Abstract
Background
Previous studies confirmed reduced retrobulbar haemodynamics in primary open‐angle glaucoma (POAG).
Aim
To investigate a correlation between retrobulbar haemodynamics and morphometric neuroretinal rim analysis in patients with POAG.
Methods
51 patients with POAG (mean (standard deviation (SD)) age 65 (11) years) were included in this clinical study. Blood flow velocities (peak systolic velocity (PSV) and end‐diastolic velocity (EDV)) of the ophthalmic artery, central retinal artery (CRA), posterior ciliary arteries (PCA) and central retinal vein were measured using colour Doppler imaging (Siemens Sonoline Sienna, Erlangen, Germany). Optic disc morphometry was carried out using scanning laser tomography (Heidelberg Retinal Tomograph II Heidelberg Egineering Heidelberg, Germany). The stereometric parameters of the neuroretinal rim (rim area, rim volume, cup shape measure and retinal nerve fibre layer (RNFL) cross‐sectional area) were used for analysis.
Results
The PSV of the CRA was significantly (p<0.001) correlated with rim area (r = 0.50) and rim volume (r = 0.51). The minimum velocities of the central retinal vein were significantly (p<0.001) correlated with rim volume (r = 0.56) and RNFL cross‐sectional area (r = 0.49). No correlations were found for the flow velocities of the ophthalmic artery and PCAs.
Conclusion
Retrobulbar haemodynamics of the central retinal artery and vein are correlated with the neuroretinal rim damage in POAG.
Ocular haemodynamics have been postulated to be relevant in glaucomatous optic neuropathy, besides mechanical intraocular pressure (IOP)‐related optic nerve damage and ganglion cell loss.1,2 Glaucomatous optic neuropathy results in a reduction of the neuroretinal rim with changes in optic disc morphometry and glaucomatous excavation of the optic nerve head. Histopathological studies investigated a link between neuroretinal rim loss and capillary drop‐out in glaucoma.3,4 A controversial debate is under way as to whether the capillary loss in glaucoma is a primary factor in the disease or a secondary phenomenon. In addition to optic disc changes, systemic and local vascular risk factors have been identified in glaucoma in the past.5 Systemic and local vascular disease may result in vasosclerosis, capillary dropout, vasospasm and autoregulatory dysfunction contributing to impaired ocular blood flow.1,5,6,7,8 Blood flow velocities of retrobulbar vessels—that is, the central retinal artery, ophthalmic artery, and nasal and temporal short posterior ciliary arteries—can be measured by means of colour Doppler imaging (CDI). CDI is an ultrasound technique combining a simultaneous B mode ultrasound image with Doppler frequency shifts.9,10 Various studies comparing patients with POAG with controls confirmed reduced flow velocities and increased resistive indices of the ophthalmic artery, central retinal artery and posterior ciliary arteries.11,12,13,14,15 The relationship between retrobulbar haemodynamics and morphological disc damage—that is, neuroretinal rim loss—has not been evaluated.
This clinical study was carried out to investigate a correlation between retrobulbar haemodynamics in POAG and the morphological disc damage measured using confocal scanning laser tomography. A reduction of retrobulbar flow velocities in POAG related to neuroretinal rim loss of the optic nerve head is postulated.
Patients
Patients with POAG exhibited glaucomatous visual field loss confirmed in at least two visual field examinations. Visual field examinations were carried out with the Humphrey Field Analyzer (Model 750, Humphrey‐Zeiss, San Leandro, California, USA) using the achromatic 24–2 full threshold or Swedish interactive thresholding algorithm technique. Glaucomatous visual field loss was defined following the guidelines of the European Glaucoma Society. Field loss was considered significant if: (a) the glaucoma hemifield test was abnormal; (b) three points were confirmed with p<0.05 probability of being normal (one of which should have p<0.01), not contiguous with the blind spot; or (c) corrected pattern standard deviation (CPSD) was abnormal, with p<0.05.16 IOP was measured using Goldmann applanation tonometry. All patients with POAG had at least two IOP readings >21 mm Hg in their medical history. Patients with diabetes mellitus, visual acuity of <20/40 or media opacities preventing image acquisition with retinal tomography were excluded from the study. Adherence to the Declaration of Helsinki for research involving human beings was confirmed. Informed consent was obtained from all patients.
