Foveal Hypoplasia in CRB1-Related Retinopathies.

The CRB1 gene plays a role in retinal development and its maintenance. When disrupted, it gives a range of phenotypes such as early-onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA), retinitis pigmentosa (RP), cone-rod dystrophy (CORD) and macular dystrophy (MD). Studies in CRB1 retinopathies have shown thickening and coarse lamination of retinal layers resembling an immature retina. Its role in foveal development has not yet been described; however, this retrospective study is the first to report foveal hypoplasia (FH) presence in a CRB1-related retinopathy cohort. Patients with pathogenic biallelic CRB1 variants from Moorfields Eye Hospital, London, UK, were collected. Demographic, clinical data and SD-OCT analyses with FH structural grading were performed. A total of 15 (48%) patients had EOSRD/LCA, 11 (35%) MD, 3 (9%) CORD and 2 (6%) RP. FH was observed in 20 (65%; CI: 0.47-0.79) patients, all of whom were grade 1. A significant difference in BCVA between patients with FH and without was found (p = 0.014). BCVA continued to worsen over time in both groups (p < 0.001), irrespective of FH. This study reports FH in a CRB1 cohort, supporting the role of CRB1 in foveal development. FH was associated with poorer BCVA and abnormal retinal morphology. Nonetheless, its presence did not alter the disease progression.

Identifying Meibomian Gland Dysfunction Biomarkers in a Cohort of Patients Affected by DM Type II.

(1) Background: Meibomian gland dysfunction (MGD) among patients with diabetes mellitus (DM) is a common manifestation of dry eye syndrome (DES). (2) Methods: The purpose of this study is to identify clinical parameters and biomarkers useful to improve the follow-up and the treatment of these patients. We have used an ocular surface disease index (OSDI) questionnaire, Schirmer test I/II, tear film break-up time (TF-BUT), fluorescein plus lissamine green staining, Marx's line (ML), and meibomian gland (MGs) morphology using Sirius® Topographer (CSO, Costruzione Strumenti Oftalmici, Florence, Italy). Blood sample analysis included glucose, glycated hemoglobin, lipid profile, cortisol, dehydroepiandrosterone sulfate (DHEA-S), androstenedione (ASD) and testosterone. (3) Results: Cortisol and ASD were positively correlated with an increase of MG tortuosity, and an Increased level of triglycerides was associated with a reduction of MGs length. DHEAS levels lowered with age and were associated with ocular surface staining. (4) Conclusions: Future studies, perhaps including meibum lipid analysis and tear cytokine levels, may also further elucidate the connection between these parameters, MG architecture and function.

Long-term outcomes of margin-controlled excision for eyelid melanoma.

OBJECTIVES: To provide evidence for long-term outcomes for margin-controlled excision of eyelid melanoma. METHODS: Retrospective single-centre observational case series of patients treated for eyelid melanoma between 2007 and 2016, with a minimum of 5-year follow-up. Tumour excision involved rush-paraffin en face horizontal sections and delayed repair (Slow Mohs; SM). RESULTS: Twenty-two cases were seen with a survival of 91% (two deaths from nodular and lentigo maligna melanoma) and seven with melanoma in situ (MIS). Invasive melanoma includes eight lentigo maligna melanoma, four nodular, two amelanotic and one desmoplastic. Mean Breslow thickness was 6 mm for invasive (range 0.5-26). Mean excision margin for MIS was 3 mm (range 2-5 mm) and for invasive was 5 mm (range 2-10). Further excisions were performed in nine (41%); two went on to recur. Local recurrence was 36%; six invasive (27%) at a mean of 24 months (range 1.5-5 years) and two for MIS at a mean of 15 months (range 1-1.5 years). Imaging occurred for suspected advanced disease. Sentinel node biopsy was not performed. Advanced melanoma therapy was performed in two cases. No vitamin D testing occurred. CONCLUSIONS: Survival rates are in line with 90% overall survival in the UK. Prescriptive excision margins are not applicable in the periocular region and margin-controlled excision with a delayed repair is recommended, but patients need to know further excision may be needed to obtain clearance. Evidence recommending vitamin D therapy needs to be put into clinical practice. In addition, upstaging of MIS occurred advocating excision rather than observation of MIS. More studies are needed to determine the best management of eyelid melanoma.

