Blepharotomy Versus Levator Recession With Adjustable Sutures for Correction of Upper Eyelid Retraction in Thyroid Eye Disease.

PURPOSE: To compare outcome, complications and surgical time of blepharotomy versus levator recession with adjustable sutures (LRWAS) for correction of upper eyelid retraction in thyroid eye disease. METHODS: In the period 2019-2023, we performed a prospective randomized comparative study between blepharotomy and LRWAS. We examined patients, recorded time consumption, and obtained photographs preoperatively, 1 day, 1 week, 3 months, and 6 months after surgery. Outcome was categorized according to Mourits and Sasim`s classification from 1999 (perfect-acceptable-unacceptable). RESULTS: A total of 30 patients (25 women) with a median (range) age of 51.5 (34-74) years at surgery were included. A significant different (p < 0.01) median operation time was found between blepharotomy (41.5 (17-105) minutes) and LRWAS (68 (35-101) minutes). Median time from operation to last examination was 6 (6-18) months. Fifteen patients (24 eyelids) were operated with blepharotomy and 15 patients (25 eyelids) with LRWAS. Preoperative median margin reflex distance 1 was 6.5 (5-8) mm, and at final visit, median margin reflex distance 1 was 3.5 (3-4) mm after blepharotomy and 3.5 (2-5.5) mm after LRWAS. Reoperation was performed in 11 eyelids, 10 due to overcorrection and 1 because of a residual retraction. Significantly more eyelids needed reoperation after LRWAS (n = 9) compared with blepharotomy (n = 2). At final examination, a perfect or acceptable result was found in 14 (93%) patients after both procedures. Significantly shorter total duration of all visits was observed after treatment with blepharotomy (50 (35-70) minutes) compared with LRWAS (65 (40-115) minutes). Wound dehiscence occurred in 1 patient after blepharotomy, and 1 postoperative infection was observed after LRWAS. CONCLUSION: We demonstrate equally high success rates after blepharotomy and LRWAS for correcting upper eyelid retraction in thyroid eye disease, but blepharotomy is less time-consuming and implies fewer reoperations.

Ectropion. / Ektropion.

In ectropion, the eyelid margin - typically the lower eyelid - is turned outward. This condition is becoming increasingly common due to the ageing population. Ectropion is classified as either acquired or congenital, with the former being the most prevalent. Acquired ectropion is further divided into involutional, paralytic, mechanical and cicatricial subtypes. Involutional ectropion is the most common where there is no patient population bias. This clinical review provides an overview of ectropion.

Outcomes of Patients With Graves Disease 25 Years After Initiating Antithyroid Drug Therapy.

CONTEXT: Graves disease (GD) is a leading cause of hyperthyroidism. Detailed investigations and predictors of long-term outcomes are missing. OBJECTIVE: This work aimed to investigate the outcomes in GD 25 years after initiating antithyroid drug treatment, including disease course, clinical and biochemical predictors of relapse, and quality of life. METHODS: A retrospective follow-up was conducted of GD patients that participated in a randomized trial from 1997 to 2001. Demographic and clinical data were obtained from medical records and questionnaires. Biobank samples were analyzed for inflammatory biomarkers and compared with age- and sex-matched healthy individuals. RESULTS: We included 83% (182/218) of the patients from the original study. At the end of follow-up, normal thyroid function was achieved in 34%. The remaining had either active disease (1%), spontaneous hypothyroidism (13%), or had undergone ablative treatment with radioiodine (40%) or thyroidectomy (13%). Age younger than or equal to 40 years, thyroid eye disease (TED), smoking, and elevated levels of interleukin 6 and tumor necrosis factor receptor superfamily member 9 (TNFRS9) increased the risk of relapsing disease (odds ratio 3.22; 2.26; 2.21; 1.99; 2.36). At the end of treatment, CD40 was lower in patients who maintained normal thyroid function (P = .04). At the end of follow-up, 47% had one or more autoimmune diseases, including vitamin B12 deficiency (26%) and rheumatoid arthritis (5%). GD patients who developed hypothyroidism had reduced quality of life. CONCLUSION: Careful lifelong monitoring is indicated to detect recurrence, hypothyroidism, and other autoimmune diseases. Long-term ATD treatment emerges as a beneficial first-line treatment option, especially in patients with young age at onset or presence of TED.

Prevalence, Risk Factors, and Clinical and Biochemical Characteristics of Alemtuzumab-Induced Graves Disease.

