The positive outcome of Graves' ophthalmopathy correlated with low TRAb (autoantibodies to thyroid-stimulating hormone receptor) titers at diagnosis and during follow-up and with prepubertal condition at diagnosis

Antoniazzi F.

Cerini R.

Dall'Agnola A.

Lauriola S.

Tat\uf2 L.

Zamboni G.

ANTONIAZZI, Franco

ZAMBONI, Giorgio

CERINI, ROBERTO

LAURIOLA, Silvana

Tatò L.

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GRAVES’ OPHTHALMOPATHY EVOLUTION STUDIED BY MRI DURINGCHILDHOOD AND ADOLESCENCEFRANCO ANTONIAZZI, MD, GIORGIO ZAMBONI, MD, ROBERTO CERINI, MD, SILVANA LAURIOLA, MD,ALBERTO DALL’AGNOLA, MD, AND LUCIANO TATO`, MDPediatric patients with Graves’ disease (n = 26) were studied longitudinally by magnetic resonance imaging of the orbits,allowing an assessment of the enlargement of the extraocular muscles and orbital volume variations. The positive outcome ofGraves’ ophthalmopathy correlated with low TRAb (autoantibodies to thyroid-stimulating hormone receptor) titers at diagnosisand during follow-up and with prepubertal condition at diagnosis. (J Pediatr 2004;144:527-31)Graves’ ophthalmopathy (GO) is a complication of Graves’ disease characterized by proptosis, caused by the enlargement ofthe extraocular muscles and augmentation of orbital connective tissue and fat.1 As opposed to adults, children withGraves’ disease rarely have severe infiltrative ophthalmopathy, and exophthalmos is generally mild, nonprogressive, andpossibly reversible.2The aim of the current study was to better understand the role of residual pubertal orbital growth in the evolution of GO.To this purpose, we did a longitudinal study on a group of children and adolescents affected by Graves’ hyperthyroidism, usingmagnetic resonance imaging (MRI) of the orbits.METHODSConsecutive Italian patients (n = 26, 21 girls) with Graves’ disease from the endocrine outpatients of our clinic took part inthe study. Informed consent was obtained from the parents of each patient before starting the study, and the local hospital ethicscommittee approved the study.At the time of diagnosis, the patients’ mean age was 10.15 ± 2.69 years (age range, 4.26-14.65 years); 13 were prepubertal,and 13 showed Tanner stage $2.The diagnosis of Graves’ disease was established by the detection of elevated serum-free T3 (FT3) and free T4 (FT4)concentrations and suppressed thyroid-stimulating hormone (TSH) levels, with high serum titers of autoantibodies to TSHreceptor (TRAb), typical thyroidal echographic pattern, and high and diffuse 99Tc thyroidal uptake. A goiter was clinically evidentat diagnosis in 22 of the 26 patients.An ophthalmic evaluation was done on all patients at diagnosis, includingmeasurements of proptosis with the use of the Hertel exophthalmometer. A value >20mm was considered diagnostic of exophthalmus.1,3 We considered patients to be affectedby GO if they had clinical signs of ocular involvement (ie, upper lid retraction, lid lag, orstaring eyes) with exophthalmus or MRI signs of muscular enlargement.MRI of the orbital region was performed shortly after the diagnosis of Graves’disease (mean age, 10.49 ± 2.61 years; range, 4.71-14.81) to discover the presence ofalterations in the contents of the orbital tissues. MRI (1.5-T superconductive magneticunit; Somatom 58, Siemens, Erlangen, Germany) was done with SE T2-weighedtransversal scans (TR/TE, 2200/90 ms), using a 5-mm slice thickness, 1-mm distanctfactor, subsequently by SE T1-weighed axial and sagittal scans (TR/TE, 550/15 ms), usinga 3-mm slice thickness, 0.5-mm distanct factor, and finally by SE T1-weighed fatsuppression coronal scan (TR/TE, 650/15 ms). In particular, we evaluated bony orbitalvolume,4,5 muscular enlargement,6 muscular fat infiltration, and increase in orbital fat.From the Pediatric Clinic and Radiol-ogy Department , University of Ver-ona, Verona, Italy.Submitted