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Clinical and Experimental Ophthalmology 2015; 43: 108–114 doi: 10.1111/ceo.12400
Original Article Twenty-four-hour intraocular pressure patterns in patients with thyroid eye disease Anjali S Parekh MD,1 Kaweh Mansouri MD MPH,1,2 Robert N Weinreb MD,1 Ali Tafreshi BS,1 Bobby S Korn MD PhD3 and Don O Kikkawa MD3 1
Hamilton Glaucoma Center, Shiley Eye Center, and 3Division of Ophthalmic Plastic and Reconstructive Surgery, Department of Ophthalmology, University of California, San Diego, La Jolla, California, USA; and 2Glaucoma Sector, Department of Ophthalmology, University of Geneva, Geneva, Switzerland
ABSTRACT
(50%), conjunctival hyperaemia (100%) and superficial punctate keratitis (20%). Tolerability of the lens was found to be 1.5 ± 0.7. Positive linear slopes of the CLS signal from wake to sleep were detected (18.0 ± 43.8 arbitrary units [a.u.]; P = 0.254), whereas at the transition from S/S to W/S a significant decrease (−62.9 ± 56.8 a.u.; P = 0.010) was found. Five patients (50%) had a significant nocturnal/sleep acrophase with the peak occurring at 6:30 a.m. The mean amplitude of the 24-h curves was 102.2 ± 52.6 a.u.
Background: To prospectively investigate the safety, tolerability and 24-h intraocular pressure (IOP) patterns in patients with thyroid eye disease (TED) using a contact lens sensor (CLS). Design: Prospective study. Participants: Ten patients with established TED. Methods: Ten eyes of 10 patients were prospectively evaluated in an ambulatory 24-h IOP monitoring session using the CLS (Sensimed AG, Lausanne, Switzerland). Patients pursued daily activities, and sleep behaviour was uncontrolled. Main Outcome Measures: Incidence of adverse events (AEs) and tolerability (scale of 0–10, increasing intolerance) were assessed. IOP patterns were evaluated using a cosinor rhythmometry model, and linear regression slopes were constructed for the transition from wake/sitting (W/S) to sleep/supine (S/S) and vice versa. Results: Mean age was 61.8 ± 21.6 years, and 90% of patients were female. Main AEs were blurred vision
Conclusions: In patients with TED, the CLS provides a safe and well-tolerated approach to 24-h IOP monitoring. After modelling the 24-h IOP curves, TED patients were found to have a morning acrophase. Key words: contact lens sensor, glaucoma, intraocular pressure, thyroid eye disease.
INTRODUCTION Thyroid eye disease (TED) is an autoimmune manifestation commonly associated with Graves’ disease. Collections of mucopolysaccharides and lymphocytes infiltrate extraocular muscles, depositing
■ Correspondence: Dr Kaweh Mansouri, Glaucoma Sector, Department of Ophthalmology, Geneva University Hospital, 22, Rue Alcide Jentzerch-1211 Geneva 14, Switzerland. Email: [email protected] Received 14 December 2013; accepted 15 July 2014. Competing/conflicts of interest: No stated conflict of interest. Funding sources: Supported by Sensimed AG (Lausanne, Switzerland), an unrestricted grant from Research to Prevent Blindness (New York, NY) and Velux Foundation (Zurich, Switzerland). Financial disclosures: AS Parekh: none; K Mansouri: Sensimed AG (C); RN Weinreb: Carl Zeiss Meditec (F, C), Heidelberg Engineering GmbH (F), Nidek (F), Optovue (F), Topcon Medical Systems (F,C), Sensimed G (C); A Tafreshi: Heidelberg Engineering GmbH (F); BS Korn: none; DO Kikkawa: none. Trial was registered at www.clinicaltrials.gov (NCT01798966). © 2014 Royal Australian and New Zealand College of Ophthalmologists
24-hour pressures in thyroid eye disease glycosaminoglycans and collagen within orbital tissues.1 This infiltrative process can lead to proptosis, diplopia, ocular surface disease, optic neuropathy, strabismus and, in some patients, elevated intraocular pressure (IOP).2 Elevated IOP in TED can be caused by restriction and compression of the globe by enlarged extraocular muscles,3 elevated episcleral venous pressure due to reduction of orbital venous drainage4 and increased mucopolysaccharide deposition in the trabecular meshwork decreasing aqueous outflow.2 It has been suggested that IOP measurements in this group can be altered when using traditional Goldmann applanation tonometry (GAT) due to the force generated in moving eyes into gaze positions opposite that of fibrotic and restricted extraocular muscles.5 Several studies have evaluated the relationship between TED and elevated IOP; however, to date no study has looked at 24-h rhythms in these patients. In the past, obtaining 24-h IOP data required frequent awakening of patients during sleep, thus inducing a potentially significant bias in IOP measurements.6 Recently, a contact lens sensor (CLS), which uses a novel approach to IOP monitoring, allows for observation of IOP patterns in ambulatory conditions and during undisturbed sleep.7,8 The purpose of this study was to prospectively investigate the safety and tolerability of the CLS in patients with TED and describe the 24-h IOP patterns obtained from this group of patients.
METHODS This study followed the tenets of the Declaration of Helsinki and was approved by the University of California at San Diego, Human Research Protections Program/Institutional Review Board. Informed written consent was obtained from all patients.
109 at the time of CLS placement and removal. Collected data included demographic information, medical and surgical history, systemic and ophthalmic medication, best-corrected visual acuity, slit-lamp examination, fundus examination, tear break-up time, keratometry, pachymetry, corneal biomechanical properties, corneoscleral profile evaluation, exophthalmometry and GAT (average of two measurements). The CLS was placed on the study eye (which was determined to be the patient’s more proptotic eye based on exophthalmometry readings), and 24-h IOP monitoring was started in an ambulatory setting. At 5 and 30 min after CLS placement, the fitting of the CLS was evaluated with regards to centring and mobility with blinking, and during push-up manoeuvre. Patients were provided with a standardized activity diary for half-hourly recording of information on sleep and wakefulness times, intake of medications and meals, physical activity, emotional status and other events. After 24 h, the CLS was removed and data from the portable recorder were transferred to a computer. The activity diary was collected, and an ophthalmologic examination was performed. Prior to removing the CLS, patients were asked to score their subjective comfort level using a number between 0 and 10 with values ranging from 0 (no discomfort) to 10 (very severe discomfort). Any change from baseline in relevant ocular parameters (visual acuity, conjunctival hyperaemia, ocular surface changes, discomfort and device intolerance) was defined as an adverse event (AE). Each recorded AE was characterized as mild, moderate or severe. Mild changes were characterized as alterations from baseline that resolved without the need for intervention, whereas moderate and severe AEs were those that required medical treatments.
