The Role of Fibrogenesis and Extracellular Matrix Proteins in the Pathogenesis of Graves' Ophthalmopathy.

Graves' ophthalmopathy (GO), or thyroid eye disease (TED), is the most frequent extrathyroidal manifestation of Graves' disease (GD). Inflammation and subsequent aberrant tissue remodeling with fibrosis are important pathogenesis. There are many proposed mechanisms and molecular pathways contributing to tissue remodeling and fibrosis in GO, including adipogenesis, fibroblast proliferation and myofibroblasts differentiation, oxidative stress, endoplasmic reticulum (ER) stress, hyaluronan (HA) and glycosaminoglycans (GAGs) accumulation in the extracellular matrix (ECM) and new concepts of epigenetics modification, such as histone modification, DNA methylation, non-coding RNAs, and gut microbiome. This review summarizes the current understanding of ECM proteins and associated tissue remodeling in the pathogenesis and potential mediators for the treatment of GO.

Stereotactic radiosurgery for orbital cavernous hemangiomas.

OBJECTIVE: The goal of this study was to assess the safety and efficacy of single-session Gamma Knife radiosurgery (GKRS) for orbital cavernous hemangiomas (OCHs). METHODS: Patients who presented with an OCH between September 1999 and May 2022 and were treated with single-session GKRS were included in this single-center cohort study. RESULTS: There were 23 patients (7 males and 16 females) in this study. The median margin dose was 12 Gy (range 11-13 Gy). The median clinical and radiological follow-ups were 45 months (range 5-190 months) and 45 months (range 6-190 months), respectively. Nine (69.2%) of 13 patients with visual acuity impairment had improvement in best corrected visual acuity. Of the 8 patients with visual field defects, 5 patients (62.5%) had complete resolution. Tumor regression was observed in 22 patients (95.7%). The mean relative reduction in tumor volume was 82.6% ± 23.7%. The relative reductions in tumor volume were 33%, 49%, 72%, 84%, and 89% at 6, 12, 24, 36, and 48 months, respectively. Adverse effects of radiation were not observed. CONCLUSIONS: GKRS appears to be safe and efficacious for treating OCHs over long-term follow-up. The treatment is associated with a high rate of regression in OCHs and remarkable improvement in both visual acuity and visual field deficits.

Self-Retained, Sutureless Amniotic Membrane Transplantation for the Management of Ocular Surface Diseases.

Amniotic membrane (AM) has anti-inflammation, anti-fibrotic, and regenerative effects. Sutureless cryopreserved AM transplantation, ProKera® (Bio-Tissue, Inc., Miami, FL, USA), is easily applied by ophthalmologists in the treatment of ocular surface diseases. This retrospective study included patients with ocular surface diseases who received ProKera® between January 2022 and May 2023. Six patients (9 eyes) with a mean age of 56.8 ± 20.8 years old (range 25-74) and a mean follow-up period of 7.8 ± 4.1 months (range 1-12) were included, including 2 of recurrent conjunctival tumors with limbal and corneal involvement (cases 1-2), 1 of pterygium with marked astigmatism (case 3) and 3 of Stevens-Johnson syndrome (SJS, cases 4-6). ProKera® was inserted after the lesion excision and deep keratectomy in cases 1-3, and no recurrence or corneal complication was noted. Cases 4-5 were discharged from the intensive care unit and presented with severe chronic SJS. Most ocular manifestations improved significantly after symblepharon release and ProKera® insertion, except for corneal conjunctivalization in 1 eye (case 5). Case 6 involved early ProKera® use at the bedside during acute SJS, resulting in complete resolution. We concluded that the adjunctive application of ProKera® can be effective for ocular surface reconstruction and provides options to intervene earlier for outpatients or patients unstable for invasive surgical intervention.

The Challenges and Therapeutic Prospects in Eye Disease.

A number of key insights into eye disease have been revealed in the past decade, which has resulted in the development of novel, effective, targeted therapies such as teprotumumab for the treatment of thyroid eye disease (also known as Graves' orbitopathy) [...].

Sympathetic ophthalmia following radiation-induced scleral necrosis in choroidal melanoma.

