Thyrotropin Receptor Autoantibody Assessment in Thyroid Eye Disease: Does the Assay Type Matter?

PURPOSE: Thyroid receptor antibodies can quantify thyroid eye disease activity, predict outcomes and aid timing of interventions. The type and generation of assay is frequently unspecified, complicating meta-analyses. To determine the clinical and biochemical relationships between a second-generation thyrotropin receptor-binding inhibition antibody (TRAb) immunoassay, detecting stimulatory and blocking antibodies, with the thyroid stimulating immunoglobulin (TSI) bridging immunoassay detecting the stimulatory component only. METHODS: Retrospective review of 100 consecutive patients attending a regional specialist service. For each patient and visit, both a TRAb and TSI were performed, and a clinical activity score (CAS) recorded. RESULTS: A significant positive correlation between TRAb and TSI (rho = 0.828, p < 0.01) but a weaker correlation between the assays and CAS (TRAb: rho = 0.439, p < 0.01; TSI: r = 0.357, p < 0.01) were found. In 10% of the episodic data, patients had a TRAb level that was disproportionately high (39.41 ± 52.84 IU/L), compared to their TSI levels (9.53 ± 12.10 IU/L) with a higher-than-average CAS (2.47 ± 1.78; range, 0-5). Within 12 months of diagnosis, a significant positive correlation between CAS and TRAb (rho = 0.503, p < 0.01) as well as between CAS and TSI (rho = 0.329, p < 0.01) were found. In patients with a diagnosis over 12 months, the correlation with CAS for both TSI and TRAb were Spearman rank correlation coefficient of 0.347 (p < 0.01) and 0.327 (p < 0.01), respectively. CONCLUSIONS: TRAb and TSI correlate strongly and to a lesser extent with the CAS. For most patients, TRAb can be replaced with the more economical TSI. TRAb also correlates better with newly diagnosed, more active patients than TSI. In a subset of patients, blocking antibodies may play a significant pathogenic role, requiring different treatment and monitoring. Further studies are required to investigate this relationship.

TFOS Lifestyle: Impact of cosmetics on the ocular surface.

In this report the use of eye cosmetic products and procedures and how this represents a lifestyle challenge that may exacerbate or promote the development of ocular surface and adnexal disease is discussed. Multiple aspects of eye cosmetics are addressed, including their history and market value, psychological and social impacts, possible problems associated with cosmetic ingredients, products, and procedures, and regulations for eye cosmetic use. In addition, a systematic review that critically appraises randomized controlled trial evidence concerning the ocular effects of eyelash growth products is included. The findings of this systematic review highlight the evidence gaps and indicate future directions for research to focus on ocular surface outcomes associated with eyelash growth products.

Inhibition of Fibrotic Contraction by Sirolimus (Rapamycin) in an Ex Vivo Model of Thyroid Eye Disease.

BACKGROUND: Thyroid eye disease (TED) is characterized by orbital inflammation and complicated by extraocular muscle fibrosis. Treatment with rapamycin/sirolimus has been reported to improve ocular motility and disease manifestations in TED. Whether this resulted from a primary antifibrotic effect on fibroblasts or was secondary to immune-suppression is unclear. METHODS: In vitro contractility studies of primary orbital fibroblasts. Cells from patients with TED and controls were treated with rapamycin [mechanistic target of rapamycin an (mTOR) inhibitor] and MHY1485 (an mTOR stimulator) as well as inhibitors upstream in the same signaling cascade (saracatinib and befatinib). RESULTS: At concentrations consistent with the therapeutic dosing range in humans, rapamycin/sirolimus significantly reduces fibrosis in orbital fibroblasts from TED patients and controls in vitro. This effect is separate from, and in addition to, its immune suppressive effect. mTOR-driven fibrotic activity is greater in TED-derived fibroblasts and can be blocked also upstream of mTOR by inhibition of src. There was no adverse effect on cell survival. CONCLUSION: The authors present evidence for a direct antifibrotic effect of rapamycin/sirolimus in primary orbital fibroblasts. Targeting mTOR signaling presents a further and adjunctive treatment of TED alongside other immune-suppressive agents. By acting downstream of IGF1-R, sirolimus may offer a cost-effective alternative to teprotumumab therapy. Clinical case reports, now supplemented by this in vitro evidence, support the initiation of a clinical trial to treat the fibrotic sequelae of TED with this already-approved agent. Such an "off-the-shelf" therapy is a welcome prospect for TED treatment, particularly one available at a low price.