Study population
Instrumentation
Ten eyes of 10 patients recruited from the Shiley Eye Center Thyroid Eye Clinic, Department of Ophthalmology, University of California, San Diego, were included in the study. Patients were enrolled in the study if they were between 18 and 90 years of age and were diagnosed with TED based on serum autoimmune dysfunction consistent with Graves’ disease as well as orbital imaging studies manifesting characteristics consistent with TED. Patients were excluded if they had contraindications for contact lens wear, severe ocular surface disease, keratoconus or other corneal ectasia, severe ocular inflammation, or known hypersensitivity to silicone, plaster or ocular anaesthesics. After enrolment in the study, patients underwent a comprehensive ophthalmologic examination both
The CLS (SENSIMED Triggerfish®, Sensimed AG, Lausanne, Switzerland) consists of a highly oxygenpermeable soft contact lens (SCL). It is approved for clinical use in Europe (CE mark) but only admitted for investigational use in the United States. The device is based on a novel approach to IOP monitoring, in which changes in corneal curvature and circumference are assumed to correspond to changes in IOP.9,10 A microprocessor embedded in the contact lens sends an output signal proportional to the contact lens strain gauge. Wireless power and data transfer are achieved using a patched periorbital antenna from where a cable is connected to a portable recorder. The device can record the IOP pattern for up to 24 h and remains active during undisturbed sleep. Three hundred data points are acquired during
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Parekh et al. acrophase: peak occurring during the nocturnal/ sleep period; and (iii) no significant acrophase: if at least one parameter from the model equation (i.e. one of the sine or cosine parameters or the intercept) did not have a significant influence on the dependent variable.12
Statistical analysis
Figure 1. Photograph of a patient after contact lens sensor (CLS) placement with the surrounding antenna for data transmission and power transfer.
a 30-s measurement period, repeated every 5 min. The output of the sensor is expressed in arbitrary units (a.u.) proportional to the electric signal corresponding to milliVolts generated by the contact lensembedded strain gauge. The device is described in more detail elsewhere (Fig. 1).7,11,12
Modelling of circadian IOP patterns Mathematical estimation of the circadian IOP rhythms was done using the cosinor rhythmometry method, which uses sine and cosine terms. The circadian IOP rhythm model resembles a cosine profile, and different formulations of it have previously been used to express 24-h IOP variations.13 The model can be written as follows: y(t) = b0 + b1 × cos ([2Π/24] × t) + b2 × sin([2Π/24] × t), where y is the observed signal in a.u. at time t, and b0, b1 and b2 are regression coefficients, estimated from the data. The periodicity of the 24-h IOP pattern is represented by the constant (2Π/24). Unbiased estimates and confidence limits of amplitude, mesor (mean) and acrophase (time of peak value) were obtained from the individual waveforms. The amplitude was defined as half the distance between the cosine-fit maximum and minimum. It represents the parameter estimate of the variation for the 24-h period. The clock time of the acrophase represents the phase timing of the rhythm. Nocturnal/sleep periods were defined through the observation of blink cessation (identified as short and high-amplitude spikes that are displayed by the software) on the CLS signal using the software zoom function and were confirmed using individual diaryreported sleep times. Patients were then classified into pattern groups based on the following definitions: (i) diurnal acrophase: peak occurring during the diurnal/wakefulness period; (ii) nocturnal
Data are expressed as mean ± standard deviation where appropriate. Categorical variables are described in terms of frequencies and percentages. The distribution of all variables was examined using the Shapiro–Wilk test of normality. Safety endpoints included the incidence of AEs and the tolerability level at each session. To assess the degree of change in CLS output over time, a regression was fit to each patient’s data from 1 h before going to sleep to 2 h into sleep and from 1 h before sleep to the end of the sleep period. The regression allowed for linear trends to be modelled. The linear slopes were tested for significance using a paired t-test. To assess the circadian rhythm of IOP patterns, a cosinor rhythmometry model, as described above, was adapted to CLS data.11 All hypothesis testing was two sided, at two-sided alpha = 0.05. All analyses were conducted using SAS Version 9.2 or higher (SAS Inc, Cary, NC, USA).
RESULTS Complete 24-h recordings were available from all 10 eyes of 10 TED patients. Three patients underwent scheduled orbital decompression for cosmetic disfigurement on the studied eye, and recordings were repeated after surgical recovery. The mean age of patients was 61.8 ± 21.6 years with a range of 21– 83 years. There were nine females and one male. Seven were Caucasian, one an Asian and two were Hispanic. Four patients had ocular alignment problems (three patients with hypertropia and one with esotropia) at the time of monitoring, and the average exophthalmometry measurements were 23.2 ± 3.3 mm. Table 1 provides an overview of clinical parameters at baseline. The safety and tolerability analysis included all 10 eyes. The mean length of CLS wear was 23.8 ± 0.4 h. The most frequent AEs were mild blurred vision (five patients, 50%), mild hyperaemia of the bulbar and palpebral conjunctiva (10 patients, 100%) and superficial punctate keratitis (two patients, 20%). There were no other complications associated with the device. All AEs were transient and resolved after CLS removal. There were no serious AEs and no safety issues in the fellow eye. On average, patients reported a tolerability level of 1.5 ± 0.7 (Table 2).
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Table 1. Clinical characteristics at baseline (values represent mean ± standard deviation) Parameter Age Ancestry Caucasian Asian Hispanic BCVA, decimal Objective refraction, D Sphere CCT, μm Baseline IOP, mmHg Strabismus Hypertropia Esotropia Average exopthalmometry measurements, mm
61.8 ± 21.6 7 (70%) 1 (10%) 2 (20%) 0.8 ± 0.3 −1.8 ± 3.4 524.8 ± 58.9 18.1 ± 3.5 4 (40%) 3 (75%) 1 (25%) 23.2 ± 3.3
BCVA, best-corrected visual acuity; CCT, central corneal thickness; D, dioptres; IOP, intraocular pressure. Table 2. Adverse events in 10 patients undergoing 24-h IOP monitoring with the CLS Adverse event
Events (n); Patients (n), (%)
Mild Blurred vision 5; 10 (50.0%) Conjunctival hyperaemia 10; 10 (100.0%) Eye complication associated with device 0; 10 (0.0%) Superficial punctate keratitis 2; 10 (20.0%) Ocular discomfort 0; 10 (0.0%) Device intolerance 0; 10 (0.0%) CLS, contact lens sensor; IOP, intraocular pressure.