Sympathetic ophthalmia (SO) is a bilateral granulomatous panuveitis. We report a rare case of SO presenting after scleral necrosis as a late complication of Gamma Knife radiotherapy for choroidal melanoma. A 55-year-old woman presented with primary choroidal melanoma in the right eye and has been treated with Gamma Knife radiotherapy with stable tumor size. Five years after radiotherapy, a pigmented protrusive uveal mass was visibly noted over the superior sclera of the same eye, corresponding to periocular soft tissue enhancement on computed tomography. Biopsies of the pigmented mass showed the absence of malignancy. One month later, acute blurred vision with signs of sympathetic ophthalmia developed in the left eye. The patient received high-dose systemic corticosteroids and immunomodulatory therapy. The intraocular inflammation in the left eye subsided with improving vision, and the uveal mass in the right eye flattened after the anti-inflammatory therapy. Scleral necrosis is a rare complication following radiotherapy for choroidal melanoma and may incite sympathetic ophthalmia, for which prompt and aggressive treatment is important to save vision, especially for the fellow eye.

Long-Term Follow-Up in IgG4-Related Ophthalmic Disease: Serum IgG4 Levels and Their Clinical Relevance.

(1) Background: To analyze the association between long-term changes in serum IgG4 levels and the clinical course of patients with IgG4-related ophthalmic disease (IgG4-ROD). (2) Methods: Retrospective analysis of 25 patients with IgG4-ROD. (3) Results: Mean age at diagnosis was 60.68 years. Fifty-six percent of patients had bilateral ocular involvement and 32% had systemic associations. The ocular structures involved were the lacrimal gland (76%), orbital soft tissue (36%), extraocular muscle (20%) and infraorbital nerve (20%). According to last follow-up, 9 (36%) patients had normalized IgG4 levels, and 16 (64%) patients had elevated IgG4 levels. Patients with normalized IgG4 levels had better response to initial steroid treatment and attained a significantly lower IgG4 level after treatment (p = 0.002). The highest IgG4 levels were at baseline and disease recurrence, and lowest after initial treatment. At final follow-up, IgG4 levels differed in patients with remission (mean 326.25 mg/dL) and stable disease (mean 699.55 mg/dL). Subgroup analysis was performed in patients with remission, categorized according to whether IgG4 levels were normalized (9 patients) or elevated (10 patients) on last follow up. The elevated group had a higher percentage of bilateral disease, lacrimal gland involvement and recurrence. (4) Conclusions: IgG4-ROD patients with a greater response to initial steroid therapy were more inclined to have normalized IgG4 levels in the long term. Some patients remained in remission despite persistently elevated IgG4 levels, and had regular follow-up without treatment.

Steroid-induced delayed diagnosis of primary vitreoretinal lymphoma with ghost brain tumor: A case report.

RATIONALE: Primary vitreoretinal lymphoma is a great masquerader and provides a diagnostic challenge.It is most frequently misdiagnosed as a chronic uveitis. Steroid treatment for presumed uveitis can interfere with the correct diagnosis of vitreoretinal lymphoma. Herein, we present a case of primary vitreoretinal lymphoma in which the correct diagnosis was delayed by short-term steroids until 2 years later. PATIENT CONCERNS: A 45-year-old woman presented with floaters and blurred vision in her right eye for 3 months. An ocular examination revealed dense vitreous cells. Three months later, she developed headache and suicidal ideation after taking a 3-week medication of oral steroid medication from another eye clinic. Brain magnetic resonance imaging revealed a tumor involving the corpus callosum and periventricular region. INTERVENTIONS: Vitreous biopsy and repeated brain biopsies were carried out for the patient. DIAGNOSIS: A brain biopsy was performed for the first time, and a vitreous biopsy was performed when steroid medication was suspended for 20 and 41 days, respectively. Both biopsies were negative for the presence of malignant cells. Follow-up magnetic resonance imaging revealed complete remission of the brain tumor. Two years later, the tumor recurred in the optic chiasm. Diffuse large B-cell lymphoma was confirmed by a second brain biopsy. OUTCOME: The patient had complete tumor remission after receiving brain radiation therapy and chemotherapy. LESSONS: Vitreoretinal lymphoma is difficult to diagnose owing to its rarity, masquerading presentation, and steroid-induced apoptosis of lymphoma cells. Physicians should consider vitreoretinal lymphoma as an important differential diagnosis in patients presenting with chronic uveitis and use steroids cautiously before making a definitive diagnosis.

