HLA-alleles associated with increased risk for extra-pulmonary involvement in sarcoidosis.

Genetic factors influence the risk for disease as well as the clinical picture seen in sarcoidosis and especially the genes localized to the human leukocyte antigen (HLA) region on chromosome 6 are of importance. The aim of this study was to further investigate associations between HLA-DRB1 alleles and the risk for extra-pulmonary manifestations (EPMs), i.e. engagement of the skin, superficial lymph nodes, eyes, nervous system, kidneys, hypercalcemia, parotid and salivary glands, heart, liver, spleen and bone marrow in Scandinavian sarcoidosis patients. One thousand patients with together with a group of 2000 healthy individuals, matched for sex and age. HLA-DRB1 alleles were determined for all patients and controls. Excluding erythema nodosum and ankle arthritis, we found 288 of 1000 patients to have EPMs. There were 383 patients with Löfgren's syndrome (LS), and among them EPM were relatively uncommon and diagnosed in only 31 (8.1%) of the patients. In contrast, among the 617 non-LS patients, 257 (41.6%) had EPM (P < 0.0001). In LS patients, the absence of HLA-DRB1*03 substantially increased the risk factor for EPM (erythema nodosum and ankle arthritis excluded) (P < 0.0001). A distinct HLA allele combination, HLA-DRB1*04/*15, was identified as a risk factor for EPM in all patients (25 of 50 with DRB1*04/15 had EPM). In conclusion, EPM are common in non-LS sarcoidosis. Furthermore, HLA-typing of sarcoidosis patients can be used in the clinic to identify patients with an increased risk for EPM.

Duration of treatment for candidemia and risk for late-onset ocular candidiasis.

PURPOSE: Few reports have been published on the optimal duration of treatment of ocular candidiasis. We have investigated the incidence of late-onset Candida chorioretinitis and endophthalmitis in patients with candidemia who did not initially receive an ophthalmologic examination. The aim was to determine the duration of initial antifungal treatment that may be sufficient to avoid this complication. METHODS: This was a long-term follow-up study of 144 patients with candidemia who survived for at least 60 days after the onset of candidemia. The frequency of early- and late-onset ocular complications due to candida infection and factors associated with ocular candidiasis were investigated. RESULTS: Fundoscopy was performed on 60 patients, revealing 12 cases of ocular candida infection (20 %). Risk factors were infection with Candida albicans compared to other Candida species (p = 0.021) and surgery due to solid tumor (p = 0.004). Only one case of late-onset ocular candidiasis occurred among the 84 candidemic patients who did not receive an initial ophthalmologic examination. For unknown reasons, this patient had received only 2 days of systemic antifungal treatment initially. CONCLUSIONS: No case of late-onset ocular candidiasis was detected in unexamined patients who received at least 14 days of antifungal treatment. Based on our results, it would appear that the recommended 2 weeks of treatment after the first negative blood culture are sufficient to avoid late-onset complications due to undiscovered Candida chorioretinitis in patients surviving for more than 60 days after the onset of candidemia.

HLA-DRB1* alleles and symptoms associated with Heerfordt's syndrome in sarcoidosis.

Heerfordt's syndrome (HS) consists in its complete form of uveitis, parotid or salivary gland enlargement and cranial nerve palsy. The objective of the present study was to analyse if there are also links between HLA-DRB1* alleles and HS, as it is a specific phenotype of sarcoidosis. 1,000 patients with sarcoidosis, out of whom 83 had symptoms associated with HS, were included in the study together with a group of 2,000 healthy individuals from the same population, matched for sex and age. HLA-DRB1* allelic groups were determined for all individuals, and comparisons were made between different disease subgroups and between patients and healthy controls. We found that the HLA-DRB1*04 allele was overrepresented in patients with symptoms associated with HS. 83 (8.3%) of all patients had one or more of the symptoms and 46 (55%) of them were HLA-DRB1*04 positive. 44 (55%) of the patients with ocular sarcoidosis, i.e. the most common symptom associated with HS, were HLA-DRB1*04 positive, compared with 35.9% of healthy controls (p=0.0008), and only 26.6% of the whole group of sarcoidosis patients (p<0.0001). HLA-DRB1*04 seems to protect against overall sarcoidosis but appears to be a significant risk factor for ocular sarcoidosis as well as for other manifestations associated with HS.

