Steven M. Couch

Teprotumumab for thyroid-associated ophthalmopathy

BACKGROUND Thyroid‐associated ophthalmopathy, a condition commonly associated with Graves’ disease, remains inadequately treated. Current medical therapies, which primarily consist of glucocorticoids, have limited efficacy and present safety concerns. Inhibition of the insulin‐like growth factor I receptor (IGF‐IR) is a new therapeutic strategy to attenuate the underlying autoimmune pathogenesis of ophthalmopathy. METHODS We conducted a multicenter, double‐masked, randomized, placebo‐controlled trial to determine the efficacy and safety of teprotumumab, a human monoclonal antibody inhibitor of IGF‐IR, in patients with active, moderate‐to‐severe ophthalmopathy. A total of 88 patients were randomly assigned to receive placebo or active drug administered intravenously once every 3 weeks for a total of eight infusions. The primary end point was the response in the study eye. This response was defined as a reduction of 2 points or more in the Clinical Activity Score (scores range from 0 to 7, with a score of ≥3 indicating active thyroid‐associated ophthalmopathy) and a reduction of 2 mm or more in proptosis at week 24. Secondary end points, measured as continuous variables, included proptosis, the Clinical Activity Score, and results on the Graves’ ophthalmopathy–specific quality‐of‐life questionnaire. Adverse events were assessed. RESULTS In the intention‐to‐treat population, 29 of 42 patients who received teprotumumab (69%), as compared with 9 of 45 patients who received placebo (20%), had a response at week 24 (P<0.001). Therapeutic effects were rapid; at week 6, a total of 18 of 42 patients in the teprotumumab group (43%) and 2 of 45 patients in the placebo group (4%) had a response (P<0.001). Differences between the groups increased at subsequent time points. The only drug‐related adverse event was hyperglycemia in patients with diabetes; this event was controlled by adjusting medication for diabetes. CONCLUSIONS In patients with active ophthalmopathy, teprotumumab was more effective than placebo in reducing proptosis and the Clinical Activity Score. (Funded by River Vision Development and others; ClinicalTrials.gov number, NCT01868997.)

IgG4-associated orbital and ocular inflammation

BackgroundIgG4-associated orbital and ocular inflammation is a relatively unknown entity characterized by sclerosing inflammation with infiltration of IgG4-positive plasma cells. Some so-called idiopathic inflammation syndromes are being re-classified as IgG4-associated inflammation with histopathologic evaluation.FindingsWe report three cases with differing manifestations of IgG4-associated ocular and orbital inflammation: a case of recurrent, treatment-refractory sclero-uveitis that was diagnosed as granulomatosis with polyangiitis with an IgG4-related component, a case of pachymeningitis with optic neuritis that resulted in permanent visual loss, and a case of orbital inflammatory pseudotumor. All three would have been incompletely diagnosed without thorough histopathologic evaluation (including immunohistochemistry).ConclusionsIgG4-associated disease is an idiopathic, multi-organ inflammatory state that can manifest as chronic, relapsing, sclerosing inflammation in virtually any organ system. There is a wide range of presentations in ocular and orbital inflammation. Ophthalmologists should keep IgG4-associated inflammation in mind when examining chronic, sclerofibrosing inflammation with multi-system involvement. The histology of biopsy specimens is crucial in making the correct diagnosis. Timely assessment may lead to fewer diagnostic tests and more targeted therapy.

Subjective and objective outcome measures in the treatment of facial nerve synkinesis with onabotulinumtoxinA (Botox).

