Trametinib for orbital plexiform neurofibromas in young children with neurofibromatosis type 1.

INTRODUCTION: Plexiform neurofibromas (PNF) in neurofibromatosis type 1 (NF1) are usually diagnosed in childhood and can grow rapidly during this period. In 10% of patients, PNF involve the orbital-periorbital area and may cause visual problems including glaucoma, visual loss from amblyopia (deprivational, strabismic, or refractive), optic nerve compression, or keratopathy. Ptosis, proptosis, and facial disfigurement lead to social problems and decreased self-esteem. Complete surgical removal involves significant risks and mutilation, and regrowth after debulking is not uncommon. Inhibitors of the RAS/MAPK pathway have recently been investigated for their activity in PNF. We administered the oral MEK inhibitor trametinib to five young children with NF1 and PNF of the orbital area, with visual compromise and progressive tumor growth; and followed them clinically and by volumetric MRI. METHODS: Treatment was initiated at a mean age of 26.8 months (SD ± 12.8) and continued for a median 28 months (range 16-51). Doses were 0.025 mg/kg/day for children aged > 6 years and 0.032 mg/kg/day for those aged < 6 years. RESULTS: Volumetric MRI measurements showed a reduction of 2.9-33% at 1 year after treatment initiation, with maximal reductions of 44% and 49% in two patients, at 44 and 36 months, respectively. No change in visual function was recorded during treatment. One child reported decreased orbital pain after 2 weeks; and another, with involvement of the masseters, had increased ability to chew food. Toxicities were mostly to skin and nails, grades 1-2. CONCLUSIONS: Trametinib can decrease tumor size in some young children with orbital PNF and may prevent progressive disfigurement.

Low-dose Bleomycin Injections for Orbital Lymphatic and Lymphatic-Venous Malformations: A Multicentric Case Series Study.

PURPOSE: Orbital lymphatic malformations (LM) are associated with ocular morbidity and facial disfigurement. Surgery is challenging and may not be effective. We describe the outcome of bleomycin injections for venous LM and lymphatic-venous malformation (LVM) malformations of the orbit in 5 tertiary referral centers between January 2010 and December 2018. METHODS: Multicenter retrospective case series, 5 oculoplastic referral centers: Sheba and Rabin Medical Centers, Israel; Mulago Hospital, Uganda; Sri Sankaradeva Nethralaya, India; and Clinique Ophtalmologique de Tunis, Tunisia. All patients diagnosed with orbital LM/LVM were assigned to successive (range 1-6) intralesional 5 international units bleomycin injections. They all underwent complete ophthalmic and orbital evaluations, orbital imaging, and ancillary testing as needed. Clinical photographs were assessed pre- and posttreatment along with objective assessments of clinical improvement. Additional injections were provided in cases of incomplete response. RESULTS: A total of 21 patients (17 women, mean ± standard deviation age 18 ± 13 years, range 2-48 years) underwent bleomycin injections. The mean injection dose was 12 ± 10 international units in 1-3 injections. There was a dramatic improvement in lesion size, appearance, proptosis, and ocular motility in 20/21 patients (95%) after a mean follow-up of 18 months. Visual acuity slightly improved after treatment (20/50-20/30; P = 0.076). No side effects were noted after bleomycin injections. CONCLUSIONS: Bleomycin injections for LM/LVM of the orbit are effective; local or systemic side effects were not seen in this series. To the best of our knowledge, this is the largest reported series of this treatment.

[PREVALENCE OF DEMODEX PARASITES IN PATIENTS WITH CHRONIC BLEPHARITIS AND HEALTHY CONTROLS IN ISRAEL].

