Alterations in retrobulbar hemodynamics in thyroid eye disease

doi:10.21203/rs.3.rs-2433788/v1

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Alterations in retrobulbar hemodynamics in thyroid eye disease

https://doi.org/10.21203/rs.3.rs-2433788/v1

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published 23 May, 2023

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Purpose: To study the orbital perfusion parameters of ophthalmic artery (OA) and central retinal artery (CRA) in inactive TED and the changes following surgical decompression.

Methods: Non-randomised clinical trial. 24 inactive moderate-to-severe TED orbits of 24 euthyroid cases underwent surgical decompression and examined again at 3 months. The peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistivity index (RI) of OA and CRA were evaluated using color doppler imaging and normative database was established using 18 healthy controls.

Results: The mean age was 39.38 +12.56 years and male: female ratio was 1: 1.18. Intraocular pressure was higher, and CRA – PSV, CRA – RI, OA – PSV, and OA – EDV were lower in TED in comparison to heathy orbits. The CRA – PSV, CRA – EDV, OA – PSV, and OA – EDV negatively correlated with proptosis and duration of thyroid disease. The area under curve of OA – PSV (95% CI:0.964-1.000, p<0.001) and OA – EDV (95% CI:0.699-0.905, p<0.001) helped in differentiating TED orbits from healthy controls, and in predicting the severity of disease. Post decompression, CRA – PSV, CRA – EDV, OA – PSV, and OA – EDV improved, with decrease in CRA – RI and OA – RI in both lipogenic and myogenic orbitopathy.

Conclusions: The orbital perfusion is reduced in inactive TED. The changes in OA flow velocities can help in differentiating inactive TED from healthy orbits and progression of TED. Sequential orbital CDI of OA and CRA can serve as an objective tool for case selection and monitoring response to surgical decompression.

Health sciences/Diseases/Endocrine system and metabolic diseases/Thyroid diseases

Health sciences/Signs and symptoms/Eye manifestations

Health sciences/Diseases/Eye diseases/Optic nerve diseases

Health sciences/Diseases/Endocrine system and metabolic diseases/Thyroid diseases

Health sciences/Signs and symptoms/Eye manifestations

Health sciences/Diseases/Eye diseases/Optic nerve diseases

Thyroid eye disease

Color doppler imaging

Perfusion biomarkers

Orbital decompression surgery

Ophthalmic artery

Central retinal artery

Resistivity index

Progression of TED to inactive stages is associated with lowering of orbital arterial perfusion indices with increase in resistivity index (RI).
Orbital decompression surgery in inactive TED leads to a lowering of RI in central retinal artery (CRA) and ophthalmic artery (OA).

What this study adds:

Doppler parameters of OA like peak systolic velocity (PSV) and end diastolic velocity (EDV) show high predictive potential for discriminating inactive TED from healthy orbits.
OA – PSV and OA – EDV may be a good tool to monitor progression of inactive TED.
Surgical decompression in inactive TED shows an increase in orbital perfusion with increase in PSV and EDV of CRA and OA.

Thyroid eye disease (TED) is an inflammatory orbital disorder, involving the extra-ocular muscle (EOM) and the adipose tissue. The natural course of TED passes through an initial active/inflammatory phase which may last 18–24 months, followed by an inactive/fibrotic phase.¹ Most of the patients show improvement with conservative management. Some patients may develop progressive severe orbitopathy necessitating aggressive steroid therapy, irradiation, or surgical decompression.² The evolution of TED is accompanied by hemodynamic alterations in the orbital cavity, studied using Colour Doppler imaging (CDI). The veins being thinner, with less elastic walls and a wider cross-sectional diameter than arteries, are affected earlier. The external compression of the superior ophthalmic vein (SOV) leads to venous dilatation, stasis, and orbital congestion.³ Prolonged stasis may result in a reversal of flow in SOV. On account of correlation between severe orbital venous stasis and dysthyroid optic neuropathy (DON)⁴, surgical decompression is recommended for inactive orbits with persistently low or reverse SOV flow.^{5, 6}

The orbital arteries, ophthalmic artery (OA), central retinal artery (CRA), and posterior ciliary artery (PCA) are evaluated in terms of peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistivity index (RI).⁷ The assessment of OA and CRA is preferred over PCA, as the small caliber and variable direction of flow makes placement of the doppler gates difficult.⁸ The flow velocities in OA and CRA tend to increase, and OA-RI is reduced in the active phase of TED.^{9, 10} The progression of TED to inactive disease shows a decrease in flow velocities, with a higher RI in CRA and OA.^{3, 5, 11} DON orbits however show a reduced OA-PSV, OA-EDV, CRA-PSV, CRA-EDV, and CRA-RI.¹² Given the reproducibility of RI due to its independence from beam/vessel angle, RI was the main hemodynamic study parameter in studies on orbital decompression surgery.^{5, 11, 13} Resolution of orbital space conflict following decompression surgery was shown to decrease the RI of CRA and OA.^{5, 11} Some studies however report that arterial RI is influenced by vascular resistance, impedance, and vascular compliance, which can cause unpredictable variations in RI for the intraocular microvessels.^{14, 15} The arterial PSV is affected by the resistance to flow, with proximal stenosis causing a proportionate reduction in PSV.¹⁶ On the other hand, EDV is influenced by vascular impedance and resistivity of the distal microcirculation.¹⁷ Hence, assessment of orbital perfusion based upon a single parameter – RI, may be fallacious.