Late capsular blockage syndrome: Clinical and anterior segment optical coherence tomography characteristics.

BACKGROUND: Late capsular blockage syndrome (CBS) is a rare phenomenon which is found after cataract surgery. The mechanism, anterior segment optical coherence tomography (OCT) presentation, and clinical characteristics are not well studied. METHODS: We studied patients who developed late CBS in Taipei Veterans General Hospital from 2012 to 2019. Age, sex, systemic disease, ocular disease, interval between cataract surgery and CBS, axial length, type of intraocular lens implanted, grading of posterior capsular opacity, refraction, visual acuity, and anterior segment OCT findings were documented. Patients are categorized into two groups according to anterior segment OCT findings. All patients underwent Nd:YAG laser capsulotomy and were prescribed a low-dose topical steroid for 7 days. Postcapsulotomy refraction and visual acuity were recorded. All the clinical data were compared in the two groups. RESULTS: This study included 18 eyes with late CBS. Patients' median age was 80 (range, 54-92) years. The mean duration between cataract surgery and CBS diagnosis was 80.28 (range 15-136) months. According to anterior segment OCT findings, we subcategorized the patients into two groups: gravel appearance (n = 7) and milky (n = 11) appearance. After laser capsulotomy, mean visual acuity improved 0.18 ± 0.10 on the LogMAR. A significant myopic shift in refraction after laser capsulotomy was noted in the gravel appearance group compared to the milky appearance group ( p = 0.027). No patient developed complications or needed further treatment for CBS during the median follow-up of 14.5 months (range 1-84 months). CONCLUSION: High-resolution anterior segment OCT is useful for analyzing patients with late CBS. Our study implies that the two types of CBS presentation indicate different causes of late CBS formation, as well as distinct clinical presentation and postlaser capsulotomy refractive outcome. In addition, YAG laser capsulotomy is a safe late CBS treatment modality.

Navigational Transmaxillary Endoscopic Approach for Inferomedial Tumors.

Orbital tumors encompass a heterogeneous range of histopathology and usually variable in location. Traditionally, transconjunctival medial orbitotomy is used to access the medial orbital wall. However, it creates potential risk of soft tissue sequelae such as scarring, lid contracture, or entropion/ectropion. For the lesions close to the orbital apex, increased risk of optical nerve injury should be cautious during orbitotomy procedure. Transnasal endoscopic approach to the orbital walls has been applied since 1999. Although it provides good surgical visualization and prevents the soft tissue and neural complications, the narrow nasal corridor increases the surgical complexity. Extensive sphenoethmoidectomy is usually required to gaining access. Furthermore, the resultant medical orbital defect is difficult to repair. The maxillary sinus is the largest paranasal sinuses which is located beneath the orbital floor. It provides an ample working space for instrumentation. Meanwhile, repair of the orbital floor defect is feasible and with high degree of accuracy under navigation control. In this report, we propose a novel computer-assisted endoscopic protocol to excise the medial orbital tumors with immediate repair of the wall defect.

Management of Delayed Complications of Hydrogel Scleral Buckles.

(1) Background: hydrogel scleral buckles (HSB)-related complications can happen decades after implantation, although this material has been retrieved for a long time. Due to its fragile texture, ensuring the complete removal of this material and avoiding complications are challenging. Incomplete removal, iatrogenic complication, recurrent retinal detachment, and infection could occur. (2) Methods: chart review of patients who developed delayed HSB-related complications and received removal of HSB in Taipei Veterans General Hospital from 2004 to 2021. The presenting symptoms, prior diagnosis before referral, clinical findings, image features, surgical technique, operative findings, and outcome were analyzed. Detailed surgical procedure and tips for removal were demonstrated in the study. (3) Results: a total of eleven patients were identified. The presenting symptoms include limitations to extraocular movement (ten eyes, 90.9%), ocular redness (eight eyes, 72.7%), ocular fullness (eight eyes, 72.7%), pain (six eyes, 54.5%), and exposed ocular foreign body (five eyes, 45.5%). Of note, six patients (54.5%) have monocular glaucoma and four of them have intractable high intraocular pressure. All patients underwent surgeries to smoothly remove swollen HSB via transcutaneous or transconjunctival approach. Most symptoms improved after surgery and no cases developed surgical-related complications. (4) Conclusions: although HSB have been off the market for decades, delayed complications are still emerging. Clinicians should remain alert for potential complications for patients with prior HSB surgeries. Early diagnosis and meticulous management can help to safely remove the expanded HSB and reduce the associated complications.