Factors influencing pre-injection aspiration for hyaluronic acid fillers: A systematic literature review and meta-analysis.

Pre-injection aspiration of hyaluronic acid filler is a well-recognized yet controversial safety technique. Many consider aspiration to be an important safety measure to prevent inadvertent intravascular filler injection. To assess factors influencing pre-injection aspiration by understanding the relationship between aspiration time and a range of product, needle, and procedural characteristics. We conducted a systematic review and meta-analysis of data, adopting the preferred reporting items for systematic reviews and metaanalyses guidelines. Our literature search identified four articles presenting data on variables associated with aspiration time for different HA filler brands. Statistical models pooling data from the four articles suggest a robust association between aspiration time and a filler's elastic modulus (G'), drop weight (cohesivity), and cross-sectional area of the needle lumen. However, there is insufficient evidence to confirm a robust association between aspiration time and HA concentration, viscous modulus (G″), needle length, and pullback volume. A deeper understanding of the relationship between product, needle, and procedural characteristics, and aspiration time can provide a sound base for discussing the role of pre-injection negative aspiration as a safety measure. The understanding of the effect of various factors on preinjection aspiration would further benefit from studies under clinical conditions.

Improving aseptic injection standards in aesthetic clinical practice.

The rise in popularity and demand for nonsurgical injectable aesthetic procedures is inherently accompanied by an increase in reported complications, particularly those related to infection. Aseptic technique is under the control of aesthetic practitioners and can be modified to minimize the potential for cross-contamination and infection. This should be a key consideration during all clinical procedures, particularly those involving breach of the skin's natural defenses and the use of soft tissue filler. A consensus group of five UK expert aesthetic clinicians were convened to discuss current best practice for aseptic techniques in medical aesthetics. The aim of the consensus group was to recommend a step-by-step procedure to achieve optimal aseptic practice in private clinics, and define important considerations for reducing infection risk during the whole patient journey: pre-, during- and postaesthetic procedure. Recommendations were based on current evidence and extensive clinical experience. Various procedure recommendations were made to achieve and maintain a high standard of asepsis and infection control. Guidance was divided into three phases for patients and health care professionals, covering preprocedure (including patient selection), during-procedure, and postprocedure considerations. Although adherence to standard hospital guidance on handwashing and cleanliness measures is a cornerstone of controlling cross-contamination, aesthetic clinics carry a high potential risk of infection-particularly as popular treatments with dermal fillers primarily involve the face. This expert consensus guidance recommends procedures to mitigate the potential risks of asepsis.

Update on the clinical assessment and management of thyroid eye disease.

PURPOSE OF REVIEW: To offer an update on advances and controversies in the assessment, investigation and treatment of thyroid eye disease (TED), a disfiguring orbital autoimmune disease, which can manifest with diplopia and threaten not only sight - but also life. RECENT FINDINGS: Developments in biomarkers and imaging are helping to tailor the management of patients. Emerging therapies target different pathways in the disease and are informed by studies into TED pathogenesis: the last 2 years has, for example, seen the culmination of a two-decade long bench-to-bedside story in which an original focus on the IGF1 receptor has translated into an effective treatment for proptosis in thyroid eye disease. Whether this will result in a real-world reduction in TED-related morbidity will depend on access; commercial pricing decisions may preclude widespread adoption of novel therapies. SUMMARY: Thyroid eye disease research is enjoying a renaissance with advances in both monitoring and treatment coupled with a renewed emphasis on a holisitic approach, which includes aesthetic care for patients; this is perhaps the most exciting time to be part of the international thyroid eye disease community in decades - for physicians, surgeons and patients. The commercial window for break-through drugs are narrowing with an array of new therapeutic agents in the pipeline over the coming decade.