Purpose: To evaluate the Sunnybrook Facial Grading System (SFGS) and Facial Clinimetric Evaluation Scale (FaCE Scale) instrument outcome measures pre- and 30-day posttreatment of facial nerve synkinesis with botulinum toxin with attempts to correlate the 2 scales. Methods: An IRB approved retrospective review of 22 patients with facial nerve synkinesis where the surgeon completed the SFGS and the patient completed the FaCE prior to receiving onabotulinumtoxinA therapy, the SFGS, and FaCE scales were completed again 1 month later. Results: Of the 22 patients, 9 complete datasets were analyzed. Mean patient age was 59.8; 8 (89%) women and 1 (11%) men. Overall SFGS composite score decreased from 57.6 ± 20.9 to 45.2 ± 13.5, (p = 0.001). SFGS subdomain synkinesis significantly improved (p < 0.001), while voluntary movement significantly decreased (p = 0.002). A difference in the resting symmetry was not statistically significant (p = 0.08). The FaCE scale composite score significantly improved from 40.9 ± 9.5 to 47.6 ± 11.9, (p = 0.03). FaCE subdomains facial comfort (p = 0.005) and social function (p = 0.009) significantly improved, while oral function, eye comfort, facial movement, and lacrimal control did not. The &Dgr; pre/post-SFGS composite score did not correlate with the &Dgr; pre/post-FaCE composite score (rs= −0.318). Subdomain analysis demonstrated significant negative correlation between &Dgr; pre/post-SFGS synkinesis score and &Dgr; pre/post-FaCE eye comfort score (rs = −0.826, p < 0.01). Conclusions: Significant improvement was seen in objectively reported synkinesis following botulinum toxin therapy. An improvement was noted in the overall subjective facial nerve functioning following therapy along with improvement in social functioning and facial comfort. A meaningful negative correlation was noted when comparing the SFGS “synkinesis” subdomain with the FaCE scale subdomain “eye comfort”, implying improvement in eye comfort with control of synkinesis.

Topical 5-fluorouracil for the treatment of periocular actinic keratosis and low-grade squamous malignancy.

Purpose: To evaluate the efficacy and safety of topical 5% fluorouracil (5-FU) cream in the treatment of periocular actinic keratosis and squamous cell carcinoma in situ. Methods: A retrospective case series including 14 patients treated with topical 5-FU cream, 13 patients with actinic keratosis and 1 patient with squamous cell carcinoma in situ. All patients were treated with an initial 2-week course of twice-daily 5-FU application followed by mild ophthalmic antibiotic ointment applied until the epithelium healed. Additional 14-day courses of therapy were prescribed as clinically indicated if residual lesion was present or recurrence occurred. Charts were reviewed for location of lesion, marginal involvement, residual lesion at follow up, recurrence, and ocular adverse events. Results: Six patients had upper eyelid lesions and 8 patients’ lesions involved the lower eyelid. Marginal involvement was seen in 9 patients. All patients completed an initial 14-day course of twice-daily therapy. Five patients with actinic keratosis required a second 14-day course of therapy, 3 for residual lesion and 2 for recurrence at follow-up visits. The patient with squamous cell carcinoma in situ was treated with 3 courses. Average follow up was 38 months with a range of 4 to 142 months. No clinically detectable lesion was seen in any patient at final follow up. Two patients experienced transient ocular adverse effects, including 1 patient with mild keratopathy and another with chemosis. Conclusions: The use of 5% 5-FU has been described in the treatment of noninvasive squamous neoplasia. This article describes the authors experience with lesions involving the eyelid, including the eyelid margin. Expected dermatologic inflammation occurred following treatment regimens, and mild transient ocular adverse effects were seen in 2 patients. Topical 5-FU may be useful in the treatment of periocular actinic keratoses and squamous cell carcinoma in situ.

Reply Re: "Comparison of preferences between onabotulinumtoxinA (Botox) and incobotulinumtoxinA (Xeomin) in the treatment of benign essential blepharospasm".

To the Editor: We thank Drs. Giacometti and Yen for their response demonstrating the proper method for fully reconstituting incobotulinumtoxinA. Merz, manufacturer of commercially available incobotulinumtoxinA, recommends reconstitution via gently mixing with saline, rotating and inverting the vial 2 to 4 times to ensure all the lyophilized powder is off the rubber stopper. We agree that failure to properly reconstitute incobotulinumtoxinA may result in a more weakly concentrated solution than desired. Although not explicitly listed in our methodology, the inversion method has always been used to reconstitute incobotulinumtoxinA at Ophthalmic Plastic and Cosmetic Surgery, Inc. Therefore, it is unlikely that improper reconstitution would account for our findings. We would like to highlight again that the standardization of the biologic activity and true “equivalent” dosing paradigms of new biologics is difficult and therefore could account for our study findings. We look forward to further studies comparing effectiveness of incobotulinumtoxinA toxin and onabotulinumtoxinA.