for publication Jan 13, 2003;last revision received Nov 20, 2003;accepted Jan 12, 2004.Reprint requests: Dr Franco Anto-niazzi, Clinica Pediatrica-Universita´ diVerona, Policlinico ‘‘GiambattistaRossi’’, Piazza Ludovico AntonioScuro, 10 I-37134 Verona, Italy.E-mail: franco.antoniazzi@univr.it.0022–3476/$ - see front matterCopyrightª 2004 Elsevier Inc. All rightsreserved.10.1016/j.jpeds.2004.01.033GO Graves’ ophthalmopathyMRI Magnetic resonance imagingTRAb Autoantibodies to thyroid-stimulating hormone receptorTSH Thyroid-stimulating hormone527Table. Age, pubertal stage, opthalmologic signs, intraorbital volume, MRI pattern, TRAb levels both atdiagnosis (I) and at the end of follow-up (II), and clinical outcome of patients studiedAge at MRI (y)Pubertal stage(Tanner) Proptosisa (mm) Orbital volume (cm3)bPatient I II I II I R I L II R II L I R I L II R II L1 10.5 14.3 Ph2, B2 Ph4, B4 23 21 20 19 24.5 24.4 25.6 25.62 6.5 8.6 Ph1, G1 Ph1, G1 22 23 20 20 24.3 24.4 25.3 25.210 8.2 16.7 Ph1, B1 Ph5, B5 24 23 20 19 24.3 24.2 25.5 25.514 9.9 17.4 Ph1, B1 Ph4, B4 20 22 18 18 24.5 24.7 26.0 26.115 6.2 10.7 Ph1, B1 Ph2, B2 20 20 18 18 25.0 25.1 26.0 25.924 10.5 14.6 Ph1, B1 Ph4, B4 23 22 20 20 23.0 23.0 24.2 24.1Group A(n = 6)8.7 ± 1.9 13.7 ± 3.4 5 Prepub1 Pub1 Prepub5 Pub22.0 ± 1.7e 21.8 ± 1.2e 19.3 ± 1.0 19.0 ± 0.9 24.2 ± 0.7 24.3 ± 0.7 25.5 ± 0.7 25.4 ± 0.76 12.5 14.7 Ph3, B3 Ph4, B4 20 19 24 23 27.0 26.8 27.4 27.38 13.8 21.3 Ph3, B3 Ph5, B5 20 22 20 21 26.5 26.5 27.0 27.017 14.3 17.4 Ph4, B4 Ph5, B4 19 19 22 23 26.5 26.5 26.9 27.021 11.8 15.3 Ph2, B2 Ph4, B4 22 22 21 20 28.0 28.0 29.1 29.026 14.8 19.2 Ph3, G3 Ph5, G5 22 21 21 20 27.8 27.8 28.1 28.2Group B(n = 5)13.4 ± 1.2 17.6 ± 2.7 5 Pub 5 Pub 20.6 ± 1.3h 20.6 ± 1.5h 21.6 ± 1.5i 21.4 ± 1.5i 27.2 ± 0.7 27.1 ± 0.7 27.7 ± 0.9 27.7 ± 0.93 13.6 21.0 Ph3, B3 Ph5, B5 19 19 19 18 25.9 25.8 26.4 26.44 4.7 6.9 Ph1, B1 Ph1, B1 17 18 18 18 22.1 22.2 22.7 22.85 13.2 15.2 Ph3, B3 Ph4, B5 20 20 19 20 26.8 26.8 27.2 27.37 11.5 13.5 Ph2, B2 Ph3, B3 18 18 19 18 24.5 24.5 24.9 24.89 10.9 14.6 Ph2, B2 Ph4, B4 18 18 18 18 23.0 23.1 23.8 23.811 10.5 13.0 Ph1, B1 Ph2, B3 19 20 19 20 24.7 24.8 25.2 25.312 10.1 20.2 Ph1, G1 Ph5, G5 20 20 20 19 25.0 25.0 26.5 26.513 13.6 20.2 Ph3, B3 Ph5, B5 18 18 19 18 27.1 27.1 27.6 27.716 8.8 12.9 Ph1, G1 Ph2, G2 18 17 18 17 26.0 26.0 27.1 27.118 7.5 12.5 Ph1, B1 Ph2, B3 17 17 18 18 24.7 24.7 25.7 25.819 11.3 17.6 Ph2, B3 Ph5, B5 20 19 19 18 27.0 26.9 27.7 27.620 8.8 14.7 Ph1, B1 Ph3, B4 17 17 19 18 22.0 22.0 23.0 23.022 12.7 17.2 Ph2, G2 Ph4, G4 20 20 19 19 28.5 28.5 29.6 29.723 7.8 13.8 Ph1, B1 Ph3, B3 19 18 20 20 24.2 24.1 25.5 25.625 8.4 15.3 Ph1, B1 Ph3, B4 18 19 19 19 26.0 26.2 27.2 27.3Group C(n = 15)10.2 ± 2.7 15.2 ± 4.0 8 Prepub7 Pub1 Prepub14 Pub18.5 ± 1.1 18.5 ± 1.1 18.8 ± 0.7 18.5 ± 0.9 25.2 ± 2.0 25.3 ± 1,9 26.0 ± 2.1 26.1 ± 2.0Group A, Patients with ophthalmopathy improvement or regression; group B, patients with ophthalmopathy persistence or worsening; group C, patientswithout GO. Data are expressed as mean ± SD or median and range (min-max).aSeparate value of right (R) and left (L) eyes (in mm) measured by Hertel exophtalmometer.bSeparate value of right (R) and left (L) orbital volume (in cm3).cTRAb U/I (normal values <15 U/I) values are expressed as median and range (min-max).dOutcome of thyroid disease: MT, medical therapy; S, surgery: near-total thyroidectomy; CR, complete remission.eP < .0001 vs group C.fP < .05 vs group C and (P < .001) vs group B.gP < .05 vs group C.hP < .01 vs group C.iP < .001 vs group C.jP < .001 vs group C.kP < .01 vs group C and (P < .05) vs group A.Red, reduced; Prepub, prepubertal; Pub, pubertal.In our experience, normal values for orbital volume(cm3) are as follows: female subjects: 22.6 ± 3.1 (5-10 years),25.5 ± 2.8 (11-15 years), and 26.1 ± 2.5 (16-20 years); malesubjects: 23.8 ± 3.3 (5-11 years), 26.3 ± 2.7 (12-16 years), and27.2 ± 1.8 (17-21 years). Patient data referred to thispopulation, and the values were expressed also as SD score(measured value minus mean)/standard deviation.528 Antoniazzi et alThe medial and lateral rectus muscles were measured onaxial scans; the superior rectus and the levator palpebrasuperior muscles were measured together as a single superiormuscle group; diameters of the superior muscle group, theinferior rectus muscle, and the superior oblique muscle weremeasured on coronal scans.7 The diameter of each muscle wasmeasured at its maximum. Extraorbital muscles were consid-The Journal of Pediatrics  April 2004Table. continuedObital volume (SDs) Muscular enlargement at MRI TRAb U/Ic% D Orbital Volume I II I II I II Outcomed4.5 0.6 0.1 + + (red) 185 55 S4.0 0.2 0.4 + Almost  102 32 MT6.0 0.5 0.2 + (right ++) Almost  405 120 CR6.0 0.6 0.1 + + (red) 73 18 CR4.0 0.8 1.1 +  21 20 MT5.0 0.1 0.5 + + (red) 160 85 MT4.9 ± 0.9f 0.4 ± 0.3 0.2 ± 0.5 131 (21-405)g 26 (12-85)1.5 0.5 0.7+ 400 258 S2.0 0.4 0.4 + + 82 12 CR1.5 0.4 0.3  + 280 256 S3.5 0.9 1.3 + + 260 188 S1.2 0.6 0.5 + + 102 10 CR1.9 ± 0.9 0.5 ± 0.2 0.6 ± 0.4 260 (82-400)j 188 (10-258)k2.0 0.1 0.1   33 25 S2.5 0.2 0.0   41 38 MT1.5 0.5 0.6   27 32 MT1.5 0.4 0.2   110 54 MT3.5 0.1 0.6   55 48 S2.0 0.7 0.1   68 24 MT6.0 0.4 0.4   31 45 S2.0 0.6 0.6   28 22 CR4.0 0.7 0.3   110 87 MT4.0 0.7 0.1   55 18 MT2.5 0.5 0.6   38 10 CR4.5 0.2 0.9   98 16 CR4.0 0.8 1.4   68 25 CR5.5 0.5 0.0   45 18 CR4.5 1.1 0.6   68 75 S3.3 ± 1.5 0.4 ± 0.4 0.2 ± 0.6 55 (27-110) 25 (10-87)ered enlarged when diameters were $+2 SD of our personaldata; specifically, medial rectus $4.7 mm, lateral rectus $4.6mm, superior group $5.3 mm, inferior rectus $5.8 mm, andsuperior oblique $4.0 mm.A second MRI was performed with the the sameMRI apparatus and identical measures used, after a meanperiod of 4.86 ± 2.28 years (range, 2.02-10.13) and atGraves’ Ophthalmopathy Evolution Studied By MRI During Childhood andAdolescencea mean age of 15.35 ± 3.54 years (range, 6.91-21.27).At this stage, each patient was euthyroid: 9 were incomplete remission, 8 were receiving L-thyroxine replace-ment treatment after near total thyroidectomy, and 9 werereceiving combined treatment with L-thyroxine and pro-pylthiouracil. All patients and their parents were non-smokers.529Serum titers of anti-TRAb were measured by ra-dioreceptor assay (TRAK-Assay, BRAHMS DiagnosticaGmbH, Berlin, Germany), with the use of the TSH receptorisolated from porcine thyroid; the intra-assay and interassaycoefficients of variation were < 7.2% and < 13.2%, re-spectively. The analytical sensitivity of this assay was 2.4 U/L.Results are expressed as mean ± SD and as median andrange. Statistical analysis was performed with the use of theunpaired Student t test, with the Bonferroni correction whenappropriate and v2 analysis and Mann-Whitney nonparamet-ric test in the case of abnormal distribution. All statisticalanalyses were performed with the use of a data analysis system(StatView 4.5, Abacus Concepts, Inc, Berkeley, Calif) run onan Apple PowerMac computer. Statistical significance was setat a value of P < .05.RESULTSThe Table shows age, pubertal stage, ophthalmologicsigns, intraorbital volume, MRI pattern, and TRAb levels ofthe patients studied, both at diagnosis and at the end offollow-up. Values of calculated intraorbital volume arereported as absolute numbers (cm3) and in SD scorescompared with the normal data referring to the same agegroup. Muscular swelling is reported as present (+) or absent ifthe dimensions of extraocular muscles were or were not greaterthan the normal limit for our population.Clinical signs of GO and exophthalmos were evident atthe time of diagnosis in 8 of 26 patients. The remainingpatients showed no symptoms or signs of ocular involvementat this time. MRI