Saccadic eye movement velocity measured with the infrared reflection and search coil eye-tracking systems in patients with thyroid-associated ophthalmopathy.

BACKGROUND: Assessment of changes in saccade velocity may be useful in the early detection of thyroid-associated ophthalmopathy (TAO). Two eye-tracking systems were used to measure the velocity of saccadic eye movements in patients with TAO. METHOD: Fourteen patients with active TAO and 14 healthy controls were enrolled for recordings with two eye-tracking systems: the magnetic scleral search coil (MSC; Skalar Medical) and the infrared reflection systems (IR; Orbit XY-1000). The MSC is generally considered the "gold standard" method for tracking of rapid eye movements. The IR system uses novel computer technology and is based on sampling of reflected infrared light from the surface of the eyes. Main sequence plots constructed from the recorded saccadic peak velocity and amplitude were analyzed for differences between patients and healthy controls. RESULTS: There were no significant differences between patients with TAO and healthy controls in the constructed main sequence plots of maximum velocity (V(MAX)) and the slope constant (C). CONCLUSIONS: Main sequence analysis of saccadic eye movements was not useful for detecting TAO in this experimental setting with either of the two eye-tracking methods. This is hypothesized to be due to compensation for the early orbital changes in TAO by neural adaptation of the saccades in the brain stem. The contradictory results between this and previous studies cannot be easily explained. We assume that there is a large heterogeneity in the saccadic eye movement performance in both the normal population and the TAO-population. Also, differences in the study design may cause dissimilar outcomes and hence incoherent conclusions. A non-invasive recording system that is able to generate a minimum amount of intra- and inter-individual variability and a study design where normal variability can be reduced to a minimum may be useful for future identification of early eye muscle changes in TAO.

Graves' hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine--a prospective, randomized study. Thyroid Study Group.

To analyze the benefits and risks of three common treatments, we randomly assigned 179 patients with Graves' hyperthyroidism as follows: 60 patients, 20-34 yr of age (young adults), received antithyroid drugs for 18 months (medical) or subtotal thyroidectomy (surgical), and 119 patients, 35-55 yr of age (old adults), received medical, surgical, or radioiodine (iodine-131) treatment. The follow-up time was at least 48 months. Antithyroid drugs, surgery, or iodine-131 treatment normalized the mean serum hormone levels within 6 weeks. The risk of relapse was highest in the medically treated young and old adults (42% vs. 34%), followed by that in those treated with iodine-131 (21%) and that in the surgically treated young and old adults (3% vs 8%), respectively. Elevated TSH receptor antibodies at the end of medical therapy or increasing TSH receptor antibodies values after medical or surgical treatment increased the probability of relapse. Development or worsening of ophthalmopathy was not associated with relapse per se. Ninety percent of the subjects in all groups were satisfied with the treatment they received. No significant difference in sick-leave due to Graves' or other diseases was seen during the first 2 yr after initiation of therapy. The increased risk of ophthalmopathy in patients with high serum T3 levels, especially when treated with iodine-131, and the relatively high frequency of relapse after treatment with antithyroid drugs are important factors to consider when selecting therapy for Graves' disease.

Immunohistochemical staining of normal and Graves' extraocular muscle.

Extraocular muscle biopsies from normal individuals and five patients with Graves' ophthalmopathy were analyzed by immunohistochemical staining. Fibroblasts in normal extraocular muscle as well as Graves' extraocular muscles expressed HLA-class II antigens, but the muscle cells did not. There was an increase of interstitial tissue in Graves' extraocular muscles but no visible damage to the muscle cells. In four of the biopsies from Graves' patients the cellular reaction was very weak. In the fifth patient the reaction was more pronounced with macrophages predominating, but with few lymphocytes and almost equal amounts of B and T cells. We could not confirm the earlier described specific extraocular muscle antibodies in sera from Graves' patients and conclude that there seems to be an activation of orbital fibroblasts in Graves' ophthalmopathy. This may contribute to the pathogenesis of the disease.

Does early administration of thyroxine reduce the development of Graves' ophthalmopathy after radioiodine treatment?

