Phenotypes of Thyroid Eye Disease.

PURPOSE: To describe a new classification system of thyroid eye disease (TED) based on the phenotypic features (clinical and radiologic) of the disease. METHODS: Clinical features, photographic, and orbital imaging of TED patients were considered in relation to their natural history and treatment response in the experience of the author. Phenotypically distinct categories of patients were identified and described. RESULTS: Six phenotypes of TED are observed: 1) congestive (active inflammatory), 2) "white eye" expansion, 3) "hydraulic" apex, 4) "white eye" apex, 5) cicatricial active, and 6) cicatricial passive. CONCLUSIONS: The observable characteristics of TED are determined by the underlying pathophysiology of the disease. TED is heterogeneous in its underlying pathogenesis, clinical manifestations, and response to medical and surgical treatment modalities. Several previous categorizations of the clinical appearance of TED exist, but they are dichotomous and underrepresent the heterogeneity of the disease. The authors present clinical and radiologic features of 6 different classes or phenotypes of TED and their response to different treatments.

Imaging Investigation of Thyroid Eye Disease.

INTRODUCTION: Thyroid eye disease (TED), is a term referring to the extrathyroidal manifestation of Grave's disease, a disorder which is currently the most common cause of hyperthyroidism and is characterised by underlying autoimmunity.The pathogenic course of the disease can be broadly classified into two stages, an early inflammatory and a late fibrotic stage. These stages are reflected in clinical severity and activity classifications, such as Clinical Activity Score and Class 0: No signs or symptoms, 1: Only signs, no symptoms (e. g. lid retraction), 2: Soft tissue involvement, 3: Proptosis, 4: Extraocular muscle involvement, 5: Corneal involvement, 6: Sight loss (NOSPECS). Classifications based on the latter, have important implications in treatment decisions since patients in the early active stage of the disease are more likely to respond to anti-inflammatory and immunosuppressive therapies, whereas patients in the late fibrotic stage require different therapeutic approaches, including rehabilitative surgery. METHODS: We reviewed cases of TED investigated with CT and Magnetic Resonance Imaging (MRI) in our department. We assessed the findings of imaging studies and their role in the clinical investigation of patients with TED as well as in the differential diagnosis from other disorders. RESULTS: Imaging has a significant role in the investigation of TED, however a consensus on the use of different imaging modalities in the course of disease has yet to be reached. Nevertheless, imaging and specifically CT and MRI can have a vital role in the initial diagnosis of clinically atypical presentation of TED, in surgical planning, as well as in the differential diagnosis from other orbital disorders. CONCLUSION: In this review, we attempt to present current trends in imaging investigation of TED. Rather than focusing on the findings of each imaging modality separately, we present the two main imaging modalities focusing on CT and MRI, in the context of pathogenic stages of the disease.

Supraorbital notch and foramen: positional variation and relevance to direct brow lift.

PURPOSE: Forehead paresthesia after brow lift is well-documented with rates as high as 40.7%. The authors describe an anatomical study to identify the variation in position of the supraorbital notch/foramen to define safe limits for deep dissection during this procedure. METHODS: Sixty-six orbits from 23 dry skulls and 9 formalin-fixed cadavers were analyzed photographically using ImageJ software. The cadaveric specimens were dissected using a coronal incision, which allowed the inferior resection of the frontalis muscle and periosteum. The exit point of the supraorbital neurovascular bundle was noted as a foramen or notch. The position of the supraorbital notch or foramen was recorded in relation to the midline as defined by the sagittal suture at the level of the highest point of the supraorbital rim. The distance and angle for each foramen/notch were calculated. RESULTS: Thirty-three percent of orbits had a foramen. The average distance from the midpoint to the foramen was 25.24 mm (standard deviation 3.78 mm) and to the notch was 22.69 mm (22.69 mm). The range of distance between the midpoint and the foramen/notch was 17.62 to 32.35 mm. The average angle between the horizontal meridian and the foramen was 81/57° (standard deviation 4.69°). CONCLUSIONS: A wide variation in anatomy was seen. Greater caution is required when performing deep dissection around the supraorbital notch because of the variation in position of the supraorbital foramen.

Factors Predicting Long-term Outcome and the Need for Surgery in Graves Orbitopathy: Extended Follow-up From the CIRTED Trial.

