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Introduction: The aim of this study was to evaluate the dose effect and the resulting binocular single vision for inferior oblique muscle recession in patients with Grave's orbitopathy., Methods and Patients: The evaluation covered all patients (n = 13) between 2010-2013 treated with recession of the inferior oblique muscle for vertical deviation caused by inferior fibrosis of the contralateral eye. The inclusion criterion was a small vertical squint angle with excyclotorsion. The corrected vertical squint angle was 3.75° [7 pdpt] (median, min 1.5° [3 pdpt], max 8° [16 pdpt]) in primary position and 5.5° in adduction [11pdpt] (median, min 3°[6 pdpt], max 9°[18pdpt]). Excyclotorsion was 4° [8 pdpt] (median, min 1° [2 pdpt], max 9° [18 pdpt]). Elevation was only slightly impaired and the side difference was 5° (median). The recession distance was preoperatively determined: 0.5° squint angle reduction per mm recession distance (calculation from patients who received surgery before 2010)., Results: Inferior oblique recession generated a good field of binocular single vision (BSV) for all patients. All patients reached BSV in the central area (20°) and within 30° of downgaze. Sixty nine percent of the patients were completely diplopia free in downgaze. Diplopia persisted in more than half of the patients in up gaze outside 15°. Squint reduction was 0.5° [1 pdpt] [0.45-0.67]/per mm recession distance in primary position and 0.65° [1.3 pdpt] [0.55-0.76]/per mm for the vertical deviation in adduction. Excyclotorsion was reduced to ≤ 2° in 77 % of the patients., Conclusion: Inferior oblique muscle recession can be very successfully performed on the contralateral eye in patients with mild inferior rectus muscle fibrosis. Surgery at the contralateral yoke muscle prevents the risk of overeffect with resulting diplopia in downgaze, which could occur if small distance recession had been performed at the inferior rectus muscle. An overeffect in relation to inferior oblique recession will only cause diplopia in upgaze, which is much less troublesome in daily routine., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: The aim of this study was to compare outcomes of lower lid lengthening with and without an additional temporal tarsorrhaphy., Methods: Lower lid lengthening was performed in 39 patients (16 without tarsorrhaphy [group 1], 23 with tarsorrhaphy [group 2]) via a posterior subtarsal transconjunctival ac-ess. A bovine pericardial transplant (Tutopatch, length = amount of retraction + 4 mm) was placed between the recessed retractors and the tarsus., Results: Mean preoperative lower lid retraction was 2.3 mm in group 1 and 2.6 mm in group 2 (n. s.). Lower lid lengthening and simultaneous tarsorrhaphy resulted in significantly increased reduction of lower lid retraction: 2.3 mm (1.5 - 4.5) (p = 0.003) compared to patients without tarsorrhaphy: 1.4 mm (0 - 3.0). Patients with tarsorrhaphy presented a higher success rate concerning the elimination of lagophthalmos (success = lagophthalmos ≤ 0.5 mm: 21 / 23 (91.3 %) as opposed to patients without tarsorrhaphy: 8 / 16 (50 %); (p = 0.004). Scleral show was eliminated in 78 % of group 2 in comparison to only 50 % in group 1 (p = 0.06)., Conclusions: Lower lid lengthening should be combined with simultaneous temporal tarsorrhaphy in patients with lower lid retraction exceeding 1.5 mm. The tarsorrhaphy increases the effect of lower lid lengthening by about 1 mm., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: In motility disorders related to Graves' orbitopathy, recession of fibrotic eye muscles is the treatment of choice. Correction of very large squint angles can be difficult, since the distance of recession is limited by the necessity to maintain a sufficient arc of contact. A new technique of tendon elongation has been developed in order to maintain sufficient arcs of contact even in patients with large horizontal squint angles, especially after orbital decompression surgery. The established dose-effect relationship cannot simply be conveyed to inferior rectus muscle surgery, due to a different impact of simple recession on inferior and medial rectus muscles., Methods: Recession of the inferior rectus muscle was performed in 10 patients with simultaneous suturing of bovine pericardium (Tutopatch). This procedure was performed as primary surgery in 7 patients (2 after orbital decompression) and as secondary procedure in 3 patients. Squint angle (far distance), bulbus excursion movements and field of binocular single vision were evaluated pre- and postoperatively., Results: Alignment (far distance) was achieved in 8 of 10 cases at the final follow-up examination. Two patients required corrective prisms. Visual fields were virtually free of diplopia in all patients. The dose-response effect for tendon elongation of the inferior rectus muscle was identical to that for the simple recession of this muscle. There were no complications., Conclusions: The new technique of tendon elongation using a bovine pericardium graft is applicable in large vertical squint angles (with or without prior bony orbital decompression) as well as for corrections after insufficient simple recessions (by realignment of the muscle and secondary suturing of the graft). Functional improvement can thus be achieved through surgery of a single muscle, keeping the other muscles in reserve for further interventions (lowering the risk of postoperative anterior segment ischaemia). There is a dose effect analogous to large horizontal squint angles in Graves' orbitopathy (dosing formula: 1 mm inferior rectus recession [including graft] leads to 2.0° vertical angle reduction). This corresponds to simple recessions of the inferior rectus muscle but differs from tendon elongations of the medial rectus muscles., (© Georg Thieme Verlag KG Stuttgart · New York.)