INTRODUCTION: Previous studies demonstrated the potential pathogenic relationship between infestation of the eyelashes by the parasite Demodex and chronic blepharitis, whereas other studies did not demonstrate such relations and concluded that Demodex is a normal eyelid flora. AIMS: This study examines the prevalence of Demodex in patients with blepharitis compared to a healthy control group in Israel, in order to further explore and establish its pathogenic role in cases of chronic blepharitis. METHODS: A case-control study was conducted including 110 participants: 60 patients with chronic blepharitis attending a tertiary medical center and 50 subjects with no signs of blepharitis. Six to eight eyelashes were epilated from each participant and studied microscopically for the presence of Demodex by a blinded examiner. Fluorescein stain was added to the "clean" samples in order to reduce the false negative results. RESULTS: Demodex were identified on the eyelashes of 44 patients with blepharitis (73.3%) and 20 controls (40%) (p<0.001). After adjusting for age, blepharitis was still a significant risk factor for the presence of Demodex (OR=2.96, CI 95% 1.2-7.3). CONCLUSIONS: This study supports previous studies demonstrating pathogenic relationship between Demodex infestation of the eyelashes to chronic blepharitis. The authors recommend epilating 6-8 lashes of patients with blepharitis for microscopic identification of these parasites. Fluorescein stain may have a limited role in the recognition of Demodex in parasite free samples.

Use of a silicone shield to protect the optical cylinder following osteo- and osteo-odonto-keratoprosthesis (O/OKP) procedures.

PURPOSE: To describe the placement of a silicone shield to protect the optical cylinder following osteo-keratoprosthesis or osteo-odonto-keratoprosthesis (O/OKP) procedures in four patients. METHODS: In this retrospective observational study, we reviewed all patients who underwent O/OKP in our tertiary medical centre. We found four patients in whom a protective cellphone silicone shield (VisionGuard+, Zagg, Utah, USA) was cut with a 3 mm dermal punch and placed on the polymethyl methacrylate (PMMA) optical cylinder of an O/OKP 3-4 months after implantation to either correct or prevent abrasions. RESULTS: The first patient presented with a severely abraded OOKP optic that reduced BCVA from 6/6 to 6/20. The shield smoothed the optical surface and filled minor scratches, leading to BCVA improvement to 6/9. In the subsequent three patients, the optic was relatively clear, and the shield was used as a preventive measure. In two patients, the shield fell off after a few weeks and was replaced. CONCLUSIONS: Placing a protective silicone shield on the optical cylinder of an O/OKP can prevent permanent abrasions and, in an already scratched polymethyl methacrylate (PMMA) optic cylinder, improve vision by smoothing the surface. This intervention can be clinically significant, considering that the optical cylinder cannot be removed after implantation.

The initial rate of tumour response to vismodegib treatment, can predict a complete response outcome for periocular LA-BCC.

PURPOSE: To establish a model to predict treatment outcome of periocular locally advanced basal cell carcinoma (POLA BCC) based on initial response to treatment with vismodegib (ErivedgeTM), a sonic hedgehog inhibitor. DESIGN: Subgroup analysis of data from the STEVIE study database. METHODS: Analysis of medical history, treatment protocol, and treatment outcome of POLA BCC tumours in a STEVIE study population of 244 POLA BCC patients treated with ≥1 dose of vismodegib. RESULTS: A predictive model for complete response (CR) was established based on the initial treatment response. A cutoff value of 20% reduction in tumour size at 3 months of treatment identified the patients with a high probability (82.76%) to achieve CR. A second cutoff value of 67.7% reduction in tumour size at 6 months of treatment improved the prediction to a 95.42% probability of a CR outcome. CONCLUSIONS: A treatment model was constructed based on the prediction of a CR outcome and the initial response to vismodegib treatment at 3 and 6 months. The study result provide significant new insights can facilitate decision-making on treatment management according to tumour response in patients with POLA BCC.

Primary cemiplimab treatment for orbital squamous cell carcinoma is effective and may alleviate the need for orbital exenteration.

