Konstantinos I. Papageorgiou

Increased Expression of TSH Receptor by Fibrocytes in Thyroid-Associated Ophthalmopathy Leads to Chemokine Production

CONTEXTnThe molecular basis for anatomically dispersed clinical manifestations in Graves disease (GD) eludes our understanding. Bone marrow-derived, pluripotent fibrocytes represent a subset of peripheral blood mononuclear cells and infiltrate the orbital and thyroid tissues in GD. These cells may be involved in the pathogenesis of thyroid-associated ophthalmopathy (TAO).nnnOBJECTIVEnThe objective of the study was to quantify fibrocyte display of functional cell surface TSH receptor (TSHR), identify the profile of chemokines they express after TSHR activation, and determine whether circulating TSHR(+) peripheral blood fibrocytes are more frequent in situ in patients with TAO.nnnDESIGN/SETTING/PARTICIPANTSnUsing a newly developed technique, fibrocytes were directly identified in peripheral blood from 31 patients with TAO and 19 healthy subjects receiving care at a multidisciplinary academic center.nnnMAIN OUTCOME MEASURESnThe frequency in situ of fibrocytes (collagen 1(+), CD45(+), CD34(+), CD14(+), CD86(+) peripheral blood mononuclear cells) was assessed by multiparameter flow cytometry and correlated to clinical disease activity and smoking status. Levels of TSHR-displaying fibrocytes and their response to TSH and TSHR-activating antibody, M22, were measured by flow cytometry, Luminex, and real-time PCR.nnnRESULTSnThe levels of TSHR expression by fibrocytes are substantially higher than those found in orbital fibroblasts. Moreover, the frequency of TSHR(+) fibrocytes in patients with TAO was greater than that in healthy subjects in situ. Their abundance is not influenced by disease activity or smoking history. These cells produce high levels of several cytokines and chemokines including IL-8, regulated upon activation, normal T cell expressed and secreted, and monocyte chemoattractant protein-1 when treated with TSH or M22. TSH induces IL-8 production at the pretranslational level. This induced cytokine can be detected in intact fibrocytes ex vivo.nnnCONCLUSIONSnFrequency of circulating TSHR(+) fibrocytes is markedly increased in patients with TAO, and they express proinflammatory chemokines in response to TSH. Because they infiltrate both orbit and thyroid in GD, they may represent the link between systemic immunoreactivity and organ-specific autoimmunity.

Thyroid-Associated Periorbitopathy: Eyebrow Fat and Soft Tissue Expansion in Patients With Thyroid-Associated Orbitopathy

OBJECTIVEnTo compare soft tissue and fat volumes in the supraorbital area of healthy patients and patients with thyroid-associated orbitopathy (TAO) using 3-dimensional reconstruction software.nnnMETHODSnThe superiolateral orbital area was delineated on a bony framework. Three-dimensional reconstruction and volumetric calculation of the retro-orbicularis oculi fat (brow fat), galeal fat (including the retro-orbicularis oculi fat), and soft-tissue muscle were performed.nnnRESULTSnWe analyzed 100 computed tomographic scans from 48 patients with TAO and 52 control subjects. All patients showed an age-related increase of fat volumes. The mean total eyebrow volume was greater in patients with TAO vs healthy control subjects (Pxa0<xa0.001). Galeal fat (Pxa0=xa0.02) and retro-orbicularis oculi fat (Pxa0=xa0.01) volumes were significantly higher in patients with TAO vs control subjects. Soft-tissue muscle volume decreased with age in healthy females but remained constant in the aging female group with TAO. Both total volume and brow thickness did not appear to change with age in healthy patients but exhibited an increase in the female population with TAO.nnnCONCLUSIONSnThis study brings into focus the clinicopathologic entity of thyroid-associated periorbitopathy. Three-dimensional evaluation of computed tomographic scans can provide information on volumetric changes in the eyebrow profile of patients with TAO. Further investigation of the biologic and morphologic changes of eyebrow fat and soft tissue in patients with TAO may help better characterize, classify, and guide their treatment.