The correlation between CLS measurements and values predicted from cosinor fitting was r = 0.64 (Spearman’s correlation). When evaluating the entire study group, this model overall indicated a nocturnal/sleep acrophase, with the peak occurring at 06:30 a.m. (Fig. 2). Specifically, five patients (50%) had a significant nocturnal/sleep acrophase, whereas two (20%) patients had a significant diurnal acrophase, and the remainder (30%) had no significant acrophase. The mean amplitude of the 24-h curves was 102.2 ± 52.6 a.u. To study the CLS signal change from the wake/ sitting (W/S) to the sleep/supine (S/S) state and vice versa, linear regressions were fitted to the transition from the wake to the sleep period. On average, linear slopes from 1 h before sleep to 2 h into sleep (18.0 ± 43.8 a.u.; P = 0.254) and to the end of the sleep period were not statistically significant (9.6 ± 84.4 a.u.; P = 0.741), indicating a weak elevation of IOP at the sleep–wake transition. At the morning transition from S/S to W/S, however, there was a significant decrease of the CLS signal
(−62.9 ± 56.8 a.u.; P = 0.010). IOP peaks were defined as an increase in the CLS signal of over 90 a.u. and lasting for more than 30 min. On average, patients had 13.7 ± 2.8 peaks over the 24-h period, with 9.1 ± 3.1 during the wake and 5.2 ± 1.6 during the sleep period (P = 0.02). For three patients with repeated CLS monitoring after orbital decompression surgery, exophthalmometry measurements decreased by 3.75 ± 0.35 mm. When evaluating linear slope changes, these patients had preoperative W/S S/S slopes (2 h into sleep) of 27.2 ± 26.3 a.u. (P = 0.216) that changed to 37.2 ± 22.7 a.u. (P = 0.105) postoperatively (P = 0.06). The morning transition of S/S to W/S slopes was –64.8 ± 26.2 a.u. (P = 0.050) and −28.2 ± 78.3 a.u. (P = 0.597), respectively (P = 0.041).
DISCUSSION In the current study, we have demonstrated that the CLS is a safe and well-tolerated device in patients with TED. This is notable given that these patients are more proptotic and theoretically more susceptible to contact lens-related problems. All 10 study patients were able to undergo the full cycle of 24-h monitoring with the CLS without requiring removal or interruption. The safety profile in this cohort of TED patients was similar, if not better than previously reported in healthy subjects and glaucoma patients. Mansouri and Shaarawy7 described initial clinical experience with the first-generation CLS in 15 glaucoma patients. They reported one case of corneal erosion (7%) and four cases of superficial punctate keratitis (27%). These findings were later confirmed by De Smedt et al.14 in 10 healthy subjects. In their cohort, three subjects (30%) had corneal micro-erosion s that were treated prophylactically with antibiotic eyedrops. Lorenz et al.15 evaluated safety of CLS wear in a mixed group of healthy subjects and glaucoma patients, and found a statistically significant difference in conjunctival oedema, conjunctival erythema, epithelial micro-erosions and lid oedema before and after CLS wear. However, these differences were not statistically significant when the study eyes and the fellow eyes were compared.15 Our group has previously studied the safety of repeated use of the current generation of CLS in glaucoma patients.12 We found that 82.5% of patients reported some degree of blurred vision, whereas 80% had hyperaemia of the bulbar and palpebral conjunctiva, and 15% had superficial punctate keratitis. With an average comfort value of 1.5, we found that CLS was well tolerated in these patients.7 CLS tolerability in TED patients was similar if not slightly better than the tolerability previously reported in both healthy patients14 and glaucoma patients.12 The similarities in safety and tolerability,
© 2014 Royal Australian and New Zealand College of Ophthalmologists
CLS (mV)
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600 550 500 450 400 350 300 250 200 150 100 50 0 –50 –100 –150 –200 –250 09:00 12:00 15:00 18:00 21:00 00:00 03:00 06:00 09:00 12:00 15:00 Time Observed CLS
Figure 2. An example of a patient’s raw 24-h contact lens sensor (CLS) data (blue line) and the superimposed cosinor modeling (red line). The peak acrophase for this recording is seen at 6:30 a.m.
