Reactivation After Teprotumumab Treatment for Active Thyroid Eye Disease.

PURPOSE: To determine the recurrence and reactivation rates after teprotumumab therapy for active thyroid eye disease. DESIGN: Retrospective consecutive case series. METHODS: This was a study of all patients followed for active thyroid eye disease at the Cole Eye Institute, Cleveland Clinic, treated with teprotumumab between May 2020 and May 2021. Patients with less than 6 months follow-up after completion of infusions were excluded. The primary outcome measure was reactivation, defined as a regression in proptosis (increase of ≥2 mm in either eye and to within ≤2 mm of pre-treatment level and Clinical Activity Score [CAS] worsening of 2 points or greater). Secondary outcome was diplopia response. RESULTS: A total of 21 patients were included in the study. The average long-term improvement in proptosis in the eye with more proptosis after teprotumumab was 1.57mm (range, -3 to 4 mm). Of the 17 initial responders, there were 8 reactivations (47%) and 2 isolated proptosis regressions (12%); Overall, 7 of 21 patients (33%) responded throughout the study period. Average time to regression was 12.25 months (range, 2-22.5 months). There was no statistically significant change in diplopia at final visit in any subgroup (P = 0.68 to >.99). CONCLUSIONS: At most, 33% of patients demonstrate continued response 2 years after teprotumumab treatment. The proptosis and CAS regression occurs in the setting of disease reactivation in 80% of regressions. Teprotumumab treatment appears to offer minimal long-term improvement in diplopia.

Clinical Outcome and Technical Nuances After Resection of Orbital Cavernous Venous Malformations-A Single-Center Experience.

BACKGROUND: Cavernous venous malformations (CVMs) represent the most common benign intraorbital lesions. Enlarging or symptomatic CVMs (progressive proptosis or visual disturbances) are treated by surgical resection. For this, a variety of different surgical approaches have been described. The aim of this study was to present a contemporary series of orbital CVMs treated via open microsurgical approaches. METHODS: In this study, patients who underwent resection of orbital CVMs between 2002 and 2019 were included. Presenting symptoms were noted and neuro-ophthalmologic examinations performed pre- and postoperatively. For surgical resection, the location of the orbital CVM and its relation to the orbital anatomy led to decision-making for appropriate approaches. A comparison between anatomical location and surgical outcome was performed. RESULTS: Overall, 35 patients with orbital CVMs were included. Most common presenting symptoms were progressive proptosis (43%) and visual disturbances (34%). Most common location was the lateral quadrant (37%) followed by the superior quadrant (20%). A subfrontal craniotomy was performed in 40% of cases followed by a supraorbital craniotomy including the orbital rim in 34% of cases. For surgical excision, a cryo-probe was used in 30 patients, and complete resection was feasible in all cases. Location of a CVM within the superior quadrant was associated with improved postoperative recovery of visual acuity. No differences for clinical outcomes were observed depending on the surgical approach. CONCLUSIONS: Resection of orbital CVMs is indicated in patients with visual disturbances or progressive proptosis. In these, microsurgical approaches can be used with minimal morbidity for complete removal of these well-circumscribed lesions.

Spontaneous subperiosteal orbital hematoma in a patient with chronic sinusitis.

Periorbital swelling is a common presentation to the emergency department (ED), and its etiology can range from benign to acutely vision-threatening. Orbital subperiosteal hematoma is a rare ED diagnosis that is typically associated with trauma, though can infrequently occur spontaneously in the setting of sudden elevations in cranial venous pressure, bleeding diathesis, and sinusitis. We present a case of a 55-year-old female with a history of chronic sinusitis who presented to the ED with a three-day history of left-sided periorbital swelling along with painful extraocular movements and markedly decreased visual acuity following a cross-country road trip through elevation. Contrast computed tomography scan of the orbits revealed a large extraconal collection in the subperiosteal space causing significant mass effect on the left globe, along with findings of diffuse sinonasal disease bilaterally. Intravenous antibiotics were started immediately and the patient underwent surgical incision and drainage of the subperiosteal space, where she was diagnosed with a spontaneous subperiosteal orbital hematoma secondary to chronic sinusitis. Within the literature, there are fewer than 20 case reports of orbital subperiosteal hematoma secondary to sinusitis. The purpose of this case report is to assist emergency physicians in considering the rare but potentially vision-threatening condition of spontaneous subperiosteal orbital hematoma within their differential diagnosis of patients with periorbital swelling and proptosis, as well as to provide an approach to management within the ED.