A Three-Dimensional Construct of the Aging Eyebrow: The Illusion of Volume Loss

BACKGROUNDnThe eyebrows and eyebrow fat pads, key structures in upper facial aesthetics, are particularly vulnerable to age-related changes.nnnOBJECTIVESnIn this study, the authors compare the impact of aging on the eyebrows and eyebrow fat pad volume in men and women through three-dimensional (3D) volumetric analysis.nnnMETHODSnElectronic medical records of patients seen at the Jules Stein Eye Institute in the Division of Orbital and Ophthalmic Plastic Surgery between 2005 and 2010 were reviewed. Patients were included if they had undergone investigative imaging of the orbit for unilateral pathology. Computed tomography (CT) scans of patients with Graves disease diagnosis, extensive orbital trauma, and/or previous eyebrow surgery were excluded. A total of 52 CT scans (24 men and 28 women) were retained for analysis. A 3D reconstruction software was used to analyze the scans and calculate volumes of the retroorbicularis oculi fat (ROOF), galeal fat (ROOF and subcutaneous fat), and soft tissue muscles.nnnRESULTSnGaleal and brow fat volumes showed a significant positive trend toward enlargement in women (P values of .01 and .05, respectively). Although men showed a tendency toward fat enlargement with age, this was not statistically significant. Soft tissue-muscle volume decreased significantly in aging women (9.32 mm(3)/y) (P = .02). Data indicated that soft tissue volume in men tended to increase with age (3.92 mm(3)/y) but not significantly (P = .36). Neither total volume nor brow thickness appeared to change significantly in women (P = .56, P = .73). In men, total volume and brow thickness showed weak evidence of increasing with age (P = .12, P = .22). Linear regressions of Hertel measurements with and without sex interaction showed no statistically significant trend between the amount of proptosis and the galeal or brow fat.nnnCONCLUSIONSnAlthough overall eyebrow volume does not change with age, the relative contribution of fat and soft tissue to the total volume does seem to change. This pattern also differs between males and females. As women age, the fat volume increases and the soft tissue volume decreases. In men, the shift from soft tissue volume to fat volume is less pronounced. Although many clinicians have been drawn to the concept of fat volume deflation as a key element of facial aging, this study does not support this perspective in the eyebrow fat pad. An increasingly refined understanding of the dynamics of facial aging is mandatory for clinical diagnosis and will likely provide the framework from which to develop more innovative treatment options.

Histopathology of brow fat in thyroid-associated orbitopathy

Purpose: We propose that brow enlargement seen in patients with thyroid-associated orbitopathy (TAO) occurs secondary to the autoimmune process in Graves disease and that the changes in brow fat are histologically identical to those seen in orbital fat. Methods: With informed consent, brow and orbital fat was obtained from patients with TAO and from patients with no significant past medical history undergoing orbital decompression, blepharoplasty, and/or brow fat removal. Histologic examination was performed on the orbital and brow fat. Results: Fat histologies obtained from patients with TAO and those without known systemic disease were compared. Specimens from patients with TAO showed an increase of fibrosis and fibrous septae. Furthermore, certain biologic markers, including insulin-like growth factor 1 receptor &bgr; (IGF-1R&bgr;) and thyroid-stimulating hormone receptor (TSHR), were increased in the fat obtained from patients with TAO. This was identical in both the brow and the orbital fat. Fat from patients with no significant past medical history showed normal fat histology, absence of fibrous septae, and decreased marker expression. Conclusion: Graves disease is a systemic autoimmune disease that affects patients in a variety of ways. In addition to the orbital changes seen in these patients, we have observed an increase in the brow fat compartment. We are intrigued to find that the histologic changes are identical in both the orbital and the brow fat of patients with TAO. The increased IGF-1R&bgr; and TSHR expression in both the brow and the orbital fat further support their role as putative markers in patients with Graves disease.

Aesthetic considerations in upper eyelid retraction surgery.