The roles of thyroid hormones and thyrotropin (TSH) in the development of Graves' ophthalmopathy are not clear. Some studies suggest a protective effect of thyroid hormones on experimental exophthalmos and an adverse effect of increased TSH levels. In September 1988 we introduced early thyroxine (T4) administration after 131I therapy for hyperthyroidism caused by Graves' disease. We carried out a retrospective study of records from all patients with this disease treated with 131I for 4 years. During the first 2 years 248 patients were treated (group A). They received T4 when the serum concentration of TSH and/or T4 indicated hypothyroidism. During the next 2 years 244 patients were treated (group B). They were all given 0.05 mg of T4 daily, starting 2 weeks after therapy, and 0.1 mg after a further 2 weeks. With a follow-up of 18 months, 45 patients (18%) in group A and 27 patients (11%) in group B developed or deteriorated in an already present ophthalmopathy (p = 0.03, relative risk = 1.64, 95% confidence interval = 1.05-2.55). Twenty-six patients in group A required specific therapy for the ophthalmopathy (e.g. antithyroid drugs, steroids, etc.) compared to 11 patients in group B (p = 0.02, relative risk = 2.33; 95% confidence interval = 1.18-4.60). Our results suggest that early administration of T4 after 131I therapy reduces the occurrence of Graves' ophthalmopathy.

The effect of lithium on amphetamine-induced locomotor stimulation.

A behavioural study was performed to investigate how lithium interacts with monoamine mechanisms. Acute lithium pretreatment partially antagonized amphetamine-induced locomotor stimulation in mice. A rather small dose of L-dopa, which had no stimulant effect on locomotor activity of its own, caused a dose-dependent antagonism of the lithium-induced suppression of the amphetamine-induced locomotor stimulation. Additionally, acute lithium pretreatment had no effect on the apomorphine-clonidine-induced locomotor stimulation after elimination of presynaptic activity by means of pretreatment with reserpine and alpha-MT. Our interpretation of these results is that the inhibitory effect on amphetamine-induced locomotor stimulation is likely to be mediated via presynaptic mechanisms (i.e., decreased release of catecholamines or inhibition of catecholamine synthesis or a combination of both mechanisms) and, further, lithium seems to have no effect at or beyond the catecholamine receptors. However, the possibility that lithium may increase the activity in neuronal systems antagonizing the catecholamine neurons cannot be excluded.

Surgical treatment of thyroid eye disease.

Thyroid eye disease may result in exophthalmos, diplopia, and eyelid malpositions, which can be corrected with different surgical procedures. Several techniques for decompressing the orbit have been described, and the advantages and disadvantages of the techniques are discussed. Our own results of the transantral approach are briefly summarized. Eye muscle surgery should be performed after an orbital decompression, and it is not unlikely that more than one muscle operation will be needed in order to achieve single vision. A number of operative procedures for eyelid surgery have been described, and the results of the various methods are generally good.

Radioiodine treatment, ablation, and ophthalmopathy: a balanced perspective.

In some patients with Graves' disease, ophthalmopathy develops or deteriorates after initiation of therapy for hyperthyroidism. The possible relationship between the management of hyperthyroidism and the course of ophthalmopathy has been addressed in several studies but with conflicting results. The overall impression, when comparing these studies, is that there is no definite difference between the three forms of therapy for hyperthyroidism with regard to the course of ophthalmopathy, although there are more studies suggesting that 131I carries a higher risk for aggravating the eye disease. However, many of these studies are retrospective, contain few patients, have a short follow-up time, and include patients who have received more than one type of treatment. We performed a prospective study in which patients were randomized to either antithyroid drugs, subtotal thyroidectomy, or 131I. We found that 33% of the patients treated with 131i deteriorated compared with 10% and 16% of patients treated with antithyroid drugs and surgery, respectively (p = 0.02). The risk was greater when patients had very high pretreatment thyroid hormone levels. On the other hand, patients treated with 131I were given thyroxine later than the other patients, although this fact did not appear to be of importance for the results. In another retrospective study, we showed that early administration with thyroxine can reduce the risk for ophthalmopathy, and we now are undertaking a prospective study in which treatment with antithyroid drugs is compared with 131I treatment and early thyroxine. Our guidelines for ablative therapy in patients with progressive ophthalmopathy are presented.