Aim: To investigate optic nerve function using the pattern-reversed visual evoked cortical potentials (VECP) before and after bony orbital decompression in dysthyroid optic neuropathy (DON) due to Graves' disease., Methods: A total of 30 eyes of 15 patients (n=14 female) were observed over 30 ± 13 months after bony three-wall orbital decompression. We examined visual acuity (VA), VECP P100 amplitudes and latencies, as well as proptosis using Hertel's exophthalmometry., Results: Mean logarithm of the minimum angle of resolution (logMAR) VA increased, statistically significantly, by 2.4 lines during 30 ± 13 months (from 0.38 ± 0.25 before surgery to 0.14 ± 0.1 at the end of observation, p=0.0001). All eyes maintained or improved vision by at least one line. Mean postoperative reduction of proptosis was 6.4 ± 3 mm. While VECP P100 amplitudes improved significantly, P100 latencies remained abnormal in 18 eyes (60%) during follow-up of 10 ± 7 months. Nine eyes (30%) with previous latency defects improved in at least one check test, five of which normalised completely. Worsening was evident in seven eyes (23%), and three previously normal eyes developed new pathological latencies. P100 latencies in 14 eyes (47%) remained unchanged., Conclusion: After decompression surgery, DON remission was observed in all patients regarding vision and VECP amplitudes. New or persistent P100 latency defects were seen in 60% of eyes after surgery. DON is considered to be caused by compressive ischaemic damage, which further underlines the importance of early decompression surgery.

