ART vetenskapliga studier och publikationer. ART är CE-märkt och verifierad med utmärkt reslutat i ett stort antal studier och vetenskapliga publikationer.


New methods to evaluate the effect of conventional and modified crosslinking treatment for keratoconus
Beckman Rehnman, Jeannette
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)

Abstract [en]


Today corneal crosslinking with ultraviolet-A photoactivation of riboflavin is an established method to halt the progression of keratoconus. In some cases, when the refractive errors are large and the visual acuity is low, conventional corneal crosslinking may not be sufficient. In these cases it would be desirable with a treatment that both halts the progression and also reduces the refractive errors and improves the quality of vision.


The aims of this thesis were to determine whether mechanical compression of the cornea during corneal crosslinking for keratoconus using a sutured rigid contact lens could improve the optical and visual outcomes of the treatment, and also to find methods to evaluate the effect of different corneal crosslinking treatment regimens.


In a prospective, open, randomized case-control study, 60 eyes of 43 patients with progressive keratoconus, aged 18-28 years, planned for routine corneal crosslinking, and a corresponding age- and sex-matched control group was included. The patients were randomized to conventional corneal crosslinking (CXL; n=30) or corneal crosslinking with mechanical compression of the cornea during the treatment (CRXL; n=30).

Biomicroscopy, autorefractometry, best spectacle corrected visual acuity, axial length measurement, Pentacam® HR Scheimpflug photography, pachymetry, intraocular pressure measurements and corneal biomechanical assessments were performed before treatment (baseline) and at 1 month and 6 months after the treatment.

One of the articles evaluated and compared the optical and visual outcomes between CXL and CRXL, while the other three articles focused on methods to evaluate treatment effects. In Paper I, the corneal light scattering was manually quantified from Scheimpflug images throughout the corneal thickness at 8 measurements points, 0.0 to 3.0 mm from the corneal centre, in patients treated with CXL. In Paper IV the corneal densitometry (light scattering) was measured with the Pentacam® HR software, in 4 circular zones around the corneal apex and at 3 different depths of the corneal stroma, in both CXL and CRXL treated corneas. Paper III quantified the biomechanical effects of CXL in vivo.


Corneal light scattering after CXL showed distinctive spatial and temporal profiles and Applanation Resonance Tonometry (ART) -technology demonstrated an increased corneal hysteresis 1 and 6 months after CXL. When comparing the refractive and structural results after CXL and CRXL, CRXL failed to flatten the cornea, and the treatment did not show any benefits to conventional CXL treatment, some variables even indicated an inferior effect. Accordingly, the increase in corneal densitometry was also less pronounced after CRXL.


Analysis of corneal light scattering/densitometry shows tissue changes at the expected treatment location, and may be a relevant variable in evaluating the crosslinking effect. ART -technology is an in vivo method with the potential to assess the increased corneal hysteresis after CXL treatment. By refining the method, ARTmay become a useful tool in the future. Unfortunately, CRXL does not improve the optical and visual outcomes after corneal crosslinking. Possibly, stronger crosslinking would be necessary to stabilize the cornea in a flattened position.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2015. , 57 p.

Umeå University medical dissertations, ISSN 0346-6612 ; 1746


Keyword [en]

Keratoconus, crosslinking, light scattering, densitometry, keratometry, hysteresis, intraocular pressure


National Category

Research subject

URN: urn:nbn:se:umu:diva-110531ISBN: 978-91-7601-336-6OAI: diva2:862560


Public defence
2015-11-20, Hörsal 914, Unod B 9, Norrlands universitetssjukhus, Umeå, 09:00 (Swedish)


Hjortdal, Jesper, professor


Lindén, Christina, professor
Behndig, Anders, professor
Hallberg, Per, docent

Available from: 2015-10-30 Created: 2015-10-22 Last updated: 2015-10-30Bibliographically approved

List of papers
1. Spatial distribution of corneal light scattering after corneal collagen crosslinking
2. Initial results from mechanical compression of the cornea during crosslinking for keratoconus
3. Increased corneal hysteresis after corneal collagen crosslinking: a study based on applanation resonance technology
4. Treatment Effect and Corneal Light Scattering With 2 Corneal Cross-linking Protocols: A Randomized Clinical Trial



The pressure difference between eye and brain changes with posture


Artikel publicerad i en av världens mest ansedda vetenskapliga tidskrifter.