Efficacy and safety of tripterygium glycosides for active moderate to severe Graves' ophthalmopathy: a randomised, observer-masked, single-centre trial.

BACKGROUND: Tripterygium glycosides (TG) has been used to treat a spectrum of inflammatory and autoimmune diseases. Our preliminary studies have shown that TG is effective in the treatment of active Graves' ophthalmopathy (GO). OBJECTIVE: We aimed to compare the efficacy and tolerability of TG with intravenous methylprednisolone (iv.MP) in patients with active moderate-to-severe GO. METHODS: This study was an observer-masked, single-centre, block-randomised trial. Patients with active moderate-to-severe GO were randomly assigned to receive iv.MP (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks) or with TG (20 mg tablet three times per day for 24 weeks). The primary endpoints were the overall response rate and the patients' quality of life at 12 and 24 weeks. RESULTS: In this study, 161 patients were enrolled and randomised from 2015 to 2019. A total of 79 were randomly assigned to receive iv.MP and 82 to receive TG. A greater overall response rate was found in the TG group compared with the iv.MP group at week 24 (90.2% vs 68.4%, P = 0.000). Similarly, the patients' quality of life of the TG group showed a significantly higher response than the iv.MP group at week 24 (89.02% vs 72.15%, P = 0.001). The TG therapy showed a better CAS response than the iv.MP (91.5% vs 70.9% improved, P < 0.05), and up to 91.2% of patients were inactive. Also, the TG group showed a significantly higher improved rate of diplopia, proptosis, visual acuity, soft tissue involved and the decrease of eye muscle motility than the iv.MP group at week 24. Significantly more patients in the iv.MP group than the TG group experienced adverse events. CONCLUSION: Compared with iv.MP treatment, TG therapy is more effective and safer for patients with active moderate to severe GO.

Unilateral periorbital swelling in children: avoid delays in diagnosis.

A 10-year-old child had painful periorbital swelling in the left eye. It was diagnosed as preseptal cellulitis and treated with oral antibiotics. Three days later, the ocular condition worsened so the child was referred for further management. On examination, the child had a temperature of 102 °F. Ocular examination revealed proptosis, restricted ocular movements and a relative afferent pupillary defect in the left eye. Ocular examination of the right eye was normal. There was a history of recurrent episodes of cold in the past. CT scan orbit and sinuses revealed signs of orbital cellulitis with sinusitis on the left side. The child was treated with parenteral antibiotics and endoscopic sinus surgery. A child presenting with unilateral periorbital swelling needs to be thoroughly evaluated. It is important to differentiate orbital cellulitis from preseptal cellulitis. Orbital cellulitis is an emergency and delay in diagnosis can lead to vision and life-threatening intracranial complications.

Invasive fungal disease misdiagnosed as tumour in association with orbital apex syndrome.

Invasive sino-orbital aspergillosis is a rare cause of orbital apex syndrome (OAS) in immunocompetent patients and often misdiagnosed as tumour because of its aggressive nature and invasive patterns. We report a 23-year-old immunocompetent man presenting with painful progressive loss of vision, ophthalmoplegia and proptosis of the right eye suggestive of OAS. MRI with gadolinium contrast showed an enhancing heterogeneous mass filling the paranasal sinuses, extraconal space and extending up to the right orbital apex. A functional endoscopic biopsy reported as invasive sino-orbital aspergillosis. He was started on intravenous voriconazole and maximal surgical debridement was done. He gradually regained his vision to 20/30 in the right eye. A review of literature reported several such cases which were managed medically or surgically but with poor visual recovery. This case highlights the need for awareness among clinicians for early diagnosis and treatment to prevent vision loss and better survival.

Long-term ophthalmic anatomical and functional outcomes after surgical removal of intraorbital foreign bodies.