Background: Graves' disease (GD) is an autoimmune disease that typically affects the thyroid gland. Thirty to sixty percent of patients also suffer from orbital inflammation. Retrobulbar radiotherapy for Graves' orbitopathy (GO) has been used for decades, though there is no direct evidence for the influence of dose and fractionation schedules on various signs and symptoms. Indeed, optimal fractionation schedules and recommended total irradiation doses are still a matter of discussion. Our aim was to investigate treatment efficacy of retrobulbar irradiation for GO at different total absorbed doses and fractionation schedules., Methods: A retrospective evaluation of 129 patients who were examined before, as well as 6-8 months after irradiation with different treatment schedules at eight radiotherapeutic departments. Total absorbed doses were 12, 16, or 20 Gy. All patients were additionally treated with systemic application of corticosteroids. Treatment efficacy was evaluated through assessment of proptosis, horizontal and vertical ocular motility and of clinical activity (CAS). Overall group and individual responses were evaluated. Treatment response was defined as inactivation of GO, reduction of proptosis by at least 2 mm, improvement of motility by > or = 8 degrees or unchanged normal parameters., Results: Prior to irradiation, neither age, disease duration, gender distribution, smoking behavior or serologic parameters, nor clinical activity or severity stages varied significantly between groups. Neither did outcome measures, except proptosis, differ significantly. Retrobulbar irradiation led to inactivity of GO in approximately 80% of patients, with no significant group difference. After irradiation with 16 and 20 Gy, vertical motility improved in a significantly higher percentage of patients than after irradiation with 12 Gy. Median improvement of vertical motility in responding patients was excellent in all groups (15 degrees at 12 Gy, 10 degrees at 16 Gy, 10 degrees at 20 Gy). Horizontal motility did not change significantly., Conclusion: If the aim of retrobulbar irradiation is primarily to reduce soft-tissue signs, lower doses are sufficient. If a patient also suffers from dysmotility, doses exceeding 12 Gy may be more effective.

Genotypes of the T393C SNP of GNAS1, a gene that encodes for the Galphas subunit of G proteins have been significantly associated with the clinical course in a variety of cancers. Since this SNP may also influence the course of Graves' disease (GD) and, especially, Graves' ophthalmopathy (GO), we determined genotype and allele frequency in a series of 359 patients, which were referred to our clinic within 6 months of the onset of GO. Among them, 336 patients also suffered from associated hyperthyroidism. Data on relapse and remission rates 12 months after termination of a 1 year antithyroid drug therapy was available for 276 patients. As controls, 820 healthy individuals were recruited. Our data suggest that the T393C SNP does not represent a risk factor for the development of both GD and GO. It was, however, significantly associated with the course of hyperthyroidism (p=0.013) and a similar trend was evident for the course of GO (p=0.093). Homozygous TT carriers showed a significantly increased risk (p=0.03) for hyperthyroidism to relapse (OR 2.4; 95% CI 1.1-5.4). Also, the TT genotype was associated with significantly increased serum TRAb levels (CC+CT: 5.4 IU/l vs. TT: 9.3 IU/l). This is probably caused by increased G-Protein susceptibility to TSHR-mediated stimulation through TRAb. Genotyping of the T393C SNP of GNAS1 may become a useful additional tool to predict the clinical course of GD and GO. This may allow the clinician to identify patients at risk for more severe courses of disease and to come to more timely decisions for treatment.

Objective: Graves' ophthalmopathy (GO) is clinically associated with autoimmune thyroid disease, and autoantibodies to thyroidal antigens, especially to the TSH-receptor (TRAb), might be involved in the disease process. While there is mounting evidence that TRAb are associated with GO at the onset of the disease, so far no studies have looked at the association between thyroidal autoantibodies and the clinical outcome of GO therapy. The aim of this retrospective study was to evaluate whether TSH binding inhibitory immunoglobulins (TBII) and thyroid stimulating antibodies (TSAb) are still associated with the clinical activity and severity of GO after the completion of anti-inflammatory therapy. In addition, we wanted to elucidate whether thyroid peroxidase (TPO) or thyroglobulin (TG) autoantibodies (TPOAb and TGAb) are in any way related to GO. DESIGN PATIENTS AND MEASUREMENTS: Clinical activity score (CAS) and the severity of GO (modified NOSPECS score) were assessed in 108 patients with GO after steroid therapy and, if indicated, orbital irradiation. Patients were grouped according to their clinical presentation and autoantibody levels (TBII, TSAb, TPOAb and TGAb) were measured. After therapy for hyperthyroidism, all patients were clinically euthyroid but showed clear heterogeneity for GO 4-12 months after the end of anti-inflammatory therapy. Fifty-two patients had inactive GO, 41 had moderately active and 15 still had very active (non-responsive) GO. Concerning severity, 27 patients had mild GO, 64 moderately severe and 17 severe GO., Results: TBII titres were still positive in 14 (93%) of 15 patients in the non-responsive group (CAS > 6) compared to 22 (42%) of 52 patients (P < 0.001) with post-therapeutic inactive GO (CAS