Periocular hyaluronic acid fillers: applications, implications, complications.

PURPOSE OF REVIEW: The use of dermal filler in the periocular area is increasing - both for functional and aesthetic indications. Hyaluronic acid fillers dominate the market; these treatments offer an alternative to some surgical procedures with the advantage of instant results, minimal healing time and low complication rates. However, success depends on judicious selection of patients, products and procedures to achieve favourable outcomes. This article reviews current understanding of the principal complications in the periocular area and their management. RECENT FINDINGS: Hyaluronic acid is a ubiquitous, biodegradable, nonspecies-specific molecular substrate with limited potential for immunogenic reactions. However, in the periocular area, such products can migrate and last significantly longer than the expected filler lifespan. Contamination or subsequent immune stimulation can trigger delayed-onset inflammatory reactions. Though minor vascular occlusions are not uncommon, cases of blindness secondary to facial filler injections are thought to be rare. Timely enzymatic degradation with injectable hyaluronidase can be effective in the treatment of some such complications. But recent studies demonstrate lack of penetration through arterial walls and optic nerve sheath, casting doubt on the role of retrobulbar hyaluronidase in the management of vision loss because of embolism with hyaluronic acid filler. SUMMARY: Hyaluronic acid fillers represent an emerging and important addition to the armamentarium of the oculofacial plastic surgeon with their use in the aesthetic field also expected continue to rise. The oculoplastic facial surgeon, armed with a thorough knowledge of facial anatomy, safe injection planes and the means of minimizing and treating complications is in the best position to lead clinically in the use of this well tolerated and effective treatment modality.

Sirolimus (rapamycin) for the targeted treatment of the fibrotic sequelae of Graves' orbitopathy.

BACKGROUND: Rapamycin (alternatively known as sirolimus) is a macrolide immunosuppressant commonly used for organ transplantation. It acts both on lymphocytes through the mechanistic target of rapamycin (mTOR) pathway to reduce their sensitivity to interleukin-2 (IL-2) and, importantly, also has anti-fibrotic properties by acting on myofibroblasts. The latter have been implicated in the pathogenesis of thyroid eye disease (TED). AIM: To describe successful treatment and reversal of extraocular muscle fibrosis in TED with sirolimus. METHODS: Case report and literature review with clinic-pathological correlation. RESULTS: A patient with Graves' orbitopathy (GO) developed significant ocular motility restriction, which was unresponsive to steroids and conventional immunosuppression. Unlike these prior treatments, rapamycin therapy improved the diplopia and fields of binocular single vision over a period of months. There were no adverse effects directly attributable to the treatment. CONCLUSION: With its low renal toxicity and ability to specifically target the underlying fibrotic pathways in GO, rapamycin may prove a useful adjunct to standard immunosuppressive regimes. We encourage further reporting of case series or the instigation of controlled trial.

Clinical pathophysiology of thyroid eye disease: The Cone Model.

The clinical features of thyroid eye disease are dictated by the orbit's compartmentalisation; particularly, the muscle cone, which is delimited by the rectus muscles, their inter-muscular septa and the posterior sclera. The cone is anchored to the orbit apex and contains the posterior globe, the muscle bellies, a fat pad, and the blood circulation, optic nerve, and CSF sheath. It is surrounded by mobile extraconal fat, retained by the orbital septum.Thyroid eye disease is caused by expansion of muscle bellies and fat within the cone. Mechanical properties of the cone determine that the disease partitions into three phases: circumferential expansion, with forward displacement of extraconal fat; axial elongation, with increasing cone pressure; impedance of posterior venous outflow, with cone oedema and venous flow reversal.Venous flow reversal can be observed in the conjunctival circulation. It is initially transient, accompanying rises in cone pressure caused by eye movements, but later becomes permanent. It is a useful clinical sign that locates diseased muscles and anticipates venous compressive crises.Strabismus arises when inflamed rectus muscles, swollen by hydrated glycosaminoglycans, lose contractility and compliance. The incomitance is moderated by increasing stiffness affecting all the rectus muscles, as they are stretched during cone expansion.Immunomodulation, which rapidly reduces cone volume, relieving muscle elongation and stiffness, may paradoxically unmask strabismus. However, ciclosporin A suppresses late post-inflammatory fibrosis and only 4 of 71 patients so-treated required strabismus surgery.The cone model also accounts for the variety of clinical presentations of thyroid eye disease.

