Twenty-four hours intraocular pressure in keratoconic eyes assessed by applanation tonometry and Tono-Pen AVlA

INTRODUCTION

It is established that elevated intraocular pressure (IOP)is the main risk factor for the onset and progression of primary open angle glaucoma (POAG). Advanced Glaucoma Intervention Study (AGIS) demonstrated that longterm IOP changes are related to the progressive visual field deterioration in patients with low mean IOP measurements, but not in patients with high mean IOP measurements.

It is broadly accepted that IOP varies according to a 24-hour cycle. For some authors, the daily curve of intraocular pressure(DCPo) based on IOP measurements acquired by applanation tonometry at 6:00, in the dark, with the patient lying down in bed, is very important in establishing the diagnosis of glaucoma suspect and assessing IOP in glaucoma.Keratoconus is an ectatic corneal disease, with noninflammatory progressive thinning and anterior projection that results in an irregular conical shape. It is an asymmetrical bilateral condition that appears at youth. Topographic (inferior steepening, inferior-superior asymmetry, and irregular astigmatism) and clinical (conical protrusion, corneal stromal thinning, Fleischer ring and Vogt striae) signals are commonly considered together for staging and diagnosing the disorderEmerging ocular imaging technologies, such as Pentacam(Oculus Inc, Wetzlar, Hesse, Germany), have yielded precious information with regards to corneal and anterior ocular segment assessment.Diagnosing keratoconus has been refined by corneal pachymetric arrangement, curvature (elevation)maps, corneal volume and anterior segment information, all of which have been generated using a variety of currently available equipment.Proper IOP measurement is essential to the follow-up treatment and diagnosis of glaucoma. Goldmann applanation tonometer (GAT) is the gold standard method for IOP measurement. But, it might be interfered by variations in corneal thickness, structure, and curvature. Corneal alterations due to keratoconus may probably lead to inaccurate determining IOP in this status. Prior researchers have demonstrated that GAT tends to under evaluate IOP in keratoconic patients primarily because of differences in the cornea’s biomechanical properties and characteristically reduced corneal thickness. And also, some studies showed evidence that the IOP values of the dynamic contour tonometry(DCT) and a corneal-compensated IOP value (IOPcc) obtained by the ocular response analyzer (ORA) are less influenced by central corneal thickness (CCT) than GAT measurement,and should be considered more suitable to evaluate IOP in keratoconus.

Multiple linear regression models were built using TPA IOP as the dependent variable and covariates (cGAT, nGAT,Pentacam parameters: corneal astigmatism, maximum Ambrosio relational thickness (ART-Max), Belin/Ambrosio enhanced ectasia total deviation value (BAD-D), anterior chamber depth (ACD) as independent variables; since all of them expressed a-value<0.05 in univariate analysis. In order to account for multicollinearity stepwise regression was used,which is a combination of forward and backward selection techniques. In stepwise regression, all variables are checked at each step to see if their significance has been reduced below a certain point. Variables with a-value less than 0.05 are included in the model whereas if-value goes above 0.1 the variable is removed. Seeking to find the model with the greatest generalization capacity, five-fold cross-validation was used. Using the K-fold averaging cross-validation model selection procedure yielded the following equation:TPA IOP=5.49+0.775×cGAT-0.015×ACD-0.299×corneal astigmatism with an average2 of 0.708 (95%CI 0.686 to 0.730), which means that these 3 covariates account for an average of 70.8% of the variance in TPA IOP.

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SUBJECTS AND METHODS Ethical Approval Keratoconi

c patients attended at S?o Geraldo Eye Hospital were included. Written informed consent was acquired from all patients, and investigation that acceded to the tenets of the Declaration of Helsinki started after the approval of the protocol by Ethics Committee of Federal University of Minas Gerais. All participants underwent a detailed ophthalmologic examination.

As far as we are aware, this is the first study to investigate changes in IOP during DCPo in keratoconic eyes, obtaining cGAT, nGAT and TPA IOP profiles, and also to assess correlations among these IOP measurements. Even though irregular corneas could interfere in IOP applanation measurements, we decided to use GAT, Perkins and TPA due to the fact that with them we were able to perform IOP 6:00measurement with the patient lying down in bed and in the dark. Although the IOP values of DCT and IOPcc values obtained by ORA are less influenced by CCT than GAT measurement, and should be considered more suitable to evaluate IOP in keratoconus, is technically impracticable to perform all measurements of the DCPo with these instruments.Iwaszkiewiczassessed IOP diurnal fluctuations of 73 keratoconic eyes, however, he used a pneumotonometer, and IOP at 6:00was not evaluated. In fact, the author took IOP measurements only from 7:00to 10:00He found the mean upper value of 19.24±2.84 mm Hg for right eye and 18.06±2.80 mm Hg for left eye. These values are higher than our mean IOP values, and means oscillation of IOP in a day equalized 7.00±2.41 mm Hg in the right eye and 6.00±2.38 mm Hg in the left eye, also higher than our findings. However, there are few reports using pneumotonometer, mainly in keratoconus, so it is difficult to know how accurate it would be in DCPo.