Background: In Graves' ophthalmopathy squint can be corrected in about two-thirds of the patients with a single recession of an inferior or medialis rectus muscle. The dose-effect correlation is linear over a wide range. Combined vertical and convergent misalignments are rare. The aim of this study was to evaluate the dose-effects in combined recessions of medialis and inferior rectus muscles., Material and Methods: The dose-effect of combined recessions (one side medialis and inferior n = 28, both sides medialis and one side inferior n = 9) was evaluated. The control groups were patients with Graves' ophthalmopathy, who had single inferior recession (n = 187), single medialis recession (n = 37) and bilateral medialis recession (n = 44)., Results: Small hypotropias (up to 5 degrees ) at the eye with the poorer abduction disappear after single (17 of 21) or bilateral (11 of 19) medialis recessions. This obvious influence of horizontal recession on the vertical angle leads to a higher dose-effect for the inferior recessions in combined surgery, and was stronger for bilateral cases (from 2.0 degrees to 2.7 degrees /mm recession) than for unilateral cases (from 2.0 degrees to 2.2 degrees /mm recession). The dose-effect for medialis recession in combined surgery increased for the unilateral procedures only from 1.7 degrees to 1.8 degrees /mm recession and not for the bilateral medialis recession., Conclusions: The dose-effect for combined medialis and inferior recessions is enhanced and varies to a much higher degree in comparison to single muscle recessions. Because of the higher variability, patients who need both medialis and inferior recession should be better operated in separate sessions, beginning with the horizontal muscle(s).

Purpose: We evaluated the relationship between ocular surface damage, elevated lid aperture/impaired Bell's phenomenon and reduced tear production in thyroid-associated ophthalmopathy (TAO). Suspecting a possible role of autoantibodies specific for TSH receptor (TSHR), we further investigated TSHR expression in the healthy lacrimal gland (LG)., Methods: A total of 48 patients with active TAO and 26 controls were examined for basal tear secretion, Rose Bengal and fluorescein staining, impression cytology (IPC), break-up time (BUT), and blinking (lid width, lid closure, ocular surface, upward excursion). Healthy LGs were investigated immunohistochemically for expression of TSHR., Results: Thyroid-associated ophthalmopathy patients showed significant ocular surface damage (Rose Bengal staining score: TAO: 2.0 [0-5] versus controls: 0 [0-0.4]; IPC score: TAO 3.0 [0-8] versus controls: 0 [0-1], and BUT: TAO: 3.0 seconds [0-9 seconds] versus controls: 19.5 seconds [13-35.4 seconds]), and significantly reduced tear secretion (TAO: 10 mm [3-20 mm] versus controls: 17 mm [10-27 mm]). Ocular surface damage correlated significantly with tear secretion (r = - 0.35) but not significantly with mechanical alterations (impaired upgaze [r = - 0.34] and ocular surface increase [r = 0.32]). We firstly demonstrate that lacrimal acinar cells physiologically express TSHR., Conclusions: As ocular surface damage in TAO significantly correlates with reduced tear production, LG impairment appears to be a major cause of ocular surface drying. Intriguingly, physiological expression of TSHR by LG suggests that, in thyroid disease, autoantibodies may bind to lacrimal TSHR and, perhaps via aberrant signal transduction, contribute to LG impairment and, hence, dry eye syndrome.

