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BRIEF REPORT |
Endocrine Unit (P.P., S.F.), Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; School of Clinical Medical Sciences (P.K.-T.), University of Newcastle upon Tyne, Newcastle upon Tyne NE1 7RU, United Kingdom; and Department of Ophthalmology (C.N., J.D.), Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, United Kingdom
Address all correspondence and requests for reprints to: Dr. P. Perros, Endocrine Unit, Freeman Hospital, Freeman Road, Newcastle upon Tyne NE7 7DN, United Kingdom. E-mail: petros.perros{at}ncl.ac.uk.
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Abstract |
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Objective: The objective of this study was to document the course of GO after radioiodine therapy.
Design: This was a prospective observational study. Patients were assessed at baseline and 2, 4, 6, and 12 months after radioiodine therapy.
Setting: The study was conducted at a tertiary referral center.
Patients: Seventy-two GO patients with minimally active eye disease participated in the study.
Intervention: A fixed dose of radioiodine was administered. T4 was commenced 2 wk later to prevent hypothyroidism.
Main Outcome Measures: Change in activity and severity of GO were analyzed.
Results: Exophthalmometer readings, the width of the palpebral aperture, diplopia scores, and the clinical activity score improved significantly. By clinically significant criteria, the eye disease improved in four patients (transiently in three of the four cases), most likely attributable to the natural course of the disease. No patient’s eyes deteriorated.
Conclusions: Radioiodine is not associated with deterioration of GO in patients with minimally active eye disease when postradioiodine hypothyroidism is prevented.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResults and DiscussionReferences |
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResults and DiscussionReferences |
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). The sample size was predetermined and based on published data (2). Forty-one patients were previously documented to have moderate to severe disease including 10 with optic neuropathy (defined as presence of at least two of the following criteria: reduced visual acuity; impaired color vision; abnormal visual fields). The high proportion of patients with optic neuropathy reflects the tertiary nature of our center serving a population of about 3 million. Clinical characteristics are shown in Table 1. The study was approved by the chairman of the institutional ethics committee.
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Methods
Ophthalmological assessments were performed by two experienced ophthalmologists (J.D. and C.N.) or by senior trainees in ophthalmology, who had undergone GO assessment training and were supervised by J.D. or C.N. A detailed description of the ophthalmological assessments can be found elsewhere (4). Soft tissue signs were graded as absent, mild, moderate, or severe. Proptosis was measured using an exophthalmometer (Oculus, Boston, MA). Palpebral aperture was measured with patients relaxed and fixating on a distant target in the primary position. Diplopia was classified as absent, intermittent, inconstant, and constant. Corneal integrity was assessed by slitlamp examination. Visual function was assessed by corrected Snellen acuity, afferent pupil responses, Ishihara color plates, and funduscopy. The clinical activity score (CAS) was assessed at each visit (1). A self-assessment questionnaire was completed at each visit. Deterioration or improvement of GO was defined according to published major and minor criteria (2).
Inclusion criteria
All patients were older than 18 yr and had minimally active eye disease defined as absence of chemosis, no history of deterioration in eye symptoms in the preceding 2–3 months, and a CAS of 3 or less.
Evaluation of thyroid function
Serum TSH was measured by a two-site sandwich assay (Immuno-1, Bayer Diagnostics, Newbury, Berkshire, UK). Serum free T4 (FT4) was measured by a competitive immunoassay using chemiluminescent, polyclonal antibodies (Bayer Diagnostics). The reference ranges for FT4 and TSH were 10–26 pmol/liter and 0.3–4.5 mU/liter, respectively.
Statistical analysis
The statistical package SPSS (version 11; SPSS, Inc., Chicago, IL) was used. Differences between baseline and follow-up data were compared by using Student’s paired t tests or Wilcoxon ranked sum tests.