Differential expression of phosphorylated MEK and ERK correlates with aggressive BCC subtypes.

Basal cell carcinoma (BCC) is associated with aberrant Hedgehog (HH) signalling through mutational inactivation of PTCH1; however, there is conflicting data regarding MEK/ERK signalling in BCC and the signalling pathway interactions in these carcinomas. To address this, expression of active phospho (p) MEK and ERK was examined in a panel of 15 non-aggressive and 14 aggressive BCCs. Although not uniformly expressed, both phospho-proteins were detected in the nuclei and/or cytoplasm of normal and tumour-associated epidermal cells however, whereas phospho-MEK (pMEK) was present in all non-aggressive BCCs (14/14), phospho-ERK (pERK) was rarely expressed (2/14). In contrast pERK expression was more prevalent in aggressive tumours (11/14). Interestingly, pMEK was only localized to the tumour mass whereas pERK was expressed in tumours and stroma of aggressive BCCs. Similarly, pERK (but not pMEK) was absent in mouse BCC-like tumours derived from X-ray irradiated Ptch1+/- mice with stromal pERK observed in myofibroblasts of the aggressive variant as well as in the tumour mass. RNA sequencing analysis of tumour epithelium and stroma of aggressive and non-aggressive BCC revealed the upregulation of epidermal growth factor receptor- and ERK-related pathways. Angiogenesis and immune response pathways were also upregulated in the stroma compared with the tumour. PTCH1 suppressed NEB1 immortalized keratinocytes (shPTCH1) display upregulated pERK that can be independent of MEK expression. Furthermore, epidermal growth factor pathway inhibitors affect the HH pathway by suppressing GLI1. These studies reveal differential expression of pERK between human BCC subtypes that maybe active by a pathway independent of MEK.

The Genetic and Clinical Features of FOXL2-Related Blepharophimosis, Ptosis and Epicanthus Inversus Syndrome.

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 (FOXL2) gene. It shows autosomal dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic subtypes have been described, both involving the same craniofacial features: type I, which is associated with premature ovarian failure (POF), and type II, which has no systemic features. The genotype-phenotype correlation is not fully understood, but it has been hypothesised that type I BPES involves more severe loss of function variants spanning the whole gene. Type II BPES has been linked to frameshift mutations that result in elongation of the protein rather than complete loss of function. A mutational hotspot has been identified within the poly-alanine domain, although the exact function of this region is still unknown. However, the BPES subtype cannot be determined genetically, necessitating informed genetic counselling and careful discussion of family planning advice in view of the associated POF particularly as the patient may still be a child. Following puberty, female patients should be referred for ovarian reserve and response assessment. Oculofacial features can be managed with surgical intervention and regular monitoring to prevent amblyopia.

Diplopia Following the Insertion of a Canalicular Bypass Tube: Etiology, Risk Factors, Management, and Outcomes.

PURPOSE: To report the etiology, management, and possible risk factors for diplopia after canalicular bypass surgery. METHODS: A multicenter retrospective, noncomparative case series of patients who developed diplopia following canalicular bypass surgery were assessed. RESULTS: Twenty-four cases of diplopia were identified across 12 institutions. Tubes were inserted as a primary procedure with external dacryocystorhinostomy (DCR) (1; 4%) or without DCR (10; 42%) or as a secondary procedure after external (8; 33%) or endonasal (5; 21%) DCR. Factors predisposing to local damage were noted in 17 (71%): these factors included preexisting autoimmune/inflammatory condition (7 cases), medial canthal tumor resection (5 cases), preoperative radiotherapy (2 cases), 2 drug treatments (topical and systemic), and 1 local surgery. Horizontal diplopia was due to restriction of abduction and first noted at a median of 3.5 months (mean: 17.8 months, range: 1 day to 112 months) and persisted in 23 (96%) cases with a mean restriction of -2, affecting primary gaze in 4 patients and activities of daily living in 13 (42%). Seventeen patients received various treatments: 10 were operated on resulting in cure in 1 and improvement in 9. A stable degree of diplopia persisted in all but one patient. CONCLUSIONS: Restriction of abduction causing horizontal diplopia is a rare complication with canalicular bypass surgery and a notably high proportion occurred after tube placement without DCR; carunculectomy was not ubiquitous. Although in some the diplopia may be improved with intervention, the chance of cure is low. This complication should probably be included during informed consent for canalicular bypass tubes.