To the best of our knowledge, there is a dearth of literature on the changes in OA-PSV, OA-EDV, CRA-PSV, and CRA-EDV with varying severity of TED and type of orbitopathy. There is also limited information on changes in arterial flow parameters following surgical decompression in TED orbits. Hence, this study was conducted to explore the variations in colour doppler parameters in inactive TED and the changes associated with orbital decompression surgery in inactive moderate-to-severe TED.

A prospective, non-randomised clinical trial was conducted between March 1, 2020, to October 31, 2021 at a tertiary eye care institute. Institutional ethics committee clearance was obtained (No.1/IEC/MAMC/70/05/2019/No511, dated 01/11/2019) and the study was registered with the Clinical trials registry of India (No. CTRI/2020/02/023388, registered on 17/02/2020). The study was carried out in accordance with the tenets of the Declaration of Helsinki and a written informed consent was obtained from the study participants prior to enrolment in the study.

The study population comprised of consecutive Graves’ disease patients, euthyroid for the past 6 months, between the ages of 18–65 years age, with moderate-severe inactive TED in at least one orbit. Exclusion criteria comprised of known cases of diabetes, coronary artery disease, dyslipidaemia, atherosclerosis, pregnant or lactating females, hypertension, patients on diuretic medications, orbital space occupying lesions, exposure keratopathy, one eyed patients and optic neuropathy other than DON. Active smokers or patients with history of smoking in the past one year were not included in the study. The TED cases were screened for disorders affecting the blood viscosity like polycythemia vera using hematocrit parameter, and all deranged cases were excluded. The orbit with greater proptosis was selected for surgical decompression. The contralateral orbits, termed as ‘fellow orbits’ were kept under observation without surgical intervention.

A detailed history of ocular and systemic diseases was elicited. The best-corrected visual acuity (BCVA) assessed and documented in logMAR form, extraocular muscle movement, upper and lower eyelid retraction, pupillary reactions and fundus examination were performed.

Exophthalmometry was done using Hertel’s exophthalmometer (Handaya Co. Ltd, Tokyo, Japan). The measurements were performed at enrolment and repeated three months after intervention. The disease severity was graded as per EUGOGO guidelines.¹⁸ Moderate-severe TED was diagnosed based upon the presence of two or more of the signs, proptosis of ≥ 3 mm above the normal for gender and Indian race, lid retraction of ≥ 2 mm, inconstant or constant diplopia (Grade 3 or 4), or moderate to severe soft tissue involvement. The orbits with mild soft tissue involvement, lid retraction < 2 mm, exophthalmos < 3 mm above normal for gender and race, and no or intermittent diplopia, were graded as mild TED.

EOM movements were analysed in the field of action of the superior rectus muscle (elevation) due to inferior rectus restriction, and for the lateral rectus muscle (abduction) due to medial rectus restriction. The movement limitation was graded as 0 (no limitation), 1 (< 25% limitation), 2 (up to 50% limitation), 3 (75% limitation), or 4 (complete absence of eye movement from primary gaze). The scores for elevation and abduction were added to get muscle restriction index (mRI) varying from 0 to 8. The orbits with mRI scores ≤ 2/8 were classified as lipogenic (Type-1) orbitopathy and mRI > 2/8 were labeled as myogenic (Type-2) orbitopathy.^{19, 20}

Disease activity in the TED orbits was defined as per the modified CAS scoring.²¹ At the initial visit, one point was allotted for each of the signs, resting orbital ache, gaze evoked pain, redness of eyelids, redness of conjunctiva, swelling of caruncle or plica, swelling of eyelids and chemosis. On the follow-up visit at six weeks, one point was awarded for increase in exophthalmos ≥ 2 mm, decrease in eye motility of ≥ 8⁰, and worsening of visual acuity. Orbits with a score of < 3/7 at the initial visit or < 4/10 at the follow-up visit were classified as an inactive disease. Patients with inactive disease at the initial visit were enrolled in the study.

The color vision using Hardy-Rand-Rittler pseudoisochromatic plates and contrast sensitivity with Functional acuity contrast test were also assessed preoperatively. The intraocular pressure (IOP) was performed in relaxed sitting position in the primary gaze using Goldmann applanation tonometry (GAT). The visual field analysis was done using standard automated perimetry with 24 − 2 SITA-Standard strategy (Humphrey Field Analyzer, Carl Zeiss Meditech, Dublin, CA, USA) with appropriate near correction wherever required. The diagnosis of DON was based on reduction of BCVA of two or more Snellen lines, color vision defect, presence of optic disc swelling, relative afferent pupillary defect (RAPD)²², alteration in contrast sensitivity and visual field defects.²³

The TED orbits were imaged using a 128 slice multi-detector computed tomography (CT) scanner (Somatom Definition, Siemens Medical Solutions, PA, USA). The coronal section halfway between the posterior sclera and the orbital apex was chosen. The transverse dimensions of the horizontal and vertical extra-ocular muscles (EOM) were analysed. The horizontal muscle index was expressed as the percentage of the orbital width occupied by the medial and lateral rectus muscles. The vertical index was calculated in a similar way using inferior and superior rectus - levator palpebrae superioris complex. Barret index (BI) was taken as the higher of the two obtained muscle indices.²³ Considering the maximum impingement on the optic nerve by EOM, BI > 67% was taken as a high-risk factor for optic neuropathy²⁴, and these orbits were labelled as probable DON orbits.