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Results and Discussion |
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Most patients remained clinically euthyroid and had normal serum FT4 associated with normal or low serum TSH (Table 2). Hypothyroidism (FT4 < 10 pmol/liter) was avoided in the majority of cases. The dose of T4 was adjusted at 2, 4, and 6 and between 6 and 12 months in 25.6, 22.5, 22.5, and 14% of cases, respectively. T4 was withdrawn and antithyroid drugs were reintroduced for 2–6 months in five patients who were clinically and biochemically thyrotoxic 2–6 months after radioiodine therapy. In three of these, carbimazole was withdrawn before completion of the study without recurrence of thyrotoxicosis; the remaining two patients received further doses of radioiodine after completion of the study. The median dose of T4 at 12 months was 125 µg (range, 50–200 µg).
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The CAS declined from baseline (Table 2
) and reached statistical significance at 6 and 12 months. Soft tissue swelling scores did not change. The width of the palpebral aperture declined significantly at 4 and 6 months. Proptosis readings declined significantly at 2 and 6 months. Diplopia scores improved significantly at 12 months. Corrected visual acuity did not change. No significant changes in self-assessment were noted from baseline.
Overall change
Using the definition of overall change on the basis of major and minor criteria (2), there was a transient improvement in GO in three patients (one at 4 months and two at 6 months) and sustained improvement in one patient (from 6 months onward). No patient deteriorated.
The influence of radioiodine on the course of GO has been a subject of controversy for several years (1, 5). In 1998 Bartalena et al. (2) reported the most comprehensive study to date on the effects of radioiodine on the eyes of patients with Graves’ disease: this study showed that radioiodine was associated with a small but significant risk of deterioration or new emergence of GO, preventable by a 3-month course of prednisone. Release of thyroid antigens leading to an exaggerated autoimmune response against shared thyroid-orbital antigen(s) is a plausible hypothesis for this observation (1). A protective effect of antithyroid drugs on the eyes is a possible interpretation of these data, although direct evidence is lacking (1). Three of the patients reported in our study received carbimazole therapy after radioiodine therapy for 2–6 months because they developed symptomatic thyrotoxicosis. Exclusion of these cases from analysis did not change the level of significance of any of our findings. Hypothyroidism may also have a detrimental effect on the eyes of patients with GO (1). Tallstedt et al. (3), demonstrated that the incidence of deterioration or new emergence of GO after radioiodine therapy was significantly reduced by commencing T4 therapy after 2 wk. Hypothyroidism was prevented in 94.5% of cases in our study, and stable thyroid status may have contributed to the lack of deterioration of the eyes. Smoking habits, a risk factor for GO (1), did not change during the course of the observation period. The overall improvement noted in our patients in this study probably reflects the natural history of this disease.
The apparently different outcomes between our study and that of Bartalena et al. (2) could be explained by the fact that fewer of our patients developed hypothyroidism after radioiodine therapy, and our patients were selected for having minimally active eye disease. We suggest that the latter was the principal reason for the absence of a detrimental effect of radioiodine in our study.
Studies showing radioiodine to be a risk factor for GO have had an impact on clinical practice, particularly the recommendation that prophylactic glucocorticoids should routinely be used in conjunction with radioiodine (6).
Our study demonstrates that radioiodine is not associated with deterioration of GO in patients whose eyes are minimally active and in whom hypothyroidism after radioiodine is prevented/blunted by early administration of T4. In such patients glucocorticoid prophylaxis is unnecessary and undesirable because of side effects, but avoidance of hypothyroidism is important. Endocrinologists who are trained and confident in assessing the CAS of patients with GO may use the same selection criteria as this study for identifying patients who do not require prophylactic steroids after radioiodine (CAS 
3 in the absence of chemosis and a clear history that the eye disease has not deteriorated in the preceding 2–3 months). Otherwise such patients should be referred to an ophthalmologist for detailed assessment. Early introduction of T4 after radioiodine therapy prevents hypothyroidism; however, close monitoring is required as shown by the frequent need to adjust the dose of T4. For patients with active GO, radioiodine therapy should either be deferred or used in conjunction with prophylactic glucocorticoids.
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Footnotes |
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Abbreviations: CAS, Clinical activity score; FT4, free T4; GO, Graves’ ophthalmopathy.
Received March 8, 2005.
Accepted June 17, 2005.
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References |
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