Graves orbitopathy is both disabling and disfiguring. Medical therapies to reduce inflammation are widely used, but there is limited trial data beyond 18 months of follow-up. METHODS: Three-year follow-up of a subset of the CIRTED trial (N = 68), which randomized patients to receive high-dose oral steroid with azathioprine/placebo and radiotherapy/sham radiotherapy. RESULTS: Data were available at 3 years from 68 of 126 randomized subjects (54%). No additional benefit was seen at 3 years for patients randomized to azathioprine or radiotherapy with regard to a binary clinical composite outcome measure (BCCOM), modified European Group on Graves' Orbitopathy score, or Ophthalmopathy Index.Clinical Activity Score (CAS), Ophthalmopathy Index, and Total Eye Score improved over 3 years (P < .001). However, quality of life at 3 years remained poor. Of 64 individuals with available surgical outcome data, 24 of 64 (37.5%) required surgical intervention. Disease duration of greater than 6 months before treatment was associated with increased need for surgery [odds ratio (OR) 16.8; 95% CI 2.95, 95.0; P = .001]. Higher baseline levels of CAS, Ophthalmopathy Index, and Total Eye Score but not early improvement in CAS were associated with increased requirement for surgery. CONCLUSION: In this long-term follow-up from a clinical trial, 3-year outcomes remained suboptimal with ongoing poor quality of life and high numbers requiring surgery. Importantly, reduction in CAS in the first year, a commonly used surrogate outcome measure, was not associated with improved long-term outcomes.

Lessons from the past: cribra orbitalia, an orbital roof pathology.

AIMS: To define a computed tomography protocol that may be used in future clinical practice for the reliable detection and analysis of cribra orbitalia. MATERIALS AND METHODS: Two osteological assemblages from the Museum of London were used to select 13 cribratous skulls and 5 non-cribratous skulls. Area of cribra orbitalia was measured using image analysis. Morphology of cribra orbitalia, orbital roof density and the associated optic canal diameter was analysed using computed tomography reconstructions. RESULTS: The presence of cribra orbitalia was associated with changes in the internal diploë layer as well as the cortical bone table. A novel radiological grading system and protocol was developed to identify the pathology. A decrease in the orbital roof density by 210 Hounsfield units and a reduction in the optic canal diameter, up to 1 mm, were found to be associated with the presence of cribra orbitalia. CONCLUSIONS: The occurrence of cribra orbitalia is found to be associated with stenosis of the optic canal, and could explain a proportion of cases ofoptic nerve entrapment. This study provides a guideline for radiologists and oculoplastic surgeons to help detect the presence of cribra orbitalia in suspected patients.

A cadaveric study of the morphometric relationships and bony composition of the caucasian nasolacrimal fossa.

AIMS: To describe the morphometric relationships and bony composition of the nasolacrimal fossa in a Caucasian population with particular reference to the lacrimo-maxillary suture (LMS). METHODS: Forty-seven orbits from 24 formalin fixed cadavers were exenterated. Morphometric measurements were taken between anatomical landmarks forming the lacrimal fossa on the medial orbital wall. RESULTS: The mean recorded distance from the anterior lacrimal crest (ALC) to the posterior lacrimal crest (PLC) and the LMS were 8.8 mm (± 1.6) and 4.3 mm (± 1.1), respectively. In 25.5% of the orbits the LMS was at the mid-vertical line (MVL), defined as a line equidistant from the ALC and PLC. In 42.5% the LMS was located anterior to the MVL toward the ALC. In 66% of the orbits the LMS was at or within one standard deviation (SD) of the MVL. The LMS was >1 SD away from the MVL toward the ALC and PLC in 19% and 15% of orbits, respectively. CONCLUSIONS: In a quarter of the orbits in our Caucasian population the nasolacrimal fossa was formed equally by the maxillary and lacrimal bones. However, in nearly a third of the cases the LMS was located closer to the PLC, indicating predominance of the thicker maxillary bone. This may result in greater difficulty in initiating the surgical osteotomy when performing a dacryocystorhinostomy. These data contribute to our understanding of the variation in lacrimal fossa anatomy and encourage further studies in different racial groups.

A cadaveric study of the morphometric and geometric relationships of the orbital apex.

