Graves' disease complicated by concurrent thyroid eye disease and pretibial myxedema successfully treated with teprotumumab.

We report a 51-year-old woman with thyroid eye disease and biopsy-proven pretibial myxedema that was subsequently treated with teprotumumab with improvement.

2022 Update on Clinical Management of Graves Disease and Thyroid Eye Disease.

The management of hyperthyroidism and extrathyroidal manifestations of Graves disease remains complex. Considerations that include patient preference, age, comorbidity, pregnancy, tobacco smoking, and social determinants of health must all be weaved into a cohesive management plan. A multidisciplinary team is required to manage all aspects of Graves disease, particularly thyroid eye disease, for which new therapeutic options are now available.

Novel treatment of recurrent orbital venolymphatic malformation with sirolimus and rivaroxaban.

Orbital venolymphatic malformations are rare vascular malformations that typically appear early in life and harbor acute and chronic threats to vision. Historically, there are four categories of management: observation, medication, sclerotherapy, and surgery. Currently, there is neither a gold standard for treatment nor randomized control trials comparing treatments.The authors present a 20-year-old male who presented with spontaneous hemorrhage of an orbital venolymphatic malformation occurring with increased frequency and involving more of the posterior orbit. Surgery and sclerotherapy were not feasible options due to the extensive intraorbital and intracranial involvement of the venolymphatic malformation. Systemic steroids treated symptoms but was not curative. To this end, a combination of sirolimus, an mTOR inhibitor, and rivaroxaban, a factor Xa inhibitor, were used to reduce the size of the lesion and minimize the risk of thromboembolic events. This treatment has successfully kept the patient's symptoms in remission for greater than 2 years.

Posttraumatic Encapsulated Orbital Lipoma.

A 43-year-old white male sought treatment for swelling of the left brow, which started after sustaining direct blunt trauma to the left bony orbit 6 months prior. Magnetic resonance imaging with contrast showed a 5.6 × 2.7 mm T1 bright focus at the anterior aspect of the left supraorbital rim. On the postgadolinium fat-saturated axial T1 images, the lesion demonstrated fat signal but was not suppressed in T1 with fat suppression. Upon excision, the lesion was found to be an encapsulated orbital rim lipoma, which was unexpected given the hyperintensity on T1 with fat suppressed magnetic resonance imaging. The lesion did not return after excision. Orbital lipomas are rare benign neoplasms with only a handful of cases in literature. This is the first report of a posttraumatic encapsulated lipoma presenting on the brow or orbit. Although rare, lipomas should be on the differential of post-traumatic lesions affecting the orbit and the orbital rim.

Comparison of Revision Rates of Anterior- and Posterior-Approach Ptosis Surgery: A Retrospective Review of 1519 Cases.

PURPOSE: To compare revision rates for ptosis surgery between posterior-approach and anterior-approach ptosis repair techniques. METHODS: This is the retrospective, consecutive cohort study. All patients undergoing ptosis surgery at a high-volume oculofacial plastic surgery practice over a 4-year period. A retrospective chart review was conducted of all patients undergoing posterior-approach and anterior-approach ptosis surgery for all etiologies of ptosis between 2011 and 2014. Etiology of ptosis, concurrent oculofacial surgeries, revision, and complications were analyzed. The main outcome measure is the ptosis revision rate. RESULTS: A total of 1519 patients were included in this study. The mean age was 63 ± 15.4 years. A total of 1056 (70%) of patients were female, 1451 (95%) had involutional ptosis, and 1129 (74.3%) had concurrent upper blepharoplasty. Five hundred thirteen (33.8%) underwent posterior-approach ptosis repair, and 1006 (66.2%) underwent anterior-approach ptosis repair. The degree of ptosis was greater in the anterior-approach ptosis repair group. The overall revision rate for all patients was 8.7%. Of the posterior group, 6.8% required ptosis revision; of the anterior group, 9.5% required revision surgery. The main reason for ptosis revision surgery was undercorrection of one or both eyelids. Concurrent brow lifting was associated with a decreased, but not statistically significant, rate of revision surgery. Patients who underwent unilateral ptosis surgery had a 5.1% rate of Hering's phenomenon requiring ptosis repair in the contralateral eyelid. Multivariable logistic regression for predictive factors show that, when adjusted for gender and concurrent blepharoplasty, the revision rate in anterior-approach ptosis surgery is higher than posterior-approach ptosis surgery (odds ratio = 2.08; p = 0.002). CONCLUSIONS: The overall revision rate in patients undergoing ptosis repair via posterior-approach or anterior-approach techniques is 8.7%. There is a statistically higher rate of revision with anterior-approach ptosis repair.

Volumization of the Brow at the Time of Blepharoplasty: Treating the Eyebrow Fat Pad as an Independent Unit.