Aim: To characterise periorbital immune cells (stages, kinetics) in active and inactive thyroid associated ophthalmopathy (A-TAO; I-TAO)., Methods: In orbital tissue cryosections of patients with A-TAO (n = 15), I-TAO (n = 11), and healthy controls (n = 14), adipose and fibrovascular areas were evaluated for MHC II(+) cells, CD45(+) total leukocytes, myeloid cells (CD33(+) monocytes; CD14(+) macrophages; mature RFD7(+) macrophages; RFD1(+) dendritic cells (DCs)), and lymphoid cells (CD4(+) T cells; alphabeta and gammadelta T cells; CD20(+) B cells). Results are expressed as medians and 5% confidence intervals., Results: In fibrovascular septae, a surge of CD33(+) immigrants clearly correlating with disease activity generated significantly increased (p<0.05) percentages of CD14(+) and RFD7(+) macrophages. Intriguingly, CD4(+) cells were mostly gammadelta T cells, while alphabeta T helper cells were much less frequent. Successful treatment rendering TAO inactive apparently downregulates monocyte influx, macrophage differentiation, and T cell receptor expression. Similar trends were recorded for adipose tissue. Interestingly, RFD1(+) DCs were completely absent from all conditions examined., Conclusion: A-TAO coincides with periorbital monocyte infiltration and de novo differentiation of macrophages, but not DCs. The authors discuss a novel potential role for inflammatory CD4(+) gammadelta T cells in TAO. Successful treatment apparently downregulates orbital monocyte recruitment and effects functional T cell knockout.

Background: In patients with Graves' disease, smoking considerably increases the incidence and severity of thyroid associated ophthalmopathy (TAO). The authors sought to determine if smoking also influences the course of TAO during treatment, and the efficacy of therapy., Methods: 41 smokers and 19 non-smokers with moderate untreated TAO were included in this prospective study. All patients were treated with steroids and, 6 weeks after the beginning of drug therapy, with orbital irradiation. Follow up was performed 1.5, 4.5, 7.5, and 12 months after the beginning of the study. Proptosis, clinical activity score (CAS), and motility were evaluated. The extent of smoking was derived from the concentration of the haemoglobin adduct N-2-hydroxyethylvaline (HEV), a parameter of long term smoking., Results: There was no difference in the clinical manifestations of TAO between smokers and non-smokers at the beginning of treatment. However, CAS decreased (p<0.05) and motility improved (p<0.02) significantly faster and to a greater extent in non-smokers than smokers. Inverse correlations between the CAS decrease and the HEV levels observed 4.5 and 7.5 months after the beginning of treatment and between the improvement of motility and the HEV levels after 1.5, 4.5, and 7.5 months indicated a dose dependence. Mean HEV levels did not vary much during the follow up period and were significantly different in smokers (mean 5.4 (SD 2.7) micro g/l) and non-smokers (mean 1.8 (1.3) micro g/l; p<0.01)., Conclusion: Smoking influences the course of TAO during treatment in a dose dependent manner. The response to treatment is delayed and considerably poorer in smokers.

The aim of ocular muscle surgery in Graves' disease is to determine how an optimal normalization of ocular motility disorders - diplopia, compensatory head posture, eyelid dispositions - can be achieved. The results of ocular muscle surgery of fibrotic ocular muscles allow the following conclusions to be drawn. Correcting the motility disorder can be precisely dosed by recessing only one fibrotic ocular muscle with a strabismic angle of up to 15 degrees. This leads to reproducible and dependable results, with a dose-effect coefficient independent of the initial strabismus angle. Indications as to the amount of surgery and which side should be varied according to horizontal an vertical deviations, and are also dependent on the compensatory head posture. Improvement of the binocular visual field is possible in nearly all cases. Over corrections occur more often when the muscle is not directly fixed at the sclera but adjusted on the following day. The time factor is important both before and after the operation. Before the operation, the motility status should have been stable for at least six months. Postoperatively, within the first few days, an insufficient correction should be expected, however this should not lead to premature revision of the amount of surgery. The surgery of the vertical rectus muscles influences the eyelid position. The upper lid retraction is improved with surgery on the vertical extraocular muscle and depends on prior upper lid motility. In contrast, an increase in lower lid retraction is not dependent on an inferior rectus recession. The results permit a precise series of steps to be drawn up in Graves' disease regarding surgical indications, proportionally correcting each side, and the dosage of ocular muscle operations.