Fitted CLS
particularly compared with previously studied glaucoma patients, is not surprising as both TED and glaucoma patients are known to have some degree of ocular surface disease. In glaucoma, ocular surface disease is pharmacologic whereas in TED it is usually secondary to exposure. As a result, these patients may not feel significantly different from their baseline when the CLS is placed in the eye. Tolerability of the CLS in TED patients is of significant practical importance. In the past, a significant limitation of studying IOP in TED patients was related to the fact that traditional GAT measurements can be altered because of the force required to move eyes into primary position, and currently no standardized technique for IOP measurements has been established. Furthermore, single IOP measurements may fail to reflect a patient’s true IOP range.16,17 By using a methodology based on 288 continuous 30-s measurements over 24 h, the CLS significantly minimizes the impact of measurement error of single measurements. Moreover, because the CLS follows all eye movement, gaze position may be is of less significance. Characterization of the 24-h IOP monitoring with the cosinor rhythmometry model showed that one half of the patients had their acrophase during the nocturnal/sleep period. On average, the acrophase occurred at 6:30 a.m. in TED patients. A previous study evaluating 24-h IOP in glaucoma patients found that 62.9% of patients had their acrophase during the nocturnal period; however, in the majority of patients this occurred significantly earlier than TED patients, between 1:00 am and 3:00 am.11,12 B Mottet et al. (pers. comm., 2012) evaluated 24-h IOP in 10 healthy subjects at four visits using the CLS and non-contact tonometry. They reported a mean acrophase at 7:35 a.m. Although the most significant contributor to a nocturnal acrophase is believed to be
the recumbent position assumed during sleep,18,19 advancing age and alterations in hormonal and neural activity influence the 24-h IOP rhythm.18 When comparing the late morning acrophase found in this group of TED patients with the results of the aforementioned studies, TED 24-h IOP rhythm patterns are closer to those of healthy subjects than to glaucoma patients. It has been previously shown that IOP increases when individuals go from W/S to S/S and decreases when patients go from S/S to W/S.17,18 To study this change, linear slopes were constructed from 1 h before sleep to 2 h into sleep, and from 1 h before awakening to 1 h after awakening. In previous studies done on untreated glaucoma and healthy patients, a statistically significant positive linear slope for the transition into sleep was found.12 In this group of TED patients, however, the wake to sleep transition was not statistically significant. At the transition from S/S to W/S, however, there was a significant decrease of the CLS signal (−62.9 ± 56.8 a.u.; P = 0.010). This finding could indicate a potentially altered circadian outflow mechanism in TED patients. We speculate that this difference in TED patients may also be a result of increased orbital congestion and retrobulbar tension. When evaluating the before and after recordings of the three patients who underwent orbital decompression, we observed a borderline increase of the W/S slope (P = 0.06). These findings are suggestive of the re-establishment of what has been postulated to be the physiological IOP pattern (e.g. IOP increase at transition to the S/S state),6 after orbital decompression possibly by lowering daytime IOPs due to less orbital congestion. This hypothesis, if confirmed in an adequately powered study, would be consistent with several other studies evaluating IOP before and after orbital decompression.2,20–23
© 2014 Royal Australian and New Zealand College of Ophthalmologists
24-hour pressures in thyroid eye disease Signal amplitude provides an indication of overall variability of IOP in the 24-h period adjusted for short-term artefacts. TED patients had amplitudes (102.2 ± 52.6 a.u.) similar to those found in glaucoma and glaucoma suspect patients On previously studied (143.6 ± 108.1 a.u.).11 average, TED patients had 13.7 ± 2.8 peaks during the 24-h period, similar to untreated (15.0 ± 4.1) and treated glaucoma patients (14.9 ± 3.4) (K Mansouri, unpublished data, 2012). This study is limited by several factors. The study size was small, and there was no control group. Patients had various amounts of disease activity in terms of both orbitopathy and systemic disease. There were differing amounts of orbital congestion and subsequent exophthalmos as well. Long-term follow up and reproducibility of the patient recordings were not evaluated nor were correlations between IOP recordings and systemic medications, previous treatments and disease activity done. Also, because patients did not have elevated baseline IOPs, they may not be representative of those TED patients at risk of developing glaucoma. The interpretation of the results of this new technology has challenges. These include processing large amounts of data on continuous measurements that are collected over time compared with a single measurement obtained when using GAT. Another complicating factor is that the output signal is not displayed in millimetres of mercury but in an arbitrary unit (a.u.) proportional to the electric signal (in mV) generated by the contact lens-embedded strain gauge. At present, no calibration to mmHg is available for the CLS.11 Despite these challenges, the objective of the study was to assess the safety, tolerability and describe the IOP patterns of TED patients with the new CLS. The aim of the data collected here was not to verify or disprove previous studies describing the relationship between IOP and TED, but rather to provide new analyses and interpretation algorithms to personalize and potentially improve the management of patients with TED.24 In conclusion, the CLS provides a safe and welltolerated approach to 24-h IOP monitoring in TED patients. Findings from this study suggest that despite some similarities to circadian IOP patterns in both healthy subjects and glaucoma patients, TED patients may have distinctive circadian IOP patterns. Future studies are needed to evaluate the reproducibility of these results and associated clinical significance.
ACKNOWLEDGEMENTS The authors wish to thank Katherine Whipple, MD, Jeffrey Liu, MD, and Syril Dorairaj, MD for their assistance in data collection.