OBJECTIVE: Atypical Graves disease (GD) is a common complication in multiple sclerosis (MS) patients treated with alemtuzumab. We present epidemiological, clinical, and biochemical characteristics of alemtuzumab-induced GD. METHODS: Retrospective follow-up study of MS patients treated with alemtuzumab from 2014 to 2020, including clinical course of GD, pregnancy outcome, and thyroid eye disease (TED). RESULTS: We enrolled 183 of 203 patients (90%, 68% women) treated with alemtuzumab at 4 hospitals in Norway. Seventy-five (41%) developed thyroid dysfunction, of whom 58 (77%) had GD. Median time from the first dose of alemtuzumab to GD diagnosis was 25 months (range, 0-64). Twenty-four of 58 GD patients (41%) had alternating phases of hyper- and hypothyroidism. Thyrotropin receptor antibodies became undetectable in 23 of 58 (40%) and they could discontinue antithyroid drug treatment after a median of 22 (range, 2-58) months. Conversely, 26 (44%) had active disease during a median follow-up of 39 months (range, 11-72). Two patients (3%) received definitive treatment with radioiodine, 6 (10%) with thyroidectomy. Nine developed TED (16%), 7 had mild and 2 moderate to severe disease. Four patients completed pregnancy, all without maternal or fetal complications. Patients who developed GD had a lower frequency of new MS relapses and MRI lesions than those without. CONCLUSION: GD is a very common complication of alemtuzumab treatment and is characterized by alternating hyper- and hypothyroidism. Both remission rates and the prevalence of TED were lower than those reported for conventional GD. Pregnancies were uncomplicated and GD was associated with a lower risk of subsequent MS activity.

Molecular Biomarkers in Thyroid Eye Disease: A Literature Review.

PURPOSE: Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves disease. Patients may be severely affected with eyelid retraction, exophthalmos, diplopia, pain, and threatened vision. Autoantibodies against thyroid-stimulating hormone receptor and insulin-like growth factor 1 receptor have shown associations with pathophysiological and clinical traits. Autoantibodies against thyroid-stimulating hormone receptor is in current clinical use as biomarker, but not with unambiguous diagnostic performance. A biomarker with high diagnostic accuracy and/or prognostic capability would be of immense value in diagnosing TED, especially in subclinical cases or when TED precedes the thyroid dysfunction. This article is a literature review on molecular biomarkers of TED. METHODS: A literature search was performed using PubMed and Embase. Studies on molecular biomarkers in blood, tear fluid, and urine were included in the review. RESULTS: Forty-six papers were included, of which 30, 14, and 2 studies on biomarkers in blood, tears, and urine, respectively. Fourteen of the papers evaluated the diagnostic performance of various biomarkers, 12 in blood and 2 in tears. Most studies evaluated single biomarkers, but 3 tested a panel of several markers. Except for autoantibodies against thyroid-stimulating hormone receptor, the reported diagnostic performances for the biomarkers were not confirmed in independent cohorts. In 32 studies, no or insufficient performance data were given, but the findings indicated involvement of various biologic mechanisms in TED including inflammation, oxidative stress, fibrosis, lipid metabolism, and ocular surface microflora. CONCLUSIONS: Currently, serum autoantibodies against thyroid-stimulating hormone receptor is the only molecular biomarker with clinical utility in patients with TED. Several potential biomarkers have been investigated, and particularly panels of multiple biomarkers in tears are promising. To improve patient care, biomarkers in TED should be studied further.

Systemic Activation of the Kynurenine Pathway in Graves Disease With and Without Ophthalmopathy.

CONTEXT: Graves disease (GD) is one of the most common autoimmune disorders. Recent literature has shown an immune response involving several different inflammatory related proteins in these patients. OBJECTIVE: This work aimed to characterize the kynurenine pathway, activated during interferon-γ (IFN-γ)-mediated inflammation and cellular (T-helper type 1 [Th1] type) immunity, in GD patients with and without thyroid eye disease (TED). METHODS: We analyzed 34 biomarkers by mass spectrometry in serum samples from 100 patients with GD (36 with TED) and 100 matched healthy controls. The analytes included 10 metabolites and 3 indices from the kynurenine pathway, 6 microbiota-derived metabolites, 10 B-vitamers, and 5 serum proteins reflecting inflammation and kidney function. RESULTS: GD patients showed significantly elevated levels of 7 biomarkers compared with healthy controls (omega squared [ω2] > 0.06; P < .01). Of these 7, the 6 biomarkers with the strongest effect size were all components of the kynurenine pathway. Factor analysis showed that biomarkers related to cellular immunity and the Th1 responses (3-hydroxykynurenine, kynurenine, and quinolinic acid with the highest loading) were most strongly associated with GD. Further, a factor mainly reflecting acute phase response (C-reactive protein and serum amyloid A) showed weaker association with GD by factor analysis. There were no differences in biomarker levels between GD patients with and without TED. CONCLUSION: This study supports activation of IFN-γ inflammation and Th1 cellular immunity in GD, but also a contribution of acute-phase reactants. Our finding of no difference in systemic activation of the kynurenine pathway in GD patients with and without TED implies that the local Th1 immune response in the orbit is not reflected systemically.