Plug-related canaliculitis: a rare or underdiagnosed disease?

CLINICAL RELEVANCE: Conjunctivitis, chalazion and blepharitis are routinely managed by optometrists. However, it is especially important to consider the diagnosis of canaliculitis in patients with chronic or recurrent conditions. BACKGROUND: This study aimed to report the clinical features, radiological findings and treatment outcomes in patients with plug-related canaliculitis. METHODS: This retrospective study included patients with canaliculitis secondary to plug insertion between 2007 and 2020. All data regarding epidemiological characteristics, clinical presentation, isolated microorganisms, computed tomography imaging findings, treatment, and outcomes were analysed. RESULTS: A total of 20 plug-related canaliculitis from 19 patients (18.3%) among all 109 cases of canaliculitis were identified. All patients with plug-related canaliculitis were females with a past history of lacrimal plug insertion for dry eye (mean age: 58.2 years). Most patients were initially treated as conjunctivitis with the mean time lapse to a diagnosis of 5.2 months. The average time from plug insertion to onset of symptoms was 5.1 years. Eighteen patients underwent canaliculotomy, and one patient received lacrimal irrigation. Plugs were identified in 18 cases, with SmartPlug in 13 cases (72%), followed by EaglePlugTM (two cases), Herrick Lacrimal Plug (two cases), and migrated FCI Painless Plug (1 case). Cultures of discharge, concretions, and/or infected plugs mostly revealed Pseudomonas aeruginosa (42%). Orbital computed tomography in four cases with SmartPlug revealed central radiolucency with surrounding soft-tissue enhancement. No recurrent canaliculitis was observed throughout a mean follow-up period of 13.7 months. No patient needed re-plugging after canaliculotomy and plug removal, with only one required additional lubricants for recurrent dry eye. CONCLUSION: Plug-related canaliculitis is often underdiagnosed due to late onset and similar symptoms to common ocular diseases. Awareness of plug insertion history as well as meticulous removal of the plug, concretion and/or granulation tissue is important for early diagnosis and to ensure a good outcome.

The Clinical Feature and Treatment Outcome of Ocular Melanoma: A 34-Year Experience in a Tertiary Referral Center.

Malignant melanoma can arise from melanocytes in various structures of the eye, orbit, and ocular adnexa. We reviewed the clinical features and long-term results of all subjects with histologically proved melanoma originating from any of the ocular and periocular structures in a tertiary referral center. Overall, 88 patients including 47 men were recruited. The tumor was primarily located in the uvea, followed by the conjunctiva, orbit, eyelid, and lacrimal sac. Patients with uveal melanoma were diagnosed at a relatively younger age (47.0 years), while those with orbital and eyelid melanomas were older at presentation (79.5 years and 78.5 years, respectively). The overall local recurrence rate was 9% at a median follow-up of 41.0 months, among which orbital and eyelid melanomas recurred most commonly. The overall mortality rate was 41% in a median duration of 27.2 months (IQR, 13-58 months) from diagnosis, with the highest for lacrimal sac melanoma, followed by melanoma of the orbit, uveal, conjunctiva, and eyelid. Despite prompt local control, the risk for metastasis and mortality was high. Therefore, efficient modalities for early diagnosis and treatment of ocular melanoma are necessary.

The Role of Oxidative Stress and Therapeutic Potential of Antioxidants in Graves' Ophthalmopathy.