The orbital blood flow was assessed using color doppler imaging with a 7.5 MHz linear-array transducer on the Philips HD 11 Ultrasound system (Philips Medical Systems, Best, The Netherlands) by a single-blinded experienced radiologist (SG). The patient lay supine with a forward head elevation of 30^o. The patient was instructed to close the eye being examined, while fixating straight ahead with the other eye. The probe was placed axially with minimal pressure over the closed eyelids. The central retinal artery (CRA) was localized in the retrolaminar region 1–3 mm behind the optic nerve head. The ophthalmic artery (OA) was imaged around 20 mm behind the globe where it crossed the optic nerve from the lateral to the medial aspect⁷. The Doppler waveform and the velocity parameters – peak systolic velocity (PSV), end diastolic velocity (EDV) and resistivity index (RI) were noted in CRA and OA. The measurements were taken twice, and the average score was considered for the final analysis.

$$Resistivity index \left(RI\right)= \frac{Peak systolic velocity \left(PSV\right)-End diastolic velocity \left(EDV\right)}{Peak systolic velocity \left(PSV\right)}$$

The Doppler velocity measurements were repeated in both orbits three months post-surgical decompression.

The normative values of color doppler imaging were established from 18 age and sex-matched healthy controls who presented to the hospital, for refractive correction, after obtaining informed consent.

Surgical Technique Of Decompression:

Lateral and inferior orbital wall with fat decompression was performed by a single experienced surgeon (RG) under general anesthesia.

The superior lid crease incision was extended to the lateral orbital rim, the periosteum was incised and the lateral canthal tendon was disinserted. The decompression of the lateral and inferior wall was performed using the High-speed micromotor system (Karl Storz company, Tuttlingen, Germany) using the drill handpiece with a conical tip. The fat was removed from superolateral and inferolateral pockets. Hemostasis was achieved and the periosteum was closed with interrupted bites of polygalactin (Vicryl Rapid™ 5/0, Ethicon Inc, Somerville, NJ, USA) suture. The muscle layer and skin were closed with interrupted bites of absorbable, multifilament polygalactin (Vicryl Rapid™ 6/0, Ethicon Inc, Somerville, NJ, USA) and running non-absorbable silk (Mersilk 6/0, Ethicon, Somerville, NJ, USA) sutures respectively.

Statistical Analysis:

The statistical calculations were done using statistical package for social science software (SPSS v26.0). The data was assessed for normality using Kolmogorov-Smirnov test. The quantitative data was expressed as mean ± standard deviation (SD). The quantitative data with skewed distribution was analysed as median (interquartile range, IQR). The Doppler parameters between the TED orbits and healthy controls were compared using ANOVA test and post-hoc analysis. Multiple regression analysis for each doppler parameter at enrolment was performed using step-wise approach to include a parameter for p < 0.05 and exclusion of a parameter for p > 0.1. The t – scores and p–values were then calculated for each parameter. The area under the receiver operating characteristic (AUROC) curve with 95% confidence interval was generated for each of the colour doppler indices to evaluate the sensitivity, specificity, positive likelihood ratio (LR+) and negative likelihood ratio (LR-) to distinguish TED orbits from healthy orbits, to predict the severity of TED, and to distinguish probable DON from non-DON orbits. The parameters at enrolment were compared at three-month follow-up using paired t-test. The changes in parameters between the surgical decompression group and fellow orbits were compared using ANCOVA test. The p-value < 0.05 was taken as statistically significant.

A total of 48 orbits of 24 Graves’ disease patients were enrolled in the study. The mean age was 39.38 ± 12.56 years and a male: female ratio of 1:1.18. A single patient had a history of hypothyroidism and the remaining 95.8% (23/24) cases were diagnosed with hyperthyroidism. The duration of thyroid disorders ranged from 12 to 216 months (median = 48 months, IQR = 36–84 months), and the TED complaints from 6 to 120 months (median = 21 months, IQR = 12–36 months). None of the enrolled cases were active smokers. One (4.2%) patient had a past history of tobacco intake, with an abstinence period of three years prior to enrolment.