First published: 15 July 2016
DOI: 10.1002/ana.24713


Anders Eklund PhD, Gauti Jóhannesson MD, PhD, Elias Johansson MD, PhD, Petter Holmlund MSc, Sara Qvarlander PhD, Khalid Ambarki PhD, Anders Wåhlin PhD, Lars-Owe D. Koskinen MD, PhD, Jan Malm MD, PhD




The discovery of a posture-dependent effect on the difference between intraocular pressure (IOP) and intracranial pressure (ICP) at the level of lamina cribrosa could have important implications for understanding glaucoma and idiopathic intracranial hypertension and could help explain visual impairments in astronauts exposed to microgravity. The aim of this study was to determine the postural influence on the difference between simultaneously measured ICP and IOP.


Eleven healthy adult volunteers (age = 46 ± 10 years) were investigated with simultaneous ICP, assessed through lumbar puncture, and IOP measurements when supine, sitting, and in 9° head-down tilt (HDT). The trans–lamina cribrosa pressure difference (TLCPD) was calculated as the difference between the IOP and ICP. To estimate the pressures at the lamina cribrosa, geometrical distances were estimated from magnetic resonance imaging and used to adjust for hydrostatic effects.



The TLCPD (in millimeters of mercury) between IOP and ICP was 12.3 ± 2.2 for supine, 19.8 ± 4.6 for sitting, and 6.6 ± 2.5 for HDT. The expected 24-hour average TLCPD on earth—assuming 8 hours supine and 16 hours upright—was estimated to be 17.3mmHg. By removing the hydrostatic effects on pressure, a corresponding 24-hour average TLCPD in microgravity environment was simulated to be 6.7mmHg.


We provide a possible physiological explanation for how microgravity can cause symptoms similar to those seen in patients with elevated ICP. The observed posture dependency of TLCPD also implies that assessment of the difference between IOP and ICP in upright position may offer new understanding of the pathophysiology of idiopathic intracranial hypertension and glaucoma. Ann Neurol 2016;80:269–276


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Graefe's Archive for Clinical and Experimental Ophthalmology

November 2015, Volume 253, Issue 11, pp 1979-1983
First online: 13 August 2015

Age-dependency of ocular parameters: a cross sectional study of young and elderly healthy subjects


  • G. JóhannessonAffiliated withDepartment of Clinical Science, Ophthalmology, Umeå University Email author
  • , P. HallbergAffiliated withDepartment of Radiation Sciences, Umeå UniversityCentre for Biomedical Engineering and Physics, Umeå University
  • , K. AmbarkiAffiliated withDepartment of Radiation Sciences, Umeå UniversityCentre for Biomedical Engineering and Physics, Umeå University
  • , A. EklundAffiliated withDepartment of Radiation Sciences, Umeå UniversityCentre for Biomedical Engineering and Physics, Umeå University
  • , C. LindénAffiliated withDepartment of Clinical Science, Ophthalmology, Umeå University


To investigate the effect of aging on ocular parameters, including intraocular pressure (IOP), measured with different tonometry methods in healthy young (HY) and healthy elderly (HE) subjects and to study the effect of corneal parameters on tonometry methods.

In this prospective, cross-sectional study, fifty eyes of 50 HY subjects (28 females, 22–31 years of age) and 43 eyes of 43 HE subjects (22 females, 64–79) were included. IOP was measured with four tonometry methods in a standardized order: ocular response analyser (ORA), dynamic contour tonometry (DCT), applanation resonance tonometry (ART) and Goldmann applanation tonometry (GAT). Other measurements included axial length (AL), central corneal thickness (CCT), corneal curvature (CC), anterior chamber volume (ACV), corneal hysteresis (CH) and corneal resistance factor (CRF).

