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Purpose: Retrobulbar irradiation is used as a standard therapy for thyroid-associated orbitopathy. The evidence of its effectiveness is, however, scarce. Doses from 2.5 to 20 Gy have been recommended., Methods: Forty-three patients with active thyroid-associated orbitopathy were irradiated with 2.4 Gy and 43 with 16 Gy. Five measures of outcome were used: (1) appearance of the eye region, documented with photographs; (2) Hertel exophthalmometry; (3) range of vertical eye movements; (4) eye muscle thickness (sum of three MRI sections across the eight rectus eye muscles); and (5) complaints, indicated on a visual analog scale., Results: At 3 and 6 months after irradiation, no difference between 2.4 and 16 Gy was found in any of the five outcome measures (p between 0.099 and 0.993; Kruskal-Wallis test, Holm correction). Most outcome measures were slightly, but not significantly, improved in both the 2.4 and the 16 Gy groups. Patient complaints had improved significantly in both groups and the eye muscle thickness was significantly reduced in the 2.4 Gy group after 6 months., Conclusion: The lack of a difference between 2.4 and 16 Gy is compatible with four different interpretations: (1) the irradiation could be ineffective; (2) the maximal effect could be already reached at 2.4 Gy; (3) the maximal effect could lie between 2.4 and 16 Gy; and (4) the effect could increase beyond a threshold of >or=16 Gy. From general experience with inflammatory disease, the last two possibilities are unlikely; only the first two interpretations carry some probability. Although the design of the study did not allow a distinction between these two possibilities, we conclude that retrobulbar irradiation for thyroid-associated orbitopathy should not exceed 2.4 Gy.

Purpose: Thyroid eye disease (TED) can be a functionally disabling condition if ocular muscle involvement causes diplopia. The extraocular muscle restriction creates a reduced or eccentric field of binocular single vision (BSV). Orbital radiotherapy is now widely used in the treatment of TED, and although it has been reported as improving ocular motility, there have been few quantitative studies of the effect of treatment on ocular motor function., Methods: Retrospective case note review of patients undergoing orbital radiotherapy for TED between 1992-1998 identified 79 case records. A total of 27 patients had diplopia in primary position or a significantly reduced binocular field before undergoing radiotherapy. The fields of BSV were analyzed pretreatment and at 3, 12, and 24 months after therapy to assess any improvement in function. We used the field of BSV as an outcome measure because it can be quantified and is a good indicator of functional ability., Results: None of the 12 patients with double vision in primary position pretreatment regained a central binocular field with radiotherapy alone. Of the 15 patients with a central but reduced binocular field, 8 (53%) remained unchanged with treatment. In 4 patients (26.6%), there was an improvement in the field, while in 3 (20%) the field deteriorated. In all, 12 patients (44%) went on to require strabismus surgery., Conclusions: Orbital radiotherapy alone is ineffective in treating restrictive thyroid myopathy and improving binocular function.

Purpose: To determine the ultrastructural localisation of glycosaminoglycans (GAGs) in the extraocular muscles (EOMs) of patients with thyroid-associated ophthalmopathy (TAO) and to see whether the quantity and type of GAGs present in blood and urine are markers of the disease., Methods: Biopsies of affected EOMs were taken and studied by transmission electron microscopy (TEM). These were either fixed conventional for TEM, or in 0.5% tannic acid and others for immunogold staining. Serum hyaluronan (HA) was measured using a radioimmunoassay in patients with TAO as well as control subjects, and urinary GAG levels assessed by photometric quantitation of hexuronic acid after reaction with carbazole. The excretion pattern of the urinary GAGs was determined by discontinuous electrophoresis., Results: TEM showed that there is a marked expansion of the endomysial space in TAO EOM biopsies as compared with non-TAO strabismus specimens. This is caused by an increased number of collagen fibres, interspersed with a granular amorphous material surrounding striated collagen fibres shown to be hyaluronan by immunogold staining. In contrast, serum hyaluronan concentrations were similar in TAO and control patients, although there was a statistically significant difference in the urinary GAG excretion between the two groups of patients examined. By discontinuous electrophoresis, chondroitin sulphate and heparan sulphate were present in both patients and controls., Conclusion: GAGs and in particularly HA are present at the EOM level in patients with recently inactive TAO. However, serum levels of HA and urinary GAGs are not sensitive indicators for their presence within the EOMs.