PURPOSE: To analyze the anatomical and functional ophthalmic parameters after the surgical removal of various intraorbital foreign bodies. METHODS: A retrospective analysis of medical records was performed featuring detailed history, ophthalmic examination, orbital computed tomographic scans, treatment details, and outcomes. The analyzed anatomical factors included extraocular movements, the position of the eyeball (proptosis, dystopia, and enophthalmos), and fullness of orbital sulci. The functional assessment was based on visual acuity, pupillary reactions, and diplopia. The outcomes were defined as complete, partial, and failure after a minimum follow-up of 1 year. RESULTS: Of 32 patients, the organic and inorganic intraorbital foreign bodies were surgically removed from 18 (56.25%) and 14 (43.75%) orbits, respectively. At presentation, anatomically the extraocular movement restriction, proptosis/dystopia/enophthalmos, and orbital sulcus fullness were noted in 26 (81.25%), 24 (75%), and 15 (46.88%), respectively. Functionally, diminished visual acuity, diplopia, and pupil abnormalities were seen in 27 (84.38%), 14 (43.75%), and 8 (25%), respectively. After intraorbital foreign body removal at a mean follow-up of 14 months, the improvement of anatomical factors (same sequence) were observed in 8 (30.77%), 20 (83.33%), and 12 (80%), respectively. In functional factors (same sequence), the improvement was noted in none (0%), 13 (92.86%), and 5 (62.5%), respectively. Hence, the majority of patients (n = 20, 62.5%) achieved partial success, while 8 (25%) had complete success. Four (12.5%) had treatment failure despite similar management protocols. CONCLUSION: The anatomical outcomes are better than the functional outcomes after surgical removal of the intraorbital foreign bodies. The visual acuity does not improve considerably after the surgical removal of intraorbital foreign bodies. Overall, the wooden intraorbital foreign bodies have poorer anatomical and functional prognosis.

Quantitative analysis of extraocular muscle volume and exophthalmos reduction after radiation therapy to treat Graves' ophthalmopathy: A pilot study.

PURPOSE: The aim of this study was to provide radiological information on the inherent response of Graves' ophthalmopathy after radiation therapy. METHODS: Quantitative analysis of extraocular muscle volume was performed on 96 involved extraocular muscles in a total of 16 patients. A total of 48 computed tomography images were analyzed. Exophthalmos was also measured. The percentage reductions in extraocular muscle volume and exophthalmos length were determined and compared to the pre-radiation therapy values at 6-, 12-, and 24-month follow-up. RESULTS: The median follow-up time was 21.5 months (range: 7.2-29.4 months). The mean reduction in relative tumor volume compared to the pre-radiation therapy extraocular muscle volume was 46.1% (range: 33.3%-58.8%). The mean relative extraocular muscle volumes were 71.5% at 6 months, 59.2% at 12 months, and 54.3% at 24 months after radiation therapy. The volume of the involved extraocular muscles decreased rapidly within the first 12 months of follow-up. The mean pre-radiation therapy length of exophthalmos was 21.7 mm (range: 17.6-26.1 mm). The mean percentages of exophthalmos length by comparison with the pre-radiation therapy length were 96.7% at 6 months, 92.3% at 12 months, and 88.5% at 24 months after radiation therapy. Exophthalmos decreased slowly and steadily during the follow-up period. CONCLUSION: Quantitative volumetric analysis of the pattern of extraocular muscle volume reduction and exophthalmos length reduction in response to radiation therapy will allow clinicians to better understand the effect of radiotherapy on Graves' ophthalmopathy.

A Prospective, Randomized, Double-blind, Placebo-controlled Study of Orbital Radiotherapy for Graves' Ophthalmopathy.