The presenting complaints were bulging eyes in 58.3% (14/24), dryness in 25% (6/24), and double vision in 16.7% (4/24) and the mean logMAR BCVA was 0.017 ± 0.05. The color vision, contrast sensitivity, visual fields, pupillary reactions, and fundus examination were unremarkable. There were 24 orbits with moderate-to-severe TED in the surgical decompression group. Among these, 7 orbits with Barrets’ index ≥ 67% were labelled as probable DON orbits. The remaining 17 orbits were labelled as non-DON orbits. The fellow orbits included 7 moderate-to-severe TED and 17 mild TED and none of these cases qualified to be labelled as probable DON orbits.

The median CAS value at the time of enrolment was 1 (IQR = 1–2) in the orbits undergoing surgery, and 1 (IQR = 0.75–1) in the fellow orbits. (p-value = 0.012). The mean proptosis was 26.17 ± 1.3 mm in the orbits undergoing surgical decompression, and 22.0 ± 2.8 mm among the fellow orbits (p-value < 0.001). 29.2% (7/24) cases had a bilateral symmetrical disease with a difference in proptosis of ≤ 2 mm.

The mean IOP of the orbits undergoing surgical decompression was comparable with the fellow orbits, but was significantly higher than healthy controls (Table – 1).

On comparison of doppler parameters at enrolment, with reference values of healthy controls (Table − 1), a significant reduction in CRA – PSV, CRA – RI, OA – PSV, and OA – EDV was noted in the TED orbits. Significant differences were also noted between CRA – PSV, CRA – EDV, OA – PSV, OA – EDV, and OA- RI among the TED orbits undergoing surgery and fellow orbits.

Multiple regression analysis was performed for each doppler parameter at enrolment (Table − 2). OA – EDV showed the strongest negative correlation with proptosis and duration of thyroid disorder. OA – PSV had a significant negative correlation with proptosis and TED duration, and OA-RI with IOP and proptosis. Also, CRA – PSV showed negative correlation with IOP and thyroid disorder duration, while CRA – EDV correlated negatively with proptosis and thyroid disorder duration. However, CRA – RI showed no correlation with age, proptosis, IOP, duration of thyroid disorder or duration of TED.

The ROC analysis compared the doppler indices between the TED and healthy orbits (Figure – 1). OA – PSV and OA – EDV showed strong predictive power with AUROC > 0.8. Using the Youden ratio, a cut-off velocity of 25.4 cm/s for OA – PSV was found for prediction of inactive TED (sensitivity of 91.7% and specificity of 100%). The estimated cut-off velocity of OA – EDV in predicting inactive TED was 4.2 cm/s (58.3% sensitivity and 100% specificity) (Table − 3). CRA – EDV was found to have the least discriminatory significance amongst healthy and TED orbits.

ROC analysis to discriminate inactive mild from moderate-to-severe TED showed maximal AUROC of 0.881 for OA – EDV and 0.81 for OA – PSV (Figure – 2). The estimated cut-off value for OA – EDV was 3.23 cm/s (sensitivity 71% and specificity of 94.1%) and for OA – PSV was 15.4 cm/s (sensitivity of 83.9% and specificity of 76.5%) (Table – 3). Other doppler parameters with sufficient discriminatory power were CRA – OSV, CRA – EDV, and OA – RI. CRA – RI was found to have the least significance in discrimination of severity of disease.

ROC analysis used to differentiate between probable DON and non-DON orbits showed maximal AUROC of 0.770 for OA – EDV and 0.728 for OA – PSV (Figure – 3). The estimated cut-off values were 2.8 cm/s (sensitivity of 85.7%, specificity of 68.3%) for OA – EDV, and 11.3 cm/s (sensitivity of 85.7%, specificity of 65.9%) (Table – 3). The remaining doppler parameters of CRA – PSV, CRA – EDV, CRA – RI, and OA – RI had no significant discriminatory power.

Three months post decompression, there was a significant reduction in proptosis and IOP, an increase in CRA-PSV, CRA – EDV, OA – PSV, OA – EDV, with reduction in OA – RI, and CRA – RI (Table – 4) (Figs. 4, 5). The fellow orbits did not show any significant changes in any parameter on re-examination after 3 months (Figure – 6). On comparison with healthy controls, the decompressed orbits at 3 months follow-up showed insignificant differences in CRA – PSV (p-value = 0.59) and OA – EDV (p-value = 0.585), while a significant increase was noted among OA – PSV (p-value < 0.001), and CRA – EDV (p-value = 0.015), with a significant reduction in CRA – RI (p-value < 0.001), and OA – RI (p-value < 0.001). On comparing the healthy orbits with the fellow orbits at three months follow-up, a persistent significant reduction was noted in CRA – PSV (p-value = 0.003), CRA – RI (p-value = 0.012), OA – PSV (p-value < 0.001), OA – EDV (p-value = 0.004), and OA – RI (p-value < 0.001).

ANCOVA test was used to compare the changes at three-month follow-up visit between the surgically decompressed orbits and fellow orbits under observation. Significant reduction in IOP and proptosis, with an increase in CRA – PSV, CRA – EDV, OA – PSV, and OA – EDV were noted (Table – 4). CRA – RI and OA – RI were however not significantly affected when compared between the two groups.

