Mri Application On Measuring Disease Activity And Predicting Therapeutic Outcome Of Orbital Radiation In Thyroid Associated Ophthalmopathy

BackgroundThyroid associated ophthalmopathy (TAO; also known as Graves ophthalmopathy and thyroid eye disease) is an autoimmune and inflammatory orbital disease associated with thyroid, which has an highest incidence (accouting for about 20%) in orbital disease of adults in our country and abroad. The clinical manifestations of TAO stem from a combination of increased extraocular muscle and orbital fat volume resulting from inflammatory and fibrosis in orbital tissue, which include fearing of light, dacryorrhea, foreign body sensation, diplopia and dim sight. The spectrum of eye manifestations rangs from lid lag and retraction to proptosis, ophthalmoplegia, conjunctivitis, chemosis, and corneal ulceration, to loss of vision. Especially, proptosis destroys the patients, physiognomy, therefore impacts living quality.From the observations on the natural history and therapy effect of TAO, it comprises active phase in which the state of disease may progress rapidly and stable phase in which the clinical symptoms ease gradually or maintain stably. Medical treatment is effective in active phase and less effectve in stable phase. It should be selected surgical treatment in in stable phase. Although TAO is well known as an autoimmune disease, its exact etiology and pathogenensis is not very clear. Therefore, the treatment of TAO is a difficulty and hot spot in thyroid disease, and the determination of activity of TAO is the most difficult.The determination of activity of TAO is complicated. The "golden standard" for assedssment of the disease activity should be biopsies of the retrobulbar tissues, which can provide detailed information, but they are seldom used in clinical practice because of operation with difficulty and high risk. Clinical activity score(CAS) is the most commonly used and accepeted method in determination activity of TAO. The principle of CAS is that symptoms and signs of orbital inflammation are similar to the general inflammation which display red, swelling, pain, dysfunction. It indirectly reflects the inflammation state of the eyelids, conjunctiva, caruncle, lacrimal gland, upper eyelid to muscle, extraocular muscle, optic nerve by 10 index. It is easy to do without other special eximations, and can partially predict the outcome of the immunosppressive treatment or orbital irraditon. But it failes in obtaining objective and accurate scores and loses coincidence to pathology.Because CAS is an unsatisfactory method, some instrument inspection and laboratory tests are used to assist the evaluation of the activity of TAO in recent years.Ultrasound has been widely used to check eye disease. A-mode ultrasonography applies for measuring the thickness of extraocular muscle. A and B-mode ultrasonography can also explain the changes in the internal structure of muscle, which can be used to identify the active phase or stable phase of TAO. If muscle shows high echo which can be explained by muscle tissue fibrosis, the disease is inactive; if muscle shows low echo which can be illustrated by a broad muscle tissue edema, the diseaseis stable. Advantages of ultrasonography are cheap, simple, non-invasive, but there are some defaults that the accuracy depends on the operator's skill and the measurement of the inferior rectus can not be operated because of the prominent bone.Octreotide scintigraphy is worked by the principle that radiolabled somatostatin analogue octreotide can bind to the receptors expressed by the lymphocytes and fibrolasts which they play an important role in orbital inflammation of TAO. Tracers correlate well with clinical activity, possibly because lymphocytes and fibrolasts infiltrate more in active phase than stable phase. Therefore it can speculate TAO phases of activity by measuring the absorption rate of orbital octreotide. Octreotide scintigraphy reported in the literature of foreign is highly sensitive and specific but it faults in expensive cost and the disadvantage of radioactive damage.MRI (magnetic resonance image) as a non-invasive imaging method, the information from T1 can show the fine anatomic structures of extraocular muscles, retrobulbar fat and the optic axis, et al. But the information from T2 can show the earliest pathological changes and is the most sensitive index. Extraocular muscles are the most