CONTEXT: Although widely used for more than 85 years, the efficacy of radiotherapy for Graves' ophthalmopathy (GO) has not been established convincingly. OBJECTIVE: To evaluate the efficacy of radiotherapy for GO. DESIGN: Prospective, randomized, internally controlled, double-blind clinical trial in a tertiary care academic medical center. PARTICIPANTS: The patients were ethnically diverse males and females over age 30 seen in a referral practice. The patients had moderate, symptomatic Graves' ophthalmopathy (mean clinical activity score, 6.2) but no optic neuropathy, diabetes, recent steroid treatment, previous decompression, or muscle surgery. Forty-two of 53 consecutive patients were enrolled after giving informed consent and fulfilling study entry criteria. Eleven eligible patients declined to participate because of inconvenience, desire for alternative therapy, or concern about radiation. INTERVENTION: One randomly selected orbit was treated with 20 Gy of external beam therapy; sham therapy was given to the other side. Six months later, the therapies were reversed. MAIN OUTCOME MEASURES: Every 3 months for 1 year, we measured the volume of extraocular muscle and fat, proptosis, range of extraocular muscle motion, area of diplopia fields, and lid fissure width. Effective treatment for GO will modify one or more of these parameters. RESULTS: No clinically or statistically significant difference between the treated and untreated orbit was observed in any of the main outcome measures at 6 months. At 12 months, muscle volume and proptosis improved slightly more in the orbit that was treated first. CONCLUSIONS: In this group of patients, representative of those for whom radiotherapy is frequently recommended, we were unable to demonstrate any beneficial therapeutic effect. The slight improvement noted in both orbits at 12 months may be the result of natural remission or of radiotherapy, but the changes are of marginal clinical significance.

A New Era in the Treatment of Thyroid Eye Disease.

PURPOSE: Improved understanding of thyroid eye disease (TED) pathogenesis has facilitated identification of a targeted molecular approach for TED treatment offering the potential to halt or slow disease progression in a nonsurgical manner. Herein, we provide a summary of the current knowledge of TED management, followed by discussion of a novel insulin-like growth factor-1 receptor (IGF-1R) antagonist antibody and its potential to change the course of the disease. DESIGN: Perspective. METHODS: Review of the literature and authors' experience. RESULTS: Many publications demonstrate IGF-1R overexpression in TED, and its activation as an autoantigen as a critical factor in TED pathogenesis. Several in vitro studies demonstrate that IGF-1R inhibition attenuates downstream molecular events including cytokine and hyaluronan production, and cellular differentiation. These observations led to the hypothesis that blocking IGF-1R may abrogate the clinical progression of TED. The recent completion of phase 2 and 3 randomized, placebo-controlled trials demonstrate the efficacy and safety of teprotumumab, a fully human monoclonal IGF-1R antagonist antibody, in patients with moderate-to-severe, active TED. Both the phase 2 and the recent phase 3 study results demonstrate that more patients with active TED receiving teprotumumab experienced a meaningful improvement in proptosis. CONCLUSIONS: Current TED treatment strategies target inflammation and symptoms, but do not modify the disease course. Therefore, proptosis as well as strabismus and its resulting diplopia often remain, impacting patient well-being and quality of life over the long term. Targeted molecular therapy using teprotumumab demonstrates disease-modifying benefits with the potential to shift the paradigm for TED treatment.

A novel FAM20C mutation causes a rare form of neonatal lethal Raine syndrome.

Raine syndrome is a rare, autosomal recessive, osteosclerotic bone dysplasia due to pathogenic variants in FAM20C. The clinical phenotype is characterized by generalized osteosclerosis affecting all bones, cerebral calcifications, and craniofacial dysmorphism. Most cases present during the neonatal period with early lethality due to pulmonary hypoplasia and respiratory compromise while only few affected individuals have been reported to survive into adulthood. FAM20C is a ubiquitously expressed protein kinase that contains five functional domains including a catalytic domain, a binding pocket for FAM20A and three distinct N-glycosylation sites. We report a newborn infant with a history of prenatal onset fractures, generalized osteosclerosis, and craniofacial dysmorphism and early lethality. The clinical presentation was highly suggestive of Raine syndrome. A homozygous, novel missense variant in exon 5 of FAM20C (c.1007T>G; p.Met336Arg) was identified by targeted Sanger sequencing. Following in silico analysis and mapping of the variant on a three-dimensional (3D) model of FAM20C it is predicted to be deleterious and to affect N-glycosylation, protein folding, and subsequent secretion of FAM20C. In addition, we reviewed all published FAM20C mutations and observed that most pathogenic variants affect functional regions within the protein establishing evidence for an emerging genotype-phenotype correlation.