INTRODUCTION: To define the morphometric and geometric relationships which exist at the orbital apex. MATERIALS AND METHODS: Forty-seven orbits from twenty-four formalin-fixed Caucasian cadavers were exenterated and the relevant sutures, fissures and foramina identified. Measurements were taken from the optic canal to anatomical landmarks located along the medial wall, inferior wall and lateral wall of each orbit. Based on the mean results the geometric angles between the different anatomical structures were calculated and used to create three-dimensional models. RESULTS: The mean distances from the midpoint of the optic canal to the superior orbital fissure, inferior orbital fissure and anterior ethmoidal foramen were 10.22 mm, 29.56 mm and 21.65 mm, respectively. The mean distances from the anterior ethmoidal foramen to the superior and inferior orbital fissures were 24.27 mm and 31.93 mm, respectively. The mean distance between the tips of the superior and inferior orbital fissures was 27.70 mm. The mean distances directly from the tips of the superior and inferior orbital fissures and the anterior ethmoidal foramen to the orbital rim were 39.23 mm, 17.11 mm and 18.94 mm, respectively. These values were used to calculate geometric values and create three-dimensional models. DISCUSSION: The orbital apex is a congested structure and the practicing orbital surgeon must have an intimate knowledge of its contents. We have presented novel data, which in conjunction with radiology may be used as both a navigational aid to plan orbital surgery and to guide the surgeon intraoperatively to assess proximity to key anatomical structures.

Morphometric and geometric anatomy of the caucasian orbital floor.

INTRODUCTION: To describe the morphometric and geometric relationships of the orbital floor in a Caucasian population. MATERIALS AND METHODS: Exenterations of 47 orbits from 24 formalin fixed cadavers were performed. Morphometric measurements were taken between anatomical landmarks located along the orbital floor and the orbital apex. The mean measurements were used to calculate geometric data. These results were analysed according to sex and side and compared to results from other ethnic populations. RESULTS: The average distances from the infraorbital foramen to the nasolacrimal fossa, inferior orbital fissure, optic canal and inferior orbital rim were 20.67 mm (± 2.42), 25.40 mm (±2.70), 43.23 mm (±3.35) and 8.95 mm (± 1.53), respectively. The average distances from the tip of the infraorbital groove to the tip of the inferior orbital fissure, lateral aspect of the inferomedial strut, optic canal and the intersection with the inferior orbital fissure were 14.08 mm (±2.41), 12.12 mm (±2.42), 35.02 mm (±3.17) and 20.05 mm (± 2.87), respectively. The distances from the tip of the inferior orbital fissure to the optic canal and the intersection with the inferior orbital groove were 29.56 mm (±2.73) and 13.37 mm (±2.76), respectively. DISCUSSION: Orbital surgeons should be aware of the morphometric relationships of the orbital floor due to the degree of variation that exists between different ethnic groups. Geometric data may be used to provide orbital surgeons with a navigational template that can be used to plan surgery and as a guide intraoperatively.

Combined immunosuppression and radiotherapy in thyroid eye disease (CIRTED): a multicentre, 2 × 2 factorial, double-blind, randomised controlled trial.