Graves' ophthalmopathy (Graves' disease) is a grave, rare immunological inflammatory reaction of the postorbital connective, adipose and ocular muscle tissue. Graves' disease occurs only within the scope of immunothyropathies and constitutes the most frequently encountered extrathyroidal manifestation. Typical symptoms are a result of the volume increase of the postbulbar connective and adipose tissue and of the interstitial swelling of the ocular muscles. Clinically, we find a spectrum of increasingly grave changes in the orbita, such as infiltration of the eyelid and connective tissue, exophthalmos, swelling of the muscles, damage to the cornea and involvement of the optic nerve with loss of vision. Regarding functional impairment of the optic nerve (optic nerve compression), orbita decompression represents an operative ultima ratio. Between January 1992 and April 1997, 11 patients (22 orbitae) from a group of more than 600 patients with Graves' disease with vision involvement were treated surgically. All treatment data were documented prospectively. Surgical intervention was performed only in cases where a progressive loss of vision existed in spite of retrobulbar irradiation and high-dose glucocorticoid therapy. Surgical therapy consisted of decompression of the medial, inferior and lateral orbital wall and of the orbital contents via combined bi-coronary and anterior access. The long-term results demonstrated improved vision conditions with 17 of the 22 eyes operated on. Parameters such as vision, exophthalmos, VEP, motility, double vision and field of vision were documented pre- and post-operatively. The prediction of post-operative deviations of the bulb axis was limited, and these were rectified through secondary displacements of the ocular muscle. No complications worth mentioning were encountered. In extreme events of therapy-resistant Graves' ophthalmopathies with progressive loss of vision, the three-wall decompression method has proved to be the correct one.

Eye muscle surgery in Graves' disease is conducted to normalize eye motility disorders-diplopia, abnormal head posture, eyelid malposition. A review of the literature to determine the results of eye muscle surgery on the fibrotic eye muscles indicated the following: Correction of the motility disorder can be done precisely by recessing only one fibrotic eye muscle with a strabismus angle of up to 15; this leads to reproducible and dependable results, with a dose-effect coefficient independent of the initial strabismus angle. Indications vary as to how much to do as well as which side, dependent on whether the deviation is horizontal or vertical and whether the head posture is abnormal. Improvement of the fusional visual field is possible in nearly all cases. Hypercorrections occur more often when the muscle is not directly fixed at the sclera but adjusted on the following day. The time factor is important both before and after the operation: before the operation, the motility situation should have been stable for at least 6 months; postoperatively, a correction should be expected, which is not yet sufficient in the first few days; this should not lead to premature revision. Surgery on the vertical rectus muscles influences eyelid position: upper-lid retraction is improved and depends on the previous upper-lid motility; in contrast, an increase in lower-lid retraction is not dependent on recession of the inferior rectus. The results reported permit a precise series of steps to be drawn up as regards indication, the proportion of correction of each side, and eye muscle operations in Graves' disease.

Antithyroid drugs (AD) still represent the most widely chosen therapy for hyperthyroidism of Graves' disease. Since their interaction with iodine is still poorly understood, this was addressed in multicenter clinical trials. The interaction of iodine and methimazole was studied in 260 patients from iodine deficient countries. Whereas patients with very low iodine supply needed low doses of methimazole, patients with even slightly increased iodine supply needed high doses of methimazole to remain euthyroid. In another study of 1256 patients side effects of AD were shown to be dose-dependent. Immunological markers of thyroid autoimmunity disappear in most patients during treatment with AD although with many exceptions. Remissions after treatment with AD may represent disease heterogeneity within a spontaneous disease course and the spectrum of relapsing hyperthyroidism over euthyroidism to hypothyroidism. Lastly therapeutic strategies in thyroid eye disease have not provided evidence which therapy is superior.