common site involved in TAO. The initial inflammation, extraocular muscle shows hyperemia, edema, inflammatory cell infiltration, which extraocular muscles show increased T2 signal in MRI; inflammation of the middle of a large number of inflammatory cells to produce glycosaminoglycans (GAG), causing water to accumulate, abdominal muscle hypertrophy, which MRI clearly shows that swelling of extraocular muscles, higher T2 signal in MRI. The higher water content; the higher T2 signal show. Therefore, MRI for evaluation of TAO activity is a very effective means of inspection.There are some means of determination the T2 signal level.1) The method of T2WI brightness gray-scale imaging has the advantages of intuitive and getting information directly from the film and faults in only qualitativity, subjectivity.2) The method of T2 relaxation time can provide the most authentic information of the pathology, which has the advantage of objectivity and quantifiablity. But the process is more cumbersome and require a specific sequence scan generated at the host, and by the strength of magnetic resonance imaging devices, and the comparability is poor. 3) T2 signal intensity ratio is a relative value which compare extraocular muscles of the T2 value with the ipsilateral temporal muscle T2 values on T2WI, and has the advantages of objectivity, quantitativity and good comparability.T1WI imaging of MRI can also show fine anatomy imaging and three cross-section imaging of orbit, and can be used to observe and quantitativly measure the degree of exophthalmos, extraocular muscle size and changes in optic axis. The sensitivity of MRI is superior to CT, and can provide a more objective basis for clinical treatment of the orbit.In conclusion, MRI has higher resolution and spatial resolution of the rganization, whcih is superior to CT, B-mode ultrasonography, and can demonstrate the involved tissues and pathological stage of TAO clearly, so as to guide effectively the clinical treatment, with good application prospects. In this study, MRI images of patients with TAO were anaylized. Furthermore, MRI images of different activity phases of patients with TAO were compared with each other. And the relation between MRI and clinical activity score were also anaylized. At the end, the effect of MRI in the evaluation of TAO activity and efficacy of the orbital radiation was explored.Chart 1 MRI application on measuring disease activity in TAO Objectives1. To demonstrate MRI signs of active and inactive TAO defined by CAS.2. To explore the influence of MRI on measuring the activity in TAO. Materials and methods1. Patients data:84 TAO cases were consecutivly collected in Dept. of Endocrinology and Metabolism, Nanfang Hospital,38 males and 46 females, Aging 20～70yrs. TAO was diagnosed by Bartleys standard. Inclusion criteria:fitting the diagnostic criteria; excluding other causes of eye disease. Exclusion criteria: NOSPECS score wasl, only signs, no symptoms. Signs include:reduced blink (Stellwag symptoms), two reduced cohesion (Mobius levy), moving slowly on the eyelids (Von Graefe sign), to the point of view, the forehead wrinkled skin should not (Joffroy levy).Control groups:Normal control group:17 healthy adults were selected,9 males and 8 females, aging 32～60yrs.2. Clinical index measurement. Activity of TAO was evaluated by clinical activity score (CAS). Activity staging was advised by Prof. Mourits, CAS>4 as active stage, CAS<4 as inactive stage. Scores were obtained in the severer side.3. MRI examination plans. All the cases were examined by MRI scan, Siemens Magnetism Vision Plus 1.5T. Scanning plan included spin echo sequence, STIR (Short TI Inversion recovery) sequence, SE dual-echo sequence and SE dual-echo sequence with dispose suppression. MRI signs of orbital tissues were confirmed by 2 skilled radiological doctors.4. Statistical analysis. All values are expressed as mean±standard deviation(x±s). Statistical analysis was performe using the statistical package SPSS for Windows Version 13.0. MRI data of health people and TAO patients, active and stable phase TAO patients were analyzed using two independent-sample t-test. The relation between MRI data of TAO patients and CAS were analyzed using spearman relation. In the basline data, the comparison of the proptiong of gender is analyzed using Chi-squre test. It meaned significantly difference when P≤0.05.Results1. MRI manifestations of normal group, active