PURPOSE: Loss of volume in the sub-brow fat pad with associated descent of the eyebrow is a common anatomical finding resulting in both functional and aesthetic consequences. A variety of techniques have been described to address brow position at the time of blepharoplasty. To our knowledge, none of these techniques treat the sub-brow fat pad as an isolated unit. Doing so enables the surgeon to stabilize and volumize the brow without resultant tension on the blepharoplasty wound. The authors describe a technique for addressing volume loss in the eyebrow with associated brow descent that treats the sub-brow fat pad as an isolated unit. METHODS: A retrospective review of all patients undergoing brow ptosis repair by a single surgeon (J.W.S.) over an 11-month period was performed. RESULTS: Eighteen patients and 33 brows underwent the technique described. Patients were followed for an average of 11 weeks (range: 4 weeks to 20 weeks). All patients preoperatively displayed both visually significant dermatochalasis and brow descent below the orbital rim. Evaluation of pre- and postoperative photos demonstrates successful volumization of the brow with skin redraping without focal dimpling or undue tension on the eyelid wound. CONCLUSIONS: Performing a dissection that allows the sub-brow fat pad to be elevated in isolation from the overlying orbicularis and underlying periosteum allows for volumization and of the brow without compromising closure. This technique is a safe and effective means of volumizing the brow and treating secondary brow descent.

Neuropathic Pain Following Poly-L-Lactic Acid (Sculptra) Injection.

Injectable fillers have become a prevalent means of facial rejuvenation and volume expansion. While typically well tolerated, serious complications have been reported. The authors present a case in which an otherwise healthy female with a history of multiple filler injections including poly-L-lactic acid, developed 3 weeks of neuropathic pain in the left temporal fossa following injection. To the best of the authors knowledge, neuropathic pain has not been reported as a complication following poly-L-lactic acid injection. The patient was treated with an injection of steroid and long-acting anesthetic with resolution of symptoms.

Histopathologic Characterization of the Expression of Vascular Endothelial Growth Factor in a Case of Retinopathy of Prematurity Treated With Ranibizumab.

PURPOSE: To characterize the expression of vascular endothelial growth factor (VEGF) in a patient with retinopathy of prematurity (ROP) treated with ranibizumab (Case 1) and compare it with a case of ROP without treatment (Case 2), a case of a premature baby without ROP (Case 3), and a case of a baby without history of ROP or prematurity (Case 4). DESIGN: Observational case series. METHODS: The eyes of the deceased babies were removed postmortem and were sent to the Florida Lions Ocular Pathology Laboratory, where they were processed. The specimens were immunostained using an antibody against VEGF. RESULTS: All eyes except for the eyes in Case 4 disclosed positive VEGF staining. Positive staining was present within the nerve fiber layer, inner plexiform layer, and inner and outer nuclear layers and within the spindle-shaped cell population in the vanguard in Case 1. In the posterior pole, positive staining was only observed at the level of the nerve fiber layer. This case also demonstrated less positive staining when compared with Case 2, where positive staining was found within all layers of the retina. CONCLUSION: Less VEGF staining was observed within the retina of the eyes treated with ranibizumab when compared with the VEGF staining in Case 2. This supports the idea that anti-VEGF agents are effective in reducing the amount of VEGF present in the retina. Furthermore, the fact that some expression of VEGF remains in the immature retina after injection supports the idea that anti-VEGF agents can suppress uncontrolled neovascularization without completely blocking the vascular drive for the vascularization of the immature retina.

Wingtip Flap for Reconstruction of Full-Thickness Upper and Lower Eyelid Defects.

PURPOSE: Pentagonal wedge resection is a technique used to address a wide variety of eyelid pathology. This procedure frequently results in excess skin at the apex of the wound, commonly known as a "dog ear." A variety of methods have been described to address the cutaneous redundancy, the most classic of which is the Burow's triangle repair. The authors present a technique to address the anterior lamellar excess that avoids placement of a vertical scar traversing the pretarsal and preseptal portion of the affected eyelid. The repair moves the preseptal closure of the wound temporally, away from the moving portion of the eyelid. The horizontal incision that transposes the vertical closure temporally is concealed in the eyelid crease. METHODS: A retrospective review of all patients undergoing this technique for eyelid reconstruction was undertaken. The surgical technique is described in detail. RESULTS: The procedure has been performed on 7 patients (8 eyelids). Patients were followed for an average of 12 weeks. Indications for surgery were floppy eyelid syndrome requiring horizontal shortening of the upper eyelid and neoplastic lesions involving the upper or lower eyelid. There were no complications. All patients had a satisfactory outcome with regard to function and cosmesis. CONCLUSIONS: Full-thickness excision of the central two-thirds of the lower and upper eyelid is used extensively to manage a wide variety of conditions. The authors present a technique for addressing the anterior lamellar closure with notable advantages over previously described methods. The major advantages of this technique are that it results in a vertical closure that is horizontally displaced from the primary action of the levator aponeurosis and avoids anterior and midlamellar scarring of the upper and lower eyelid that may inhibit vertical movement. In addition, the cutaneous scar is more easily concealed.