Purpose: Classically, the aesthetic outcomes of eyelid retraction surgery in patients with thyroid-associated orbitopathy have been described in reference to eyelid margin position and marginal reflex distance. A critically important component of upper eyelid contour is the tarsal platform show (TPS). With this study, the authors aimed to assess the hypothesis that modification of the tarsal platform in posterior eyelid retraction surgery has a significant effect on the final aesthetic outcome. Methods: In a retrospective, observational, case-cohort study, the authors reviewed the medical records of 36 patients with thyroid-associated orbitopathy who underwent primary eyelid retraction surgery by 1 surgeon. Patients who underwent eyelid retraction surgery at the time of orbital decompression were excluded. The surgical technique consisted of posterior approach conjunctival release of Müeller muscle and graded recession of the levator aponeurosis. To address lateral flare, dissection was carried toward the lateral orbital rim with spreading of the lateral horn of the levator aponeurosis. Outcome measures were millimeters of TPS, millimeters of brow fat span, and symmetry of the eyelid margin position. Randomized preoperative and postoperative standardized photographs were evaluated in masked fashion by 4 surgeons to grade cosmetic outcomes. Results: Fifteen patients (24 eyelids) met the inclusion criteria. Mean follow-up period was 6 months (range, 3–12). Mean TPS increased from 2.27 mm (standard deviation, 1.9 mm) to 4.77 mm (standard deviation, 1.7 mm; p < 0.05). Mean brow fat span remained unchanged, from 13.22 mm (standard deviation, 2.2 mm) to 13.25 mm (standard deviation, 1.9; p > 0.05). Evaluation of the aesthetic outcomes (eyelid contour, eyelid symmetry, and TPS) by 4 masked observers characterized the relevance of TPS in the postoperative aesthetics of eyelid contour and symmetry. Conclusions: In upper eyelid retraction surgery, the ability to control the TPS has a significant impact on the final aesthetic outcome. Posterior approach eyelid retraction surgery can control eyelid contour and can represent an ideal surgical approach in carefully selected patients. However, it has limited ability to control upper orbital volume and eyebrow and orbital fat (brow fat span). This can result in relative overelongation of the TPS. Factors such as ethnic characteristics, bony asymmetry, brow fat span, and premorbid TPS influence cosmetic outcomes achieved by the anterior or posterior approach. For optimal aesthetic results in eyelid retraction surgery, the decision for anterior versus posterior approach should be individualized.

Refining the goals of oculofacial rejuvenation with dynamic ultrasonography.

Volume enhancement/restoration addresses a key component of facial aging and plays an increasingly central role in facial rejuvenation. Advancing our understanding of the structure and morphology of facial aging-and the changes that can be induced with currently-available fillers-will optimize treatment and provide a consensus for appropriate selection of agents and procedures. By elucidating anatomic relationships-particularly dynamic relationships-ultrasonography may facilitate the selection and application of rejuvenation agents and procedures such as lower eyelid blepharoplasty with hyaluronic acid reinforcement of the middle lamella and lateral canthal retinaculum, en glove lysis and dermal fat grafting in the retractor plane for lower eyelid retraction, posterior girdle effect with high-viscosity fillers for malar festoons, dynamic analysis of hyaluronic acid within the levator plane for upper eyelid retraction, and serial distribution and integration of autologous fat injection in the lower lid compartments. In this article, the authors describe use of dynamic high-resolution ultrasonography as a tool in defining and improving the outcomes of periocular facial rejuvenation.

Topical Plasminogen as Adjunctive Treatment in Recurrent Ligneous Conjunctivitis.

Ligneous conjunctivitis is a rare, autosomal recessive, membranous conjunctivitis characterized by a deficiency in type 1 plasminogen. The absence of normal plasmin activity results in the formation of fibrin-rich, membranous material that typically manifests on the palpebral conjunctiva. Surgical treatment often causes irritation of the conjunctiva and accelerated recurrence of pseudomembranes. In this interventional case report, the authors document the results of treatment with topical plasminogen following conjunctival pseudomembrane excision in a 32-year-old woman. The patient underwent pseudomembrane excision in the OS followed immediately by hourly topical application of plasminogen eye drops. The plasminogen was prepared from pooled human plasma purchased under Food and Drug Administration approval from DiaPharma. Follow-up evaluation at 1 week, 1 month, and 5 months showed no evidence of recurrent pseudomembranous change. Adjunctive topical plasminogen application appears to be an effective and safe method of controlling pseudomembrane recurrence in patients with ligneous conjunctivitis.

High-resolution ultrasound as an effective and practical tool to analyze eyebrow profile expansion in thyroid-associated periorbitopathy.

