Methotrexate as an Adjuvant in Severe Thyroid Eye Disease: Does It Really Work as a Steroid-Sparing Agent?

PURPOSE: To compare the efficacy and safety of adjunctive oral methotrexate with intravenous pulsed methylprednisolone against methylprednisolone alone in the treatment of severe thyroid eye disease. METHODS: Retrospective review of clinical data of patients with severe sight-threatening thyroid eye disease with compressive optic neuropathy treated with methylprednisolone with and without methotrexate. Eye disease outcome measures (e.g., VISA inflammatory score and vision) at 0, 3, 6, 12, and 18 months were recorded. RESULTS: There were 72 subjects including 33 who had methylprednisolone alone and 39 with methylprednisolone with methotrexate. There were no statistical differences in demographics and baseline measures of disease activity or vision between the 2 treatment groups. No significant statistical differences in the cumulative dosage of methylprednisolone or occurrence of restrictive myopathy, raised intraocular pressure, proptosis, and exposure keratopathy between the groups at 0, 3, 6, 12, and 18 months were found. However, subjects who received methylprednisolone with methotrexate had better visual acuity of more than 2 lines on Snellen chart (p = 0.026) and VISA inflammatory score (p = 0.034) at 3 months, but no differences at 6, 12, and 18 months. Three patients who received methylprednisolone with methotrexate had transient worsening of liver function. No patient developed severe adverse reaction. CONCLUSIONS: The results demonstrated improved vision and disease activity at 3 months in the combination treatment group. This may suggest that the addition of methotrexate to methylprednisolone is beneficial for accelerating suppression of disease activity and hastens visual recovery. Addition of methotrexate to methylprednisolone did not reduce the requirement for steroids.

What is the aim of immunosuppressive treatment in patients with graves' orbitopathy?

PURPOSE: The EUGOGO criteria and the clinical activity score (CAS) have been used as outcome measures to report response rates for patients after pulsed intravenous methylprednisolone (PIM) therapy. This study compares the results after PIM for both criteria and evaluates the number of rehabilitative surgeries performed in relation to treatment outcome. METHODS: This was a retrospective review of patients with active moderate-to-severe Graves' orbitopathy (GO) treated with PIM (cumulative dose of 4.5 to 5 g). The EUGOGO criteria or improvement in CAS (≥2 points) was used as the primary outcome measure. Baseline characteristics were examined to evaluate any determinants of treatment response. Additional immunosuppressive therapy after PIM and rehabilitative surgical procedures for all patients within a 2-year period were also recorded. RESULTS: Thirty-two patients were identified. Using the EUGOGO criteria, an improvement was seen in 38%, no change (stabilization) in 47%, and worsening of the disease in 15%. The response rate using the CAS was 63%. According to the EUGOGO criteria and the CAS, 20% (4/20) and 33% (4/12) of nonresponders required additional immunosuppressive treatment after PIM. None of the responders required additional immunosuppressive therapy. There was a reduction of 0.5 surgeries per patient for responders using either outcome measures. CONCLUSIONS: In this study, PIM alone stabilizes active GO in 85% and reduces the severity of GO in 38% of the patients. Despite incongruent response rates obtained using the EUGOGO criteria and the CAS, both outcome measures were good predictors for additional immunosuppressive treatment and additional rehabilitative surgeries in nonresponders.

Neuroendocrine tumors of the orbit--clinicopathological findings in 3 more cases of this rare entity and review of the literature.

INTRODUCTION: Neuroendocrine orbital tumors are rare occurrences. They are poorly characterized histologically and a spectrum of different cell types exists. This short case series studies the various tumor morphologies as well as the patients' clinical profiles. METHODS AND MATERIALS: Patients treated and followed up at the Singapore National Eye Centre over a period of 8 years from 1(st) January 2002 to 31(st) December 2009 were identified from the orbital tumor board results. The case notes of patients with the diagnosis of neuroendocrine tumors were analysed, and a review of the literature performed. RESULTS: Three patients are described in this series. The history, clinical examination findings, imaging findings as well as tumor histology were described. The mean age was 63 years, and 2 patients were male. All presented with proptosis. Only one patient had systemic symptoms on presentation. All patients had surgical excision of the tumor and two had adjuvant radiotherapy of the orbit. Median follow-up period was 3.5 years. DISCUSSION: Patients with a biopsy-proven diagnosis of orbital neuroendocrine tumors should be monitored even when systemic examination fails to identify peripheral disease. Such examination should always include a full endoscopic gastrointestinal review.

Orbital cellulitis in children-medical treatment versus surgical management.