Hedgehog Pathway Inhibition for Locally Advanced Periocular Basal Cell Carcinoma and Basal Cell Nevus Syndrome.

PURPOSE: To review our experience treating patients with the Hedgehog pathway inhibitor, vismodegib, in patients with orbital or periocular locally advanced or metastatic basal cell carcinoma (BCC) or basal cell nevus syndrome. DESIGN: Retrospective interventional case series. METHODS: We reviewed all patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome treated with the Hedgehog pathway inhibitor, vismodegib, at a comprehensive cancer center from 2009 through 2015. Reviewed data included age; sex; American Joint Commission on Cancer tumor, node, metastasis staging system designation; type and grade of drug-related side effects; response to treatment; duration of follow-up, and status at last follow-up. RESULTS: The study included 10 white men and 2 white women; the median age was 64.5 years. Ten patients had locally advanced BCC; 2 had basal cell nevus syndrome. Among the patients with locally advanced BCC, 5 had T3bN0M0 disease at presentation; 1 each had T3aN0M0, T3bN1M0, T2N1M1, T4N1M1, and T4N2cM1 disease. Overall, 3 patients had a complete response, 6 had a partial response, and 3 had stable disease at last follow-up. Two patients developed progressive disease after a complete response for 38 months and stable disease for 16 months, respectively. All patients developed grade I drug-related adverse effects, most commonly muscle spasms (12 patients), weight loss (10), dysgeusia (9), alopecia (9), decreased appetite (5), and fatigue (4). Five patients developed grade II adverse effects. At last follow-up, none of the 5 patients presenting with T3bN0M0, nor the patient with T3bN1M0 disease, had required orbital exenteration. CONCLUSION: Hedgehog pathway inhibition produces a significant clinical response in most patients with locally advanced or metastatic orbital or periocular BCC or basal cell nevus syndrome and can obviate orbital exenteration in some patients. Drug-related adverse effects are manageable in most patients.

The transeyelid midface lift.

The transeyelid approach to midface lift is an elegant approach for mild descent of malar soft tissue. The subciliary approach is the most commonly used and technically less challenging for surgeons experienced in facelift techniques. This technique in midface rejuvenation also has the advantage of ease of combining with other periocular and mid and upper face rejuvenation, such as blepharoplasty and forehead lift. Complication is rare with lid malposition, scaring, and temporary nerve function impairment being the most common.

Activation of AMP-activated protein kinase prevents lipotoxicity in retinal pericytes.

PURPOSE: The recent FIELD study demonstrated that the lipid-lowering agent fenofibrate significantly reduces the development and progression of diabetic retinopathy (DR). These results suggest that lipids may play a causal role in DR. They also suggest that AMP-activated protein kinase (AMPK) activation could account for these findings given that fenofibrate is an AMPK activator. The authors previously demonstrated that free fatty acids, in addition to hyperglycemia, can induce apoptosis in retinal pericytes (PCs), the first cells lost in the diabetic retina. Incubation with the saturated fatty acid palmitate, but not the monounsaturated fatty acid oleate, elicited cytotoxicity in a manner dependent on oxidative stress, NF-κB activation, and ceramide accumulation. In this study, the authors explored whether AMPK can downregulate these pathways and, in doing so, protect PCs from apoptosis. METHODS: PCs were incubated with palmitate or oleate to determine whether the factors previously linked to lipotoxicity were uniquely increased by palmitate. The effects of AMPK activation on these parameters and on apoptosis were concurrently examined. RESULTS: Only palmitate increased NF-κB activation, ceramide and diacylglycerol mass, and apoptosis. Activation of AMPK with AICAR or, where used, expression of a constitutively active AMPK prevented all these effects. In contrast, both palmitate and oleate markedly increased oxidative stress, and the activation of AMPK did not prevent this. CONCLUSIONS: AMPK activation prevents the metabolic abnormalities and apoptosis specifically caused by palmitate in cultured PCs. Pharmacologic agents that activate AMPK in the diabetic retina may warrant consideration as a therapeutic option to avert PC apoptosis and to maintain microvascular homeostasis.

Role of c-Cbl-dependent regulation of phospholipase Cgamma1 activation in experimental choroidal neovascularization.