Switchover study of onabotulinumtoxinA to incobotulinumtoxinA for facial dystonia.

IMPORTANCE: When making a cost-saving it is important to ensure there is no loss of efficacy. BACKGROUND: Clinical effectiveness and efficiency of incobotulinumtoxinA compared to onabotulinumtoxinA in facial dystonia is unclear. Our aim is to evaluate switching from onabotulinumtoxinA to incobotulinumtoxinA in the treatment of essential blepharospasm (EB), hemifacial spasm (HFS) and aberrant facial nerve regeneration (AFR). DESIGN: A retrospective study of a prospective, single-masked switchover audit from onabotulinumtoxinA to incobotulinumtoxinA. PARTICIPANTS: Twenty essential EB, 12 HFS and six AFR patients. METHODS: A switchover from stable onabotulinumtoxinA to incobotulinumtoxinA using a 1:1 unit ratio and contemporaneous efficacy measures. Two nurse injectors performed the injections over a period of 6 years. Each masked patient received three onabotulinumtoxinA and three incobotulinumtoxinA over a minimum of 2 years. MAIN OUTCOME METHODS: At each visit, a blepharospasm disability score (BDS), Jankovic score (JS), subjective improvement (SI), duration of maximum effect (DME) and complications were recorded. A cost comparison per unit dose was made. RESULTS: Twenty EB, 12 HFS and six AFR received 114 onabotulinumtoxinA and 114 incobotulinumtoxinA treatments. Both brands had similar efficacy, but SI (P < .01) and DME (P < .05) were higher in the HFS group with incobotulinumtoxinA. Complications included bruising (two onabotulinumtoxinA, one incobotulinumtoxinA) and ptosis (three onabotulinumtoxinA, zero incobotulinumtoxinA). OnabotulinumtoxinA was 33% pricier. CONCLUSION AND RELEVANCE: Switching from onabotulinumtoxinA to incobotulinumtoxinA did not result in an inferior outcome for the treatment of facial dystonia and led to a cost-saving for the department.

Reporting outcomes of hyaluronic gel filler as a treatment for epiblepharon.

PURPOSE: Epiblepharon occurs when an extra skin fold overlaps on the eyelid margin with the isolated form mainly seen in children of east Asian origin. If symptomatic and the use of conservative measures such as lubricants have failed, surgery is usually indicated. This traditionally involves everting sutures or combined skin excision, such as a modified Hotz procedure. However, a temporizing non-surgical alternative to a skin removal procedure, especially if the natural history is for improvement as the child grows older, would be ideal. METHODS: This is a retrospective single-centre case review of epiblepharon cases treated with hyaluronic acid (HA; Restylane, Galderma UK) treated in the past 5 years by a single surgeon (RM). Institutional review board approval was obtained. Success is defined as improvement or stabilization of the class and/or keratopathy score of the epiblepharon. RESULTS: Five patients were identified with epiblepharon between 2012 and 2017 who had hyaluronic acid filler to 8 eyelids. Six eyelids had improvement, 1 remained stable and 1 was worse equating to an 87% success rate; however, 2 opted for reversal using hyaluronidase due to aesthetic reasons. Two went on to have further surgery as they partially responded to filler treatment. CONCLUSION: This study provides further proof of concept that HA is a simple non-surgical and reversible option that may avoid the need for surgery for epiblepharon in selected cases. It may even be considered in older children or adolescents with the caveat that fullness may require hyaluronidase to dissolve.