Based upon the mRI scores, there were 15 lipogenic and 9 myogenic orbitopathy cases. Post-decompression, there was a significant reduction in proptosis, IOP and OA-RI, and an increase in CRA – PSV, CRA – EDV, OA – PSV, and OA – EDV in both the subgroups. The reduction in CRA – RI reached statistical significance in the myogenic orbitopathy group (p-value = 0.001), but not in lipogenic orbitopathy group (p-value = 0.438). (Table − 5)

The study presented in this report, evaluated the flow parameters of CRA and OA in inactive moderate-severe TED and the changes following orbital decompression using CDI.

The mean age at enrolment in our study was 39.38 ± 12.56 years. Similar age groups have been described in demographic studies on Indian population, ^{25, 26} We observed female: male ratio of 1.18: 1. Though the reported female: male ratio in the US population was 6.05: 1²⁷, a higher male preponderance with female: male ratio of 1.12: 1 and 0.89: 1 was observed in Indian population.^{25, 26} Severe TED has been associated with male gender²⁸, therefore exclusive inclusion of moderate-severe TED in our study, could have resulted in high number of male participants. The referral bias and delay in seeking healthcare among females in the Indian subcontinent could be another contributing factor.

The orbital blood flow parameters in GD can be altered by hyperthyroidism, raised systemic blood pressure, increased IOP and orbital inflammation.²⁹ In this study, none of the patients were hypertensive and all patients had a stable thyroid profile for at least 6 months prior to enrolment.

Raised IOP has been associated with reduction in OA – PSV, CRA – PSV, OA – EDV, and CRA – EDV, with increase in OA – RI and CRA – RI.³⁰ The mean IOP of orbits planned for decompression in our study being 18.75 ± 1.65 mm Hg, though significantly higher (p-value < 0.001) than healthy controls, was within the normal range of 10–21 mm Hg.³¹

The Doppler indices in inactive TED have been variably reported in previous studies. Yanik et al compared inactive TED with healthy controls and found increase in PSV and EDV of OA and CRA in TED cases.³ The OA – RI was observed to be lower with no significant changes in CRA – RI in inactive TED cases when compared to healthy controls.^{3, 10} In contrast Perez-Lopez et al observed significantly higher OA - RI and CRA – RI among inactive TED cases planned for orbital decompression.¹¹ In confirmed GD cases, eyes diagnosed as early DON on the basis of pathologic contrast sensitivity and static perimetry, were found to have significantly lower PSV, EDV and RI for CRA as compared to the group without early DON.¹² In our study, at enrolment, the CRA – PSV, CRA – RI, OA – PSV, and OA - EDV were significantly reduced in the orbits planned for decompression as compared to healthy controls but showed no abnormality in colour vision, contrast sensitivity or visual fields. The CRA – EDV and OA – RI, though reduced, did not reach statistical significance. We also observed a strong negative correlation between PSV and EDV of OA and CRA with duration of thyroid disorder and TED. Amongst the studied doppler parameters, PSV and EDV of OA showed the highest sensitivity and specificity, while CRA - RI had the least predictive potential in discriminating healthy from inactive TED and mild from moderate to severe TED. CRA – RI has been criticised previously for representing a distortion of the retinal autoregulatory mechanisms in Graves’ disease, where hyperdynamic circulation may lead to intense vasoconstriction in the retinal microcirculation.³² Also, proptosis in TED causes a passive stretch on the orbital vasculature, and affects the vessel contractility and resistivity.³ Hence, arterial RI as a standalone parameter, may be a fallacious predictor of hemodynamic changes in the orbit.

These differences in the doppler parameters in the inactive phase itself, suggests dynamism of orbital changes even after subsidence of clinically apparent disease activity. The reduction in flow with passage of time, possibly reflects eventual occurrence of irreversible changes in orbital vasculature. Though Lesin et al using ROC analysis demonstrated CRA flow having highest predictive potential for detecting early DON¹², our ROC analysis showed OA parameters as better predictors for early detection of TED and its transition to severe forms of TED. ROC analysis also showed higher predictive potential for OA parameters amongst probable DON orbits, with apical crowding, possibly due to extrinsic compression of the OA at the orbital apex.

Proptosis is a major determinant of TED severity in EUGOGO classification. The exophthalmometric measurements were shown to correlate positively with CRA – RI in euthyroid GD cases without TED.²⁹ However, in TED cases, no definite correlation of proptosis and the doppler flow parameters could be established before,⁹ or after decompression.¹¹ We observed a significant negative correlation of proptosis with CRA – PSV, CRA – EDV, OA – PSV, OA – EDV, and positive correlation with OA – RI in TED orbits prior to decompression. Three months post-surgical decompression, following significant reduction in proptosis, the PSV and EDV of CRA and OA increased along with decrease in RI of CRA and OA.