The results of orbital decompression for thyroid eye disease are presented in a cohort of 33 patients. It was performed by an external Patterson approach in 21 individuals and in 13 by an endonasal endoscopic approach. The endoscopic approach was entirely comparable in respect of improvement in axial proptosis, giving a mean improvement of 4.4 mm as compared with a mean of 3.8 mm for the external approach, and produced a demonstrable improvement in visual acuity and perception of colour in three individuals, where this was compromised, and was associated with fewer complications.

TAO is characterized by an autoimmune process affecting the orbital contents. T cells have been suggested to have a major role in pathogenesis, but so far only limited data are available to clarify the extraocular muscle (EOM)-infiltrating T cell phenotype, antigenic reactivity and cytokine profile in TAO patients. In the present study, biopsies of affected EOM were taken and the infiltrating T cells isolated and expanded in vitro with mitogen. Their phenotype was determined by flow cytometric (FACS) analysis and compared with peripheral blood-derived T cell lines, treated in the same way from the same patient. Cytokines present in the supernatant after mitogen stimulation of the T cell lines were assayed by ELISA. In addition, cytokine mRNA present at the time of biopsy was determined by rapid RNA extraction from EOM and reverse transcription-amplification with specific cytokine oligonucleotide probes (IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL- 15, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha)). In the T cell lines from two patients, proliferation assays were carried out with antigens derived from thyroid gland, EOM and a thyrotropin (TSH) receptor preparation. Most T cell lines were CD4+, CD45RO+, and TCR alpha/beta+, both from the EOM and the peripheral blood. A wide variety of cytokines was detected by analysis of supernatants or mRNA, but the profiles were not identical comparing the two approaches. However, IL-4 was detected by both. Dose-dependent proliferation was observed in response to thyroid extract in a biopsy-derived T cell line. In conclusion, EOM-infiltrating T cells from patients with TAO, expanded in vitro, were chiefly CD4+ and produced a mixture of cytokines, including IL-4. The proliferation data suggest that there are thyroid-reactive T cells in EOM.

TAO is an autoimmune condition characterized by mononuclear cell infiltration of the extraocular muscles (EOM) and/or the orbital fat/connective tissue with associated deposition of glycosaminoglycans (GAG) in the interstitial spaces. In this study, the presence and distribution of the vascular adhesion molecules intercellular adhesion molecule-1 (ICAM-1), endothelial-leucocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1) and the leucocyte integrins CD11a/CD18, CD11b/CD18, CD11c/CD18 were investigated. Nineteen EOM biopsies were collected from 17 patients with early (n = 6) and late (n = 13) TAO as well as from 12 non-TAO control patients. Consecutive cryostat sections of these biopsies were immunostained with MoAbs to the above-mentioned molecules and haematoxylin and eosin. Primary antibody binding was visualized using an avidin-biotin system. In early untreated TAO specimens, the interstitial and perimysial connective tissue surrounding EOM fibres and numerous mononuclear cells stained strongly for ICAM-1. In contrast, the vascular endothelial cells (ulex lectin-positive) stained strongly for ELAM-1 (E-selectin), VCAM-1 as well as ICAM-1. In late disease, the same distribution of immunoreactivity for ICAM-1, ELAM-1 and VCAM-1 was observed, but with significantly lower staining. The leucocyte integrins (CD11a, CD11b, CD11c) were again expressed at significantly higher levels in early TAO specimens compared with late TAO specimens and were minimal or absent in the EOM biopsies harvested from control patients. In conclusion, increased expression of adhesion molecules studied correlated with early active disease and was reduced in later stages.

Purpose: To investigate whether adults with infantile strabismus but without latent nystagmus have abnormalities of horizontal motion detection., Methods: Eleven adult subjects with infantile esotropia but without latent nystagmus and 15 control subjects were required to detect the onset of motion and drift direction of a sinusoidal, spatial frequency grating that moved with linearly increasing velocity. The grating was presented monocularly in paracentral vision at an eccentricity of 16.5 degrees with a field size of 18 degrees. The contrast of the grating was just above contrast threshold for visibility., Results: The mean velocity threshold for detection of motion was raised significantly in the patient group compared with the control group. Nine of the 11 subjects with infantile esotropia demonstrated directional asymmetry for the detection of motion. Thresholds were elevated more often when the grating was moving nasally in the squinting eye and temporally in the nonsquinting eye, and raised thresholds were more prevalent in the squinting eye., Conclusions: The findings indicate that in infantile esotropia, the presence of motion perception deficits are not always associated with the development of latent nystagmus. The predominance of nasally directed motion deficits in the squinting eye and temporally directed motion deficits in the nonsquinting eye was unexpected and may have been caused by abnormal development of cortical motion processing.