PURPOSE: To evaluate the effectiveness of cemiplimab, a Programmed-cell-death-1(PD-1) protein inhibitor, for the treatment of cutaneous periocular-locally-advanced squamous-cell-carcinoma (POLA-SCC) with orbital-invasion. METHODS: Multicentre real-world retrospective study. Demographic and clinical data were collected and analysed for patients with biopsy-proven POLA-SCC(AJCC-T4) with orbital-invasion who were treated with cemiplimab at one of four tertiary medical centres in 2019-2022. RESULTS: The cohort included 13 patients, 8 males and 5 females, of median age 76 years (IQR65-86). The median duration of treatment was 5.0months (IQR3.5-10.5) and the median follow-up time, 15.0 months (IQR10.5-30). The overall response rate was 69.2%. Complete response was documented in seven patients (53.8%), partial response in two (15.4%), stable disease in one (7.7%), and progressive disease in two (15.4%); in one patient (7.7%), response was not evaluable. Six complete responders (46.1% of the cohort) received no further treatment and did not have a recurrence during an average follow-up of 6.14 (±6.9) months from treatment cessation. None of the patients underwent orbital-exenteration. The majority of adverse events were mild (grade-1), except for a moderate increase in creatinine level (grade-2), severe bullous dermatitis (grade-3), and myocarditis (grade-5) in one patient each. Four patients (30.7%) died during the follow-up period, all of whom had an Eastern-Cooperative-Oncology-Group score of 4 at presentation. CONCLUSIONS: To our knowledge, this is the largest study to date on cemiplimab therapy for cutaneous POLA-SCC with orbital-invasion. Treatment was shown to be effective, with an overall response rate of 69.2%. Cemiplimab holds promise for the treatment of patients with tumours invading the orbit as it may alleviate the need for orbital exenteration.

Vismodegib improves quality of life in patients with periocular locally advanced basal cell carcinoma: subgroup analysis, STEVIE trial.

OBJECTIVES: To evaluate the effect of locally advanced periocular basal cell carcinoma (POLA-BCC) on health-related quality of life (HRQoL) and the benefit of vismodegib treatment among participants in the Safety Events in Vismodegib (STEVIE) trial between 2011 and 2017. METHODS: The STEVIE trial was conducted in patients with BCC (all anatomic locations) who were treated with vismodegib in 28-day cycles. Patients completed the Skindex-16, a validated questionnaire for the analysis symptoms, emotions, and functioning, at baseline, on day 1 of cycle 2, on day 1 of cycle 7, and at the end-of-study visit. For the present study, data mining techniques were used to construct an ophthalmic database of the STEVIE study. Skindex-16 scores were compared among patients with POLA-BCC between baseline and follow-up and between patients with POLA-BCC and patients with locally advanced BCC on other sites of the head and face (controls). RESULTS: The cohort included 169 patients with POLA-BCC and 428 patients with non-periocular head BCC. Patients with POLA-BCC had a significantly worse overall functioning score at baseline than controls (p = 0.038) and a lower score specifically in activities of daily living (p = 0.001). At the last follow-up, patients with POLA-BCC showed significant improvement in scores for functioning (100%), symptoms (100%), and emotions (75%) relative to baseline. CONCLUSIONS: Secondary analysis of the results of the STEVIE trial showed that the HRQoL of patients with POLA-BCC is significantly impaired and can be greatly improved with vismodegib treatment.

Orbital Lymphatic-Venous Malformation Accompanied by an Intraocular Vascular Malformation: A Rare Case Study.

Lymphatic-venous malformations (LVMs) are development defects that result in abnormal connections between the lymphatic and venous systems. The authors describe a 7-weeks-old female infant who presented with a right orbital LVM extending to the ipsilateral cheek and subconjunctiva of the right eye, intracranial developmental venous anomalies in the right cerebellum, and a significant right eye intraocular retinal vascular malformation. Since orbital LVM is usually diagnosed in infancy or childhood, pediatric ophthalmologists should actively look for intraocular vascular malformations as such findings can poorly affect a patient's vision.

Outcomes of Vismodegib for Periocular Locally Advanced Basal Cell Carcinoma From an Open-label Trial.