Recommended management of inactive moderate-to-severe TED involves systemic or local administration of corticosteroids, systemic targeted therapy like teprotumumab, localised orbital radiotherapy and surgical decompression. The conventional medical management with corticosteroids reduces the orbital inflammation and improves the muscle swelling without any change in the proptosis.²⁹ Medical management was shown to improve the CRA – RI and OA – RI towards the mean normative values in 80% (8/10) cases of TED.^{29, 33} The targeted medical therapy has shown to significantly reduce proptosis over 24 weeks of administration in active moderate-to-severe disease, with a significant reduction in EOM and orbital fat volume.³⁴ However, no correlation of orbital hemodynamic changes with teprotumumab treatment is available to the best of our knowledge. Surgical decompression resolves the space – volume conflict, improves ocular perfusion,³⁵ reduces proptosis,^{5, 11, 36} decreases retro-bulbar pressures³³ and lessens the IOP.^{11, 37} Perez-Lopez et al observed a median reduction of 6% in OA – RI and 5% in CRA – RI post-operatively in inactive TED orbits in the Spanish population.¹¹ Another study from Iran described similar outcomes.⁵ Our study also showed a significant median reduction of 4.7% in OA – RI and 6.2% in CRA – RI three months post-surgery. We observed a median increase of 117% in OA -PSV, 160% in OA – EDV, 46% in CRA – PSV, and 72% in CRA – EDV in post decompression orbits with insignificant changes in the fellow orbits at three-months follow-up. Since we included only inactive TED cases maintaining euthyroid status for six months prior to enrolment, the doppler parameter derangement was possibly due to extrinsic compression and stretching of the retrobulbar vessels which was relieved after surgery.

Analysis of difference in response between myogenic and lipogenic orbitopathy subgroups after treatment with glucocorticoids and orbital irradiation by Kurioka et al showed inconsistent results.²⁹ They reported a decrease in CRA-RI in 4/8 (50%) cases of myogenic orbitopathy and 2/4 (50%) cases of lipogenic orbitopathy, with an increase in CRA-RI values in the rest of the cases. In our study following surgical decompression, decrease in OA – RI was seen amongst both sub-groups, however it reached statistical significance only in lipogenic subgroup. The CRA – RI also showed reduction in both subgroups, reaching statistical significance in the muscle-predominant orbitopathy group only. The individual parameters of CRA – PSV, CRA – EDV, OA – PSV, and OA - EDV, improved significantly in both sub-groups three months post-surgery.

The main limitation of our study was inability to evaluate the long-term alterations in orbital hemodynamics after surgical decompression and its impact on progression of DON. The impact of residual orbital inflammation at three-months post decompression surgery on hemodynamics could not be accurately demonstrated. The strict exclusion of diseases affecting orbital hemodynamics and smoking may have created a selection bias, and the findings of the study may not be applicable to TED cases with other systemic diseases affecting the orbital vasculature. In absence of VEP, the possibility of missing subclinical DON cannot be ruled out. We could not elicit any doppler correlation in orbits with clinically evident DON, due to strict exclusion criteria.

In summary, we have shown reduction in orbital perfusion in mild and moderate-to-severe inactive TED cases as compared to healthy controls. The monitoring of OA flow velocities can help in discriminating inactive TED from healthy orbits and predict progression of mild TED towards more severe forms. An improvement in OA and CRA perfusion parameters occurs in both lipogenic and myogenic orbitopathies following surgical decompression. Therefore, in addition to the conventional scoring systems for evaluation of activity and severity, sequential orbital CDI of OA and CRA can serve as an objective response tool in management of TED.

Conflicts of Interest: None.

Financial Disclosures: None

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Table 1: Comparison of healthy controls, TED orbits planned for surgical decompression, and fellow orbits. (CRA – Central retinal artery, EDV – End diastolic velocity, IOP – Intra-ocular pressure, NA – Not applicable, OA – Ophthalmic artery, PSV – Peak systolic velocity, RI – Resistivity index, SD – Standard deviation, TED – thyroid eye disease)

Parameters	Healthy controls (1)	TED orbits (2)	Fellow Orbits (3)	ANOVA test (p-value)	Post-hoc analysis
Parameters	Healthy controls (1)	TED orbits (2)	Fellow Orbits (3)	ANOVA test (p-value)	1 vs 2	1 vs 3	2 vs 3
IOP, Mean (SD) (mm Hg)	16.0 (1.5)	18.67 (1.5)	18.25 (1.8)	< 0.001	< 0.001	0.001	0.47
Proptosis, Mean (SD) (mm)	NA	26.17 (1.3)	22.0 (2.8)	NA			< 0.001
CRA - PSV, Mean (SD) (cm/s)	12.71 (3.3)	8.40 (2.8)	10.50 (3.9)	0.001	< 0.001	0.04	0.04
CRA - EDV, Mean (SD) (cm/s)	2.97 (1.0)	2.33 (0.87)	3.39 (1.7)	0.018	0.11	0.29	0.005
CRA - RI, Mean (SD)	0.77 (0.05)	0.72 (0.07)	0.68 (0.08)	0.002	0.03	0.001	0.13
OA - PSV, Mean (SD) (cm/s)	33.06 (4.3)	12.69 (5.4)	16.43 (7.8)	< 0.001	< 0.001	< 0.001	0.04
OA - EDV, Mean (SD) (cm/s)	7.27 (2.5)	3.23 (1.3)	5.66 (3.1)	< 0.001	< 0.001	0.04	0.001
OA - RI, Mean (SD)	0.77 (0.05)	0.74 (0.07)	0.65 (0.1)	< 0.001	0.22	< 0.001	< 0.001