The mean IOP (HY/HE; mmHg ± standard deviation (SD)) was 12.2 ± 2.2/14.1 ± 3.5 with GAT. IOP was significantly higher (difference ± standard error) in HE compared to HY measured with an ORA (+3.1 mmHg ± 0.6), GAT (+1.9 ± 0.6) and DCT (+1.6 ± 0.6). No significant difference was found in IOP measured with ART. CH and ACV were significantly lower in HE compared to HY. There was no difference between the groups in CCT, CC, AL or CRF. No tonometry method was dependant on CCT or CC.

IOP measured with an ORA and via DCT and GAT was higher in HE compared to HY Swedish subjects, while IOP measured with ART did not differ between the groups. In these homogeneous groups, tonometry methods were independent of CCT and CC.

Intraocular pressure Age dependency Central corneal thickness Corneal curvature Ocular response analyser Dynamic contour tonometry Applanation resonance tonometry



BMC Ophthalmol. 2015; 15: 36.

Published online 2015 Apr 10. doi:  10.1186/s12886-015-0028-9

PMCID: PMC4409994


Repeatability and reproducibility of applanation resonance tonometry: a cross-sectional study

Laura Ottobelli Paolo Fogagnolo, Paolo Frezzotti, Stefano De Cillà, Elena Vallenzasca, Maurizio Digiuni, Ruggiero Paderni, Ilaria Motolese, Simone Alex Bagaglia, Eduardo Motolese, and Luca Rossetti



To assess repeatability (intra-observer variability) and reproducibility (inter-operator variability) of intraocular pressure (IOP) measurements with servo-controlled Bioresonator Applanation Resonance Tonometry (ART) and to evaluate possible influential factors.

The study included 178 patients (115 glaucoma and 63 controls; one eye per subject). IOP was measured once with a Goldmann applanation tonometer (GAT) and twice by ART (ART1, ART2), in randomized sequence, by a single operator to assess intra-operator variability. Each ART measurement consisted on 3 readings. To assess inter-operator variability 2 evaluators performed 2 measurements each (in random order) on the same patient. Repeatability and reproducibility were assessed by the coefficient of variation (CoV) and intraclass correlation coefficient (ICC).

In the entire cohort, ART1 was 0.4 ± 2.2 mmHg (-7.0 to 5.7 mmHg) higher than ART2 (p = 0.03) regardless of test order. Intra-operator CoV was 7.0% ± 6.3%, and ICC was 0.80-0.92. Inter-operator CoV ranged between 5.7% ± 6.1% and 8.2% ± 7.2%, and ICC between 0.86 and 0.97. ART1 and 2 were respectively 1.7 ± 3.1 and 1.3 ± 3.1 mmHg higher than GAT (p < 0.01). Test-retest difference with ART fell within ±1 mmHg in 41% of cases, within ±2 mmHg in 70%, within ±3 mmHg in 85%. 15% had a test-retest difference higher than ± 3 mmHg; Bland-Altman 95% intervals of confidence were -3.9 and +4.6 mmHg. Results were unaffected by age, diagnosis, central corneal thickness, keratometry, operator, randomization sequence.

In most cases ART repeatability and reproducibility were high, with no differences due to patients’ characteristics. ART measurements overestimated GAT by a mean of 1.3-1.7 mmHg.


Applanation resonance tonometry, Glaucoma, Goldmann applanation tonometry, Repeatability, Reproducibility


An applanation resonator sensor for measuring intraocular pressure using combined continuous force and area measurement.


Invest Ophthalmol Vis Sci. 2003 Jul;44(7):3017-24.


Eklund A1, Hallberg P, Lindén C, Lindahl OA.

Author information




For diagnostic purposes and for follow-up after treatment, it is important to have simple and reliable methods for measuring intraocular pressure (IOP). The purpose of this study was to develop a new applanation method for IOP measurement that uses combined continuous force and area measurement and to develop and evaluate an applanation resonator sensor (ARS) tonometer based on that method.


The tonometer was developed and evaluated in an in vitro porcine eye model, in which enucleated eyes were pressurized with a saline column. A model assuming that the applanation principle is valid over a certain interval of contact area was proposed. Continuous contact area was measured with a resonator sensor device, and contact force was measured with a force transducer, both mounted together in one probe. Reference IOP was measured in the vitreous chamber (IOP(VC)) with a standard fluid pressure transducer.