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REFERENCES 1. Nassr MA, Morris CL, Netland PA, Karcioglu ZA. Intraocular pressure change in orbital disease. Surv Ophthalmol 2009; 54: 519–44. 2. Danesh-Meyer HV, Savino PJ, Deramo V, Sergott RC, Smith AF. Intraocular pressure changes after treatment for Graves’ orbitopathy. Ophthalmology 2001; 108: 145– 50. 3. Gomi CF, Yates B, Kikkawa DO, Levi L, Weinreb RN, Granet DB. Effect on intraocular pressure of extraocular muscle surgery for thyroid-associated ophthalmopathy. Am J Ophthalmol 2007; 144: 654–7. 4. Konuk O, Onaran Z, Ozhan Oktar S, Yucel C, Unal M. Intraocular pressure and superior ophthalmic vein blood flow velocity in Graves’ orbitopathy: relation with the clinical features. Graefes Arch Clin Exp Ophthalmol 2009; 247: 1555–9. 5. Kikkawa DO, Cruz RC Jr, Christian WK et al. Botulinum A toxin injection for restrictive myopathy of thyroid-related orbitopathy: effects on intraocular pressure. Am J Ophthalmol 2003; 135: 427–31. 6. Liu JH, Weinreb RN. Monitoring intraocular pressure for 24 h. Br J Ophthalmol 2011; 95: 599–600. 7. Mansouri K, Shaarawy T. Continuous intraocular pressure monitoring with a wireless ocular telemetry sensor: initial clinical experience in patients with open angle glaucoma. Br J Ophthalmol 2011; 95: 627–9. 8. Mansouri K, Weinreb R. Continuous 24-hour intraocular pressure monitoring for glaucoma – time for a paradigm change. Swiss Med Wkly 2012; 142: w13545. 9. Leonardi M, Pitchon EM, Bertsch A, Renaud P, Mermoud A. Wireless contact lens sensor for intraocular pressure monitoring: assessment on enucleated pig eyes. Acta Ophthalmol 2009; 87: 433–7. 10. Leonardi M, Leuenberger P, Bertrand D, Bertsch A, Renaud P. First steps toward noninvasive intraocular pressure monitoring with a sensing contact lens. Invest Ophthalmol Vis Sci 2004; 45: 3113–7. 11. Mansouri K, Liu JH, Weinreb RN, Tafreshi A, Medeiros FA. Analysis of continuous 24-hour intraocular pressure patterns in glaucoma. Invest Ophthalmol Vis Sci 2012; 53: 8050–6. 12. Mansouri K, Medeiros FA, Tafreshi A, Weinreb RN. Continuous 24-hour monitoring of intraocular pressure patterns with a contact lens sensor: safety, tolerability, and reproducibility in patients with glaucoma. Arch Ophthalmol 2012; 130: 1534–9. 13. Liu JH, Kripke DF, Hoffman RE et al. Nocturnal elevation of intraocular pressure in young adults. Invest Ophthalmol Vis Sci 1998; 39: 2707–12. 14. De Smedt S, Mermoud A, Schnyder C. 24-hour intraocular pressure fluctuation monitoring using an ocular telemetry sensor: tolerability and functionality in healthy subjects. J Glaucoma 2012; 21: 539–44. 15. Lorenz K, Korb C, Herzog N et al. Tolerability of 24-hour intraocular pressure monitoring of a pressuresensitive contact lens. J Glaucoma 2013; 22: 311–6. 16. Barkana Y, Anis S, Liebmann J, Tello C, Ritch R. Clinical utility of intraocular pressure monitoring outside of
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Parekh et al. normal office hours in patients with glaucoma. Arch Ophthalmol 2006; 124: 793–7. Liu JH, Zhang X, Kripke DF, Weinreb RN. Twentyfour-hour intraocular pressure pattern associated with early glaucomatous changes. Invest Ophthalmol Vis Sci 2003; 44: 1586–90. Mansouri K, Weinreb RN, Liu JH. Effects of aging on 24-hour intraocular pressure measurements in sitting and supine body positions. Invest Ophthalmol Vis Sci 2012; 53: 112–6. Friberg TR, Sanborn G, Weinreb RN. Intraocular and episcleral venous pressure increase during inverted posture. Am J Ophthalmol 1987; 103: 523–6. Dev S, Damji KF, DeBacker CM, Cox TA, Dutton JJ, Allingham RR. Decrease in intraocular pressure after
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orbital decompression for thyroid orbitopathy. Can J Ophthalmol 1998; 33: 314–9. Ohtsuka K. Intraocular pressure and proptosis in 95 patients with Graves ophthalmopathy. Am J Ophthalmol 1997; 124: 570–2. Kalmann R, Mourits MP. Prevalence and management of elevated intraocular pressure in patients with Graves’ orbitopathy. Br J Ophthalmol 1998; 82: 754–7. Adenis JP, Robert PY, Lasudry JG, Dalloul Z. Treatment of proptosis with fat removal orbital decompression in Graves’ ophthalmopathy. Eur J Ophthalmol 1998; 8: 246–52. Mansouri K, Medeiros FA, Tafreshi A, Weinreb RN. Validity of the results of a contact lens sensor? – reply. JAMA Ophthalmol 2013; 131: 697–8.
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Clinical and Experimental Ophthalmology 2015; 43: 108–114 doi: 10.1111/ceo.12400
Original Article Twenty-four-hour intraocular pressure patterns in patients with thyroid eye disease Anjali S Parekh MD,1 Kaweh Mansouri MD MPH,1,2 Robert N Weinreb MD,1 Ali Tafreshi BS,1 Bobby S Korn MD PhD3 and Don O Kikkawa MD3 1
Hamilton Glaucoma Center, Shiley Eye Center, and 3Division of Ophthalmic Plastic and Reconstructive Surgery, Department of Ophthalmology, University of California, San Diego, La Jolla, California, USA; and 2Glaucoma Sector, Department of Ophthalmology, University of Geneva, Geneva, Switzerland
ABSTRACT
(50%), conjunctival hyperaemia (100%) and superficial punctate keratitis (20%). Tolerability of the lens was found to be 1.5 ± 0.7. Positive linear slopes of the CLS signal from wake to sleep were detected (18.0 ± 43.8 arbitrary units [a.u.]; P = 0.254), whereas at the transition from S/S to W/S a significant decrease (−62.9 ± 56.8 a.u.; P = 0.010) was found. Five patients (50%) had a significant nocturnal/sleep acrophase with the peak occurring at 6:30 a.m. The mean amplitude of the 24-h curves was 102.2 ± 52.6 a.u.
Background: To prospectively investigate the safety, tolerability and 24-h intraocular pressure (IOP) patterns in patients with thyroid eye disease (TED) using a contact lens sensor (CLS). Design: Prospective study. Participants: Ten patients with established TED. Methods: Ten eyes of 10 patients were prospectively evaluated in an ambulatory 24-h IOP monitoring session using the CLS (Sensimed AG, Lausanne, Switzerland). Patients pursued daily activities, and sleep behaviour was uncontrolled. Main Outcome Measures: Incidence of adverse events (AEs) and tolerability (scale of 0–10, increasing intolerance) were assessed. IOP patterns were evaluated using a cosinor rhythmometry model, and linear regression slopes were constructed for the transition from wake/sitting (W/S) to sleep/supine (S/S) and vice versa. Results: Mean age was 61.8 ± 21.6 years, and 90% of patients were female. Main AEs were blurred vision
Conclusions: In patients with TED, the CLS provides a safe and well-tolerated approach to 24-h IOP monitoring. After modelling the 24-h IOP curves, TED patients were found to have a morning acrophase. Key words: contact lens sensor, glaucoma, intraocular pressure, thyroid eye disease.
