for early diagnosis, identification of high-risk disease, planning medical and surgical intervention, and assessing response to therapy. Evaluation of the activity and severity of TED is based on a number of clinical features: appearance and exposure, periorbital tissue inflammation and congestion, restricted ocular motility and strabismus, and dysthyroid optic neuropathy. The authors review these clinical features in relation to disease activity and severity. RESULTS: Several classification systems have been devised to grade severity of these clinical manifestations. These include the NO SPECS Classification, the European Group on Graves Orbitopathy severity scale, the Clinical Activity Score of Mourits, and the VISA Classification as outlined here. The authors compare and contrast these evaluation schemes. CONCLUSIONS: An accurate clinical assessment of TED, including grading of disease severity and activity, is necessary for early diagnosis, recognition of those cases likely to develop more serious complications, and appropriate management planning. The VISA Classification grades both disease severity and activity using subjective and objective inputs. It organizes the clinical features of TED into 4 discrete groupings: V (vision, dysthyroid optic neuropathy); I (inflammation, congestion); S (strabismus, motility restriction); A (appearance, exposure). The layout follows the usual sequence of the eye examination and facilitates comparison of measurements between visits and data collation for research.

Soft Tissue Metrics in Thyroid Eye Disease: An International Thyroid Eye Disease Society Reliability Study.

PURPOSE: To determine the reliability of 3 scales for assessing soft tissue inflammatory and congestive signs associated with thyroid eye disease. METHODS: This was a multicentered prospective observational study, recruiting 55 adults with thyroid eye disease from 9 international centers. Six thyroid eye disease soft tissue features were measured; each sign graded using 3 scales (presence/absence [0-1], 3-point scale [0-2], and percentage [0-100]). Each eye was graded twice by 2 independent raters. Accuracy (fraction of agreement) was calculated between the 2 trials for each rater (intrarater reliability) and between raters for all trials (interrater reliability) to determine the most sensitive scale for each feature that maintained a threshold of agreement greater than 0.70. Trial, intrarater reliability, and interrater reliability were determined by accuracy measurement of agreement for each inflammatory/congestive feature. RESULTS: Fifty-five patients had 218 assessments for 6 thyroid eye disease metrics. The intrarater reliability for each feature was consistently better than the interrater reliabilities. Using an agreement of 0.70 or better, for the interrater tests, conjunctival and eyelid edema could be reliably measured using the 0-1 or 0-2 scale while conjunctival and eyelid redness could only be reliably measured with the binary 0-1 scale. Caruncular edema and superior conjunctival redness could not be measured reliably between 2 raters with any scale. The percentage scale had poor agreement unless slippage intervals of >20% were allowed on either side of the measurements. CONCLUSIONS: Of the specific periocular soft tissue inflammatory features measured between raters in the Clinical Activity Score and Vision, Inflammation, Strabismus, Appearance scales, edema of the eyelids and conjunctiva could reliably be measured by both 0-1 and 0-2 scales, erythema of the eyelid and bulbar conjunctiva could reliably be measured only by the 0-1 scale, and the other parameters of superior bulbar erythema and caruncular edema were not reliably measured by any scale.