Importance: The outcomes of vismodegib treatment in a relatively large cohort of study participants with periocular locally advanced basal cell carcinoma (POLA-BCC) may guide physicians when considering this treatment. Objective: To report the outcomes of vismodegib treatment in patients with POLA-BCC in the Safety Events in Vismodegib (STEVIE) study. Design, Setting, and Participants: This post hoc subgroup analysis from the STEVIE single-arm, multicenter, open-label cohort study screened all 1215 participants for ocular or periocular involvement and identified 244 participants with POLA-BCC or metastatic BCC. Data for the first STEVIE trial were collected from 167 treatment locations in 36 countries from June 30, 2011, to June 14, 2017. This post hoc analysis was performed from April 1 to August 31, 2019. Main Outcomes and Measures: Response to treatment and adverse events. Results: Ocular or periocular involvement was found in 244 of 1215 STEVIE participants (20.1%), who constituted the analytic sample. The median age of the study participants was 72.0 (interquartile range [IQR], 60.0-82.0]) years, and they included 143 men (58.6%). Locally advanced BCC was diagnosed in 238 of the 244 participants (97.5%) and metastatic BCC, in 6 (2.5%). The median duration of exposure to vismodegib was 40.0 (IQR, 20.0-78.0) weeks, specifically 39.7 (IQR, 19.9-76.0) weeks for POLA-BCC and 92.4 (IQR, 53.2-163.0) weeks for metastatic BCC. Sixty-nine participants (28.3%) sustained serious adverse events (alopecia, muscle spasms, dysgeusia, weight loss, decreased appetite, asthenia, ageusia, nausea, fatigue, and diarrhea). Two hundred thirty-two study participants (95.1%) sustained more than 1 adverse effect. The overall mean (SD) number of drug-related adverse effects per study participant by first adverse event, regardless of the severity, was 5.48 (3.84). Discontinuation of vismodegib treatment owing to an adverse event was recorded in 58 participants (23.8%). During the study, 22 participants (9.0%) died, 70 (28.7%) achieved complete response, and 94 (38.5%) achieved partial response. Conclusions and Relevance: Vismodegib was well tolerated by the study participants with POLA-BCC. The safety of vismodegib treatment according to the STEVIE trial findings is consistent with that reported in previous studies. These data may be helpful when considering vismodegib for patients with POLA-BCC.

Investigating animal models of optic neuropathy: An accurate method for optic nerve and chiasm dissection in mice.

BACKGROUND: Numerous disorders affecting the optic nerve require histological examination of whole length optic nerves and chiasm. Most methods employed to study the histopathology of the optic nerves in animal models of human diseases involve resection of a short retrobulbar section after eye globe exenteration, commonly obtained in mice. This approach might affect the morphology of the optic nerve, thus limiting accurate identification of pathological changes in the tissue. Some histological studies were performed on longer or more posterior parts of the anterior visual pathway included the chiasm. However, an accurate replicable protocol for such whole length (eye globe to chiasm) dissection is currently unavailable in published literature. NEW METHOD: Here we describe a protocol for dissecting the whole length of the optic nerves and chiasm through a craniotomy incision. RESULTS: We describe in detail the stages necessary for exposing the optic nerves, the chiasm and the optic tracts, and for detaching them with minimal traction. COMPARISON WITH EXISTING METHOD: The existing replicable method provide only a sample of the retrobulbar optic nerve and the sample might be affected by traction. Our protocol provides a whole length specimen of the optic nerve and chiasm without concern of traction artifacts. CONCLUSIONS: We present a simple and straightforward approach to isolate the complete anterior visual pathway in the mouse for histopathological evaluation.

Gene-Related Response of Basal Cell Carcinoma to Biologic Treatment with Vismodegib.

We aimed to characterise the response of locally advanced basal cell carcinoma (BCC) to systemic treatment with Vismodegib, a Hedgehog pathway inhibitor, by changes in the expression levels of Hedgehog pathway genes. Data were collected prospectively on 12 patients treated systemically for locally advanced BCC. Biopsy samples taken on admission and after treatment cessation were analysed pathologically and with the NanoString nCounter system to quantify the expression of 40 Hedgehog signaling pathway genes. Findings were compared before and after treatment, between complete and partial responders, and with localised BCC samples from 22 patients. Sixteen Hedgehog pathway genes changed significantly from before to after treatment. GAS1 was the only gene with a significantly different expression at baseline between complete responders (6 patients) and partial responders (4 patients) to Vismodegib (P = 0.014). GAS, GLIS2 and PRKACG1 showed different expression before treatment between the locally advanced and localised BCCs. The baseline expression level of GAS1 appears to be predictive of the response of locally advanced BCC to systemic Vismodegib treatment. A change in expression of many Hedgehog pathway genes, albeit expected by the known activity of Vismodegib, may nevertheless serve as an indicator of the response potential of the tumour.