Purpose: Clinical, radiographic, and molecular studies have shown that patients with thyroid-associated orbitopathy exhibit volumetric expansion of eyebrow tissues. This clinicopathologic entity has been termed thyroid-associated periorbitopathy. The goal of this study was to determine whether high-resolution ultrasonography could be used to reliably quantify thyroid-associated periorbitopathy. Methods: Institutional review board approval was obtained. The internal case-control study consisted of 12 subjects with unilateral-asymmetric thyroid-associated orbitopathy. High-resolution ultrasonography using a 15-MHz probe (Logiq p6) was performed by a single operator. Measurements were obtained 0.5 cm cephalad to the superior orbital rim at the midpupillary sagittal level. For each subject and tissue layer thickness (total tissue, dermis fat, retro-orbicularis oculi fat), the measured values on the less affected side were subtracted from those on the more severely diseased side. Summary statistics were used to analyze results. Results: High-resolution ultrasonography effectively demonstrated asymmetric expansion of total eyebrow tissue (p < 0.0001) and retro-orbicularis oculi fat (p = 0.0003). No significant difference in dermis fat thickness was found between the 2 sides (p = 0.2). Hertel exophthalmometry measurements were statistically different between the 2 sides (p = 0.002). Conclusions: This study demonstrates that high-resolution ultrasonography independently confirms previously published studies of retro-orbicularis oculi fat expansion in patients with thyroid-associated orbitopathy. Compared with CT, MRI, and tissue biopsy, high-resolution ultrasonography is a more practical and cost-effective way to quantify and track thyroid-associated periorbitopathy over time. With its potential for real-time tissue assessment, high-resolution ultrasonography may be best suited for future studies of the dynamic relationship between globe and periorbital structures.

Ultrasonographic visualization of lower eyelid structures and dynamic motion analysis.

AIMnTo define the ultrasonographic structure of normal lower eyelid anatomic compartments and their spacial relationship in dynamic motion.nnnMETHODSnHigh resolution ultrasound (15MHz) was performed on the lower eyelids of 7 normal subjects. Movements of the lower eyelid and its compartments were visualized with ultrasound. In addition, the maximal excursion area of the lower eyelid fat compartments and retractor motions was measured before and after motion.nnnRESULTSnThe orbicularis muscle could be seen as an echolucent structure between the dermis and the echodence fat pads. Lower eyelid fat pad seems to be divided into 2 compartments as range of motion and direction of movement of each of them varies. It seems that these compartments have also different behavior. The measured profile area of the visible normal lower eyelid fat pads during movement of globe from up-gaze to down-gaze decreased by 50%. Order of movement of lower eyelid structures seems to be as follows: after globe movement fist we see retractor movement, anterior orbital fat pad, then skin and septum, and finally movement of inferior fat pad.nnnCONCLUSIONnUltrasound represents a noninvasive tool for the visualization of lower eyelid morphology. Expanding its application could help us understand the compartmental changes in physiological eyelid movement, in aging and diseased study populations, as well as assess operative outcomes.

Ultrasonographic motion analysis of lower eyelid compartments in patients with chronic thyroid associated ophthalmopathy

Purpose To present the qualitative and quantitative ultrasonographic findings of lower eyelid compartments in patients with chronic thyroid associated ophthalmopathy (TAO) compared to normal subjects. Methods In a prospective study, dynamic and static ultrasonographic investigation, applying high resolution (15 MHz) ultrasound was performed to assess the lower eyelid, in 15 TAO patients that were in chronic phase and 10 normal subjects. The thickness and echogenisity of dermis, orbicular oculi muscle, lower eyelid retractor muscle, lower eyelid fat pads, and their qualitative relationships during vertical excursion of the globe were evaluated in static and dynamic investigation. Correlation of ultrasonic and clinical findings was evaluated. Results The mean age of the patients was 41.82 ± 7.4 years, and the controls were age-matched (mean age, 42.8 ± 5.6 years). Mean proptosis of the involved eyes was 3.3 mm, and mean lower lid retraction was 2.4 mm in chronic TAO group. Pattern of fat motion was blocky in chronic TAO patients compared to normal jelly motion of the fat in normal cases. In analyzing the range of motion, the difference was significant in the motion of both superficial and deep fat pockets between the two groups (P < 0.001). Limitation of fat motion correlated both with proptosis and lower eyelid retraction (Pearson correlation coefficient = −0.77 vs −0.43, P < 0.001). Fibrotic changes of lower lid fat pads appear in the tissue around the septum on observation. Considering the ultrasound findings, a new staging method is proposed in this study that starts with the appearance of echodense points, getting worse in fine bands, progresses to thick bands and ends in cord formation in the lower lid fat pocket that determines total fibrosis. Conclusion Development of a series of static and dynamic changes in ultrasound is related to the clinical findings in chronic phase of TAO. The limitation of motion and fibrotic changes of lower eyelid fat pads were more detectable in cases with a more severe proptosis and lower lid retraction. It is considered that ultrasound findings can be a representative of the severity of involvement in the chronic phase of the TAO.