Immune reconstitution after alemtuzumab therapy for multiple sclerosis triggering Graves' orbitopathy: a case series.

Alemtuzumab-a monoclonal antibody targeting the CD52 glycoprotein expressed by most mature leucocytes-effectively decreases relapse rate and disability progression in early, relapsing-remitting multiple sclerosis (MS). However, secondary autoimmune disorders complicate therapy in nearly 50% of treated patients, with Graves' disease being the most common. Rarely, thyroid eye disease (TED) ensues; only seven such cases have been reported. Our aim was to analyse the largest series of MS patients developing thyroid eye disease after alemtuzumab treatment. We performed a retrospective chart review of MS patients treated with alemtuzumab (1995-2018) and subsequently identified by their treating physicians as having developed TED and referred to our ophthalmology service. As an original trial centre for alemtuzumab, our hospital has treated approximately 162 MS patients with this novel therapy. In total, 71 (44%) developed thyroid dysfunction, most of whom (87%) developed Graves' disease, with ten (16%) referred for ophthalmological evaluation. Two developed active orbitopathy following radioiodine treatment; one occurred after cessation of anti-thyroid drug treatment. Three developed sight-threatening disease requiring systemic immunosuppression, with one refractory to multiple immunosuppressants. The remaining patients were treated conservatively. TSH-receptor antibody (TRAb) levels were significantly raised in all cases, when ascertained. We report sight-threatening as well as mild TED in MS patients after treatment with alemtuzumab. Endocrine instability, radioiodine treatment and positive TRAb are all likely risk factors. The data support at least 6-monthly biochemical and clinical assessment with a low threshold for referral to an ophthalmologist, particularly for those with higher TRAb levels who may be at greater risk of orbitopathy.

Serial TSH-receptor antibody levels to guide the management of thyroid eye disease: the impact of smoking, immunosuppression, radio-iodine, and thyroidectomy.

The Thyrotropin receptor antibody (TRAb) is the main driver of Graves' disease (GD) and its most common extra-thyroidal manifestation: thyroid eye disease (TED). Though key to diagnosis, it has not been used routinely as a marker of disease activity or to guide treatment. Here we demonstrate, through a retrospective review of 105 patients with TED, that serial TRAb levels vary with time, correlate with disease activity and are affected by smoking and endocrine control. Such serial measurements can guide the modern management of thyroid eye disease, helping to prevent the more serious manifestations. We show that surgical thyroidectomy is associated with a reduction in antibody levels and a reduced rate of TED reactivation when compared to radio-iodine ablation where the stimulating antigen is not removed. This provides a molecular explanation for epidemiological studies showing radio-ablation being associated with an increased risk of orbitopathy. To demonstrate the effect of our clinical approach on a patient population, we then compared the incidence and severity of TED in a clinic in a period before and after the introduction of serial TRAb measurements. Despite an increase in disease incidence and severity at presentation over the two-decade study period, our approach saw a significant reduction in the need for surgical intervention for this orbital disorder.

T2-relaxation mapping and fat fraction assessment to objectively quantify clinical activity in thyroid eye disease: an initial feasibility study.