Dry eye after Lester Jones tube insertion for epiphora.

Purpose: To report the occurrence of dry eye after Lester Jones tube (LJT) insertion. Methods: Retrospective case series from a single unit. The dacrocystorhinostomy (DCR) was carried out using both endoscopic and external approachs; however, insertion of LJT used the same method as either a primary or secondary procedure. Dry eye as an outcome measure was only confirmed after three separate visits using the presence of both patient symptoms and dry eye signs with none preceding tube insertion. Results: Fifty-four patients underwent consecutive LJT insertion over a 5-year period. Mean age was 52.6 (range 25-73 years). The majority were female 39 (72%). Revision surgery was required in 15 (27%) with 3 or more occurring in 6 (11%). In total, 9 patients developed dry eyes (17%). Mean age was 60 (range 47-73) years, 5 females and 4 males. Four of the dry eye individuals had undergone primary LJT insertion and the remaining five received their first LJT 6-24 (mean 15) months post-DCR. Two dry eye patients had previously undergone LASIK and radiotherapy. Conclusion: A risk of dry eye following LJT placement is higher than the literature suggests. This should be considered and counseled, especially in those who have underlying pre-disposing factors. Ease of removal may be a desirable attribute in such cases.

Long-term outcome of flexible onabotulinum toxin A treatment in facial dystonia.

PURPOSE: The purpose of this study was to assess the long-term outcome of onabotulinum used to treat facial dystonia and compare a flexible and fixed treatment regimen. METHODS: This was a retrospective comparative study looking at benign essential blepharospasm (BEB), hemifacial spasm (HFS) and aberrant facial nerve regeneration synkinesis (AFR) treatment with onabotulinum toxin A (Botox®) over a minimum of 10 years. Fifty-one patients were recruited into the study, with each dystonia subgroup having 17 patients. Blepharospasm disability score (BDS), subjective improvement score (SIS), duration of maximal effect (DME) and complications were recorded at each visit. RESULTS: The mean age was 63 years and gender predominately female. Thirty-seven patients underwent flexible treatment intervals compared to 14 fixed treatment intervals, averaging 3.4 and 4 per annum, respectively. Mean BDS significantly improved from 6 to 3 at last review across all 3 groups, with the highest effect on BEB. BDS improvement was greater in flexible intervals. SIS remained similar for all three conditions during follow-up, but in those undergoing flexible intervals, SIS increased by a small margin compared to fixed interval. Mean DME was 10.5 weeks across all dystonias, but increased progressively only in the flexible interval group. Complications included ptosis (30%), dry eye (14%) and lagophthalmos (8%). CONCLUSION: Flexible onabotulinum provided better long-term relief on BDS for facial dystonia than a fixed regimen. Flexible interval treatment may also provide better patient satisfaction and longer DME compared to fixed treatment. Both have similar complication rates. With flexible treatment however, fewer injections were required over 10 years, leading to cost saving.

Stroke-induced resolution of primary blepharospasm: evidence for the lenticular nucleus as a control candidate.

Primary blepharospasm is an adult-onset focal dystonia characterised by involuntary contractions of the orbicularis oculi, leading to bilateral spasmodic closure of the eyelids. While spasms of this muscle constitute the hallmark of disease, other motor manifestations include increased spontaneous blinking and apraxia of eyelid opening. Originally misdiagnosed as a psychiatric condition, blepharospasm is now well established as being of neurological origin although questions remain as to its pathophysiological mechanisms.We report a 66-year-old woman who had a 14-year history of primary blepharospasm which completely resolved following a left medial cerebral artery thromboembolic infarct of the lenticular nucleus. This report provides supporting evidence of the lenticular nucleus as a key structure mediating the disease which can lead to functional blindness.

MicroRNA and transcriptome analysis in periocular Sebaceous Gland Carcinoma.