PURPOSE: Activation of phospholipase Cγ1 (PLCγ1) by vascular endothelial growth factor receptor (VEGFR)-2 is necessary for proliferation and tube formation of endothelial cells in vitro. Previous work has demonstrated that Casitas B-lineage lymphoma (c-Cbl) promotes ubiquitination of PLCγ1 and suppression of its tyrosine phosphorylation. This study was designed to evaluate the importance of PLCγ1 and c-Cbl in experimental choroidal neovascularization (CNV). METHODS: The role of PLCγ1 was studied in three models of angiogenesis: the endothelial cell culture system, the chorioallantoic membrane (CAM) assay, and the laser-induced CNV model. Endothelial cells were analyzed for the role of PLCγ1 in promoting tube formation. CAMs were incubated with pharmacologic agents that either inhibit or stimulate PLCγ1. CNV was induced in wild-type and c-Cbl-knockout mice, and the progression of CNV was evaluated by fluorescein angiography. RESULTS: Activation of PLCγ1 was necessary for tube formation of endothelial cells. PLCγ1 stimulation increased the growth of blood vessels and conversely, PLCγ1 inhibition decreased the growth of blood vessels in the CAM model. CNV lesions in the c-Cbl-knockout mice were significantly greater in number, more confluent, and increased in size with time, compared with those in the control wild-type mice. CONCLUSIONS: The data show that PLCγ1 plays an important role in angiogenesis. Loss of c-Cbl results in enhanced CNV in the eye. The study also shows that c-Cbl plays an important role in ocular angiogenesis, suggesting that modulation of c-Cbl activity or inhibition of PLCγ1 would be a compelling target for antiangiogenesis therapy.

Differential regulation of angiotensin II-induced expression of connective tissue growth factor by protein kinase C isoforms in the myocardium.

Protein kinase C (PKC) and angiotensin II (AngII) can regulate cardiac function in pathological conditions such as in diabetes or ischemic heart disease. We have reported that expression of connective tissue growth factor (CTGF) is increased in the myocardium of diabetic mice. Now we showed that the increase in CTGF expression in cardiac tissues of streptozotocin-induced diabetic rats was reversed by captopril and islet cell transplantation. Infusion of AngII in rats increased CTGF mRNA expression by 15-fold, which was completely inhibited by co-infusion with AT1 receptor antagonist, candesartan. Similarly, incubation of cultured cardiomyocytes with AngII increased CTGF mRNA expression by 2-fold, which was blocked by candesartan and a general PKC inhibitor, GF109203X. The role of PKC isoform-dependent action was further studied using adenoviral vector-mediated gene transfer of dominant negative (dn) PKC or wild type PKC isoforms. Expression of dnPKCalpha, -epsilon, and -zeta isoforms suppressed AngII-induced CTGF expression in cardiomyocytes. In contrast, expression of dominant negative PKCdelta significantly increased AngII-induced CTGF expression, whereas expression of wild type PKCdelta inhibited this induction. This inhibitory effect was further confirmed in the myocardium of transgenic mice with cardiomyocyte-specific overexpression of PKCdelta (deltaTg mice). Thus, AngII can regulate CTGF expression in cardiomyocytes through a PKC activation-mediated pathway in an isoform-selective manner both in physiological and diabetic states and may contribute to the development of cardiac fibrosis in diabetic cardiomyopathy.

Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic States: a possible explanation for impaired collateral formation in cardiac tissue.

BACKGROUND: Inadequate angiogenic response to ischemia in the myocardium of diabetic patients could result in poor collateral formation. Yet, excessive neovascularization in the retina causes proliferative diabetic retinopathy. Since vascular endothelial growth factor (VEGF) is the major angiogenic factor expressed in response to hypoxia, we have characterized expression of VEGF and its receptors in retina, renal glomeruli, aorta, and myocardium in insulin-resistant and diabetic states. Methods and Results- The expression of mRNA and protein for VEGF and its receptors, VEGF-R1 and VEGF-R2, in the myocardium was decreased significantly by 40% to 70% in both diabetic and insulin-resistant nondiabetic rats. Twofold reductions in VEGF and VEGF-R2 were observed in ventricles from diabetic patients compared with nondiabetic donors. In contrast, expression of VEGF and its receptors were increased 2-fold in retina and glomeruli from diabetic or insulin-resistant rats. Insulin treatment of diabetic rats normalized changes in both cardiac and microvascular tissues. Insulin increased VEGF mRNA expression in cultured rat neonatal cardiac myocytes. CONCLUSIONS: The results documented for the first time that differential regulation of VEGF and its receptors exist between microvascular and cardiac tissues, which can be regulated by insulin. These results provide a potential explanation for concomitant capillary leakage and neovascularization in the retina and inadequate collateral formation in the myocardium of insulin-resistant and diabetic patients.