Prostaglandin analogue drops for the treatment of soft tissue expansion and exophthalmos in patients with inactive thyroid eye disease.

OBJECTIVE: Thyroid eye disease (TED) is characterized by an inflammatory response leading to soft tissue expansion within the bony orbit, which may cause exophthalmos. Studies of glaucoma patients reported periorbital fat atrophy after treatment with prostaglandin analogue drops. We hypothesize that owing to this side effect, prostaglandin analogue drops may benefit patients with TED-induced exophthalmos. DESIGN: Interventional prospective pilot study. PARTICIPANTS: Five adults with inactive TED and exophthalmos treated with a single daily drop of bimatoprost to both eyes for 6 months. METHODS: The effect of treatment was evaluated by clinical examinations, Hertel exophthalmometry, marginal reflex distance (MRD), and comparison of digital photographs from before and after treatment by 3 masked oculoplastic surgeons. Patients' subjective satisfaction was recorded as well. RESULTS: Hertel exophthalmometry showed an improvement in exophthalmos after treatment in 3 patients and no change in 2. Both MRD1 and MRD2 increased (for MRD2 p = 0.007). Two observers correctly identified the photograph taken after treatment in 4 patients, and the third observer correctly identified 2 patients and was indecisive about the others. Four patients reported an improvement in their appearance, although additional eyelid retraction was observed. Adverse effects were minimal. CONCLUSION: Topical prostaglandin analogue treatment of TED-associated exophthalmos appears safe. Although this pilot study was statistically underpowered to show positive results, our findings suggest a treatment-related reduction in periorbital fat volume in most cases and a subjective improvement in appearance. These findings have potential implications for the treatment of exophthalmos in the clinical setting, but more research is required.

Efficacy of Vismodegib for the Treatment of Orbital and Advanced Periocular Basal Cell Carcinoma.

PURPOSE: To evaluate the effectiveness of vismodegib, a Hedgehog pathway inhibitor, in treating orbital and advanced periocular basal cell carcinoma (BCC) in Israeli multidisciplinary medical centers. DESIGN: Retrospective case series. METHODS: Background, treatment, and outcome data were retrospectively collected from the medical records of all patients with locally advanced and metastatic orbital or periocular BCC treated with vismodegib in 2012-2017 at 2 tertiary medical centers. RESULTS: The cohort included 21 patients (16 male) of median age 76 years with periocular (n=6) or orbital (n=15) BCC. Median duration of treatment was 9 months, with follow-up of 26 months (range 9-60 months) overall and 17 months after treatment cessation. Clinical response was complete in 10 patients, partial in 10 patients, and stable in 1 patient. Among the complete responders, 5 maintained a complete response at 16 months, and 3 who stopped treatment had a recurrence 8 months later. Almost all treatment-related adverse reactions were graded 1 or 2 (low-grade). The most common grade 1 or 2 complications were muscle spasm (76%), followed by dysgeusia (57%), alopecia (47%), weight loss (47%) and decreased appetite (19%). The only grade 3 or 4 adverse event was hepatotoxicity (10%). Eight patients discontinued treatment because of side effects. Five patients died, most from reasons unrelated to vismodegib therapy, except for 1 patient who died from possibly treatment-related sepsis (grade 5 adverse event). CONCLUSIONS: To our knowledge, this is the only study generated outside the United States and Europe, and it represents the largest study to date on vismodegib therapy for locally advanced periocular BCC. Treatment according to an individualized maximally tolerated dose may achieve a comparable response to the ERIVANCE protocol. Longer-term studies are needed to assess prognosis.

Challenging Management of Double Vision After Functional Endoscopic Sinus Surgery-A Series of 6 Cases.