Exophthalmos in Kearns-Sayre syndrome.

Kearns-Sayre syndrome (KSS) is a rare mitochondrial DNA (mtDNA) deletion syndrome that typically presents before 20 years of age and is characterized by chronic progressive external ophthalmoplegia, pigmentary retinopathy, and a combination of cardiac conduction defects, cerebellar ataxia, and elevated cerebrospinal fluid protein levels. The mtDNA defects interfere with oxidative phosphorylation and can affect a number of cellular energy processes in various organs. We report the case of a 15-year-old girl with KSS that was uniquely associated with bilateral, symmetrical exophthalmos.

Post-traumatic carotid-cavernous fistula with bilateral proptosis simulating cavernous sinus thrombosis.

A 48-year-old woman presented with bilateral non-pulsatile proptosis and ophthalmoplegia after 3 days following blunt orbital trauma. It was associated with fever, malaise and loss of vision in right eye. She was provisionally diagnosed with cavernous sinus thrombosis and was treated with intravenous antibiotics with no improvement. A subtle bruit was present on examination, and digital subtraction angiography revealed a right direct (type A) carotid-cavernous fistula (CCF). The patient underwent right coil embolisation of direct CCF. On follow-up at 4 months, her proptosis resolved completely and extraocular movements improved.

A novel FAM20C mutation causing hypophosphatemic osteomalacia with osteosclerosis (mild Raine syndrome) in an elderly man with spontaneous osteonecrosis of the knee.

Raine syndrome is characterized by FGF23-mediated hypophosphatemic osteomalacia with osteosclerosis caused by mutations in the FAM20C gene. We report a case of a 72-year-old man who presented with rapid progressive spontaneous osteonecrosis of the knee (SONK). A full osteologic assessment including dual energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and serum analyses revealed a high bone mass in the lumbar spine and hip (DXA T-score + 7.5 and + 4.7/+4.2) with increased bone microstructural parameters in the distal radius and tibia (BV/TV 127%, 140% of the age-matched mean, respectively), as well as a low bone turnover state. Phosphate levels were low due to renal phosphate wasting and high FGF23 levels (126.5 pg/ml, reference range 23.2-95.4 pg/ml). Using gene panel sequencing, we identified a novel FAM20C heterozygous missense mutation in combination with a homozygous duplication that potentially alters splicing. Taken together, this is the first case of mild Raine syndrome with spontaneous osteonecrosis of the knee, phosphate wasting, and a pronounced trabecular high bone mass phenotype.

A comparative analysis of piezosurgery and oscillating saw for balanced orbital decompression.

Introduction: Different minimally invasive surgical approaches to the orbit allow individualized bone resection to reduce proptosis and decompress the optic nerve in patients with Graves' orbitopathy (GO). This study aims to compare piezosurgery to an oscillating saw used to resect bone from the lateral orbital wall. Methods: In a retrospective study, we analyzed balanced orbital decompressions performed on 174 patients (318 cases) with GO. An oscillating saw was used in 165 cases (saw group) and piezosurgery in 153 cases (piezo group). Peri- and postoperative complications, reduction of proptosis, new onset of diplopia and improvement of visual acuity in cases of pre-operative optic nerve compression were analyzed. Results: We observed no significant differences in the surgical outcome between the two groups. Proptosis reduction was 4.6 mm in the saw group (p < 0.01) and 5.3 mm in the piezo group (p < 0.01). Intraoperative handling of the piezosurgery device was judged superior to the oscillating saw, due to soft tissue conservation and favourable cutting properties. Duration of the surgery did not differ between the groups. No serious adverse events were recorded in both groups. Conclusion: The application of piezosurgery in orbital decompression is more suitable than an oscillation saw due to superior cutting properties such as less damage to surrounding soft tissue or a thinner cutting grove.

Teprotumumab, an insulin-like growth factor-1 receptor antagonist antibody, in the treatment of active thyroid eye disease: a focus on proptosis.

