Graves' ophthalmopathy

Ophthalmopathy develops in about 30% of patients who have Graves' disease. The pathogenesis, like that of the hyperthyroidism, is probably autoimmune in nature. The eye manifestations are diverse and include lid lag, soft tissue swelling, proptosis, corneal damage, diplopia, and optic neuropathy. The natural history is benign in 90% of patients, with gradual improvement over time. Therapeutic options include corticosteroid therapy, radiation, and surgical treatment. The last is usually the therapy of choice for severe or disfiguring ophthalmopathy.     

Treating severe Graves' ophthalmopathy

Most patients with Graves' disease have some evidence of ocular involvement, but this is commonly mild, requiring only local measures. A minority of patients (3-5%) have severe Graves' ophthalmopathy, for which the three main treatment procedures are represented by high-dose glucocorticoids, orbital radiotherapy and orbital decompression. Favourable results with medical treatment have been reported in approximately 60% of patients, with particular regard to inflammatory changes, newly developed eye muscle dysfunction and optic neuropathy. Orbital decompression is indicated in severe eye disease not responsive to glucocorticoids and/or irradiation, particularly in the presence of marked proptosis and optic neuropathy. Not conclusive or unsatisfactory results have been obtained with other medical treatment procedures, including immunosuppressive drugs, intravenous immunoglobulins and plasmapheresis. Recently favourable responses have been reported with somatostatin analogues. Rehabilitative surgery involving either the eye muscles or the eyelids is not infrequently required after medical treatment or decompression. Permanent control of thyroid hyperfunction by radioiodine or thyroidectomy is advisable when severe ophthalmopathy is present. Exacerbation of ophthalmopathy following radioiodine may occur but can be prevented by concomitant administration of glucocorticoids. Smoking deleteriously influences the course of ophthalmopathy and its response to treatment.     

Computed tomography in Graves' ophthalmopathy

The CT scan with the 160 x 160 matrix demonstrated both the normal orbital anatomy and the abnormal orbital anatomy of Graves' ophthalmopathy in great detail. In Graves' ophthalmopathy, the cardinal pathologic feature of extraocular muscle enlargement was accurately reflected on the CT scan and was a distinctive, diagnostically reliable finding. Enlargement of the medial and lateral rectus muscles and of the apex of the muscle cone were the most consistent findings. The severity of the CT scan abnormalities correlated well with clinical severity. Because muscle cone abnormality was observed characteristically in those patients with sight loss, we suggest that pressure by the extraocular muscles on the optic nerve may contribute to visual acuity loss in this disease.     

The role of radiation therapy in Graves' ophthalmopathy

Graves' ophthalmopathy can occur in 25-30% of patients with hyperthyroidism. This condition can result in serious visual disturbance and disfigurement. The treatment options for symptomatic disease are oral corticosteroids or orbital irradiation. Ten patients with Graves' ophthalmopathy were treated with external beam radiotherapy at Saint Lukes Hospital from March 1991 to February 1994. Eight of these patients had excellent response with minimal morbidity. We believe that orbital radiotherapy is effective and well tolerated, and should replace corticosteroid therapy as the initial treatment modality in these patients.     

Simultaneous occurrence of Graves' ophthalmopathy and autonomous thyroid nodules

Estimations regarding the simultaneous occurrence of Graves' ophthalmopathy and autonomously functioning thyroid nodules expect frequencies of 0.05-0.2%. Contrary to these estimated numbers, only 3 patients with these simultaneous manifestations were identified in an out patient thyroid clinic within a period of 10 years. The possible protection by the autonomous thyroid nodules against the manifestations of Graves' disease is discussed.     