A total of 51 patients with POAG (M 30, F 21; mean (standard deviation (SD)) age 65 (11) years) were included in this clinical study. One eye of each patient was randomly selected for analysis. Table 1 presents the clinical data. Forty two patients with POAG were on topical IOP lowering drugs (β blockers, carbonic anhydrase inhibitors, prostaglandins, sympathomimetics, pilocarpine or combinations; mean (SD) number of therapeutic agents 1.7 (1.2)). According to the patients' medical history, 25 patients were treated for systemic arterial hypertension, 12 patients had a systemic vascular disease (ie, myocardial infarction, cerebrovascular disease or peripheral arterial occlusive disease) and 8 patients had a history of systemic vasospasms (ie, cold hands or feet or migraine). Thirteen of the patients with POAG did not receive any systemic drugs.
Table 1 Clinical data of the patients with POAG (n = 51), mean (SD).
| Age (years) | 64.6 (10.8) |
| IOP (mm Hg) | 18.3 (4.3) |
| Mean deviation (dB) | −10.2 (8.1) |
| Pattern standard deviation (dB) | 7.1 (3.9) |
| Systolic blood pressure (mm Hg) | 142 (20) |
| Diastolic blood pressure (mm Hg) | 82 (10) |
| Heart rate (beats/min) | 68 (13) |
IOP, intraocular pressure.
Values are given as mean (SD).
Methods
All patients with POAG had a detailed ophthalmological examination, visual field testing, CDI of their retrobulbar blood vessels and a confocal scanning laser imaging of the optic disc.
Blood flow velocities of retrobulbar vessels were measured by means of CDI using a 7.5‐MHz linear phased‐array transducer (Siemens Sonoline Sienna, Germany). The transducer was gently placed on the closed upper eyelid using a coupling gel, taking care to minimise pressure on the globe. All patients were in supine position during the examination. CDI allows blood velocity measurements of the ophthalmic artery, the central retinal artery (CRA), and the temporal short posterior ciliary arteries and nasal short posterior ciliary arteries. The peak systolic velocity (PSV) and the end‐diastolic velocity (EDV) were obtained from the Doppler‐shifted spectral waves of each artery. The resistive index (Pourcelot's ratio) was calculated ((PSV−EDV)/PSV) to characterise peripheral vascular resistance of the vessels studied. Additionally, the maximum and minimum velocities of the central retinal vein were evaluated.
The Heidelberg Retina Tomograph (HRT II, Heidelberg Engineering, Heidelberg, Germany) is a confocal scanning laser ophthalmoscope for quantitative analysis of the optic nerve head topography with high optical resolution. The three‐dimensional topographic measurements are based on the superficial reflection of a diode laser (675 nm). After confocal detection of the reflected light, a topographic map of the optic disc is calculated. The observer defines the border of the optic nerve head (Elschnig scleral ring) with a contour line. A standard reference plane based on the contour line divides the cup from the rim of the optic nerve head. The standard reference plane is based on the assumption of a nerve fibre layer thickness of 50 μm at the level of the papillomacular bundle (at 350–356°). The Heidelberg Retina Tomograph generates a topographic map of the optic disc and calculates stereometric parameters for quantitative optic disc analysis. The stereometric parameters rim area, rim volume, cup shape measure and retinal nerve fibre layer (RNFL) cross‐sectional area were used for analysis.
Correlations were tested using the Fisher's r to z test after Bonferroni's multiple comparison correction. A p value <0.001 was regarded as significant.
Results
Table 2 presents the flow velocities and resistive indices of the ophthalmic artery, the CRA, the PCA, and the maximum and minimum velocities of the central retinal vein.
Table 2 Flow velocities (peak systolic velocity and end‐diastolic velocity) and resistive indices of the ophthalmic artery, central retinal artery, posterior ciliary arteries and central retinal vein.
| OA PSV (cm/s) | 32.7 (12.8) |
| OA EDV (cm/s) | 7.0 (2.9) |
| OA RI | 0.75 (0.25) |
| CRA PSV (cm/s) | 7.9 (2.1) |
| CRA EDV (cm/s) | 2.3 (0.6) |
| CRA RI | 0.70 (0.06) |
| PCA PSV (cm/s) | 7.2 (1.5) |
| PCA EDV (cm/s) | 2.5 (0.6) |
| PCA RI | 0.65 (0.07) |
| Central retinal vein maximum velocity (cm/s) | 3.6 (0.8) |
| Central retinal vein minimum velocity (cm/s) | 2.4 (0.8) |
CRA, central retinal artery; EDV, end‐diastolic velocity; OA, ophthalmic artery; PCA, posterior ciliary arteries; PSV, peak systolic velocity; RI, resistive indices.