Thyroid eye disease is a disabling autoimmune disease associated with orbital inflammation and tissue remodeling which can result in significant proptosis, leading to visual alterations and is potentially sight threatening. Current evidence indicates that autoantibodies to the insulin-like growth factor 1 receptor (IGF-1R), along with the thyroid-stimulating hormone receptor (TSHR), mediate the pathogenesis in susceptible individuals. Teprotumumab, a monoclonal IGF-1R antagonist, has demonstrated previously in a 24 week, randomized, controlled trial to produce significant changes in composite outcomes of proptosis and clinical activity score as compared with placebo. Further examination of the proptosis results reported here, indicate that the proptosis outcome (≥ 2 mm reduction) was met in 71.4% of the teprotumumab-treated patients as compared with 20% of the placebo-treated patients (p < 0.001). Additionally, the proptosis benefit was observed early in the trial (study week 6), and all individual patients demonstrated some benefit at week 24. Improvement was noted among smokers, non-smokers, men and women, and particularly those with higher levels of proptosis at baseline. The level of proptosis reduction with teprotumumab reported here is similar to that seen with decompression surgery. If these results are confirmed in the ongoing Phase 3 trial, teprotumumab will offer an alternative to surgery and its associated complications.

Clinical pattern of Retinoblastoma in Pakistani population: Review of 403 eyes in 295 patients.

OBJECTIVE: To document clinical pattern of retinoblastoma in Pakistani population. METHODS: This retrospective study, which was conducted at Department of Ophthalmology, Dow University of Health Sciences, Karachi, reviewed clinical records of patients with retinoblastoma from 1997 to 2012. Staging of disease was done by referring to retinal diagrams, RetCam images, and first magnetic resonance imaging. Ophthalmic notes, imaging reports and histopathology reports of enucleated eyes established optic nerve involvement. SPSS 21 was used for statistical analysis. RESULTS: Clinical records of 295 patients with retinoblastoma in 403 eyes were reviewed, and male to female ratio was 1.3:1. Retinoblastoma was bilateral in 106(35.93%) patients, while 118(40%) patients had hereditary pattern. Mean age at presentation was 35.98+27.63 months, while mean follow-up was 3±2 months. Leucokoria was the most common presenting feature 173(58.64%) followed by proptosis 72(24.41%). Optic nerve involvement was seen on magnetic resonance imaging or histopathology in 81(20.10%) eyes. Distant metastasis was noted in 32(10.85%) patients on first presentation. Chemotherapy with or without adjuvant treatment was given to 238(80.68%) patients. Enucleation and exentration were performed in 164(40.69%) and 12(2.98%) eyes, respectively. CONCLUSIONS: Most common presenting symptom was leucokoria followed by proptosis. Hereditary retinoblastoma was frequently seen in Pakistani children. .

A Simple Quantitative Measure of Orbital Compliance.

PURPOSE: This study evaluates the reliability of a frequently used subjective measurement of orbital compliance (0-3 scale) and describes a simple, quantitative measure with excellent intra- and interrater reliability. METHODS: Two examiners performed both measurements on 100 orbits (50 consecutive patients) from the office of 1 oculoplastics surgeon. Each measurement was obtained at 2 different time points, 10 minutes apart. For the subjective measurement, the patient was asked to close their eyes, and the globe was displaced posteriorly with digital pressure until moderate resistance was felt. This was graded on a 0 to 3 scale. For the quantitative measurement (millimeter scale), the difference in axial displacement was measured using a Hertel exophthalmometer. RESULTS: The subjective measurement (scale, 0-3) showed excellent test-retest reliability (average, 0.901) for both examiners at both time points and good interobserver reliability (average, 0.677). The quantitative measurement (millimeter scale) showed excellent test-retest reliability (average, 0.848) and very good interobserver reliability (average, 0.756). CONCLUSION: This study shows that while both methods have both excellent test-retest reliability, the interobserver reliability is slightly higher with the quantitative measurement. This suggests that the described measurement of orbital compliance is both a reasonable alternative and possibly more accurate measurement without the steep learning curve.