phase and stable TAO groups.1. The MRI performance of normal group:the thickness of the eyelids, lacrimal gland, levator and other soft tissue is without swelling, and the boundaries of levator and superior rectus is clear. Exophthalmos degree is in 12-15mm. There is no large extraocular muscles, and in STIR-MRI the signal of extraoculr muscles is slightly higher than the signal of ipsilateral temporal muscle.2. The MRI performance of active phase TAO group:CAS score in accordance with established standards of clinical stage, the group of active cases of a total of 68 cases (80.95%). The volume of Eyelid, lacrimal gland, levator and other soft tissue, extraocular muscles, fat, such as retrobullar tissue is increase slightly or significantly. Orbital tissue shows low signal in T1WI and high signal in T2WI. The signal of extraocular muscle is significantly higher than the ipsilateral temporal muscle STIR-MRI, which shows edema.3. The MRI performance of inactive phase TAO group:A total of 16 cases (19.05%). Extraocular muscles are not thick or only mildly thickened, the T2WI signal of extraocular muscle is not significantly increased. And the signal intensity is slightly higher than the ipsilateral temporal muscle in STIR-MRI.2.Comparsion of normal group, active phase and stable phase MRI data1. Comparing with normal group, the STIR signal intensity ratio of extraocular muscles is significantly increased in TAO. (t=11.297, P<0.001).2. There were no significant difference in the enlargement ratio of extraocular muscle and medial orbital fat thickness. And comparing with stable phase group, the STIR signal intensity ratio of extraocular muscles is significantly increased in active phase.(t=8.576, P<0.001).3.Relation of the STIR-MRI signal intensity ratio and the enlargement ratio of extraocular muscle with CASThere is a significant relation between the STIR-MRI signal intensity ratio of extraocular muscle between CAS. (r=0.720, P<0.001). The enlargement ratio of extraocular muscle in T1WI and medial orbital fat thickness are not relative with CAS.Conclusions1. Signal intensity ratio in STIR-MRI elevates in active stage and decreases in inactive stage, therefore it is distinctive for TAO activity staging.2. Signal intensity ratio in STIR-MRI is positively correlated with CAS, and can provide objective and quantifiable indicators to judge the activity of TAO and guide clinical treatment.Chart 2 MRI application on predicting therapeutic outcome of orbital radioationObjectivesAnalysis of the MRI data of patients with TAO, and to evaluate the efficacy of predicting the outcome of orbital radioaton.Materials and methods1. Patients data:68 TAO cases were consecutivly collected in Dept. of Endocrinology and Metabolism, Nanfang Hospital,31 males and 37 females, Aging 20～70yrs. TAO was diagnosed by Bartleys standard. Case inclusion criteria:1. The initial issuance of the thyroid-associated ophthalmopathy; 2. The age of 20-70 years old; 3. Activity patients (CAS≥4 points); 4.above NOSPECS2 level; 5. The exclusion of other causes of eye disease; 6. Has not recived glucocorticosteroid therapy or orbital radioation. Case exclusion criteria:1. Diabetic patients; 2.NOSPECS 1 level patients, only signs, no symptoms. Signs include:reduced blink (Stellwag symptoms), two reduced cohesion (Mobius levy), moving slowly on the eyelids (von Graefe sign), to the point of view, the forehead wrinkled skin should not (Joffroy levy) are positive.All patients had measurement of clinical activity score (CAS) and ophthalmology index (OI).2. MRI examination plans. All the cases were examined by MRI scan, Siemens Magnetism Vision Plus 1.5T. Scanning plan included spin echo sequence, STIR (Short TI Inversion recovery) sequence, SE dual-echo sequence and SE dual-echo sequence with dispose suppression. MRI signs of orbital tissues were confirmed by 2 skilled radiological doctors.3. treatment VARIAN2100C linear acceleratorthe(manufacturefd from United States). Fractionated doses of radiation 200cGy, total dose of 2000cGy (10 times/2 weeks), in the simulator under the positioning, size of radiation field is generally 4cm×4cm, deflection angle rack 3°～5°, in order to contralateral to avoid crystal, treatment for 2 weeks.Observation follow-up for 1 year after radiation therapy. For evaluation of efficacy of radiation therapy in patients with TAO, the change of ophthalmology index (OI) before and after orbital radiation