The purpose of the study was to identify those patients with thyroid eye disease and upper eyelid retraction who would benefit from Henderson's procedure (myotomy of Muller's superior tarsal muscle with graded division of levator aponeurotic fibres on the anterior tarsal plate). The clinical records of patients attending the Thyroid Clinic of Moorfields Hospital who had undergone Henderson's procedures were reviewed. Twenty-two patients (19 women, 3 men) had Henderson's procedures at age 35-69 years (mean 49.9), with a mean follow-up of 4.55 years. Eleven patients had bilateral upper eyelid surgery, 11 unilateral (33 eyelids). The pre-operative vertical palpebral apertures ranged from 11 to 19 mm (mean 13.95); the post-operative vertical palpebral apertures ranged from 8 to 15 mm (mean 11.45), a mean reduction of 2.5 mm (p < 0.001). Eight of twenty-two patients (36%) had further eyelid surgery and 3 of 22 (14%) had further surgery recommended because of persistent upper eyelid retraction, abnormal eyelid contour (lateral flare) and asymmetry. It is concluded that Henderson's procedure should be reserved for those patients with minor degrees of almost symmetrical upper eyelid retraction who do not have abnormalities of their eyelid contour.

An experimental study and mathematical analysis of the corneal reflex test was undertaken in spectacle wearers. In the experimental study, photographs were taken of the corneal reflex through spectacles and the conversion ratios determined as measured in degrees/mm. In the mathematical analysis, the magnification effect of the lens was elucidated by three methods: geometrical analysis; real measurement of magnification factor; and ray tracing analysis. The real measurement of the conversion ratios was in good agreement with the conversion ratios determined by the three mathematical analyses. These results clearly showed that the corneal reflex test can be clinically useful even in wearers of spectacles.

In this paper methods of visualisation of the extraocular muscle changes in thyroid eye disease are discussed. The histopathology of extraocular muscle biopsies has been studied by both light and electron microscopy to show the type of cellular infiltration and the amorphous material in the extracellular matrix. A series of questions to which answers have not yet been found concerning thyroid eye disease are posed which may help to direct new research projects. Finally, in the last part of the paper, the surgical results in a series of 41 patients having ocular muscle surgery for diplopia and/or compensatory head postures due to thyroid eye disease are described. The conclusions drawn from these results are that one should maintain the patient euthyroid, establish by orthoptic measurements that the ocular movements have been stable for at least 6 months, treat by recessing tight muscles using adjustable sutures, and aim to undercorrect the vertical deviation at the time of adjustment.

We report a spectrum of defects that were found in an 18-year-old girl who presented for investigation of primary amenorrhea. The patient was found to have Duane anomaly, left renal agenesis, absent uterus, bilateral sensorineural deafness, and bilateral preauricular skin tags and sinuses. Investigation of her family showed that her brother also had Duane anomaly, right renal agenesis, sensorineural deafness, and preauricular skin tags and that their father had preauricular skin tags. Cytogenetic analysis, including in situ hybridisation of peripheral blood lymphocytes, demonstrated a supernumerary bisatellited marker chromosome derived from the region of chromosome 22pter-q11 in the affected individuals. Our findings indicate that a gene or genes located in the region of chromosome 22pter-q11 may be associated with the Duane anomaly and the development of the urogenital tract.

We present the results of surgical treatment in 13 patients who attended Moorfields Eye Hospital with traumatic Brown syndrome between 1975 and 1990. The average age was 34 years (range, 18 to 46 years), and in 12 cases the cause was a road traffic accident. Diplopia was the indication for surgery in all cases. Most patients had two surgical procedures; but in two patients, three were required. The outcome was assessed both subjectively and objectively. Objective assessment was by analysis of the preoperative and postoperative fields of binocular single vision and Hess charts which were available for 11 patients. The Hess charts were analyzed using a new scoring system. At final follow up, subjective improvement had occurred in 7 patients, 3 patients reported no improvement, and 3 patients thought their symptoms were worse. The field of binocular single vision improved in 8 patients and was worse in 3 patients. The Hess chart improved in 8 patients and was worse in 3 patients. The management of this difficult condition is discussed.