INTRODUCTION: Ophthalmologists differ in their threshold for surgical management in paediatric patients with orbital cellulitis. We studied the management choices and outcome of children admitted with this disorder. MATERIAL AND METHODS: A retrospective review was performed on patients with orbital cellulitis admitted between January 2001 and December 2004 to a tertiary paediatric referral centre in Singapore. The patients were studied for age, associated systemic disease, medical treatment, drainage procedure undertaken, organism isolated and outcome. Statistical methods were applied for comparing medical treatment with surgical treatment with respect to recovery time, recurrence, and time between the presentation of patient and initiation of treatment. RESULTS: Twenty patients were studied. Average age was 5.5 years. 5/20 (25%) had a preceding history of upper respiratory tract infection. From CT findings, we came to know that 3/20 (15%) were due to isolated ethmoiditis, 5/20 (25%) had obstruction of the osteomeatal complex of the paranasal sinuses, 2/10 (10%) had intracranial abscesses due to frontal sinusitis. 4/20 (20%) had all 4 ipsilateral paranasal sinuses infected. 2/20 (10%) had preseptal cellulitis with posterior extension into the orbit. 2/20 (10%) had orbital cellulitis related to dacryoadenitis and 2/20 (10%) had pansinusitis with orbital soft tissue stranding. 13/20 (65%) had orbital and /or endoscopic drainage. The remainder of the patients had good immediate response to sole medical treatment and did not require surgery. The most commonly isolated organism was Staphylococcus aureus 5/20 (25%). All patients recovered within a mean of 9.6 days with no complications or functional deficit. CONCLUSIONS: Paediatric orbital cellulitis can be treated conservatively or with surgical drainage. Indications for surgery include pansinusitis, large abscesses with significant mass effect, concurrent intracranial involvement, poor response to initial medical treatment and the presence of an orbital abscess and gas. Sole medical treatment worked well in children with no orbital abscess, small or medial abscesses as they tend to have a single organism infection. This is also of particular significance in young children below the age of one where endoscopic surgery can be technically difficult. Intracranial involvement occurred in association with frontal sinusitis and affected patients had the longest duration of hospitalization.

The tear cytokine profile in patients with active Graves' orbitopathy.

PURPOSE: The primary aim of this study is to isolate cytokines specific for active Graves' orbitopathy (GO) in the tears of affected patients. The secondary aim is to identify other cytokines of interest and to look at the profile of their levels over time. METHODS: This is a prospective pilot study conducted at the Singapore National Eye Centre. A total of 10 patients with active GO and 10 patients from each of 3 control groups were recruited. The 3 control groups were the following: age-matched normal female patients, patients with GO who were clinically inactive and patients with bilateral viral conjunctivitis. Tears from patients from the control groups were collected on a single visit. For patients with active GO, tears were collected on presentation, at 6 months, 12 months and 18 months. RESULTS: Of all the cytokines examined, only IL-7 yielded a difference when the concentration in patients with active GO was compared with concentrations in all the control groups. This difference was most significant at the 18-month follow-up visit. CONCLUSIONS: Low concentrations of IL-7 in tears exhibit specificity for active GO in patients nearly 2 years from the clinical onset of activity. Although using IL-7 in tears as a biomarker for disease activity may be limited due to its late manifestation, targeting immune restitution using IL-7 may have disease modifying effects.

Tear Proteins Calcium binding protein A4 (S100A4) and Prolactin Induced Protein (PIP) are Potential Biomarkers for Thyroid Eye Disease.

There are no reliable biomarkers to predict thyroid eye disease (TED) in patients with autoimmune thyroid disease (AITD) currently. Several evidences support the involvement of the lacrimal gland in TED. The aim of our study was to quantitatively correlate the changes in tear protein profile with increasing severity of TED. Tear samples were collected from four groups of patients; AITD without TED (AITD), AITD with mild TED (mild TED), AITD with severe TED (severe TED) and normal controls. A total of 72 patients were recruited for the study. In discovery phase, isobaric tags for relative and absolute quantification (iTRAQ) 4-plex was used for quantitative proteomics analysis. For verification of results from discovery phase, sequential window acquisition of all theoretical fragment ion spectra (SWATH) was used to analyze an independent cohort from normal controls, AITD, mild TED and severe TED. Two proteins, S100A4 and PIP showed consistent dysregulation trends in the discovery and validation phase experiments. Our study demonstrated the differences in tear proteome across the spectrum of different severity and activity of TED in patients with AITD. Two tear proteins, S100A4 and PIP may serve as potential biomarkers to predict progression to severe TED in patients with AITD.

Management plan and delivery of care in Graves' ophthalmopathy patients.

Most patients with Graves' orbitopathy have mild disease that requires no or minimal intervention. For the minority of patients with moderate or severe disease, multiple medical and surgical treatments may be required at different stages. It is crucial that such patients are monitored closely and treatments applied with care in the right sequence. Medical treatments should be used as early as possible and only during the active phase of the disease. Rehabilitative surgery is indicated in the inactive phase of the disease and should follow the sequence: surgical decompression followed by eye muscle surgery, followed by lid surgery. Delivery of care in a coordinated fashion that makes use of best available expertise is important and best implemented through a Combined Thyroid Eye clinic.

Superficial keratectomy as a prelude for endothelial keratoplasty in severe bullous keratopathy with anterior stromal scarring.

Endothelial keratoplasty is usually contraindicated in end-stage forms of bullous keratopathy with extensive anterior stromal scarring, as a good visual result is not expected. We describe the use of superficial keratectomy as an initial surgical stage in performing successful endothelial keratoplasty in severe bullous keratopathy with anterior stromal scarring in a patient with previous failed penetrating keratoplasty, which resulted in a good visual outcome.