Novel inflammatory biomarkers in thyroid eye disease.

Purpose: The aim of this study is to identify biochemical inflammatory markers predicting the presence or risk of developing thyroid eye disease (TED) in patients with Graves' disease (GD). Methods: Patients with GD (n = 100, 77 females) were included from the National Norwegian Registry of Organ-Specific Diseases. Serum samples were analysed for 92 different inflammatory biomarkers using the proximity extension assay. Biomarker levels were compared between groups of patients with and without TED and healthy subjects (HS) (n = 120). Results: TED was found in 36 of 100 GD patients. Significant (P < 0.05) differences in the levels of 52 inflammatory biomarkers were found when GD patients and HS were compared (42 elevated and 10 decreased). Out of the 42 elevated biomarkers, a significantly higher serum level of interleukin-6 (IL6) (P = 0.022) and macrophage colony-stimulating factor (CSF1) (P = 0.015) were found in patients with TED compared to patients without TED. Patients with severe TED also had significantly elevated levels of Fms-related tyrosine kinase 3 ligand (FLT3LG) (P = 0.009). Furthermore, fibroblast growth factor 21 (FGF21) was significantly increased (P = 0.008) in patients with GD who had no signs of TED at baseline but developed TED later. Conclusion: We demonstrate an immunologic fingerprint of GD, as serum levels of several inflammation-related proteins were elevated, while others were decreased. Distinctly increased levels of IL6, CSF1, FLT3LG, and FGF21 were observed in TED, suggesting that these inflammatory proteins could be important in the pathogenesis, and therefore potential new biomarkers for clinical use.

Hyaluronic acid is superior to autologous fat for treatment of temporal hollowing after lateral orbital wall decompression: A prospective interventional trial.

PURPOSE: To compare injections of hyaluronic acid (HA) and autologous fat (AF) for the treatment of unsightly temporal hollowing after lateral orbital wall decompression in thyroid eye disease. METHODS: In this nonblinded prospective comparative interventional study, patients received injections of HA in the right temple and AF in the left temple. Additional injections were given when needed at follow-up after 6, 12, 18, and 24 months. Follow-up included an interview; clinical examination with an evaluation of symmetry, contour, and skin surface; and ultrasound measurements. From photographs, the temporal hollowing was graded 1-3. The main endpoints were grading of temporal hollowing and temporal soft tissue thickness. RESULTS: Seventeen patients were treated bilaterally and 12 unilaterally (five received HA and seven AF). Injection(s) of HA and AF administered at each site were a median (range) of 1 (1-4) and 2 (1-5), respectively. The total combined volume of HA injected per site was 0.9 (0.2-2.0) ml and that of AF was 3.1 (0.5-9.6) ml. At the final examination, a statistically significant difference in mean (SD) grading scores of temporal hollowing due to HA (1.18 (0.26)) compared to those of AF (1.85 (0.44)) was observed (p < 0.001). Six months after administering an injection of HA, the temporal soft tissue thickness was 2.35 (0.24) cm compared to 2.19 (0.28) cm obtained with an injection of AF (p < 0.001). By using a linear mixed-effect model and adjusting for baseline values, age, sex, and refill, the difference in favor of HA persisted at all later follow-ups. Increased fibrosis of the subcutaneous tissue developed at 5/24 sites that received AF. CONCLUSION: Injection of HA is superior to that of AF for treating temporal hollowing after lateral orbital wall decompression.

Temporal hollowing and other adverse effects after lateral orbital wall decompression.