A new scoring system for Hess charts is described. Scores for both horizontal and vertical deviations are calculated from the displacement of individual points on the Hess chart, using weighting factors for the centre, inner and outer zones. The scoring system was validated in a group of 24 patients undergoing surgery for paralytic or restrictive strabismus. Subjective scores were obtained from patients both before and after corrective surgery, and corresponding Hess charts were scored using the new system. There was a good correlation between the changes in subjective and objective score. Our scoring system has applications in both research and clinical practice, allowing objective analysis of changes in muscle balance in a variety of motility disorders.

Myasthenia gravis is typically a disease of young people in active employment who need a field of binocular single vision. Although it is systemically controllable with a good chance of spontaneous remission, persistent loss of binocularity may cause chronic disability. We report our experience of extraocular muscle surgery in five patients with stable myasthenia gravis and persistent double vision. Extraocular muscle involvement was selective, giving rise to incomitant and concomitant squints, with individual muscle overactions as well as underactions. Treatment was by conventional recession and resection procedures with the additional use of Faden and adjustable sutures where appropriate. In all five cases a larger, stable field of binocular single vision was established. It is concluded that extraocular muscle surgery may be beneficial in selected cases of myasthenia gravis.

Visual loss following strabismus is rare and usually follows inadvertent perforation of the globe at the time of surgery. Previous studies have reported that the incidence of this complication occurs in 8% to 12.1% of patients undergoing conventional strabismus surgery, and higher incidences have been reported for posterior fixation sutures. We conducted a prospective study to determine the incidence of this complication in our patients. We identified one case of globe perforation in 67 patients (100 eyes). Twenty-two patients (44 eyes) had undergone previous strabismus surgery, and there was no evidence of previous scleral perforation in this group. We discuss the recent advances in strabismus surgery which may account for this difference in the incidence of scleral perforation.

Patients with Graves' disease were questioned by postal survey about their smoking history. There were significantly more smokers in the group with ophthalmopathy than in the group with Graves' thyrotoxicosis or controls. Patients with severe eye signs smoked significantly more tobacco than did those with less serious signs.

The best systemic treatment of dysthyroid ophthalmopathy remains high dosage Prednisolone. Other methods of immunosuppression such as Azathioprine and Cyclosporin A have proved disappointing, as has plasmapheresis. Other localised means may be used and these are radiotherapy to the retrobulbar tissues or orbital decompression. These methods may be used in addition to or instead of high dose Prednisolone but some surgeons prefer to try Prednisolone as a first measure.

Cataracts may arise in association with various major and minor disorders restricting galactose metabolism, and the risk is broadly associated with the degree of galactose intolerance. A family is described in which a girl presented at the age of 7 3/4 years with cataracts, galactosuria, and partial deficiencies of the enzymes galactokinase and galactose-1-phosphate uridyl transferase. Galactose intolerance as determined by an oral test was impaired and fluctuated with variation in activity of the above galactose enzymes. Minor defects were also present in the parents and a maternal half-brother. The child has a compound disorder of galactose metabolism differing from those previously described. Assessment of galactose tolerance may be useful in the investigation of families with an incidence of cataract.

31 patients with bilateral fourth nerve palsies are considered in this paper, 25 of the cases being traumatic in origin. Quantitative estimation of the torsional defect is carried out, using special synoptophore slides and a modification of the Lees' screen technique. Inability to prove the patient's retention of fusion in the presence of torsion is discussed. Although many of the traumatic cases had been rendered unconscious for varying periods of time up to several weeks by the initial injury with the known risk of losing fusion, sixteen out of seventeen patients undergoing surgery for their diplopia had postoperative evidence of binocular single vision.

The indications for and details of the technique of adjustable sutures are fully described. Patients with vertical strabismus and fusion give significantly better results with this method. Illustrative cases of dysthyroid ophthalmopathy and superior oblique palsies are described.

Current methods of medical treatment of this difficult condition are briefly reviewed, with comments on the generally unsatisfactory response. Attention is therefore directed to surgical methods and a short history given of the various routes used for orbital decompression. The author's own results of transantral, and more recently ethmoidal, decompression are given, with a detailed description of the technique for the latter approach. An interesting frequent consequence of postoperative A pattern to the ocular movements is discussed in the light of Koornneef's concept of orbital fascial anatomy, and suggestions are made for its avoidance.