INTRODUCTION Thyroid eye disease (TED) is an autoimmune manifestation commonly associated with Graves’ disease. Collections of mucopolysaccharides and lymphocytes infiltrate extraocular muscles, depositing
■ Correspondence: Dr Kaweh Mansouri, Glaucoma Sector, Department of Ophthalmology, Geneva University Hospital, 22, Rue Alcide Jentzerch-1211 Geneva 14, Switzerland. Email: [email protected] Received 14 December 2013; accepted 15 July 2014. Competing/conflicts of interest: No stated conflict of interest. Funding sources: Supported by Sensimed AG (Lausanne, Switzerland), an unrestricted grant from Research to Prevent Blindness (New York, NY) and Velux Foundation (Zurich, Switzerland). Financial disclosures: AS Parekh: none; K Mansouri: Sensimed AG (C); RN Weinreb: Carl Zeiss Meditec (F, C), Heidelberg Engineering GmbH (F), Nidek (F), Optovue (F), Topcon Medical Systems (F,C), Sensimed G (C); A Tafreshi: Heidelberg Engineering GmbH (F); BS Korn: none; DO Kikkawa: none. Trial was registered at www.clinicaltrials.gov (NCT01798966). © 2014 Royal Australian and New Zealand College of Ophthalmologists
24-hour pressures in thyroid eye disease glycosaminoglycans and collagen within orbital tissues.1 This infiltrative process can lead to proptosis, diplopia, ocular surface disease, optic neuropathy, strabismus and, in some patients, elevated intraocular pressure (IOP).2 Elevated IOP in TED can be caused by restriction and compression of the globe by enlarged extraocular muscles,3 elevated episcleral venous pressure due to reduction of orbital venous drainage4 and increased mucopolysaccharide deposition in the trabecular meshwork decreasing aqueous outflow.2 It has been suggested that IOP measurements in this group can be altered when using traditional Goldmann applanation tonometry (GAT) due to the force generated in moving eyes into gaze positions opposite that of fibrotic and restricted extraocular muscles.5 Several studies have evaluated the relationship between TED and elevated IOP; however, to date no study has looked at 24-h rhythms in these patients. In the past, obtaining 24-h IOP data required frequent awakening of patients during sleep, thus inducing a potentially significant bias in IOP measurements.6 Recently, a contact lens sensor (CLS), which uses a novel approach to IOP monitoring, allows for observation of IOP patterns in ambulatory conditions and during undisturbed sleep.7,8 The purpose of this study was to prospectively investigate the safety and tolerability of the CLS in patients with TED and describe the 24-h IOP patterns obtained from this group of patients.
METHODS This study followed the tenets of the Declaration of Helsinki and was approved by the University of California at San Diego, Human Research Protections Program/Institutional Review Board. Informed written consent was obtained from all patients.
109 at the time of CLS placement and removal. Collected data included demographic information, medical and surgical history, systemic and ophthalmic medication, best-corrected visual acuity, slit-lamp examination, fundus examination, tear break-up time, keratometry, pachymetry, corneal biomechanical properties, corneoscleral profile evaluation, exophthalmometry and GAT (average of two measurements). The CLS was placed on the study eye (which was determined to be the patient’s more proptotic eye based on exophthalmometry readings), and 24-h IOP monitoring was started in an ambulatory setting. At 5 and 30 min after CLS placement, the fitting of the CLS was evaluated with regards to centring and mobility with blinking, and during push-up manoeuvre. Patients were provided with a standardized activity diary for half-hourly recording of information on sleep and wakefulness times, intake of medications and meals, physical activity, emotional status and other events. After 24 h, the CLS was removed and data from the portable recorder were transferred to a computer. The activity diary was collected, and an ophthalmologic examination was performed. Prior to removing the CLS, patients were asked to score their subjective comfort level using a number between 0 and 10 with values ranging from 0 (no discomfort) to 10 (very severe discomfort). Any change from baseline in relevant ocular parameters (visual acuity, conjunctival hyperaemia, ocular surface changes, discomfort and device intolerance) was defined as an adverse event (AE). Each recorded AE was characterized as mild, moderate or severe. Mild changes were characterized as alterations from baseline that resolved without the need for intervention, whereas moderate and severe AEs were those that required medical treatments.
Study population
Instrumentation
Ten eyes of 10 patients recruited from the Shiley Eye Center Thyroid Eye Clinic, Department of Ophthalmology, University of California, San Diego, were included in the study. Patients were enrolled in the study if they were between 18 and 90 years of age and were diagnosed with TED based on serum autoimmune dysfunction consistent with Graves’ disease as well as orbital imaging studies manifesting characteristics consistent with TED. Patients were excluded if they had contraindications for contact lens wear, severe ocular surface disease, keratoconus or other corneal ectasia, severe ocular inflammation, or known hypersensitivity to silicone, plaster or ocular anaesthesics. After enrolment in the study, patients underwent a comprehensive ophthalmologic examination both
The CLS (SENSIMED Triggerfish®, Sensimed AG, Lausanne, Switzerland) consists of a highly oxygenpermeable soft contact lens (SCL). It is approved for clinical use in Europe (CE mark) but only admitted for investigational use in the United States. The device is based on a novel approach to IOP monitoring, in which changes in corneal curvature and circumference are assumed to correspond to changes in IOP.9,10 A microprocessor embedded in the contact lens sends an output signal proportional to the contact lens strain gauge. Wireless power and data transfer are achieved using a patched periorbital antenna from where a cable is connected to a portable recorder. The device can record the IOP pattern for up to 24 h and remains active during undisturbed sleep. Three hundred data points are acquired during
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Parekh et al. acrophase: peak occurring during the nocturnal/ sleep period; and (iii) no significant acrophase: if at least one parameter from the model equation (i.e. one of the sine or cosine parameters or the intercept) did not have a significant influence on the dependent variable.12
Statistical analysis
Figure 1. Photograph of a patient after contact lens sensor (CLS) placement with the surrounding antenna for data transmission and power transfer.
a 30-s measurement period, repeated every 5 min. The output of the sensor is expressed in arbitrary units (a.u.) proportional to the electric signal corresponding to milliVolts generated by the contact lensembedded strain gauge. The device is described in more detail elsewhere (Fig. 1).7,11,12
Modelling of circadian IOP patterns Mathematical estimation of the circadian IOP rhythms was done using the cosinor rhythmometry method, which uses sine and cosine terms. The circadian IOP rhythm model resembles a cosine profile, and different formulations of it have previously been used to express 24-h IOP variations.13 The model can be written as follows: y(t) = b0 + b1 × cos ([2Π/24] × t) + b2 × sin([2Π/24] × t), where y is the observed signal in a.u. at time t, and b0, b1 and b2 are regression coefficients, estimated from the data. The periodicity of the 24-h IOP pattern is represented by the constant (2Π/24). Unbiased estimates and confidence limits of amplitude, mesor (mean) and acrophase (time of peak value) were obtained from the individual waveforms. The amplitude was defined as half the distance between the cosine-fit maximum and minimum. It represents the parameter estimate of the variation for the 24-h period. The clock time of the acrophase represents the phase timing of the rhythm. Nocturnal/sleep periods were defined through the observation of blink cessation (identified as short and high-amplitude spikes that are displayed by the software) on the CLS signal using the software zoom function and were confirmed using individual diaryreported sleep times. Patients were then classified into pattern groups based on the following definitions: (i) diurnal acrophase: peak occurring during the diurnal/wakefulness period; (ii) nocturnal
Data are expressed as mean ± standard deviation where appropriate. Categorical variables are described in terms of frequencies and percentages. The distribution of all variables was examined using the Shapiro–Wilk test of normality. Safety endpoints included the incidence of AEs and the tolerability level at each session. To assess the degree of change in CLS output over time, a regression was fit to each patient’s data from 1 h before going to sleep to 2 h into sleep and from 1 h before sleep to the end of the sleep period. The regression allowed for linear trends to be modelled. The linear slopes were tested for significance using a paired t-test. To assess the circadian rhythm of IOP patterns, a cosinor rhythmometry model, as described above, was adapted to CLS data.11 All hypothesis testing was two sided, at two-sided alpha = 0.05. All analyses were conducted using SAS Version 9.2 or higher (SAS Inc, Cary, NC, USA).