BACKGROUND: Standard treatment for thyroid eye disease is with systemic corticosteroids. We aimed to establish whether orbital radiotherapy or antiproliferative immunosuppression would confer any additional benefit. METHODS: CIRTED was a multicentre, double-blind, randomised controlled trial with a 2 × 2 factorial design done at six centres in the UK. Adults with active moderate-to-severe thyroid eye disease associated with proptosis or ocular motility restriction were recruited to the trial. Patients all received a 24 week course of oral prednisolone (80 mg per day, reduced to 20 mg per day by 6 weeks, 10 mg per day by 15 weeks, and 5 mg per day by 21 weeks) and were randomly assigned via remote computerised randomisation to receive either radiotherapy or sham radiotherapy and azathioprine or placebo in a 2 × 2 factorial design. Randomisation included minimisation to reduce baseline disparities in potential confounding variables between trial interventions. Patients and data analysts were masked to assignment, whereas trial coordinators (who monitored blood results), pharmacists, and radiographers were not. The radiotherapy dose was 20 Gy administered to the retrobulbar orbit in ten to 12 fractions over 2 to 3 weeks. Azathioprine treatment was provided for 48 weeks at 100-200 mg per day (dispensed as 50 mg tablets), depending on bodyweight (100 mg for <50 kg, 150 mg 50-79 kg, 200 mg for ≥80 kg). The primary outcomes were a binary composite clinical outcome score and an ophthalmopathy index at 48 weeks, and a clinical activity score at 12 weeks. The primary analysis was based on the intention-to-treat allocation and safety was assessed in all participants. This study is registered with ISRCTN, number 22471573. FINDINGS: Between Feb 15, 2006, and Oct 3, 2013, 126 patients were recruited and randomly assigned to groups: 31 patients to radiotherapy plus azathioprine, 31 to sham radiotherapy and azathioprine, 32 to radiotherapy and placebo, and 32 to sham radiotherapy and placebo. Outcome data were available for 103 patients (54 for sham radiotherapy vs 49 for radiotherapy and 53 for placebo vs 50 for azathioprine), of whom 84 completed their allocated treatment of radiotherapy or sham radiotherapy and 57 continued to take azathioprine or placebo up to 48 weeks. There was no interaction betweeen azathioprine and radiotherapy (pinteraction=0·86). The adjusted odds ratio (ORadj) for improvement in the binary clinical composite outcome measure was 2·56 (95% CI 0·98-6·66, p=0·054) for azathioprine and 0·89 (0·36-2·23, p=0·80) for radiotherapy. In a post-hoc analysis of patients who completed their allocated therapy the ORadj for improvement was 6·83 (1·66-28·1, p=0·008) for azathioprine and 1·32 (0·30-4·84, p=0·67) for radiotherapy. The ophthalmopathy index, clinical activity score, and numbers of adverse events (161 with azathioprine and 156 with radiotherapy) did not differ between treatment groups. In both groups, the most common adverse events were mild infections. No patients died during the study. INTERPRETATION: In patients receiving oral prednisolone for 24 weeks, radiotherapy did not have added benefit. We also did not find added benefit for addition of azathioprine in the primary analysis; however, our conclusions are limited by the high number of patients who withdrew from treatment. Results of post-hoc analysis of those who completed the assigned treatment suggest improved clinical outcome at 48 weeks with azathioprine treatment. FUNDING: National Eye Research Centre, Above and Beyond, and Moorfields Eye Charity.

Periocular necrotising fasciitis: a multicentre case series.

INTRODUCTION: Necrotising fasciitis (NF) is a severe infection of deep subcutaneous soft tissues with high morbidity and mortality. Periocular necrotising fasciitis (PONF) is a very rare condition with many unanswered questions about the presentation and management. We present a retrospective case series of patients with PONF from three centres in Australia and two in the UK to investigate the clinical and microbiological characteristics and outcomes and report on patients treated with antibiotics alone. RESULTS: Twenty-nine patients (20 men; 69%) with PONF were identified and followed up for between 2 months and 10 years (median 57, mean 52.6 months) between 1990 and 2013. Conditions associated with chronic immunocompromise were present in 16/29 (55%). Twenty-one (75%) recalled minor periocular trauma or an infected lesion, two having been assaulted by the same assailant. Systemic shock occurred in 6/29 (21%) patients and 1 died. Group A, ß-haemolytic Streptococcus was the most common bacterium identified (25/29, 86%). Intravenous antibiotics were used in all patients, and up to five tissue debridements were required to control the disease in 23/29 (74%); reconstructive surgery was required in 12/29 (41%) patients. One patient died from the disease and visual loss occurred in four eyes of four patients (14%). CONCLUSIONS: PONF has a better prognosis than disease elsewhere in the body, but is still associated with significant risk of visual loss and a small risk of death. Intravenous antibiotic treatment with cautious observation may be reasonable in selected patients with a low threshold for debridement.

A cadaveric study of ethmoidal foramina variation and its surgical significance in Caucasians.