Quality of life aspects and costs in treatment of Graves' hyperthyroidism with antithyroid drugs, surgery, or radioiodine: results from a prospective, randomized study.

The patients' views and costs of three different forms of treatment for Graves' hyperthyroidism were investigated. The study comprises 174 patients with Graves' hyperthyroidism who were stratified into two age groups: 20 to 34 years and 35 to 55 years. The younger group was randomly assigned to treatment with antithyroid drug plus thyroxine for 18 months or subtotal thyroidectomy, and in the older group iodine-131 was added as a third alternative. The patients' views of their therapy were based on a questionnaire formulated to identify possible differences between the three treatment forms. The costs were assessed by analyzing the official hospital reimbursement system for both outpatient and inpatient costs for a period of 2 years from the day of randomization. The results show that no significant differences in opinion were found between the five treatment groups with regard to any of the questions. Furthermore, only 10% of the patients expressed slight and 3% major hesitation to recommend the treatment form received to a friend with similar disease. Twenty percent of the patients with endocrine ophthalmopathy reported the eye problems to be much more troublesome and 14% somewhat more troublesome than the thyroid problems. The cost proportion between the medical and surgical treatment in the young group was 1:2.5 (1 = 1126 United States dollars [USD]) before and 1:1.3 (1 = 2284 USD) after inclusion of the relapse costs. The proportion between the medical, surgical, and iodine-131 treatment in the older group was 1:2.5:1.6 (1 = 1164 USD) before and 1:1.6:1.4 (1 = 1972 USD) after inclusion of the relapse costs.

Surgical treatment of hyperthyroidism: a ten-year experience.

Hyperthyroidism is treated either by antithyroid drugs, radioiodine (I131) or surgery. In Sweden, surgery is often performed in patients with large goiter or severe hyperthyroidism with infiltrative endocrine ophthalmopathy. To evaluate indications and results of surgical treatment, data from 380 patients operated on for hyperthyroidism at our department during 1986-1995 were analyzed. Twenty-six percent were referred for surgery because of failure of treatment with antithyroid drugs or I131. Ninety-one percent were subjected to subtotal thyroidectomy with a median remnant weight of less than 2 g. In the remaining patients, total thyroidectomy was performed. Transient vocal cord affection occurred in 2.6%, none of which was permanent. Prolonged postoperative hypocalcemia occurred in 3.1%, and permanent hypoparathyroidism in 1%. There was no difference in complication rate between subtotal or total thyroidectomy. In patients with Graves' disease, 5% worsened with regard to ophthalmopathy initially after surgery but later improved. Recurrent disease occurred in 2% of the patients, all of whom had undergone subtotal thyroidectomy. Surgery is not first-line therapy in all patients with hyperthyroidism. However, in experienced hands, surgery is a good therapeutic alternative that can be carried out with no mortality, few complications, and, provided that a minimal remnant is left, very few recurrences.

Thyroid associated ophthalmopathy: botulinum toxin A in the treatment of upper eyelid retraction--a pilot study.

PURPOSE: Eyelid retraction in patients with thyroid associated ophthalmopathy is a common cause of eye discomfort and a disfigured facial appearance. The aim of this pilot study was to evaluate the effects and safety of inducing a temporary partial ptosis of the eyelid through injection of botulinum toxin A into the levator palpebrae superioris muscle. METHODS: Nine patients were treated. They were followed up with ophthalmologic examinations and self-assessment questionnaires until the point at which they either required renewed treatment or had no residual effect of the first injection. Maximum follow-up time was twenty weeks. RESULTS: In all eyes but one there was a lowering of the eyelid position one week after treatment and all these patients reported an improvement of eye appearance and symptoms. There was variability in the degree of lowering of the eyelid with the same dose of injected botulinum toxin A. It was also difficult to predict the time interval needed for re-treatment. Ptosis impairing visual acuity was not a consequence of the treatment in any of the patients. One week after treatment two patients experienced increased diplopia but only one showed transient change in Lees screen measurement of eye motility. CONCLUSION: Botulinum toxin A injection may be used to lower the upper eyelid position in patients awaiting eyelid surgery. The treatment safely relieved symptoms and improved eye appearance. However, treatment was short term and difficult to predict. There is also an inherent risk of transient diplopia.