RESULTS Complete 24-h recordings were available from all 10 eyes of 10 TED patients. Three patients underwent scheduled orbital decompression for cosmetic disfigurement on the studied eye, and recordings were repeated after surgical recovery. The mean age of patients was 61.8 ± 21.6 years with a range of 21– 83 years. There were nine females and one male. Seven were Caucasian, one an Asian and two were Hispanic. Four patients had ocular alignment problems (three patients with hypertropia and one with esotropia) at the time of monitoring, and the average exophthalmometry measurements were 23.2 ± 3.3 mm. Table 1 provides an overview of clinical parameters at baseline. The safety and tolerability analysis included all 10 eyes. The mean length of CLS wear was 23.8 ± 0.4 h. The most frequent AEs were mild blurred vision (five patients, 50%), mild hyperaemia of the bulbar and palpebral conjunctiva (10 patients, 100%) and superficial punctate keratitis (two patients, 20%). There were no other complications associated with the device. All AEs were transient and resolved after CLS removal. There were no serious AEs and no safety issues in the fellow eye. On average, patients reported a tolerability level of 1.5 ± 0.7 (Table 2).
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Table 1. Clinical characteristics at baseline (values represent mean ± standard deviation) Parameter Age Ancestry Caucasian Asian Hispanic BCVA, decimal Objective refraction, D Sphere CCT, μm Baseline IOP, mmHg Strabismus Hypertropia Esotropia Average exopthalmometry measurements, mm
61.8 ± 21.6 7 (70%) 1 (10%) 2 (20%) 0.8 ± 0.3 −1.8 ± 3.4 524.8 ± 58.9 18.1 ± 3.5 4 (40%) 3 (75%) 1 (25%) 23.2 ± 3.3
BCVA, best-corrected visual acuity; CCT, central corneal thickness; D, dioptres; IOP, intraocular pressure. Table 2. Adverse events in 10 patients undergoing 24-h IOP monitoring with the CLS Adverse event
Events (n); Patients (n), (%)
Mild Blurred vision 5; 10 (50.0%) Conjunctival hyperaemia 10; 10 (100.0%) Eye complication associated with device 0; 10 (0.0%) Superficial punctate keratitis 2; 10 (20.0%) Ocular discomfort 0; 10 (0.0%) Device intolerance 0; 10 (0.0%) CLS, contact lens sensor; IOP, intraocular pressure.
The correlation between CLS measurements and values predicted from cosinor fitting was r = 0.64 (Spearman’s correlation). When evaluating the entire study group, this model overall indicated a nocturnal/sleep acrophase, with the peak occurring at 06:30 a.m. (Fig. 2). Specifically, five patients (50%) had a significant nocturnal/sleep acrophase, whereas two (20%) patients had a significant diurnal acrophase, and the remainder (30%) had no significant acrophase. The mean amplitude of the 24-h curves was 102.2 ± 52.6 a.u. To study the CLS signal change from the wake/ sitting (W/S) to the sleep/supine (S/S) state and vice versa, linear regressions were fitted to the transition from the wake to the sleep period. On average, linear slopes from 1 h before sleep to 2 h into sleep (18.0 ± 43.8 a.u.; P = 0.254) and to the end of the sleep period were not statistically significant (9.6 ± 84.4 a.u.; P = 0.741), indicating a weak elevation of IOP at the sleep–wake transition. At the morning transition from S/S to W/S, however, there was a significant decrease of the CLS signal
(−62.9 ± 56.8 a.u.; P = 0.010). IOP peaks were defined as an increase in the CLS signal of over 90 a.u. and lasting for more than 30 min. On average, patients had 13.7 ± 2.8 peaks over the 24-h period, with 9.1 ± 3.1 during the wake and 5.2 ± 1.6 during the sleep period (P = 0.02). For three patients with repeated CLS monitoring after orbital decompression surgery, exophthalmometry measurements decreased by 3.75 ± 0.35 mm. When evaluating linear slope changes, these patients had preoperative W/S S/S slopes (2 h into sleep) of 27.2 ± 26.3 a.u. (P = 0.216) that changed to 37.2 ± 22.7 a.u. (P = 0.105) postoperatively (P = 0.06). The morning transition of S/S to W/S slopes was –64.8 ± 26.2 a.u. (P = 0.050) and −28.2 ± 78.3 a.u. (P = 0.597), respectively (P = 0.041).
DISCUSSION In the current study, we have demonstrated that the CLS is a safe and well-tolerated device in patients with TED. This is notable given that these patients are more proptotic and theoretically more susceptible to contact lens-related problems. All 10 study patients were able to undergo the full cycle of 24-h monitoring with the CLS without requiring removal or interruption. The safety profile in this cohort of TED patients was similar, if not better than previously reported in healthy subjects and glaucoma patients. Mansouri and Shaarawy7 described initial clinical experience with the first-generation CLS in 15 glaucoma patients. They reported one case of corneal erosion (7%) and four cases of superficial punctate keratitis (27%). These findings were later confirmed by De Smedt et al.14 in 10 healthy subjects. In their cohort, three subjects (30%) had corneal micro-erosion s that were treated prophylactically with antibiotic eyedrops. Lorenz et al.15 evaluated safety of CLS wear in a mixed group of healthy subjects and glaucoma patients, and found a statistically significant difference in conjunctival oedema, conjunctival erythema, epithelial micro-erosions and lid oedema before and after CLS wear. However, these differences were not statistically significant when the study eyes and the fellow eyes were compared.15 Our group has previously studied the safety of repeated use of the current generation of CLS in glaucoma patients.12 We found that 82.5% of patients reported some degree of blurred vision, whereas 80% had hyperaemia of the bulbar and palpebral conjunctiva, and 15% had superficial punctate keratitis. With an average comfort value of 1.5, we found that CLS was well tolerated in these patients.7 CLS tolerability in TED patients was similar if not slightly better than the tolerability previously reported in both healthy patients14 and glaucoma patients.12 The similarities in safety and tolerability,
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600 550 500 450 400 350 300 250 200 150 100 50 0 –50 –100 –150 –200 –250 09:00 12:00 15:00 18:00 21:00 00:00 03:00 06:00 09:00 12:00 15:00 Time Observed CLS
Figure 2. An example of a patient’s raw 24-h contact lens sensor (CLS) data (blue line) and the superimposed cosinor modeling (red line). The peak acrophase for this recording is seen at 6:30 a.m.