An optimization algorithm determined the applanation interval that was optimal for calculating IOP(ARS). The corresponding time interval was 30 +/- 3 to 77 +/- 4 ms (mean +/- SD, n = 418) after initial contact. The proposed model showed a degree of explanation of R(2 [supi]) = 0.991 (n = 410, six eyes), corresponding to a correlation of r = 0.995 (n = 410) between IOP(ARS) and IOP(VC). The within-eyes precision (i.e., 95% confidence interval for the residuals between IOP(ARS) and IOP(VC)) was +/- 1.8 mm Hg (n = 410, six eyes).


In this study, the ARS method for measuring IOP was evaluated in an in vitro porcine eye model and showed high precision. The ARS method is, to the authors' knowledge, the first to combine simultaneous, continuous sampling of both parameters included in the applanation principle: force and area. Consequently, there is a potential for reducing errors in clinical IOP tonometry.



Symmetric sensor for applanation resonance tomometry of the eye.

Med Biol Eng Comput. 2006 Mar;44(1-2):54-60.


Hallberg P1, Lindén C, Bäcklund T, Eklund A.
Author information



Applanation resonance tonometry (ART) has been shown in a number of studies to be useful for measuring intraocular pressure (IOP). Data from in vitro laboratory bench testing, where the sensor was carefully centralised onto the cornea, has been very consistent with good precision in the determination of IOP. However, in a clinical study the unavoidable off-centre placement of the sensor against the cornea resulted in a reduced precision. The aim of this study was to evaluate a new design of the sensor with a symmetric sensor probe and a contact piece with a larger diameter. Two in vitro porcine eye experimental set-ups were used. One bench-based for examining position dependence and one biomicroscope-based set-up, simulating a clinical setting, for evaluating IOP(ART) precision at seven different pressure levels (1040 mmHg), set by connecting a saline column to the vitreous chamber. The reference IOP was recorded using a pressure transducer. There was no significant difference between four positions 1 mm off centre and the one centre position. The precision of the ART as compared with the reference pressure was +/- 1.03 mmHg (SD, n = 42). The design improvement has enhanced the precision of the ART in the biomicroscope set-up to be in parity with bench test results from a set-up using perfect positioning. This indicates that off-centre positioning was no longer a major contributor to the deviations in measured IOP. The precision was well within the limits set by ISO standard for eye tonometers. Therefore, a larger in vivo study on human eyes with the ART should be performed.



Clinical evaluation of applanation resonance tonometry: a comparison with Goldmann applanation tonometry.

J Glaucoma. 2007 Jan;16(1):88-93.


Hallberg P1, Eklund A, Bäcklund T, Lindén C.
Author information



The purpose of this study was to calibrate and evaluate the precision of the new applanation resonance tonometry (ART) in a clinical study designed in accordance with the International Standard Organization's requirements.


This was a prospective, randomized, single-center study, where healthy volunteers and patients participated. A total of 153 eyes were divided into 3 groups with respect to their intraocular pressure (IOP) at screening: <16 mm Hg, 16 to 23 mm Hg, and >23 mm Hg. IOP was measured with Goldmann applanation tonometry (GAT) as reference method and by ART in both a biomicroscope (ARTBiom) and a handheld (ARTHand) setup with a 10-minutes pause between methods. The mean of 6 readings was regarded as one measurement value.


Mean age of the subjects was 59 years (range 20 to 87 y). GAT showed a mean IOP of 20.0 mm Hg (range 8.5 to 43.5 mm Hg, n=153). The precision was 2.07 mm Hg for ARTBiom and 2.50 mm Hg for ARTHand, with a significant dependency for age as compared with GAT. Measurement order produced a decreasing IOP with a mean of 2.3 mm Hg between the first and last method.