The use of colour slides in the assessment of changes in soft-tissue involvement in Graves' ophthalmopathy

There is a need for more reliable and validated methods to assess the eye changes in Graves' disease. Such measurements are now available for the assessment of proptosis, eye muscle dysfunction, and optic nerve involvement. However, no validated objective measurement exists for NO SPECS class II signs. The present study compares the use of colour slides with clinical grading for assessing soft-tissue involvement. Forty-three patients were treated with retrobulbar irradiation. Pre-treatment, and 6 months post-treatment the severity of class II signs was graded from 0 to grade c in two ways; 1) Clinically, by two independent, experienced observers, who recorded their scores on the same day; 2) From colour slides, taken at the same visits, which were graded afterwards in one session independently by the same observers. Inter-observer agreement about clinical grading was low (Kappa 0.32), and was not improved by using the slides (Kappa 0.35). However, by using the clinical scores, the observers disagreed on treatment outcome in 21/43 patients (49%), whereas using the slides disagreement occurred in only 6/43 (14%, p < 0.01). It is concluded that the grading of soft-tissue involvement is highly subjective. However, the use of colour slides does provide a more reliable way to assess a treatment effect and should be used in clinical trials.     

Cytolytic T cells with Th1-like cytokine profile predominate in retroorbital lymphocytic infiltrates of Graves' ophthalmopathy

Lymphocytic infiltration of muscular and connective tissues of the retroorbital (RO) space is a histological hallmark of Graves' ophthalmopathy (GO). We have characterized some phenotypical and functional features of T cells derived from RO infiltrates of four GO patients who were submitted to orbital decompression. Fragments of RO tissue were cultured for 7 days in IL-2-conditioned medium in order to generate T cell lines of in vivo activated T cells. Phenotypical analysis of freshly isolated peripheral blood (PB) lymphocytes both from patients and four healthy controls showed a predominance of CD4+ T cells (CD4/CD8 ratios 1.9:2.5), whereas RO-derived T cell lines displayed almost equal proportions of CD4+ and CD8+ cells (CD4/CD8 ratios 0.9:1.2). RO T cell lines and PB T cells from patients and controls were then cloned using a high-efficiency cloning procedure. The phenotypical and functional features of 153 T cell clones (TCC) derived from RO infiltrates were examined and compared with those of 166 and 236 TCC derived from the PB of patients and controls, respectively. CD4/CD8 ratios ranged from 0.8-1.4 in the series of RO-derived TCC and from 1.9-2.2 in the corresponding series of PB-derived TCC. Assessment of lectin-dependent cytolytic activity showed similar proportions of cytotoxic clones in TCC derived from the PB of patients (37%) and controls (38%); most of the cytolytic TCC was CD8+. In contrast, the proportion of cytolytic RO TCC was markedly higher (106/153 = 69%), including 100% of CD8+ and the majority (59/79 = 75%) of CD4+ clones. When compared to TCC derived from the PB of both patients and controls, RO TCC showed remarkably high proportions of both CD8+ and CD4+ clones with a Th1-like cytokine profile, as documented by their ability to secrete IL-2, IFN-gamma, and tumor necrosis factor-alpha (TNF-alpha), but not IL-4 or IL-5. This study provides evidence that cytolytic T cells with Th1 profile of cytokine production predominate in RO infiltrates of GO, a pattern quite similar to those previously described in thyroid infiltrates of Hashimoto's thyroiditis or Graves' disease. The peculiar cytokine secretion profile of RO T cells may be of importance in the pathogenesis of both the tissue alterations and fibrogenic process observed in GO.     

Soluble interleukin-1 receptor antagonist serum levels in smokers and nonsmokers with Graves' ophthalmopathy undergoing orbital radiotherapy