Sebaceous gland carcinoma (SGC) is a rare, but life-threatening condition with a predilection for the periocular region. Eyelid SGC can be broadly categorised into two subtypes, namely either nodular or pagetoid with the latter being more aggressive and requiring radical excision to save life. We have identified key altered microRNAs (miRNA) involved in SGC shared by both subtypes, hsa-miR-34a-5p and hsa-miR-16-5p. However, their gene targets BCL2 and MYC were differentially expressed with both overexpressed in pagetoid but unchanged in nodular suggesting different modes of action of these two miRNAs on BCL/MYC expression. Hsa-miR-150p is nodular-specifically overexpressed, and its target ZEB1 was significantly downregulated in nodular SGC suggesting a tumour suppressor role. Invasive pagetoid subtype demonstrated specific overexpression of hsa-miR-205 and downregulation of hsa-miR-199a. Correspondingly, miRNA gene targets, EZH2 (by hsa-miR-205) and CD44 (by hsa-miR-199a), were both overexpressed in pagetoid SGC. CD44 has been identified as a potential cancer stem cell marker in head and neck squamous cell carcinoma and its overexpression in pagetoid cells represents a novel treatment target. Aberrant miRNAs and their gene targets have been identified in both SGC subtypes, paving the way for better molecular understanding of these tumours and identifying new treatment targets.

Analysis of hedgehog signaling in periocular sebaceous carcinoma.

PURPOSE: Sebaceous carcinoma (SC) is a clinical masquerader of benign conditions resulting in significant eye morbidity, sometimes leading to extensive surgical treatment including exenteration, and even mortality. Little is known about the genetic or molecular basis of SC. This study identifies the involvement of Hedgehog (Hh) signaling in periocular SC. METHODS: Fifteen patients with periocular SC patients were compared to 15 patients with eyelid nodular basal cell carcinoma (nBCC; a known Hh tumor), alongside four normal individuals as a control for physiological Hh expression. Expression of Patched 1 (PTCH1), Smoothened (SMO), and glioma-associated zinc transcription factors (Gli1 and Gli2) were assessed in histological sections using immunohistochemistry and immunofluorescence (IF) techniques. Antibody specificity was verified using Western-blot analysis of a Gli1 over-expressed cancer cell line, LNCaP-Gli1. Semi-quantification compared tumors and control tissue using IF analysis by ImageJ software. RESULTS: Expression of the Hh pathway was observed in SC for all four major components of the pathway. PTCH1, SMO, and Gli2 were more significantly upregulated in SC (P < 0.01) compared to nBCC. Stromal expression of PTCH1 and Gli2 was observed in SC (P < 0.01). In contrast, stromal expression of these proteins in nBCC was similar or down-regulated compared to physiological Hh controls. CONCLUSIONS: The Hh signaling pathway is significantly more upregulated in periocular SC compared to nBCC, a known aberrant Hh pathway tumor. Furthermore, the stroma of the SC demonstrated Hh upregulation, in particular Gli2, compared to nBCC. Targeting of this pathway may be a potential treatment strategy for SC.

The use of a pleated strip of autogenous temporalis fascia graft for frontalis suspension in recurrent poor levator function ptosis in adult patients.

PURPOSE: Poor levator function (LF) blepharoptosis can be corrected surgically using frontalis muscle suspension with a variety of materials. Autogenous grafts such as fascia lata are commonly used. The need for a remote surgical site and the risk of an unattractive leg scar makes the use of an autogenous temporalis fascia (ATF) graft appealing as the scar is concealed in the hair. We describe the use of a pleated, lengthened ATF graft that is easy to prepare and insert, and provides a cosmetically acceptable outcome. METHODS: Prospective case series describing six patients with previous multiple failed lid surgeries and recurrent poor (≤ 5 mm) LF (mean 2.87 ± 1.72 mm) ptosis. The pleated graft technique was used to yield a strip of ATF up to 18-cm long from a short 2-cm temporal incision. Eight eyelids then underwent ATF graft frontalis suspension surgery using the modified Fox pentagon technique. Outcomes included eyelid measurements with 4.5-year follow-up. RESULTS: All patients achieved good functional and esthetic outcome. The mean central palpebral aperture 6 weeks postsurgery was 7.14 ± 1.67 mm, equating to a mean increase of 3.27 mm (p < 0.05 using the paired t-test). The improvement in eyelid height was maintained at the 4.5-year follow-up in all patients, except one who died of unrelated cause. CONCLUSION: A pleated strip of ATF graft provides a simpler alternative to fascia lata grafting for frontalis suspension in poor LF ptosis in adult patients with good long-term results.