The Boström-Kugelberg pseudo-isochromatic plates. How efficient is the third edition?

The third edition of the Boström-Kugelberg pseudo-isochromatic plates was printed to the best possible visual match with the second edition. Slight colour differences between the 2 editions initiated this study where 72 colour defectives and 57 normal trichromats were tested with the plates and classified with the aid of Nagel's anomaloscope. Of the defectives, the plate test disclosed all but two anomalous trichromats. One normal subject was falsely classified as defective. The plates had to be shown twice according to the instructions since otherwise 13 of the 53 normals were misclassified. Three plates were shown to have low sensitivity; one is best used as a demonstration plate, and the other two can be deleted without lost efficiency. Forty-eight of the colour defectives were also studied with Farnsworth's lantern. The correlation between the numbers of plate and signal errors was weak. All subjects who failed the lantern test made several plate errors, but 15 subjects who passed the lantern test, made two or more errors on the plate test. The outcome of the plate test does not give evidence of the subject's lantern test performance.

Graves' ophthalmopathy and tobacco smoking.

We have studied the smoking habits in a group of patients with hyperthyroidism caused by Graves' disease. One hundred and seventy-one patients were randomized to different forms of treatment for hyperthyroidism and the outcome of this study concerning Graves' ophthalmopathy has been described previously. There were 89 smokers (52%) and 82 non-smokers (48%). Among the smokers there were 32 patients (19%) who developed ophthalmopathy or deteriorated in an already present ophthalmopathy and 57 patients who did not (33%), whereas among the non-smokers, 14 (8%) had ophthalmopathy during the study and 68 (40%) did not (p = 0.006). We could not obtain statistical significance when trying to demonstrate that smoking is a risk factor for the development of ophthalmopathy after treatment for hyperthyroidism. It was noted that smokers had higher pretreatment levels of thyrotropin-receptor antibodies (p = 0.027). In conclusion, these results support the previously described association between smoking and Graves' ophthalmopathy.

[Results of surgical correction of entropium senile by Fox's method (author's transl)]. / Ergebnisse der operativen Korrektur des Entropium senile nach Fox.

Results of surgical correction of senile entropion employing the method described by Fox are analysed and discussed, using both subjective and objective assessment criteria. Out of 64 lower eyelids that were operated on 16 to 58 months before follow-up, the functional or cosmetic result was fully satisfactory in about 70%.

Results of transantral orbital decompression in patients with thyroid-associated ophthalmopathy.

PURPOSE: To present the results of orbital decompression in patients with thyroid-associated ophthalmopathy (TAO). METHODS: Transantral orbital decompression was performed in 63 patients with TAO. In 40 patients (63%) the operation was made because of progressive ophthalmopathy not responding to medical therapy, and in 23 patients (37%) the operation was made for rehabilitative reasons. The long-term hypesthesia engaging the infraorbital nerve was assessed with a questionnaire using a Visual Analogue Scale (VAS). RESULTS: The mean proptosis reduction was 3.2 mm (range 0-8 mm). Twenty-one patients had impaired visual acuity preoperatively, and 20 improved. Altogether 30 patients (40%) had worsened ocular motility postoperatively. Forty-three patients did not have diplopia in the primary position preoperatively, and new diplopia developed in 22 of these (51%). Hypesthesia in the infraorbital nerve area was reported for half of the operated sides, but was a major cause of distress (VAS-scoring >5) to eleven patients. CONCLUSIONS: Transantral orbital decompression is indicated in patients with progressive TAO or in patients with prominent exophthalmos, and results in a good proptosis reduction, but the risk of postoperative diplopia is significant. Postoperative hypesthesia is common but often not a major problem.

[Therapy-refractory secondary open-angle glaucoma caused by epithelialization of the anterior chamber following cataract extraction]. / Therapierefraktäres sekundäres Offenwinkelglauckom durch Epithelialisierung der Vorderkammer nach Kataraktextraktion.

Histologic findings are presented which relate to a case of primary diffuse epithelial downgrowth into the anterior segment after surgery, with subsequent secondary open-angle glaucoma which resisted all attempts at therapy. Possible types of early therapy are discussed.