Values are given as mean (SD).
Table 3 presents the stereometric parameters of the optic disc evaluated with the scanning laser ophthalmoscope (Heidelberg Retina Tomograph II).
Table 3 Stereometric parameters of the HRTII used for analysis.
| Rim area (mm2) | 1.03 (0.43) |
| Rim volume (mm3) | 0.21 (0.15) |
| Cup shape measure | −0.05 (0.07) |
| Retinal nerve fibre layer cross‐sectional area (mm2) | 0.86 (0.43) |
Values are given as mean (SD).
The peak systolic velocities of the CRA were significantly correlated with rim area (r = 0.50) and rim volume (r = 0.51). The minimum velocities of the central retinal vein were significantly correlated with rim volume (r = 0.56) and RNFL cross‐sectional area (r = 0.49). The correlation of the PSV of the CRA with RNFL cross‐sectional area (r = 0.39), the correlation of the EDVs of the CRA with rim area (r = 0.40) and rim volume (r = 0.39), and the correlation of the minimum velocities of the central retinal vein with rim area (r = 0.39) did not reach significance after Bonferroni's adjustment for multiple comparisons.
Haemodynamic parameters of the ophthalmic artery and of the PCAs, and the resistive indices of the CRA were not correlated with stereometric parameters of the optic disc. The cup shape measure was not correlated with retrobulbar haemodynamics. Table 4 presents the correlation coefficients. Flow velocities of retrobulbar vessels were not significantly correlated with age or IOP, except the resistive indices of the ophthalmic artery (correlation with age: r = 0.30; p = 0.031). The IOP before CDI measurements was not correlated with the morphological disc parameters.
Table 4 Correlation coefficients and p levels of the retrobulbar haemodynamics and stereometric parameters of the optic disc.
| Rim area | Rim volume | Cup shape measure | RNFL cross‐sectional area | |
|---|---|---|---|---|
| OA PSV (cm/s) | 0.19 | 0.12 | −0.23 | −0.08 |
| OA EDV (cm/s) | 0.11 | 0.02 | −0.17 | −0.15 |
| OA RI | 0.09 | 0.10 | −0.19 | 0.01 |
| CRA PSV (cm/s) | 0.50; p<0.001 | 0.51; p<0.001 | −0.29 | 0.39; p = 0.005 |
| CRA EDV (cm/s) | 0.40; p = 0.004 | 0.39; p = 0.005 | −0.18 | 0.25 |
| CRA RI | 0.09 | 0.08 | −0.11 | 0.11 |
| PCA PSV (cm/s) | 0.04 | −0.03 | −0.19 | −0.11 |
| PCA EDV (cm/s) | 0.19 | 0.10 | −0.29 | −0.06 |
| PCA RI | −0.18 | 0.15 | 0.13 | 0.04 |
| Central retinal vein minimum velocity (cm/s) | 0.39; p = 0.005 | 0.56; p<0.001 | −0.33 | 0.49; p<0.001 |
| Central retinal vein maximum velocity (cm/s) | 0.15 | 0.11 | −0.10 | 0.08 |
CRA, central retinal artery; EDV, end‐diastolic velocity; OA, ophthalmic artery; PCA, posterior ciliary arteries; PSV, peak systolic velocity; RI, resistive indices.
A p value < 0.001 was considered significant after Bonferroni's adjustment for multiple comparisons.
Discussion
Flow velocities of the CRA and of the central retinal vein are significantly correlated with the size of the neuroretinal rim of the optic disc in POAG. Flow velocities decrease with increasing optic disc damage in glaucoma.