PURPOSE: To evaluate the outcome and late postoperative complications after lateral orbital wall decompression in a series of patients with thyroid eye disease (TED). METHODS: One hundred and three patients operated in the period 1999-2013 were invited to participate in the study, and 84 were included after a median (range) follow-up time of 124 (13-188) months. The patients were interviewed, and preoperative and postoperative data were collected from hospital records. Photographs ('selfies') were obtained from 64 patients. Wilcoxon signed-rank test was used to evaluate the change in pre- and postoperative data. RESULTS: On average, visual acuity was unchanged with a median value (range) of 1.0 (0.4-1.25) before to 1.0 (0-1.25) after surgery (p = 0.5). Intraocular pressure (IOP) was reduced from a median value (range) of 17 (9-26) to 15 (8-23) mmHg (p < 0.001). Median (range) Hertel values were 23 (15-30) mm preoperatively and 20 (12-26) mm postoperatively (p < 0.001) respectively. Mean (SD) reduction in proptosis was 3.6 (±2.1) mm. Oscillopsia was reported in 24 patients (29%), 42 (50%) experienced a change in temporal sensation, and four (5%) had new-onset diplopia. In 47 patients (56%), some degree of temporal hollowing was reported. Among 64 photographed patients, 38 (59%) had noticeable hollowing on examination of postoperative pictures. There was agreement of the patient's perception of temporal hollowing and the appearance in photographs in 26 of 37 patients (70%). CONCLUSION: Lateral orbital wall decompression has been considered a safe and effective procedure for treatment of TED. Serious side-effects are infrequent, but in rare circumstances, even blindness may occur. Less serious side-effects are relatively common. Among others, a significant number of the patients developed temporal hollowing after the procedure. The patients must be informed about the possible complications before surgery.

Long-term follow-up of patients with thyroid eye disease treated with endoscopic orbital decompression.

PURPOSE: To evaluate the outcome of endoscopic decompression in a series of patients with thyroid eye disease. METHODS: All 46 patients operated at our institution in the period 2001 to 2011 were invited for re-examination. Thirty-seven patients were included in the study and underwent a general otorhinolaryngological and ophthalmological examination. Nasal endoscopy, autoperimetry and a CT scan of the orbits and paranasal sinuses were performed. Preoperative and early postoperative data were obtained from hospital records. Re-examination was performed from 12 months to 9 years postoperatively. Paired t-test was used to evaluate the change in pre- and postoperative data. Image-guided surgery was used in two patients. RESULTS: Visual acuity improved from a median value (range) of 0.8 (0.05-1.25) to 1.0 (0.4-1.25) (p=0.006). Intra-ocular pressure (IOP) was reduced from a median value (range) of 18 mmHg (10-27 mmHg) to 14 mmHg (8-24 mmHg) (p<0.001). Median (range) Hertel values were 22.5 mm (14-29 mm) preoperatively and 19 mm (11-26 mm) postoperatively (p<0.001). Mean reduction in proptosis was 4.0 mm. At follow-up, visual fields were normal in 16/37 patients (43%) and with small defects in 12/37 patients (32%). Seventeen patients (46%) had diplopia preoperatively in one or more directions of gaze while 9 (24%) suffered from constant diplopia. After endoscopic decompression, new onset diplopia was seen in seven (19%) individuals, while worsening of diplopia occurred in eight (22%). Impaired motility in abduction and/or elevation was seen in 20 (54%) individuals before decompression and in 23 (62%) after. Strabismus surgery was performed in 22 patients. On final examination 85% of the study population were totally free of diplopia or experienced diplopia only in the peripheral field of gaze. Three patients developed sinusitis. Of these, endoscopic sinus surgery was performed in two patients, and one patient was conservatively treated. Symptoms resolved in all three patients. CONCLUSION: Endoscopic medial orbital decompression including removal of the medial floor of the orbit is a safe and effective procedure for treatment of thyroid eye disease. Navigation can be of valuable help to ensure complete resection of the bony walls. However, the majority of patients will need subsequent strabismus surgery, mainly due to significant increase of esotropia.

Levator recession with adjustable sutures for correction of upper eyelid retraction in thyroid eye disease.

PURPOSE: To examine the outcome of levator muscle recession with adjustable sutures for correcting upper eyelid retraction in thyroid eye disease. METHODS: All patients treated at Haukeland University Hospital between 2001 and 2011 were invited to participate in a follow-up examination. Preoperative measurements were obtained from medical records. The following parameters were recorded: eyelid aperture, the distance from limbus to eyelid margin, vertical motility of the eyelid in up- and downgaze, lagophthalmos, proptosis, vertical motility of the eye, and strabismus. Symmetry and eyelid contour were evaluated from photographs. Results were categorized as good, acceptable or unacceptable. RESULTS: Sixty-four out of a total of 80 patients attended the follow-up examination. Six were excluded from further analysis due to relapse of their thyroid eye disease with increased inflammation. Among the 58 remaining patients, a good result was observed in 34 patients, an acceptable result in 19 and an unacceptable result in 5. Lagophthalmos was seen in 30% of the lids preoperatively and in 7% postoperatively. A second procedure was performed in 13/80 patients, in 6 because of under-correction and in 7 because of ptosis. Wound infection occurred in 2 patients. CONCLUSION: Levator recession with adjustable sutures can be used to correct any degree of retraction. Good results can be obtained, but the procedure is time-consuming, and patients must be informed about the risk for reoperation.