Divided Eyelid Nevus: A Lid-Sparing, Staged Surgical Approach

PURPOSE To describe a method for staged partial resection of congenital divided eyelid nevus. The rationale, technique, and outcomes for this approach are described. DESIGN Retrospective chart review of a case series. METHODS Clinical records of 12 patients with divided eyelid nevus were reviewed with attention to presenting features, surgical management, histopathology, and follow-up course. Surgical approach involved the use of bipolar and thermal cautery to ablate the eyelid margin component, skin excision for cutaneous lesions, and then repair with advancement flaps or skin grafting. RESULTS Eight patients with divided nevus were treated with a staged surgical approach: 5 primarily and 3 as revision cases. Average age was 16.3 years at primary presentation (range, 2-36 years), 16.5 years at initial surgery (range 2-36 years), and 36.0 years at presentation for revision (range, 12-72 years). Primary patients required 1 (n = 3) or 2 (n = 2) surgeries. Revision patients required 2 (n = 1) or 3 (n = 2) procedures in addition to those they had already undergone. Anterior lamellar repair was by granulation (n = 2), local skin flaps (n = 3), or skin grafts (n = 3). Average follow-up was 21.6 months (range, 0-98 months). No adverse effects or malignant transformations were seen. CONCLUSIONS Patients with divided eyelid nevi often present for surgical management because of cosmetic and functional concerns. Because small-to-medium congenital nevi have a low risk of malignant transformation, total excision may not be necessary. A staged surgical approach with cautery ablation and contouring of the eyelid margin component and surgical resection of the anterior lamellar portion may be a reasonable treatment strategy for these patients.

Expression of Vascular Endothelial Growth Factor Receptors in Benign Vascular Lesions of the Orbit: A Case Series

PURPOSE Vascular lesions of the orbit, although not malignant, can cause morbidity because of their location near critical structures in the orbit. For the same reason, they can be challenging to remove surgically. Anti-vascular endothelial growth factor (VEGF) drugs are increasingly being used to treat diseases with prominent angiogenesis. Our study aimed to determine to what extent VEGF receptors and their subtypes are expressed on selected vascular lesions of the orbit. DESIGN Retrospective case series of all orbital vascular lesions removed by one of the authors (JAG) at the Mayo Clinic. PARTICIPANTS A total of 52 patients who underwent removal of vascular orbital lesions. METHODS The pathology specimens from the patients were retrieved, their pathologic diagnosis was confirmed, demographic and clinical information were gathered, and sections from vascular tumors were stained with vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor type 1 (VEGFR1), vascular endothelial growth factor receptor type 2 (VEGFR2), and vascular endothelial growth factor receptor type 3 (VEGFR3). MAIN OUTCOME MEASURES The existence and pattern of staining with VEGF and its subtypes on these lesions. RESULTS There were 28 specimens of venous malformations, 4 capillary hemangiomas, 7 lymphatic malformations, and 6 lymphaticovenous malformations. All samples stained with VEGF, 55% stained with VEGFR1, 98% stained with VEGFR2, and 96% stained with VEGFR3. Most (94%) of the VEGFR2 staining was diffuse. CONCLUSIONS Most orbital vascular lesions express VEGF receptors, which may suggest a future target for nonsurgical treatment.

Subjective and Objective Measures in the Treatment of Hemifacial Spasm With OnabotulinumtoxinA.