Cosmetic comparison of gold weight and platinum chain insertion in primary upper eyelid loading for lagophthalmos.

PURPOSE: Platinum chains are thinner than gold weights (GWs) and may confer a better eyelid curvature profile with reduced visibility. Outcomes compared eyelid measurements, cosmesis, and complications. METHODS: Forty-two primary GW and 17 primary platinum chain insertions were identified and subsequently matched for laterality, pathology, and weight of implant. Twenty-two patients were randomly allocated into 2 groups for comparison; those receiving a GW (n = 11) or platinum chain (n = 11) to formulate a retrospective case-controlled study. Primary upper eyelid loading surgery with both implants involved a standard technique of a high tarsal placement with levator recession. Blinded assessment of preoperative and 6-month postoperative photographs calculated eyelid parameters: upper marginal reflex distance and lagophthalmos. Standardized photographs were used to define cosmesis in terms of abnormal eyelid contour and prominence. RESULTS: Gold weights demonstrated an improvement in eyelid parameters. Nine eyelids had prominent implants: mild (2), moderate (3), and severe (4). Eyelid contour was affected in 7 patients, 5 with droop, and 2 with flattened contour. Platinum chain improved eyelid measurements. Mild eyelid prominence was noted in 2 cases, but eyelid contour remained normal in all patients. No complications were noted with either the GW or the platinum chain implants. CONCLUSION: Both devices are successful in treating complications of lagophthalmos. Platinum chains appear less prominent and maintain normal eyelid contour. Although more expensive, platinum chains appear to be as safe and effective as GWs yet provide better cosmesis.

Indications and outcomes for revision of gold weight implants in upper eyelid loading.

BACKGROUND: Gold weights are effective for upper eyelid loading in patients with lagophthalmos. Complications include poor cosmesis, migration, extrusion, allergy and astigmatism. The authors looked at indications for revision of primary gold weights inserted using a high pretarsal placement and outcomes following correction. METHODS: A retrospective review of 107 consecutive primary gold weight implants in 95 patients with lagophthalmos in a single centre over a 5-year period. Implant placement utilised a combined high pretarsal placement, levator recession and fixation. Revision surgery included repositioning, removal or exchange. Blinded assessment of eyelid parameters, including cosmesis, was performed by an independent reviewer using photographs from each revision case taken preoperatively and 6 months postoperatively. RESULTS: Mean follow-up 2.5 years (range 1-5) with 15/107 (14%) eyelids revised, the majority within 12 months of the primary procedure. Five eyelids required up to 3 further revisions, giving 21 revisions in total. Indications included prominent implants in 15/21 (71%) revisions; poor eyelid contour in 14/21 (67%, 9 drooped and 5 flattened eyelids); extrusion in 2/21 (10%); persistent erythema in 8/21 (29%, 5 gold allergies and 1 extrusion). Revisions consisted of platinum chain exchange (6), replacement (3), repositioning (8) and removal (4). Following final revision, eyelid contour returned to normal and five eyelids demonstrated mild prominence. CONCLUSION: High pretarsal placement was successful in treating lagophthalmos, with a complication rate of 1 in 6 requiring a revision procedure, the majority within 12 months. Main indications were unsatisfactory cosmesis from prominence of implant and poor eyelid contour.

Transient internal ophthalmoplegia after inferior oblique myectomy.

Internal ophthalmoplegia causing pupillary dilatation and loss of accommodation following damage to the ciliary ganglion is a rare complication of strabismus surgery. Here we report a case of parasympathetic neuropraxia resulting in transient internal ophthalmoplegia after inferior oblique myectomy in a 12-year-old girl. Short-term symptomatic relief was achieved with 1% pilocarpine. Normal visual function returned over several months.