Graves' ophthalmopathy (GO) is the most common extrathyroidal manifestation of Graves' disease. It is characterized initially by an inflammatory process, followed by tissue remodeling and fibrosis, leading to proptosis, exposure keratopathy, ocular motility limitation, and compressive optic neuropathy. The pathogenic mechanism is complex and multifactorial. Accumulating evidence suggests the involvement of oxidative stress in the pathogenesis of GO. Cigarette smoking, a major risk factor for GO, has been shown to induce reactive oxygen species (ROS) generation and oxidative damage in GO orbital fibroblasts. In addition, an elevation in ROS and antioxidant enzymes is observed in tears, blood, and urine, as well as orbital fibroadipose tissues and fibroblasts from GO patients. In vitro and in vivo studies have examined the efficacy of various antioxidant supplements for GO. These findings suggest a therapeutic role of antioxidants in GO patients. This review summarizes the current understanding of oxidative stress in the pathogenesis and potential antioxidants for the treatment of GO.

Effect of Pirfenidone on TGF-ß1-Induced Myofibroblast Differentiation and Extracellular Matrix Homeostasis of Human Orbital Fibroblasts in Graves' Ophthalmopathy.

Pirfenidone is a pyridinone derivative that has been shown to inhibit fibrosis in animal models and in patients with idiopathic pulmonary fibrosis. Its effect on orbital fibroblasts remains poorly understood. We investigated the in vitro effect of pirfenidone in transforming growth factor-ß1 (TGF-ß1)-induced myofibroblast transdifferentiation and extracellular matrix (ECM) homeostasis in primary cultured orbital fibroblasts from patients with Graves' ophthalmopathy (GO). The expression of fibrotic proteins, including α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), fibronectin, and collagen type I, was determined by Western blots. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for the ECM homeostasis were examined. After pretreating the GO orbital fibroblasts with pirfenidone (250, 500, and 750 µg/mL, respectively) for one hour followed by TGF-ß1 for another 24 h, the expression of α-SMA, CTGF, fibronectin, and collagen type I decreased in a dose-dependent manner. Pretreating the GO orbital fibroblasts with pirfenidone not only abolished TGF-ß1-induced TIMP-1 expression but recovered the MMP-2/-9 activities. Notably, pirfenidone inhibited TGF-ß1-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), the critical mediators in the TGF-ß1 pathways. These findings suggest that pirfenidone modulates TGF-ß1-mediated myofibroblast differentiation and ECM homeostasis by attenuating downstream signaling of TGF-ß1.

Curcumin Suppresses TGF-ß1-Induced Myofibroblast Differentiation and Attenuates Angiogenic Activity of Orbital Fibroblasts.

Orbital fibrosis, a hallmark of tissue remodeling in Graves' ophthalmopathy (GO), is a chronic, progressive orbitopathy with few effective treatments. Orbital fibroblasts are effector cells, and transforming growth factor ß1 (TGF-ß1) acts as a critical inducer to promote myofibroblast differentiation and subsequent tissue fibrosis. Curcumin is a natural compound with anti-fibrotic activity. This study aims to investigate the effects of curcumin on TGF-ß1-induced myofibroblast differentiation and on the pro-angiogenic activities of orbital fibroblasts. Orbital fibroblasts from one healthy donor and three patients with GO were collected for primary cell culture and subjected to myofibroblast differentiation under the administration of 1 or 5 ng/mL TGF-ß1 for 24 h. The effects of curcumin on TGF-ß1-induced orbital fibroblasts were assessed by measuring the cellular viability and detecting the expression of myofibroblast differentiation markers, including connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA). The pro-angiogenic potential of curcumin-treated orbital fibroblasts was evaluated by examining the transwell migration and tube-forming capacities of fibroblast-conditioned EA.hy926 and HMEC-1 endothelial cells. Treatment of orbital fibroblasts with curcumin inhibited the TGF-ß1 signaling pathway and attenuated the expression of CTGF and α-SMA induced by TGF-ß1. Curcumin, at the concentration of 5 µg/mL, suppressed 5 ng/mL TGF-ß1-induced pro-angiogenic activities of orbital fibroblast-conditioned EA hy926 and HMEC-1 endothelial cells. Our findings suggest that curcumin reduces the TGF-ß1-induced myofibroblast differentiation and pro-angiogenic activity in orbital fibroblasts. The results support the potential application of curcumin for the treatment of GO.