PURPOSE: To present 6 cases of orbital trauma, diplopia and strabismus after functional endoscopic sinus surgery (FESS). DESIGN: Retrospective observational case series. METHODS: The medical charts of suitable patients were reviewed for information on medical examination, imaging studies, the type of corrective surgery, and surgical outcomes. STUDY POPULATION: All patients with diplopia and strabismus after undergoing FESS who were treated or consulted at our institution between 2008 and 2017 were included. MAIN OUTCOME MEASURES: The presence and extent of strabismus and double vision at the end of follow-up. RESULTS: Six patients complained of diplopia after FESS; all of them had proven orbital trauma. In Cases 1-5, patients suffered medial rectus (MR) muscle transection and subsequent exotropia. Their prognosis was guarded despite prompt surgical intervention, and ranged from large exotropia when direct recovery of the MR was attempted, to primary gaze orthotropia but with minimal adduction capacity, during which vertical recti transposition was attempted. Patient 6 sustained transient diplopia, although all of his extraocular muscles appeared intact on imaging. His eye position and movement were completely resolved with conservative measures only. CONCLUSIONS: Our experience was that immediate recovery procedures to reattach the muscle in cases with proven transection of the MR muscle are futile, and that definitive corrective strabismus surgery (ie, vertical muscle transposition) has a better chance to achieve favorable results.

[Thyroid orbitopathy].

Thyroid Orbitopathy (T.O) is the most common orbital disease caused by a systemic illness. The clinical manifestations of T.O are a result of inflammation, edema and scarring of orbital tissue, and include exophthalmos, soft tissue edema, lid retraction, chemosis, exposure keratitis that can lead to corneal ulceration and perforation, ocular motility disorders and strabismus, and compressive optic neuropathy. T.O is an autoimmune disease but the exact etiology is yet to be revealed. Most cases resolve spontaneously without the need for medical or surgical intervention, but more severe cases may result in devastating visual and cosmetic results. In recent years, there has been a significant progress in the understanding of the disease and the medical and surgical treatment of T.O. This work reviews new aspects of T.O and it's surgical treatment, and include clinical photographs of patients operated on in our department.

Multiple Conjunctival Papillomas of Eyelid Margins in Pemphigus vulgaris.

Ocular involvement in pemphigus vulgaris (PV) ranges from mild conjuctivits to conjunctival blisters and rarely prominent erosions of the bulbar and palpebral conjunctiva which may be found at the eyelid margin. We report two unusual cases of PV patients presenting with multiple conjunctival papillomatous lesions of the eyelids margins.

Preoperative Visual Loss is the Main Cause of Irreversible Poor Vision in Children with a Brain Tumor.

The purpose of this study was to characterize the severe postoperative irreversible visual loss induced by optic neuropathy in some children with a brain tumor. The computerized database (2003-2008) of a neuro-ophthalmology service of a major pediatric tertiary center was reviewed for all children with severe irreversible visual loss (counting fingers or less) due to brain-tumor-related optic neuropathy at their last follow-up examination. Data on age, gender, etiology, initial symptoms, and signs, visual acuity before and after surgery and at last examination, neuroimaging findings, and treatment were collected. Of 240 children, 198 were operated. Of those, 10 (5%, 5 boys and 5 girls) met the study criteria. Data for the initial visual examination were available for eight children: one had binocular blindness (uncertain light perception, counting fingers); three had monocular blindness already at diagnosis (no light perception, counting fingers, no fixation); three had 6/60 vision in the worse eye; and one had good vision bilaterally (6/10). Four children had direct optic nerve compression, four papilledema, and three gliomas. Four children (40%; with craniopharyngioma, pineal germinoma, or posterior fossa tumor) exhibited a rapid deterioration in vision after tumor depression (one direct optic nerve compression and three increased intracranial pressure); two had monocular visual loss postoperatively; vision remained stable in four (after ≥5 follow-up visits), but did not improve. This study shows that tumor-related optic neuropathy may be associated with marked visual loss inspite of successful tumor resection; in 40% of children, the deterioration occurs perioperatively. Direct compression is the main cause of visual loss, while papilledema usually resolved without visual sequelae. However, autoregulatory changes may be responsible for rapid visual loss following decompression for chronic papilledema. Clinicians need reminding about the problem of postoperative visual loss and we speculate on how it can be avoided.