AIMS: To describe the morphometric and geometric relationships of the medial orbital wall ethmoidal foramina and the orbital apex in a Caucasian population. METHODS: 47 orbits from 24 formalin-fixed cadavers were exenterated. Morphometric measurements were taken between anatomical landmarks located on the medial orbital wall and geometric values were calculated. RESULTS: The average distances from the anterior lacrimal crest to the anterior ethmoidal foramen, posterior ethmoidal foramen and optic canal were 25.61 mm (± 2.25), 36.09 mm (± 3.86) and 43.77 mm (± 2.52), respectively. The average distances from the anterior ethmoidal foramen to the first posterior ethmoidal foramen, last posterior ethmoidal foramen and optic canal were 13.88 mm (± 3.51), 16.60 mm (± 2.19) and 21.65 mm (± 2.59), respectively. The average distances from the first and last posterior ethmoidal foramen to the optic canal were 11.63 mm (± 3.79) and 7.25 mm (± 2.59), respectively. CONCLUSION: The distance between the posterior ethmoidal foramen and optic canal is more than double the distance quoted in the surgical literature. This is due to a high incidence of ethmoidal foramina variation. Surgeons operating on the medial orbital wall of a Caucasian population must be aware of these variations as they are a source of haemorrhage and act as landmarks of proximity to the optic canal.

A cadaveric study of the cranio-orbital foramen and its significance in orbital surgery.

BACKGROUND: The cranio-orbital foramen is an osseous anatomical landmark located adjacent to the superior orbital fissure. It is a potential source of hemorrhage during deep orbital dissection because it is the location of an anastomosis between the lacrimal artery and the middle meningeal artery. The purpose of this study was to determine the incidence, location, and number of cranio-orbital foramina within a Caucasian population. METHODS: Forty-seven orbits from 24 formalin-fixed Caucasian cadavers were exenterated. If the cranio-orbital foramen was present within an orbit, its distance from the frontozygomatic suture, supraorbital notch, and Whitnall's tubercle was measured. The gender variations and asymmetric presentations of foramina were studied. RESULTS: The cranio-orbital foramen was present in 26 orbits (55 percent). The average distance from the frontozygomatic suture, supraorbital notch, and Whitnall's tubercle was 30.92 mm (±4.37 mm), 37.77 mm (±3.55 ±), and 29.69 mm (±3.89 mm), respectively. In nine orbits (19 percent), an additional accessory cranio-orbital foramen was identified. The average distance from the frontozygomatic suture, supraorbital notch, and Whitnall's tubercle was 28.56 mm (±5.00 mm), 32.64 mm (±3.20 mm), and 27.78 mm (±5.24 mm), respectively. CONCLUSION: The presence of the cranio-orbital foramen and other accessory foramina represents a source of hemorrhage that surgeons should be aware of when operating along the lateral orbital wall.

Protocol for the combined immunosuppression & radiotherapy in thyroid eye disease (CIRTED) trial: a multi-centre, double-masked, factorial randomised controlled trial.

BACKGROUND: Medical management of thyroid eye disease remains controversial due to a paucity of high quality evidence on long-term treatment outcomes. Glucocorticoids are known to be effective initially but have significant side-effects with long-term use and recrudescence can occur on cessation. Current evidence is conflicting on the efficacy of radiotherapy and non-steroid systemic immunosuppression, and the majority of previous studies have been retrospective, uncontrolled, small or poorly designed.The Combined Immunosuppression and Radiotherapy in Thyroid Eye Disease (CIRTED) trial was designed to investigate the efficacy of radiotherapy and azathioprine in combination with a standard course of oral prednisolone in patients with active thyroid eye disease. METHODS/DESIGN: Patients with active thyroid eye disease will be randomised to receive (i) azathioprine or oral placebo and (ii) radiotherapy or sham-radiotherapy in this multi-centre, factorial randomised control trial. The primary outcome is improvement in disease severity (assessed using a composite binary measure) at 12 months and secondary end-points include quality of life scores and health economic measures. DISCUSSION: The CIRTED trial is the first study to evaluate the role of radiotherapy and azathioprine as part of a long-term, combination immunosuppressive treatment regime for Thyroid Eye Disease. It will provide evidence for the role of radiotherapy and prolonged immunosuppression in the management of this condition, as well as pilot data on their use in combination. We have paid particular attention in the trial design to establishing (a) robust placebo controls and masking protocols which are effective and safe for both radiotherapy and the systemic administration of an antiproliferative drug; (b) constructing effective inclusion and exclusion criteria to select for active disease; and (c) selecting pragmatic outcome measures. TRIAL REGISTRATION: Current controlled trials ISRCTN22471573.

Treatment of upper eyelid retraction associated with thyroid eye disease with subconjunctival botulinum toxin injection.