treatmen:OI values decrease at between 3 to 9 for the significant effect that the patient's symptoms and signs improved significantly or even disappear; decrease between 1 and 2 for the effect of better:a number of symptoms and signs in patients with only a slight improvement; OI values remain unchanged for the efficacy of stability:the higher the value of the OI for the progress, that is, after radiotherapy worsened symptoms and signs. Significant effects, better efficacy is defined as effective, efficacy and stability, progress is defined as null and void. 4. Statistical analysis:All values are expressed as mean±standard deviation(x±s. Statistical analysis was performed using the statistical package SPSS for Windows Version 13.0. Logistic regression is used to analyze the relation between MRI and radiation effect. Univariate analysis:comparison between effect and ineffect group are used two sample t-test in quantitative data, or Pearsonx2 test in qualitative data. If there was heteogenity of variance, the data should be transformed first, and then analyzed. Provided that variance remained heterogeneity afer data transformed, the dta should be analyzed by Wilcoxon rank sum test. Multivariate analysis:The treatment outcome variable was dependent variable, and such signs as CAS, duration of TAO, and others were independent ones. Stepwise regression was used to select the variable, setting selected variableα=0.05, excluding variable a= 0.10. To cmparing of different STIR extraocular muscle signal intensity ratio with therapeutic efficiency in soft tissue, proptosis, extrocular muscle, Kruskal-Wallis test should be used. P≤0.05 means significant difference.Results1.Therapeutic outcome:16 cases of significant effects, better efficacy of 37 cases,13 cases of stability, progress in 2 case. The total effective rate was 77.94%.2. Relationship btweent MRI data of patients with TAO and therapeutic outcome of orbital radiation.1. Univariate anlysis:Single-factor analysis of the variables in the target orbital MRI, effective and ineffective medial orbital between the two groups in addition to external fat thickness, STIR fat suppression of extraocular muscle signal intensity ratio, the ratio of the difference between increased eye muscle. General clinical data, the two groups in addition to age, sex, TAO course, the clinical score (CAS), ophthalmology index (OI) have differences.2. Multi-factors non-conditional logistic regression model analysis of clinical score (CAS), ophthalmology index (0I), increasing the ratio of ophthalmoplegia, STIR fat suppression of extraocular muscle signal intensity ratio of 1,2 (SI1, SI2) as the impact of the effect of radiation therapy factors Logistic regression analysis step by step. One of, STIR fat suppression of extraocular muscle signal intensity ratio of 1 (OR=0.071, P=0.043), STIR fat suppression of extraocular muscle signal intensity ratio of 2 (OR=0.018, P=0.004) for the straight-line speed up the effective treatment of TAO prediction factors.2.0, greater than or equal to 2.0 in-Signal intensity ratio between 1.5 patients with TAO for the ball after the possibility of radiation therapy are effective less than 1.5 times the 14 patients with TAO and 55 times.3. Comparison of the theraptutic effect between different grade of STIR-MRI signal intensityThe overall effective rate was 77.94%, The therapeutic outcome of high-grade STIR extrocular muscle signal intensity ratio is higer than the lower well (χ2= 31.746, P<0.001, the average rank respectively is 6.86,27.75,43.27).The effect of orbital radiation in TAO, the major symptoms of soft tissue involvement and extraocular muscle symptoms effectively and improve the rates were 79.10%,72.88%, the improvement of symptoms STIR fat suppression and extraocular muscles associated letter grade intensity ratio, the higher the lower good results. Degree of improvement in exophthalmos was not obvious.Conclusion1. Orbital radiation is an effective treantment for active phase for TAO, which can significantly improve the symptoms and signs of involed soft tissue and extrocular muscle of TAO, and can improve exophthalmos too.2. The grade of STIR MRI signal intensity ratio is related with the improvement of the symptoms and signs of involed soft tissue, exophthalmos and extrocular muscle of TAO. The higher the SIR is, the better the treatment is. So it is important to predit the therapeutic effect of orbital radiation in TAO.