Interleukin-1 (IL-1) plays an important role in the pathogenesis of Graves' ophthalmopathy (GO). Impaired antagonism of the proinflammatory cytokine IL-1 by the naturally occurring IL-1 receptor antagonist (IL-1RA) has been implicated in the initiation and perpetuation of various autoimmune diseases and may play a role in the evolution of GO. Cigarette smoking appears to adversely affect the course of GO. We have evaluated the course of IL-1 alpha, IL-1 beta, and soluble IL-1RA (sIL-1RA) serum levels in smokers and nonsmokers with GO undergoing orbital radiotherapy (OR). We prospectively studied the eye status of 27 randomly selected patients (mean age 47.3 +/- 11.0 yr; 20 females; 18 smokers) with active, moderately severe GO before and 3 and 6 months following OR, respectively. None had received any previous treatment for GO, and all patients were kept euthyroid on carbimazole. Serum concentrations of IL-1 alpha, IL-1 beta, and sIL-1RA were measured using highly sensitive enzyme linked immunosorbent assay systems. Baseline sIL-1RA levels were negatively correlated with the number of cigarettes smoked before and following OR (P < 0.0001). Patients with no or minor therapeutic response to OR (n = 8), all of whom were smokers, revealed mean baseline sIL-1RA levels of 114 +/- 85 pg/mL, which increased to 172 +/- 103 pg/mL at 3 months and 149 +/- 96 pg/mL at 6 months after initiation of OR, respectively. By contrast, patients with a good clinical response (n = 19, 9 nonsmokers), revealed significantly higher baseline sIL-1RA levels at 294 +/- 148 pg/mL (P = 0.004), which increased to 845 +/- 668 pg/mL at 3 months (P = 0.01) and 634 +/- 337 pg/mL at 6 months (P < 0.001), respectively, following initiation of OR. Serum concentrations of IL-1 alpha IL-1 beta were below 3.9 pg/mL in all patients with GO who were studied, and were not correlated with gender, age, smoking status, clinical course, or outcome. Low baseline levels and impaired surge of sIL-1RA serum levels following OR were strongly correlated with smoking status and a less favorable therapeutic outcome in patients with active, moderately severe GO. Measurement of sIL-1RA may contribute to predict the therapeutic response to OR in patients with active, moderately severe GO. Strategies designed to raise local or systemic concentrations of sIL-1RA may be of benefit to patients with GO.     

Peculiarities of treating endocrine ophthalmopathy in patients with toxic goiter combined with diabetes mellitus

Thyroid pathology is among autoimmune diseases the incidence of which is now on the increase. Endocrine ophthalmology (EO) often accompanying thyroid disorders may cause deterioration or loss of vision. EO can be corrected by several methods. The most pronounced effect is achieved by x-ray therapy on the orbit and intermittent glucocorticosteroid (GCS) large-dose therapy. GCS, however, affect carbohydrate metabolism. In physiological levels, GCS effects on regulation of carbohydrate metabolism are not significant, but high GCS concentrations may provoke hyperglycemia and even steroid diabetes.     

Analysis of the IgG autoantibody repertoire in endocrine ophthalmopathy using the MegaBlot technique

The cervical spine is frequently involved in rheumatoid arthritis and yet there exists no consensus on the need to screen for cervical spine subluxations preoperatively. We reviewed retrospectively 77 patients who underwent 132 operations under general or regional anaesthesia over a 44-month period. We found that while the majority of patients had received preoperative X-ray screening for cervical spine instability, a third of the X-ray examinations done had been inadequate. Many anaesthetists did not repeat cervical spine X-rays if there were previously performed views available. We showed that a complete X-ray examination of the cervical spine should include flexion and extension stress views in addition to frontal views of the odontoid and entire cervical spine. Anterior atlantoaxial subluxation was the most common subluxation encountered in our study population. The detection of cervical spine instability was found to significantly affect anaesthetic management, favouring techniques that avoided unprotected manipulations of the neck under anaesthesia.     

Early strabismus surgery for thyroid ophthalmopathy

OBJECTIVE: To determine whether strabismus surgery during active thyroid ophthalmopathy is beneficial for selected patients. DESIGN: Case series. PARTICIPANTS: Eight patients with severe restrictive strabismus due to thyroid ophthalmopathy underwent early strabismus surgery and were followed for a minimum of 16 months after their initial surgery. INTERVENTION: All eight patients underwent strabismus surgery while their thyroid ophthalmopathy was evolving. MAIN OUTCOME MEASURES: Success was determined by the ability to fuse in the primary position at distance and near without an abnormal head position, and the absence of vision-threatening complications related to strabismus surgery. RESULTS: All eight patients achieved successful long-term alignment. Four patients (50%) required more than one operation. CONCLUSIONS: Strabismus surgery during active thyroid ophthalmopathy can result in long-term stable alignment and may be a useful alternative in selected patients with marked disability due to thyroid ophthalmopathy.     