OBJECTIVE: To study the effectiveness of botulinum toxin injections, via a subconjunctival approach, in the management of upper eyelid retraction associated with thyroid eye disease. DESIGN: Prospective, non-comparative, interventional case series. PARTICIPANTS: Eleven patients with upper scleral exposure associated with thyroid eye disease who declined conservative or conventional surgical management. INTERVENTION: One or more treatments with injections of botulinum toxin into the subconjunctival space at the superior margin of the tarsal plate, via a conjunctival approach. MAIN OUTCOME MEASURES: Upper eyelid position in relation to the upper limbus, patient satisfaction, and complications. RESULTS: All patients experienced some improvement in the amount of lid retraction after injections. The amount of lid lowering varied between patients and lasted between 1 and 40 months. A lid position acceptable to the patient was obtained in 10 patients. Four patients had ptosis lasting from 1 to 3 weeks, and three patients had transient diplopia lasting 1 day to 3 weeks. CONCLUSIONS: This subconjunctival method of botulinum toxin injection provides an effective treatment for upper eyelid retraction associated with thyroid eye disease that is easy to administer and well tolerated by patients with few side effects.

Downgaze "hang-up" of the upper eyelid in patients with adult-onset ptosis: an important sign of possible orbital malignancy.

PURPOSE: To highlight, in patients with adult-onset ptosis, the importance of upper eyelid hang-up during downgaze as a clinical sign of serious orbital disease. DESIGN: Retrospective, observational case series. PATIENTS AND METHODS: Retrospective review of the presenting clinical symptoms and signs for a series of seven patients, some referred for treatment of adult-onset ptosis, with hang-up of the upper eyelid on down-gaze. RESULTS: All patients had symptoms of upper eyelid ptosis at presentation, starting at ages ranging from 29 to 81 years (mean, 64 years; median, 70 years). All patients displayed marked hang-up of the affected upper lid on downgaze, and the levator excursion was reduced (range, 2-13 mm; mean, 9 mm) compared with the asymptomatic side. All patients with downgaze hang-up had associated orbital malignancy, but they otherwise had only minimal or no underlying orbital disease. Exophthalmometry varied between subtle (1 mm) relative enophthalmos in two cases, to mild relative proptosis (3/7 cases; range, 2-3 mm). Ipsilateral up gaze was reduced in 4 of 7 patients (57%). CONCLUSION: In contrast to patients with adult-onset blepharoptosis (resulting from dehiscence of the levator muscle aponeurosis), adults presenting with ptosis resulting from malignant infiltration of the upper orbital tissues may display hang-up of the upper eyelid in downgaze. This important sign should alert the clinician to the possibility of serious underlying orbital disease.

Pyoderma gangrenosum of the ocular adnexa: a rare condition with characteristic clinical appearances.

PURPOSE: To describe the clinical characteristics of periocular pyoderma gangrenosum and to highlight features that may encourage early diagnosis of this extremely rare condition. DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS AND METHODS: Four patients with periocular pyoderma gangrenosum were treated in the Orbital Unit at Moorfields Eye Hospital over the course of a decade. MAIN OUTCOME MEASURES: Presenting clinical features, therapy, and outcome. RESULTS: Four patients (female) between the ages of 56 and 75 years (mean, 65 years; median, 64 years) sought treatment for slowly evolving, painful, unilateral blue-gray swellings of the pretarsal tissues of the lower (1 case), upper (1 case), or both eyelids (2 cases). The swelling progressed to frank tissue necrosis and loss of full-thickness eyelid, with patchy sparing of the lid margin or lashes; in some cases, there was a very distinctive preservation of the pretarsal marginal artery across full-thickness eyelid defects. The lid loss characteristically involved the lateral one third of the lower eyelid (3 of 4 lids), the central part of the upper eyelid (3 of 4 lids) and, in one case, extending into the postseptal tissues in the inferotemporal quadrant of the orbit. In 3 patients, the pyoderma, often associated with a positive serum rheumatoid factor (three of three cases where measured), responded well to systemic immunosuppression and eyelid repair was undertaken during the quiescent phase. In a single patient, relapsing disease led to loss of the eye as a result of involvement of the globe and deep orbital tissues. CONCLUSIONS: Although an extremely rare condition, periocular pyoderma gangrenosum has a typical clinical appearance, and early recognition and immunosuppression will reduce the ocular morbidity.