Purpose: To evaluate the Sunnybrook Facial Grading System (SFGS) and Facial Clinimetric Evaluation (FaCE) Scale Instrument outcomes when treating hemifacial spasm (HFS) with onabotulinumtoxinA. Methods: An Institutional Review Board–approved retrospective review of records of 66 HFS patients treated with onabotulinumtoxinA. SFGS and FaCE surveys were completed prior to onabotulinumtoxinA therapy and at 1 month follow up. Surveys were analyzed for differences using paired Student t tests, with statistical significance set at p < 0.05. Correlations were determined using Spearman correlation (rs), with coefficients of ≥0.40 or ⩽−0.40 considered significant. Results: There were 22 complete data sets. SFGS composite score improved from mean, 56.9 (SD, 12.3) to 63.6 (SD, 12.3), p < 0.01. SFGS subdomain synkinesis score significantly improved (p < 0.01). The FaCE scale subdomain oral function significantly worsened (p = 0.05). The &Dgr; pre-/post-SFGS composite score did not correlate with the &Dgr; pre-/post-FaCE composite score (rs = 0.24). There was a significant positive correlation between SFGS composite score and FaCE social function score (rs = 0.462, p = 0.03) and between SFGS voluntary movement score and FaCE social function score (rs = 0.477, p = 0.03). Subgroup analysis of single FaCE questions demonstrated no statistical change in subjective dry eye (p = 0.30). Conclusions: There was an improvement in social functioning in treated HFS patients, which positively correlated with improvement in overall objective voluntary facial movement. There was no statistical difference in subjective dry eye symptoms. The overall SFGS composite score improved following treatment of HFS with botulinum toxin. This information can be used when counseling expected outcomes in HFS patients treated with onabotulinumtoxinA.

Carotid cavernous sinus fistulas without superior ophthalmic vein enlargement.

Purpose: Diagnosis of carotid cavernous fistula (CCF) relies on clinical findings, such as proptosis, chemosis, and pulsatile tinnitus, plus imaging features including enlargement of the superior ophthalmic vein (SOV). This study reviewed patients with CCF, with a focus on those who were clinically symptomatic but had a normal-appearing SOV on routine scans. Methods: Retrospective review was conducted on the clinical records of patients with CCF seen by ophthalmology or interventional neuroradiology, with attention to clinical and imaging features, angiography findings, management, and outcomes. Results: Forty patients presented with CCF. History of head trauma was present in 13 (average age 43.8 years; all direct or complex), while the remainder occurred spontaneously (average 66 years; 85% indirect). The most common presenting ophthalmologic signs or symptoms were proptosis (65%), binocular diplopia (60%), redness (57.5%), and chemosis (47.5%). After diagnosis, 36 underwent endovascular treatment, with successful occlusion achieved in 90% of cases for whom follow-up data was available (n = 21). Notably, 3 patients with CCF did not have SOV enlargement on any imaging modality including catheter angiography. Conclusions: In this series of patients with clinical signs of CCF, there was no radiologic evidence of enlarged SOV in 26% of patients on noninvasive imaging and in 8% on catheter angiography. To avoid inappropriate interventions or delays in diagnosis and care, it is important to recognize that CCF can exist without SOV enlargement. Patients with clinical features suspicious for CCF should undergo catheter angiography if treatment is being considered. Endovascular treatment can produce clinical improvement or resolution.

Comparison of primary and secondary enucleation for uveal melanoma

ABSTRACT We investigated operative course and post-operative findings of patients undergoing primary enucleation for uveal melanoma versus those requiring secondary enucleation after brachytherapy. A retrospective chart review was performed with IRB approval on patients receiving treatment for uveal melanoma. Patients with enucleation as initial treatment and patients enucleated after plaque brachytherapy were analyzed for demographic data, operative course, and post-enucleation outcome. Further cause analysis for secondary enucleations was investigated. No significant difference was seen in age, laterality, or gender between the primarily enucleated (n = 54) and secondarily enucleated (n = 34) groups. Greater difficulty with surgery was noted in 28/32 (87.5%) of secondary enucleations compared to 1/54 (1.8%) of primary enucleations (p < 0.0001). Operative time was >2 hours in 3/51 (6%) of primary enucleations (vs. 8 of 32, 25%, p = 0.02). Average implant size was similar in the 2 groups (20.6 mm), however 2/34 (6%) of secondary enucleations required dermis fat grafting. Post-enucleation anophthalmic ptosis occurred after 8/49 (16%) of primary cases (vs. 13/30, 43%, p = 0.02) and prosthetic enophthalmos after none (0%) of primary cases (vs. 5/30, 17%, p = 0.006). Class 2 gene expression profile was found in 6/8 (60%) of eyes enucleated for treatment failure. Secondary enucleation performed after plaque brachytherapy was technically more difficult, and had more anophthalmic socket and eyelid complications compared to primary enucleation for uveal melanoma. Primary enucleation may avoid additional surgery and morbidity in a subset of patients with contraindications to plaque brachytherapy.