The pathogenesis of Graves' disease

Graves' disease may prove to be due to a genetic defect in immune surveillance or control, which then permits a randomly mutating thyroid-directed clone of T-lymphocytes to survive, interact with previously normal thyroid cell membrane antigen, and set up a localized cell-mediated immune response. The T-lymphocytes so interacting then cooperate with and direct groups of B-lymphocytes, which consequently produce TSI's: the stimulation of the thyroid parenchymal cells is a direct result of TSI stimulation. PHA stimulates Graves' lymphocytes to produce TSI's by first stimulating T-lymphocytes, which in turn interact with B-lymphocytes, which produce the TSI's. Normal thyroid antigen can stimulate sensitized lymphocytes to produce TSI's, which in turn can interact with normal thyroid cell membranes. This and other evidence suggests that there need not be any thyroidal antigenic change necessary to initiate hyperthyroidism. Stress may be related to the immunologic induction of the disease; it appears that remissions, other than those due to thyroid cell destruction, are immunologic. Exophthalmos may also prove to be an autoimmune disorder resulting from a closely related, but possibly not identical, defect in immunologic surveillance. Other related autoimmune diseases may result from similar related defects in immunologic surveillance, as well as from the random mutation of the appropriate forbidden clone.     

An alternative technique for coronary reattachment in aortic root replacement--the "shell" button technique

A modified technique to the reattachment of the coronary ostia in the aortic root replacement is described. The left coronary ostium is excised semicircumferentially in an aortic button with its subostial quarter remained as a joint. A collagen impregnated 10-mm Dacron interposition tube graft is sutured rectangularly to the face of the button with the interrupted pledgeted horizontal mattress sutures all running through the button wall in outside-in fashion. The other end of the graft is beveled and sutured end-to-side cephalad to the aortic conduit in order to join each other with straightness assuring the distance between the right coronary button and the aortic conduit to be anastomosed directly. The left coronary button can incline passively with the long axis of the coronary graft, like a "shell", and this allows equivalent distribution of tension on the anastomosis and a straightness of the graft to create the laminar flow in it. The right coronary button is anastomosed to the aortic conduit opposite the ostium with a running over-and-over suture. This procedure has been used in a 35-year-old male with annuloaortic ectasia caused by Marfan's syndrome complicated with type A acute aortic dissection. The patient discharged on the 26th postoperative day without any complications nor angiographic problems. We found this procedure useful in terms of the security of the coronary anastomosis and geometrical arrangement of the conduits.     

The doorstop procedure. A technique for treating unstable fracture dislocations of the proximal interphalangeal joint

The unstable fracture dislocation of the proximal interphalangeal joint remains a difficult injury to manage despite the availability of a wide variety of treatment options. We describe a simple alternative method of treatment called the doorstop procedure.     

The genetic susceptibility to Graves' disease

Graves' disease (GD) develops as a result of a complex interaction between genetic susceptibility genes and likely environmental factors. Most epidemiological data support an important genetic contribution to the development of GD. The concordance rate of GD in monozygotic twins is 30-60% and in dizygotic twins 3-9%, and thyroid autoantibodies have been reported in up to 50% of the siblings of patients with GD. For many years now, HLA studies have consistently shown an increased frequency of HLA-DR3 in Caucasian patients with GD; but with only a risk ratio of 3-5. However, recent advances in human genome mapping techniques have enabled the study of many other candidate genes. Of these additional, non-HLA genes, only CTLA-4 has been consistently found to be associated with GD. Using a linkage based approach which only detects highly significant susceptibility genes we have recently reported preliminary results which demonstrated that a marker located approximately 25 cM from the TSH receptor gene on chromosome 14q31 is linked to GD and in the same vicinity as the IDDM-11 locus. Such results, if confirmed, may signal the presence of a gene family related to endocrine autoimmunity on chromosome 14q31.