confirmed exophthalmos, when it wasclinically present, by a pattern of muscular enlargement, withno muscular fat infiltration or increase in intraorbital adiposetissue. Another patient (No. 15) showed a pattern of muscularenlargement despite the absence of clinical signs of GO. MRIof the orbital region was negative in all the other patients.During follow-up, another 2 patients (Nos. 6 and 17),both pubertal at diagnosis and in a euthyroid state, showedclinical and MRI patterns of GO 15 and 22 months fromdiagnosis, respectively. They had had no clinical or MRI signsof GO at diagnosis, although high titers of TRAb wereevident at diagnosis and during follow-up.During follow-up, the patients who had had ocularinvolvement at diagnosis had almost complete regression ofclinical signs and symptoms of GO. The MRI pattern ofmuscular enlargement showed no variation in 3 patients (Nos.8, 21, and 26) who were pubertal at diagnosis; discreteregression in 3 patients (Nos. 1, 14, and 24): 2 prepubertal and1 pubertal at diagnosis; and almost complete regression in 3patients (Nos. 2, 10, and 15) who were prepubertal atdiagnosis.The increase in orbital volume between the first andsecond MRI was 3.5% ± 1.5%, but it was more significant inprepubertal rather than in pubertal patients (4.46% ± 1.60% vs2.50% ± 1.18%; P < .01).Hyperthyroid patients with GO at diagnosis and duringfollow-up had significantly higher anti-TRAb titers than those530 Antoniazzi et alwithout GO (mean ± SD: 188.2 ± 131.7 vs 58.3 ± 28.5 U/L;P < .05; median (range, minimum to maximum): 160 (21 to405) vs 55 (27 to 110) U/L). The 95% upper-level confidenceinterval between groups was 201.7 U/L, so we took this valueas a cutoff for higher risk of GO. There were no significantdifferences in other measures studied (age at diagnosis, orbitalvolume, FT3, FT4, TSH, anti-thyroglobulin antibody, andanti-thyroid peroxidase antibody levels, data not shown)among groups matched for sex, pubertal stage, and therapeuticoptions during follow-up.We subdivided all the patients showing clinical or MRIsigns of GO at diagnosis and during follow-up (11 total) into2 groups, based on the evolution of GO: 6 patients had animprovement or regression of ophthalmopathy (group A),whereas 5 showed persistence or worsening of the ophthal-mopathy (group B).The Table shows these 2 groups of patients comparedwith hyperthyroid patients without GO (group C). Atdiagnosis, 5 of the 6 patients in group A were prepubertal,whereas all 5 patients in group B were pubertal; the differencewas statistically significant by v2 analysis (P < .01). Thepatients in group A had an increase in orbital volume that wassignificantly higher than that of the children in group B(4.91% ± 0.91% vs 1.94% ± 0.92%; P < .001) and statisticallydifferent from that of group C.TRAb levels of the patients in group B were significantlyhigher at the end of follow-up than both those of the patientsin group A (P < .05) and group C (P < .01).DISCUSSIONGraves’ ophthalmopathy is less common in childrenthan in adults. Orbital signs and symptoms occur inapproximately one half of hyperthyroid children, and exoph-thalmos, when present, is usually mild.2 The cause of thisdifferent behavior of GO in hyperthyroid children and adultsis not clearly understood.Because our patients with GO had significantly higherTRAb titers than those without ophthalmopathy, elevatedTRAb titers at diagnosis6 and especially during follow-upwere associated with an elevated risk of persisting GO or itsonset during follow-up. In particular, patients with TRAblevels >200 U/L have an increased risk for GO. On thecontrary, the patients with better progression of GO had lowTRAb titers.In our pediatric patients with GO, MRI showed onlythe enlargement of the extraocular muscles. This finding istypical of the active, edematous stage of the eye disease inchildren