Table 2: Multivariate analysis between doppler parameters at recruitment with different variables. (CRA – Central retinal artery, EDV – End diastolic velocity, IOP – Intra-ocular pressure, NA – Not applicable, OA – Ophthalmic artery, PSV – Peak systolic velocity, RI – Resistivity index, TED – Thyroid eye disease)

Parameter	Multiple correlation coefficient	F - ratio (p-value)	Independent variables (t - value, p-value)
Parameter	Multiple correlation coefficient	F - ratio (p-value)	IOP	Proptosis	Age	Thyroid disorder duration	TED duration
CRA - PSV	0.66	17.51 (< 0.001)	- 3.2 (0.003)	Excluded		- 5.0 (0.001)	Excluded
CRA - EDV	0.57	10.87 (0.001)	Excluded	- 2.7 (0.01)	Excluded	- 3.6 (0.001)	Excluded
CRA - RI	Not significant
OA - PSV	0.68	18.92 (< 0.001)	Excluded	- 4.6 (< 0.001)	Excluded		- 3.5 (0.001)
OA - EDV	0.72	24.79 (< 0.001)	Excluded	- 6.0 (< 0.001)	Excluded	- 3.4 (0.002)	Excluded
OA - RI	0.47	6.5 (0.003)	- 2.5 (0.02)	3.2 (0.003)	Excluded

Table 3: Area under the receiver operating curve (AUROC) analysis of doppler parameters at enrolment comparing the healthy control orbits with thyroid eye disease (TED) orbits, mild and moderate-to-severe TED orbits, and probable DON and non–DON orbits. Youden ratio (J) has been used to calculate the discrimination cut-off, with the best sensitivity and specificity. (CI – confidence interval, CRA – Central retinal artery, EDV – End diastolic velocity, IOP – Intra-ocular pressure, LR – Likelihood ratio, NA – Not applicable, OA – Ophthalmic artery, PSV – Peak systolic velocity, RI – Resistivity index, SD – Standard deviation, TED – thyroid eye disease)

Parameter	AUROC	Standard error	95 % CI		p-value	Youden Index J	Proposed cut-off
Parameter	AUROC	Standard error	Upper	Lower	p-value	Youden Index J	Absolute value	Sensitivity	Specificity	LR +	LR -
Healthy vs TED orbits
CRA - PSV	0.774	0.057	0.868	0.654	< 0.0001	0.51	9.56	62.5	88.9	5.62	0.42
CRA - EDV	0.568	0.073	0.69	0.441	0.35	NA
CRA - RI	0.755	0.065	0.853	0.634	0.0001	0.49	0.73	60.4	88.9	5.44	0.45
OA - PSV	0.986	0.011	1	0.921	< 0.0001	0.92	25.4	91.7	100	16.5	0.09
OA - EDV	0.802	0.053	0.89	0.686	< 0.0001	0.58	4.2	58.3	100	5.25	0.47
OA - RI	0.744	0.065	0.844	0.622	0.0002	0.45	0.75	72.9	72.2	2.62	0.38
Mild vs Moderate-to-severe TED orbits
CRA - PSV	0.733	0.079	0.851	0.586	0.003	0.43	10.3	83.9	58.8	2	0.27
CRA - EDV	0.695	0.081	0.82	0.546	0.027	0.43	3.1	83.9	58.8	2	0.27
CRA - RI	0.573	0.088	0.715	0.422	0.41	NA
OA - PSV	0.81	0.072	0.909	0.671	< 0.0001	0.6	15.4	83.9	76.5	3.56	0.21
OA - EDV	0.881	0.057	0.957	0.755	< 0.0001	0.65	3.23	71	94.1	12.1	0.31
OA - RI	0.751	0.071	0.865	0.606	0.0004	0.42	0.75	41.9	100	7.7	0.58
Probable DON vs non-DON orbits
CRA - PSV	0.697	0.128	0.821	0.547	0.125	NA
CRA - EDV	0.704	0.110	0.827	0.555	0.065	NA
CRA - RI	0.625	0.107	0.761	0.474	0.24	NA
OA - PSV	0.728	0.079	0.846	0.581	0.004	0.52	11.3	85.7	65.9	2.51	0.22
OA - EDV	0.770	0.083	0.879	0.626	0.001	0.54	2.8	85.7	68.3	2.7	0.21
OA - RI	0.613	0.126	0.750	0.462	0.37	NA

Table 4: Comparison of surgically decompressed TED orbits and fellow TED orbits under observation at three months post-intervention. (CRA – Central retinal artery, EDV – End diastolic velocity, IOP – Intra-ocular pressure, NA – Not applicable, OA – Ophthalmic artery, PSV – Peak systolic velocity, RI – Resistivity index, SD – Standard deviation, TED – thyroid eye disease)