Fitted CLS
particularly compared with previously studied glaucoma patients, is not surprising as both TED and glaucoma patients are known to have some degree of ocular surface disease. In glaucoma, ocular surface disease is pharmacologic whereas in TED it is usually secondary to exposure. As a result, these patients may not feel significantly different from their baseline when the CLS is placed in the eye. Tolerability of the CLS in TED patients is of significant practical importance. In the past, a significant limitation of studying IOP in TED patients was related to the fact that traditional GAT measurements can be altered because of the force required to move eyes into primary position, and currently no standardized technique for IOP measurements has been established. Furthermore, single IOP measurements may fail to reflect a patient’s true IOP range.16,17 By using a methodology based on 288 continuous 30-s measurements over 24 h, the CLS significantly minimizes the impact of measurement error of single measurements. Moreover, because the CLS follows all eye movement, gaze position may be is of less significance. Characterization of the 24-h IOP monitoring with the cosinor rhythmometry model showed that one half of the patients had their acrophase during the nocturnal/sleep period. On average, the acrophase occurred at 6:30 a.m. in TED patients. A previous study evaluating 24-h IOP in glaucoma patients found that 62.9% of patients had their acrophase during the nocturnal period; however, in the majority of patients this occurred significantly earlier than TED patients, between 1:00 am and 3:00 am.11,12 B Mottet et al. (pers. comm., 2012) evaluated 24-h IOP in 10 healthy subjects at four visits using the CLS and non-contact tonometry. They reported a mean acrophase at 7:35 a.m. Although the most significant contributor to a nocturnal acrophase is believed to be
the recumbent position assumed during sleep,18,19 advancing age and alterations in hormonal and neural activity influence the 24-h IOP rhythm.18 When comparing the late morning acrophase found in this group of TED patients with the results of the aforementioned studies, TED 24-h IOP rhythm patterns are closer to those of healthy subjects than to glaucoma patients. It has been previously shown that IOP increases when individuals go from W/S to S/S and decreases when patients go from S/S to W/S.17,18 To study this change, linear slopes were constructed from 1 h before sleep to 2 h into sleep, and from 1 h before awakening to 1 h after awakening. In previous studies done on untreated glaucoma and healthy patients, a statistically significant positive linear slope for the transition into sleep was found.12 In this group of TED patients, however, the wake to sleep transition was not statistically significant. At the transition from S/S to W/S, however, there was a significant decrease of the CLS signal (−62.9 ± 56.8 a.u.; P = 0.010). This finding could indicate a potentially altered circadian outflow mechanism in TED patients. We speculate that this difference in TED patients may also be a result of increased orbital congestion and retrobulbar tension. When evaluating the before and after recordings of the three patients who underwent orbital decompression, we observed a borderline increase of the W/S slope (P = 0.06). These findings are suggestive of the re-establishment of what has been postulated to be the physiological IOP pattern (e.g. IOP increase at transition to the S/S state),6 after orbital decompression possibly by lowering daytime IOPs due to less orbital congestion. This hypothesis, if confirmed in an adequately powered study, would be consistent with several other studies evaluating IOP before and after orbital decompression.2,20–23
© 2014 Royal Australian and New Zealand College of Ophthalmologists
24-hour pressures in thyroid eye disease Signal amplitude provides an indication of overall variability of IOP in the 24-h period adjusted for short-term artefacts. TED patients had amplitudes (102.2 ± 52.6 a.u.) similar to those found in glaucoma and glaucoma suspect patients On previously studied (143.6 ± 108.1 a.u.).11 average, TED patients had 13.7 ± 2.8 peaks during the 24-h period, similar to untreated (15.0 ± 4.1) and treated glaucoma patients (14.9 ± 3.4) (K Mansouri, unpublished data, 2012). This study is limited by several factors. The study size was small, and there was no control group. Patients had various amounts of disease activity in terms of both orbitopathy and systemic disease. There were differing amounts of orbital congestion and subsequent exophthalmos as well. Long-term follow up and reproducibility of the patient recordings were not evaluated nor were correlations between IOP recordings and systemic medications, previous treatments and disease activity done. Also, because patients did not have elevated baseline IOPs, they may not be representative of those TED patients at risk of developing glaucoma. The interpretation of the results of this new technology has challenges. These include processing large amounts of data on continuous measurements that are collected over time compared with a single measurement obtained when using GAT. Another complicating factor is that the output signal is not displayed in millimetres of mercury but in an arbitrary unit (a.u.) proportional to the electric signal (in mV) generated by the contact lens-embedded strain gauge. At present, no calibration to mmHg is available for the CLS.11 Despite these challenges, the objective of the study was to assess the safety, tolerability and describe the IOP patterns of TED patients with the new CLS. The aim of the data collected here was not to verify or disprove previous studies describing the relationship between IOP and TED, but rather to provide new analyses and interpretation algorithms to personalize and potentially improve the management of patients with TED.24 In conclusion, the CLS provides a safe and welltolerated approach to 24-h IOP monitoring in TED patients. Findings from this study suggest that despite some similarities to circadian IOP patterns in both healthy subjects and glaucoma patients, TED patients may have distinctive circadian IOP patterns. Future studies are needed to evaluate the reproducibility of these results and associated clinical significance.
ACKNOWLEDGEMENTS The authors wish to thank Katherine Whipple, MD, Jeffrey Liu, MD, and Syril Dorairaj, MD for their assistance in data collection.
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