DCPo are described in Table 2. IOP mean at 6:00was higher than the other 4 DCPo measurements in all methods used of IOP assessment (cGAT, nGAT and TPA). Comparisons of mean DCPo values between cGAT-nGAT, cGAT-TPA,and nGAT-TPA are shown in Figures 1 and 2, and Table 3. We found that cGAT IOP DCPo mean was higher than nGAT (difference of 1.32±1.31;<0.01) and lower than TPA (difference of -1.02±2.08;=0.004), so DCPo was underestimated by nGAT and overestimated by TPA with a difference statistically significant. Moreover, nGAT was overestimated by TPA (-2.35±2.23;<0.01) with statistically significant difference (Table 3).

Each subject underwent a DCPo which was comprised of 5 IOP measurements; 4 performed with GAT (Haag-Streit,Harlow, Essex, United Kingdom) and TPA at 9:00 and 11:00, 6:00 and 10:00and in the morning of the next day at 6:00with patient lying down in bed and in the dark and before they had become erected when applanation tonometry measurement was done with Perkins applanation tonometer (Haag-Streit, Harlow, Essex, United Kingdom)followed by TPA. Considering irregular corneal astigmatism in keratoconic eyes, the prism red line of the applanation tonometer (GAT or Perkins tonometer) was placed at prism degree mark corresponding to the flattest meridian (minus cylinder) to correct intraocular pressure measurement (cGAT)of each patient; also, measurement without that astigmatism correction was done (nGAT). All IOP measurements were performed by one glaucoma specialist (Cronemberger S)and registered by another (Veloso AW). The IOP was taken sequentially with nGAT, followed by cGAT and TPA with an interval of three minutes among them. GAT was performed after a drop of 0.5% proxymetacaine hydrochloride followed by a drop of 0.25% fluorescein sodium instillation. Using TPA,10 IOP measurements were obtained with accuracy of at least 95%.

國有企業屬于股份制企業，企業的大部分控制權掌握在股東手中。由于溝通渠道廣泛，人力資源豐富，“法人”管理多家企業，這樣的管理模式導致管理不善，運行困難，無法保障少數股東的權力。同時，監事會和董事會的職責也沒有明確界定。

All statistical analyses were performed with software R version 4.0.3 (The R foundation) and SPSS Version 21 (IBM Corp., Armonk, NY, USA). Pearson correlation coefficients were calculated to report the power of linear relationship among IOP values. Anvalue of >0.5 revealed moderate significance. An evaluation of Bland-Altman correspondence was used to compare GAT and TPA values.An extent of accordance was determined as mean±2 standard deviation.

As demonstrated by some studies, appropriate IOP assessment with its measurement taken with an applanation tonometer at 6:00in bed and in the dark before the patient became erected is essential to detect IOP peaks. As a matter of fact,our study is the first to investigate IOP keratoconus peak in this way, and we found the highest DCPo mean values at 6:00independently of the way used to measure IOP (cGAT 15.0±3.8 mm Hg, nGAT 12.5±3.1 mm Hg, TPA 14.3±3.3 mm Hg).Normal and abnormal DCPo values have already been established in previous study. The normal superior value for mean IOP and variability were 14.62 mm Hg and 2.28,respectively (age of patients from 15 to 25y), and 15.93 mm Hg and 2.28, respectively (age of patients from 26 to 35y), which implies that normal superior DCPo mean limits are 16.9 and 18.20 mm Hg for 15-25y and 26-35y respectively. In the present study, all mean IOP values were under normal limits.Highest mean IOP DCPo value was observed with TPA(12.3±3.1 mm Hg), and lowest with nGAT (9.9±2.6 mm Hg) in keratoconic eyes. However, at 6:00the highest IOP mean measurement was verified with cGAT (15.0±3.8 mm Hg).Therefore, in accordance with the normal superior DCPo IOP mean limits established, an IOP equal to or more than 17 mm Hg in keratoconic eyes would require glaucoma investigation with exams such as fundoscopy and optic coherence tomography.

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