Imaging in thyroid eye disease (TED) is used to exclude other diagnoses, assess for apical crowding and plan surgery. But to quantify TED activity objectively, subjective clinical scoring assessments remain the norm. Magnetic resonance imaging (MRI) T2-relaxation times correlate with extra-ocular muscle (EOM) inflammation, but are confounded by signal from fat. We investigated whether T2-relaxation mapping in combination with fat fraction (FF) measurements could quantify disease activity in EOMs objectively. Sixty-two TED patients and six controls were enroled for coronal short tau inversion recovery (STIR), T2 multi-echo fast-spin echo and multi-echo fast-gradient echo MRI of the orbits. STIR signal intensity ratios (SIRs), T2-relaxation times and percentage FF were derived for inferior, lateral, superior and medial recti bilaterally. Twelve patients were re-scanned following immunosuppressive treatment. The results found a positive correlation for all subjects between T2 and SIR (p < 0.001), but only mean T2 differed significantly between patients and controls (p < 0.001). We measured FF in EOMs for the first time and found it greater in TED (p < 0.001). There was also a significant reduction in mean T2 after treatment, with a corresponding reduction in the clinical activity score (CAS) in almost all patients. We show that T2-relaxation times differentiate between normal and inflamed EOMs and are responsive to treatment. Combined, uniquely, with FF measurement in EOMs, an objective, quantitative marker of inflammation in TED-affected muscles could be derived. T2-relaxation times mirrored improvements in CAS after treatment, occasionally preceding them. Rarely, they diverged, suggesting limitations in the CAS as a disease burden marker.

Silent sinus syndrome.

Silent sinus syndrome is defined as a spontaneous and progressive enophthalmos and hypoglobus with hypoplasia of the maxillary sinus and resorption of the orbital floor. It is caused by atelectasis of the maxillary sinus in the presence of ipsilateral chronic hypoventilation of the sinus. The problem may be idiopathic, but the term is now also used to describe cases that follow operation or trauma. We describe three cases, each with a different aetiology, and discuss the clinical and radiographic evaluation of the condition, theories regarding its pathophysiology, and surgical correction.

Fornix fat prolapse as a sign for involutional entropion.

OBJECTIVE: To compare horizontal and vertical laxity of lower eyelids in patients with unilateral lower eyelid involutional entropion, introduce a reliable and common finding in involutional entropion, and review the literature. DESIGN: Prospective, comparative observational case series. PARTICIPANTS: Eighty patients with unilateral involutional entropion. METHODS: Horizontal laxity was measured by recording the distance between the globe and the lower eyelid margin when pulled anteriorly with the eye in primary position (digital subtraction test). Vertical laxity was gauged by recording lower lid excursion between extreme up- and downgaze. Forniceal preaponeurotic fat prolapse was assessed by pulling the lower lid margin to the level of the inferior orbital rim and comparing the meniscus of protruding fat in each fornix. Forniceal fat pad height of <2 mm was graded as grade 1, and that of >or=2 mm as grade 2. MAIN OUTCOME MEASURE: Fornix fat prolapse. RESULTS: There were 43 males and 37 females, with a mean age of 77.70 years (range, 57-93 years) (standard deviation, 7.79). There were 47 patients with right-sided and 33 with left-sided entropion. The range of horizontal lid laxity was between 7.5 and 11 mm. The amount of vertical laxity assessed by lower lid excursion between extreme up- and downgaze ranged from 2 to 5 mm. Comparison between the affected and nonaffected sides failed to show a statistical difference in horizontal or vertical laxity (0.19

The tear-drop sign: a trap door for the unwary?

We describe a patient who presented with features suggestive of an orbital blowout fracture. These were apparently confirmed on imaging and operation was planned. However, further radiological and orthoptic opinions diagnosed both a pre-existing eye condition and benign antral mucosal disease that had been misinterpreted as a single acute problem. The patient was discharged with no need for intervention.

Suture midface suspension.

OBJECTIVE: To describe a simple and effective facelift technique useful as an adjunct to other oculoplastic procedures METHODS: Retrospective, non-comparative case series. Thirty five patients undergoing suture midface suspension from 1998 to 2000. Suspension sutures were passed from the nasolabial fold to the temporalis fascia to elevate the midface and the corner of the mouth. RESULTS: A satisfactory and stable outcome is obtained in 2 years of follow up. CONCLUSION: Suture midface suspension is a safe and effective technique for the management of midface descent.