The precision obtained in both ARTBiom and ARTHand was within the limits set by the International Standard Organization standards for tonometers. The standardized procedure and the stability of the biomicroscope setup resulted in a slightly better precision as compared with the handheld setup. Despite a 10-minutes pause between measurements, the order was a significant factor, possibly because the patients were more apprehensive at the first measurement.



Introduction and clinical evaluation of servo-controlled applanation resonance tonometry.

Acta Ophthalmol. 2012 Nov;90(7):677-82. doi: 10.1111/j.1755-3768.2011.02111.x. Epub 2011 Feb 15.


Jóhannesson G1, Hallberg P, Eklund A, Lindén C.
Author information



In recent years, Applanation Resonance Tonometry (ART) has been suggested for intraocular pressure (IOP) measurements. The manual version of ART (ART(manual) ) has been further developed, and to improve usability, an automatic servo-controlled prototype (ART(servo) ) has been proposed. The aim of this study was to assess the limits of agreement (LoA) of ART(manual) and ART(servo) as compared with the reference method, Goldmann Applanation Tonometry (GAT).


This was a prospective single-centre study on 152 eyes from 77 subjects. It was designed according to International Standard Organization's (ISO) requirements for tonometers (ISO 2001). Intraocular pressure was measured six times/method in a standardized order. The ART technique has two available analysis procedures: a dynamic one that measures IOP during the indentation phase and a static one that causes a Goldmann-like measurement during two seconds of full applanation. The 95% LoA was defined as ±1.96 × standard deviation of difference against GAT.


Mean IOP for GAT was 19.1 mmHg (range: 10-37 mmHg). The 95% LoA of ART(manual) was ±4.5 mmHg for both dynamic and static analyses. The 95% LoA of ART(servo) was ±5.7 mmHg for dynamic and ±4.9 mmHg for static analyses.


This study confirms that the ART methodology is feasible. The further developed ART(manual) fulfilled the ISO standard with both the dynamic and the static analysis techniques. ART(servo) with static analysis was close to fulfilling the standard but failed to do so in the highest IOP range. ART(servo) has the potential to greatly improve usability if further development is completed.


Change in intraocular pressure measurement after myopic LASEK: a study evaluating goldmann, pascal and applanation resonance tonometry.

J Glaucoma. 2012 Apr-May;21(4):255-9. doi: 10.1097/IJG.0b013e31820719c8.


Jóhannesson G1, Hallberg P, Eklund A, Koskela T, Lindén C.
Author information



To prospectively evaluate 3 tonometry methods--the gold standard, Goldmann applanation tonometry, a new method, Pascal dynamic contour tonometry (PDCT), and a method under development, applanation resonance tonometry (ART)--with respect to intraocular pressure (IOP) measurements before, 3 and 6 months after laser-assisted subepithelial keratectomy (LASEK).


Materials and methods
One randomly assigned eye of each of 53 healthy individuals, who underwent LASEK surgery for myopia was studied. Visual acuity, central corneal thickness, corneal curvature, and IOP were measured at each visit. Six IOP measurements/methods with 5 minutes pause between methods were performed.


All tonometry methods measured a significantly lower IOP after LASEK correction by a mean of -3.1 diopters. The IOP reduction was largest after 6 months for Goldmann applanation tonometry (-1.7 ± 1.8 mm Hg) followed by ARTstat (-1.2 ± 1.5 mm Hg), PDCT (-1.1 ± 1.6 mm Hg), and ARTdyn (-1.0 ± 1.5 mm Hg). The reduction of IOP did not differ significantly between different methods (P=0.11). There was a significant further reduction of measured IOP for PDCT between 3 and 6 months (-0.5 ± 1.0 mm Hg). Uncorrected visual acuity improved significantly between 3 and 6 months postoperatively from 1.32 ± 0.28 to 1.43 ± 0.27.


All tonometry methods measured a significant, but low, reduction of IOP 3 and 6 months after LASEK. Further change in visual acuity and IOP measurements between 3 and 6 months suggest a still ongoing postoperative process.



Change in intraocular pressure measurement 2 years after myopic laser-assisted subepithelial keratectomy.


J Cataract Refract Surg. 2012 Sep;38(9):1637-42. doi: 10.1016/j.jcrs.2012.04.033. Epub 2012 Jul 11.