Reduced EDVs and increased resistive indices of the ophthalmic artery, the CRA and PCA have been reported in patients with POAG compared with controls.11,12,13,14,15 PSVs of the CRA and short PCA were found to be reduced in some studies.12,15,17,18 Satilmis et al19 reported a correlation of EDVs of the CRA with the rate of progression in glaucoma in a retrospective study. Reduced flow velocities of the CRA in patients with asymmetric POAG were found in eyes with more severe visual field loss.20 A reduction in flow velocities of the CRA may be caused by an increase in vascular resistance related to vasoconstriction or vasospasm, vasosclerosis, reduction in the cross‐section of the vessel diameters (eg, capillary loss) or rheological factors. In addition, a reduction in both PSVs and EDVs may be interpreted as a decrease in volumetric flow related to an increase in vascular resistance.21 Previous studies confirmed a correlation of EDVs of the CRA with the retinal arteriovenous passage time assessed by fluorescein angiography 22 and with the extent of capillary non‐perfusion of the optic nerve head—that is, fluorescein‐filling defects in patients with normal‐tension glaucoma.23 A reduction in retinal vessel diameters may also account for an increase in retinal vascular resistance.24
In this study, flow velocities of the CRA were related to the neuroretinal rim loss in POAG. No correlations were found for the ophthalmic artery or for the short PCA. Glaucoma is characterised by glaucomatous optic neuropathy and ganglion cell loss at the level of the retina. Thus, a reduction of retinal ganglion cells may be associated with a reduction of retinal blood flow either as a primary vascular disease or as a secondary down regulation. Furthermore, the superficial capillaries of the optic nerve head are perfused by the CRA, and capillary drop‐out at the level of the superficial neuroretinal rim and prelaminar region is a well‐known phenomenon in glaucoma.7 However, the flow velocities of the PCA that are relevant for optic disc perfusion in the prelaminar and laminar regions were not correlated with the rim loss in our study. This could be due to a higher intraindividual variability in CDI measurements of these vessels resulting in lower reliability.25 Jonas et al26 found a correlation of laser Doppler flowmetry measurements of the neuroretinal rim with the rim area of the optic nerve head in a cohort of patients with normal tension glaucoma and age‐matched controls. The laser Doppler parameter “flow” decreased with increasing neuroretinal rim loss.
In addition to the reduced flow velocities of the CRA, we found a significant correlation of the minimum velocities in the central retinal vein with the neuroretinal rim of the optic disc. A reduction in the central retinal vein flow velocities could be related to a venous congestion, possibly at the level of the lamina cribrosa. In 1997, Kaiser et al13 reported decreased flow velocities of the central retinal vein in POAG. Previous studies found decreased retinal arteriovenous passage times in patients with POAG27 and normal tension glaucoma.28 The prolonged retinal transit times may reflect an increased vascular resistance related to altered retinal microcirculation or a venous congestion. Consequently, an increase in the central retinal venous pressure29,30,31 related to decreased flow velocities in the central retinal vein could decrease ocular perfusion. Morgan studied central retinal vein pulsation pressures in glaucoma. The ophthalmodynamometric force required to induce venous pulsation was correlated with the severity of glaucomatous visual field damage.32 This phenomenon may be explained by several pathologies. An increased venous pulsation pressure may be due to an increased cerebrospinal fluid33 or orbital pressure,34 or increases in arterial blood pressure—that is, altered upstream resistance or an increase in downstream resistance of retinal veins.32,35 However, Hayreh29 stated in 2001 that there is little valid evidence so far that central retinal vein pressure plays any significant part in the optic nerve head blood flow and in ischaemia of the optic nerve. Future studies have to elucidate the pathogenetic role of central retinal venous outflow pressure and retinal vein flow velocities in glaucoma, and possible implications for retinal and optic nerve head blood flow.
To summarise, the reductions in flow velocities of the CRA and the central retinal vein emphasise the decreased retinal blood flow in POAG. The flow velocities of the CRA and the central retinal vein are considerably correlated with the morphological disc damage in patients with POAG. In contrast with considerations of optic nerve head blood flow changes in glaucoma, a reduction in flow velocities of the central retinal vessels and the correlation with morphological disc damage in glaucoma hint at altered retinal haemodynamics associated with neural tissue loss at the level of the retinal nerve fibre layer. Prospective longitudinal studies need to confirm a prognostic value of reduced retrobulbar haemodynamics in POAG.