JNK and p38 Inhibitors Prevent Transforming Growth Factor-ß1-Induced Myofibroblast Transdifferentiation in Human Graves' Orbital Fibroblasts.

Transforming growth factor-ß1 (TGF-ß1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves' ophthalmopathy (GO). However, the signaling pathways through which TGF-ß1 activates Graves' orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-ß1-induced myofibroblast transdifferentiation in human Graves' orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-ß1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-ß1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-ß1 could induce myofibroblast transdifferentiation in human Graves' orbital fibroblasts through the p38 and JNK pathways.

Primary Signet Ring Cell/Histiocytoid Carcinoma of the Eyelid: Somatic Mutations in CDH1 and Other Clinically Actionable Mutations Imply Early Use of Targeted Agents.

Primary signet ring cell/histiocytoid carcinoma of the eyelid is a rare ocular malignancy and its diagnosis is often delayed. This neoplasm presents as an insidious, diffusely infiltrative mass in the periocular area that later infiltrates the orbit. An exenteration is usually indicated; however, nearly one-third of patients develop local recurrence or metastasis. Morphologically, it resembles signet ring cell carcinoma of the stomach and breast, raising the possibility of mutations in CDH1, the gene encoding E-cadherin. To determine whether primary signet ring cell/histiocytoid carcinoma harbors the CDH1 mutation or other actionable mutations, we analyzed the tumor tissue via next-generation sequencing. We identified only one case of primary signet ring cell carcinoma of the eyelid with adequate DNA quality for sequencing from the pathological archive during the period 2000 to 2020. A comprehensive evaluation including histopathology, immunohistochemistry, and next-generation sequencing assay was performed on tumor tissue. Immunohistochemically, the tumor exhibited E-cadherin membranous staining with the aberrant cytoplasmic staining of ß-catenin. Using next-generation sequencing, we demonstrated the mutation in the CDH1 gene. In addition, other clinically actionable mutations including ERBB2 and PIK3CA were also detected. The alterations in other actionable genes indicate a need for larger studies to evaluate the pathogenesis and potential therapies for primary signet ring cell/histiocytoid carcinoma of the eyelid.

Change of Eyelid Parameters in Patients With Marin-Amat Syndrome.

PURPOSE: Marin-Amat syndrome is an acquired facial synkinesis manifesting as involuntary eyelid closure on jaw movement. The authors investigate the clinical features, especially the quantitative changes in eyelid parameters of patients with Marin-Amat syndrome. METHODS: Patients with Marin-Amat syndrome between 2015 and 2017 in a medical center were collected. Clinical features and the change of eyelid parameters, including margin reflex distance 1 (MRD-1), margin reflex distance 2 (MRD-2), and palpebral fissure height, were evaluated. RESULTS: There were 5 men and 3 women with a mean age of 76 years. All had a history of facial palsy. The mean time to onset of Marin-Amat syndrome was 4.4 years after facial palsy. Seven patients (87.5%) developed subsequent ipsilateral facial spasm after facial palsy. Most patient complaints were ptosis (62.5%) and ptosis on eating (37.5%). The mean palpebral fissure height of involved eyes decreased from 5.88 to 2 mm on jaw opening (p = 0.011), which resulted from decrease in MRD-1 (from 2.06 to 0.06 mm, p = 0.012) and MRD-2 (from 3.81 to 1.94 mm; p = 0.012). Botulinum toxin A (Botox) injection into the periorbital orbicularis muscle in 6 patients significantly relieved the change of palpebral fissure height on jaw opening compared with that before injection (9.9% vs. 68.6 %, p = 0.027). CONCLUSIONS: Most patients with Marin-Amat syndrome present with ptosis and might be overlooked or underestimated. The reduction in palpebral fissure height in our patients with Marin-Amat syndrome was due to involuntary orbicularis oculi muscle contraction, resulting in decrease of both the MRD-1 and MRD-2 on jaw opening.