Jóhannesson G1, Hallberg P, Eklund A, Koskela T, Lindén C.
Author information



To evaluate intraocular pressure (IOP) measurements 24 months after laser-assisted subepithelial keratectomy (LASEK) with 3 tonometry methods-Goldmann applanation tonometry (GAT), Pascal dynamic contour tonometry (DCT), and applanation resonance tonometry (ART)-and to compare them with measurements taken preoperatively and 3 and 6 months postoperatively.


Department of Ophthalmology, Umeå University, Umeå, Sweden.


Prospective randomized single-center.


One randomized eye per person from myopic healthy individuals who had LASEK was included. Visual acuity, central corneal thickness (CCT), corneal curvature, and IOP were measured at all time points. Six IOP measurements were performed per method, with a 5-minute lapse between methods.


The study evaluated 38 eyes. Two years after LASEK, dynamic ART was the only method that did not measure significantly lower IOP than before LASEK (mean -0.2 mm Hg ± 1.6 [SD]). The greatest difference was with GAT (mean -1.9 ± 1.7 mm Hg) followed by static ART (mean -1.2 ± 1.6 mm Hg) and then DCT (mean -0.9 ± 1.3 mm Hg). All methods measured significantly lower IOP at 3 months and 6 months.


Dynamic ART, which analyses IOP measurement during indentation, showed no significant difference in measured IOP after 24 months. The convex tip of the ART device and the continuous sampling of data during corneal indentation seem to be factors in why dynamic ART was less affected by corneal properties and therefore more suitable for IOP measurement in LASEK-treated eyes, although this must be confirmed in larger trials.


Copyright © 2012 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.



Increased Corneal Hysteresis After Corneal Collagen Crosslinking: A Study Based on Applanation Resonance Technology.

JAMA Ophthalmol. 2014 Aug 28. doi: 10.1001/jamaophthalmol.2014.3029.


Beckman Rehnman J1, Behndig A2, Hallberg P3, Lindén C2.
Author information



A reliable tool for quantification of the biomechanical status of the cornea in conjunction with corneal collagen crosslinking (CXL) treatment is needed.


To quantify the biomechanical effects of CXL in vivo.


Deisgn, setting and participants
A prospective, open, case-control study was conducted at the Department of Ophthalmology, Umeå University, Umeå, Sweden. Participants included 28 patients (29 eyes) aged 18 to 28 years with progressive keratoconus and corresponding age- and sex-matched healthy individuals serving as controls. All participants were monitored during a 6-month period between October 13, 2009, and November 5, 2012.


Main outcomes and measures
Corneal hysteresis after CXL for keratoconus.


A difference in corneal hysteresis between the control group and the patients with keratoconus was found at baseline, both with an applanation resonance tonometer (ART) and an ocular response analyzer (ORA), at mean (SD) values of -1.09?(1.92) mm Hg (99% CI, -2.26 to 0.07; P?=?.01) and -2.67 (2.55) mm Hg (99% CI, -4.05 to -1.32; P?<?.001), respectively. Increased corneal hysteresis was demonstrated with an ART 1 and 6 months after CXL, at 1.2 (2.4) mm Hg (99% CI,-0.1 to 2.5; P?=?.02) and 1.1 (2.7) mm Hg (99% CI, -0.3 to 2.6; P?=?.04), respectively, but not with ORA. A decrease in corneal thickness was seen 1 and 6 months after treatment (-24 [26] µm, P?<?.001; and -11 [21] µm, P?=?.01, respectively), and a corneal flattening of -0.6 (0.7) diopters was seen at 6 months (P?<?.001). No significant change in intraocular pressure was identified in patients with keratoconus with any method, except for an increase at 1 month with Goldmann applanation tonometry (P?=?.005).


Conclusions and relevance
To our knowledge ART is the first in vivo method able to assess the increased corneal hysteresis after CXL treatment. Given the large-scale use of CXL in modern keratoconus treatment, a tool with this capacity has a great potential value. Refinement of the ART method of measuring and quantifying corneal biomechanical properties will be a subject of further studies.


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