Parameters	TED orbits			Fellow orbits			ANCOVA test
Parameters	At recruitment	3 months post-surgery	p-value	At recruitment	3 months follow-up	p-value	Aggregate correlation (r)	F-value	p-value
IOP, Mean (SD) (mm Hg)	18.75 (1.7)	14.58 (1.9)	< 0.001	18.25 (1.8)	18.08 (1.9)	0.49	0.75	108.81	< 0.001
Proptosis, Mean (SD) (mm)	26.17 (1.3)	20.83 (1.2)	< 0.001	22 (2.8)	21.92 (2.7)	0.32	0.89	139.34	< 0.001
CRA - PSV, Mean (SD) (cm/s)	8.40 (2.8)	12.52 (4.1)	< 0.001	10.50 (3.6)	9.83 (3.0)	0.15	0.63	22.77	< 0.001
CRA - EDV, Mean (SD) (cm/s)	2.33 (0.87)	4.09 (1.7)	< 0.001	3.34 (1.7)	3.1 (1.21)	0.75	0.65	24.17	< 0.001
CRA - RI, Mean (SD)	0.71 (0.07)	0.68 (0.08)	0.023	0.70 (0.08)	0.7 (0.09)	0.46	0.48	2.32	0.13
OA - PSV, Mean (SD) (cm/s)	12.69 (5.4)	23.65 (8.3)	< 0.001	16.43 (7.8)	15.24 (6.2)	0.13	0.66	45.27	< 0.001
OA - EDV, Mean (SD) (cm/s)	3.23 (1.35)	7.48 (2.86)	< 0.001	5.66 (3.1)	4.93 (2.2)	0.051	0.65	43.56	< 0.001
OA - RI, Mean (SD)	0.74 (0.07)	0.67 (0.08)	0.001	0.65 (0.1)	0.67 (0.09)	0.31	0.45	2.3	0.14

Table 5: Comparison of lipogenic and myogenic orbitopathy in the surgically decompressed TED orbits, and fellow orbits kept under observation. (CRA – Central retinal artery, EDV – End diastolic velocity, IOP – Intra-ocular pressure, NA – Not applicable, OA – Ophthalmic artery, PSV – Peak systolic velocity, RI – Resistivity index, SD – Standard deviation, TED – thyroid eye disease)

Parameters	TED orbits						Fellow orbits
	Lipogenic orbitopathy (n = 15)			Myogenic orbitopathy (n = 9)			Lipogenic orbitopathy (n = 15)			Myogenic orbitopathy (n = 9)
	At recruitment	3 months post-surgery	p-value	At recruitment	3 months post-surgery	p-value	At recruitment	3 months follow-up	p-value	At recruitment	3 months follow-up	p-value
IOP, Mean (SD) (mm Hg)	18.75 (1.65)	14.58 (1.91)	< 0.001	18.84 (1.68)	14.52 (1.87)	< 0.001	18.27 (1.8)	18.27 (2.0)	1	18.25 (1.8)	18.08 (1.9)	0.757
Proptosis, Mean (SD) (mm)	26.17 (1.27)	20.83 (1.2)	< 0.001	25.95 (1.27)	20.84 (1.21)	< 0.001	21.67 (2.8)	21.53 (2.5)	0.89	22.0 (2.8)	21.92 (2.7)	0.92
CRA - PSV, Mean (SD) (cm/s)	8.72 (2.9)	12.31 (3.7)	0.007	7.87 (2.8)	12.87 (4.9)	0.019	11.38 (3.9)	10.51 (3.2)	0.52	10.5 (3.9)	9.83 (3.0)	0.51
CRA - EDV, Mean (SD) (cm/s)	2.51 (0.9)	3.97 (1.7)	0.008	2.03 (0.8)	4.29 (1.8)	0.005	3.79 (1.7)	3.34 (1.3)	0.41	3.39 (1.7)	3.10 (1.2)	0.51
CRA - RI, Mean (SD)	0.70 (0.08)	0.68 (0.09)	0.52	0.74 (0.06)	0.66 (0.07)	0.02	0.70 (0.08)	0.69 (0.09)	0.54	0.69 (0.08)	0.69 (0.09)	0.72
OA - PSV, Mean (SD) (cm/s)	13.16 (5.2)	22.53 (7.2)	< 0.001	11.91 (5.9)	25.52 (9.9)	0.04	18.2 (8.4)	17.1 (6.6)	0.69	16.43 (7.8)	15.24 (6.2)	0.56
OA - EDV, Mean (SD) (cm/s)	3.51 (1.5)	7.28 (2.9)	< 0.001	2.78 (1.1)	7.82 (2.8)	< 0.001	6.16 (3.4)	5.4 (2.5)	0.49	5.66 (3.1)	4.94 (2.2)	0.36
OA - RI, Mean (SD)	0.73 (0.06)	0.67 (0.07)	0.03	0.75 (0.07)	0.67 (0.10)	0.08	0.66 (0.09)	0.69 (0.09)	0.4	0.65 (0.09)	0.67 (0.09)	0.46

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Alterations in retrobulbar hemodynamics in thyroid eye disease

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