Abbreviations
CDI - colour Doppler imaging
CPSD - corrected pattern standard deviation
CRA - central retinal artery
EDV - end‐diastolic velocity
IOP - intraocular pressure
PCA - posterior ciliary arteries
POAG - primary open‐angle glaucoma
PSV - peak systolic velocity
RNFL - retinal nerve fibre layer
Footnotes
Funding: None.
Competing interests: None.
References
- 1.Flammer J, Orgül S. Optic nerve blood‐flow abnormalities in glaucoma. Progr Retinal Eye Res 199817267–289. [DOI] [PubMed] [Google Scholar]
- 2.Quigley H A. Neuronal death in glaucoma. Prog Ret Eye Res 19981839–57. [DOI] [PubMed] [Google Scholar]
- 3.Gottanka J, Kuhlmann A, Scholz M.et al Pathophysiologic changes in the optic nerves of eyes with primary open angle and pseudoexfoliation glaucoma. Invest Ophthalmol Vis Sci 2005464170–4181. [DOI] [PubMed] [Google Scholar]
- 4.Quigley H A, Hohmann R M, Addicks E M. Quantitative study of optic nerve head capillaries in experimental optic disc pallor. Am J Ophthalmol 198293689–699. [DOI] [PubMed] [Google Scholar]
- 5.Hayreh S S. The 1994 Von Sallman lecture: the optic nerve circulation in health and disease. Exp Eye Res 199561259–272. [DOI] [PubMed] [Google Scholar]
- 6.Arend O, Plange N, Sponsel W E.et al Pathogenetic aspects of the glaucomatous optic neuropathy: fluorescein angiographic findings in patients with primary open‐angle glaucoma. Brain Res Bull 200462517–524. [DOI] [PubMed] [Google Scholar]
- 7.Plange N, Kaup M, Huber K.et al Fluorescein filling defects of the optic nerve head in normal tension glaucoma, primary open‐angle glaucoma, ocular hypertension and healthy controls. Ophthal Physiol Opt 20062626–32. [DOI] [PubMed] [Google Scholar]
- 8.Plange N, Kaup M, Weber A.et al Fluorescein filling defects and quantitative morphologic analysis of the optic nerve head in glaucoma. Arch Ophthalmol 2004122195–201. [DOI] [PubMed] [Google Scholar]
- 9.Harris A, Kagemann L, Cioffi G A. Assessment on human ocular hemodynamics. Surv Ophthalmol 199842509–533. [DOI] [PubMed] [Google Scholar]
- 10.Williamson T H, Harris A. Color Doppler imaging of the eye and orbit. Surv Ophthalmol 199640225–267. [DOI] [PubMed] [Google Scholar]
- 11.Akarsu C, Bigili M Y. Color Doppler imaging in ocular hypertension and open‐angle glaucoma. Graefe's Arch Clin Exp Ophthalmol 2004242125–129. [DOI] [PubMed] [Google Scholar]
- 12.Birinci H, Danaci M, Oge I.et al Ocular blood flow in healthy and primary open‐angle glaucoma eyes. Ophthalmologica 2002216434–437. [DOI] [PubMed] [Google Scholar]
- 13.Kaiser H J, Schoetzau A, Stümpfig D.et al Blood‐flow velocities of the extraocular vessels in patients with high‐tension and normal‐tension primary open‐angle glaucoma. Am J Ophthamol 1997123320–327. [DOI] [PubMed] [Google Scholar]
- 14.Rankin S J, Walman B E, Buckley A R.et al Color Doppler imaging and spectral analysis of the optic nerve vasculature in glaucoma. Am J Ophthalmol 1995119685–693. [DOI] [PubMed] [Google Scholar]
- 15.Vécsei P V, Hommer A, Reitner A.et al Farbduplex der retrobulbären Arterien bei Normaldruck‐ und Offenwinkelglaukom. Klin Monatsbl Augenheilk 1998212444–448. [PubMed] [Google Scholar]
- 16.Greve E L, Rulo A H, Hoyng P F.Terminology and guidelines for glaucoma. Savona, Italy: Editrice DOGMA S, r. l 2003
- 17.Cellini M, Possati G L, Caramazza N.et al Colour Doppler analysis of the choroidal circulation in chronic open‐angle glaucoma. Ophthalmologica 1996210200–202. [DOI] [PubMed] [Google Scholar]