and adolescents, in which the fibrotic stage isuncommon. Moreover, MRI confirmed regression of theophthalmopathy in the 6 patients in group A, already clinicallyevidenced.During follow-up, the prepubertal patients who hada tendency to GO regression also showed an increse of orbitalvolume. Probably during pubertal development, the residualorbital growth could create a physiologic decompression witha positive effect on the evolution of GO.The Journal of Pediatrics  April 2004REFERENCES1. Larsen PR, Davies TF. Thyrotoxicosos. In: Larsen PR, KronembergHM, Melmed S, Polonsky KS, editors. Williams textbook of endocrinology.10th edition. Philadelphia (PA): Saunders; 2003.2. Gruters A. Ocular manifestations in children and adolescents withthyrotoxicosis. Exp Clin Endocrinol Diabetes 1999;107(Suppl 5):S172-4.3. Bartalena L, Pinchera A, Marcocci C. Management of Graves’ophthalmology: reality and perspectives. Endocrinol Rev 2000;21:168-99.4. Forbes G, Gorman CA, Brennan MD, Gehring DG, Ilstrup DM,Earnest F. Ophthalmopathy of Graves’ disease: computerized volume50 Years Ago in The Journal of PediaAROCKINGBEDRESPIRATOR FORUSEWITH PREMLee HF. J Pediatr 1954;44:570-3Premature infants born 50 years ago faced an enormous, uphmechanical ventilation, antibiotics, and appropriate feeding foenough to term to avoid some of the most devastating condiposed a challenge.Physicians treating respiratory ailments in adults with normaa rocking bed would enhance diaphragmatic excursion and pdevelopment of a similar technology, adapted for use inside anmanagement of infants with prolonged apnea. Challenges in tof an incubator and the need to avoid any electrical equipmenNo data were offered to demonstrate that this technology wastimulation of the rocking bed would be effective in arousicrossover studies of kinesthetic stimulation did not demonststudies, theophylline was shown to be superior.1REFERE1. Osburne DA, Henderson-Smart DJ. Kinesthetic stimulation for treatinChichester, UK: John Wiley & Sons, Ltd; 2003.Graves’ Ophthalmopathy Evolution Studied By MRI During Childhood andAdolescencemeasurments of the orbital fat and muscle. Am J Neuroradiol 1986;7:651-6.5. Bentley RP, Sgouros S, Natarajan K, Dover MS, Hockley AD. Normalchanges in orbital volume during childhood. J Neurosurg 2002;96:742-6.6. Nishikawa M, Yoshimura M, Toyoda N, Masaki H, Yonemoto T,Gondou A, et al. Correlation of orbital muscle changes evaluated by magneticresonance imaging and thyroid-stimulating antibody in patients with Graves’ophthalmopathy. Acta Endocrinol (Copenh) 1993;129:213-9.7. Ozgen A, Aydingoz U. Normative measurements of orbital structuresusing MRI. J Comput Assist Tomogr 2000;24:493-6.tricsATURE INFANTS IN INCUBATORSill battle for survival. Such fundamental treatments such asrmulations were not in widespread use. For those born closetions, common problems like the apnea of prematurity stilll lung compliance (eg, polio victims) had demonstrated thatromote gas exchange. In this paper, Dr Lee described theincubator, and proposed that it might prove helpful in thehe development of this design included the size restrictionst in the oxygen-rich environment.s effective, but it is not difficult to imagine that the repeatedng a moderately premature infant to breathe. Subsequentrate a substantial reduction in infant apneas, and, in otherThomas P. Green, MDDepartment of PediatricsChildren’s Memorial Hospital andNorthwestern University Medical SchoolChicago, IL 60614YMPD77410.1016/j.jpeds.2004.02.003NCESg apnea in preterm infants (Cochrane Review). Cochrane Library, Issue 4.531

Graves' ophthalmopathy evolution studied by MRI during childhood and adolescence.

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Graves' ophthalmopathy evolution studied by MRI during childhood and adolescence.

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