- 18.Trible J R, Costa V P, Sergott R C.et al The influence of primary open‐angle glaucoma upon the retrobulbar circulation: baseline, postoperative and reproducibility analysis. Trans Am Ophthalmol Soc 199391245–265. [PMC free article] [PubMed] [Google Scholar]
- 19.Satilmis M, Orgul S, Doubler B.et al Rate of progression of glaucoma correlates with retrobulbar circulation and intraocular pressure. Am J Ophthalmol 2003135664–669. [DOI] [PubMed] [Google Scholar]
- 20.Plange N, Kaup M, Arend O.et al Asymmetric visual field loss and retrobulbar hemodynamics in primary open‐angle glaucoma. Graefe's Arch Clin Exp Ophthalmol 2006244(8)978–983. [DOI] [PubMed] [Google Scholar]
- 21.Spencer J A, Giussani D A, Moore P J.et al In vitro validation of Doppler indices using blood and water. J Ultrasound Med 199110305–308. [DOI] [PubMed] [Google Scholar]
- 22.Huber K, Plange N, Remky A.et al Comparison of colour Doppler imaging and retinal scanning laser fluorescein angiography in healthy volunteers and normal pressure glaucoma patients. Acta Ophthalmol Scand 200482426–431. [DOI] [PubMed] [Google Scholar]
- 23.Plange N, Remky A, Arend O. Color Doppler imaging and fluorescein filling defects of the optic disc in normal tension glaucoma. Br J Opthalmol 200387731–736. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Remky A, Plange N, Klok J.et al Retinal arterial diameters in patients with glaucoma. Spektrum Augenheilk 20041825–30. [Google Scholar]
- 25.Harris A, Williamson T H, Martin B.et al Test/retest reproducibility of color Doppler imaging assessment of blood flow velocity in orbital vessels. J Glaucoma 19954281–286. [PubMed] [Google Scholar]
- 26.Jonas J B, Harazny J, Budde W M.et al Optic disc morphometry correlated with confocal laser scanning Doppler flowmetry measurements in normal‐pressure glaucoma. J Glaucoma 200312260–265. [DOI] [PubMed] [Google Scholar]
- 27.Wolf S, Arend O, Sponsel W E.et al Retinal hemodynamics using scanning laser ophthalmoscopy and haemorheology in chronic open‐angle glaucoma. Ophthalmology 19931001561–1566. [DOI] [PubMed] [Google Scholar]
- 28.Arend O, Remky A, Redbrake C.et al Retinale hämodynamik bei patienten mit normaldruckglaukom. Quantifizierung mittels digitaler scanning‐laser‐fluorescein‐angiographie. Ophthalmologe 19999624–29. [DOI] [PubMed] [Google Scholar]
- 29.Hayreh S S. Blood flow of the optic nerve head and factors that may influence it. Prog Ret Eye Res 200120595–624. [DOI] [PubMed] [Google Scholar]
- 30.Levine D N. Spontanous pulsation of the retinal veins. Microvasc Res 199856165. [DOI] [PubMed] [Google Scholar]
- 31.Meyer‐Schwickerath R, Kleinwachter T, Firsching R.et al Central venous outflow pressure. Graefe's Arch Clin Exp Ophthalmol 1995233783–788. [DOI] [PubMed] [Google Scholar]
- 32.Morgan W H, Hazelton M L, Azar S L.et al Retinal venous pulsation in glaucoma and glaucoma suspects. Ophthalmology 20041111489–1494. [DOI] [PubMed] [Google Scholar]
- 33.Firsching R, Schutze M, Motschmann M.et al Non‐invasive measurement of intracranial pressure. Lancet 1998351523–524. [DOI] [PubMed] [Google Scholar]
- 34.Hartmann K, Meyer‐Schwickerath R. Measurement of venous outflow pressure in the central retinal vein to evaluate intraorbital pressure in Graves' ophthalmopathy: a preliminary report. Strabismus 20008187–193. [PubMed] [Google Scholar]
- 35.Jonas J B. Ophthalmodynamometric assessment of the central retinal vein collapse pressure in eyes with retinal vein stasis or occlusion. Graefe's Arch Clin Exp Ophthalmol 2003241367–370. [DOI] [PubMed] [Google Scholar]