19.3.2  Patients Who Progress despite Reaching Target IOP or with Fluctuating IOP and Pulse Pressure

Abnormal auto regulation of the optic nerve blood flow seems to occur in both NTG and progressive POAG patients despite a “normalized” IOP [33]. “Primary vascular dysregulation syndrome” is considered as a main cause of abnormal auto regulation by Grieshaber et al. [8]. It is hypothesized that auto regulation in this syndrome is not properly adapted to the local needs of various organs and tissues. The vascular systems of subjects with primary vascular dysregulation syndrome tend to respond differently to various stimuli than the normal patients.

In patients with untreated POAG, Sehi et al. demonstrated that the regions of the greatest diurnal change in rim topography had significant diurnal changes in capillary blood flow. These diurnal changes were not seen in normal subjects [49].

19.3.3  NTG Patients with Migraine and or Disc Hemorrhages

Normal tension glaucoma is much more common than was previously recognized. Population surveys reveal that 35–60% of newly diagnosed patients with POAG have NTG [50]. NTG patients have a high incidence of disc hemorrhage [51]. Disc hemorrhage is considered to be a serious risk factor for the development and progression of optic disc damage in NTG as well as in POAG [7, 15, 52, 53]. Rasker et al. reported visual field deterioration in 80% of NTG patients with disc hemorrhage compared to 14% in ocular hypertension patients [54]. This finding is consistent with the OHTS study results [55]. Disc hemorrhages possibly represent impaired integrity of the vascular wall and therefore are considered a vascular risk factor in NTG.

Patients with NTG suffering from primary vascular dysregulation syndrome also suffer migraines more often than does the general population. Migraines were found to be a significant risk factor for glaucomatous optic neuropathy [56], as well as for progression in The Collaborative Normal Tension Glaucoma Study [57].

Summary for the Clinician

››OBF may be impaired in patients with cardiovascular disease, vasospasm, nocturnal hypotension and diabetes, although much of the evidence is conflicting.

››Autonomic dysregulation is an attractive theory for patients whose glaucoma continues to progress despite low IOPs.

››Disc hemorrhages may represent a vascular risk factor for glaucoma.

19.4  What are the Most Common Techniques to Measure Optic Nerve Blood Flow and what are Their Limitations?

19.4.1  Color Doppler Imaging (CDI)

CDI is a combination of ultrasound imaging with Doppler shift analysis. In the eye, it is typically used to assess hemodynamic parameters of the ophthalmic artery, central retinal artery, and posterior ciliary arteries. Two blood velocity values are measured by CDI: peak systolic velocity (PSV) and end diastolic velocity (EDV). The CDI unit calculates a resistive index (RI), which is expressed as RI = (PSV−EDV)/PSV. Based on studies of the brachial artery, the CDI provides RI data that is important for the quantification of downstream resistance [58]. However, it is unclear whether the RI represents a valid measure in terms of the retinal vasculature [59].

An important point to make about CDI is that it measures blood velocity and not blood flow. In related techniques such as transcranial Doppler (TCD) imaging, it can be assumed that a change in velocity accurately reflects changes in blood flow since the diameter of the larger cerebral vessels has been demonstrated to change minimally during provocation with hyperventilation [60]. In this situation, change in blood flow is thought to be governed by altered vascular resistance of the downstream arterioles. However, the smaller ocular vessels assessed by CDI have contractile capabilities, and therefore, any direct relationship between change in velocity and change in flow is invalid.

Another major problem with CDI is its limited resolution­ . Large vessels, such as the ophthalmic and central retinal artery, can be measured reliably but the information obtained from the smaller posterior ciliary arteries, which are abundant and tortuous, is less reliable. A further caveat is that CDI is not capable of measuring velocities slower than 1 cm/s, and due to this fact small vessels appear to have an absence of flow. Calculation of total blood flow with this instrument is therefore impossible. Finally, the interpretation of CDI results and the accurate estimation of blood flow velocity require correction for the angle of the probe relative to the measured blood vessels. This is especially problematic with small ocular vessels. Repeating a CDI test requires a skilled operator using a hand-held probe at the correct angle to reproduce an earlier assessment.

of tissue sampled by the laser beam. In addition, the HRF performs signal analysis that is required for calculating­ blood flow. This calculation results in a display of blood velocity, volume, and flow through the scanned area but all parameters are displayed in AU. A software algorithm, the automatic full field perfusion image analyzer (AFFPIA), which is an add-on to the original HRF software, can further improve the analysis of images. The AFFPIA software excludes the artifactual effect of eye movements and of Doppler shifts that are outside the valid measurement range of the photo detector (derived from relatively large diameter blood vessels) and determines blood flow in the capillary bed over the entire perfusion image. However, there can be problems in interpreting scanning laser Doppler flowmetry images because flow from the underlying choriocapillaris or deeper optic nerve head vessels may confound results.

19.4.2  Laser Doppler

Flowmetry (LDF)

In this technique laser light is directed towards the vascularized tissue where there are no visible large vessels. What is actually being measured is the flux of red blood cells (RBCs) through the illuminated volume of the tissue. This is a relative value of blood flow since the measurement represents the product of velocity and volume. Since there are differences in scattering properties between individuals, due to vascular density and orientation, it is invalid to compare results between patients. However, reproducibility within an individual patient is considered to be high [61].

The technique is based on the scattering theory of light in a tissue that was formulated by Bonner and Nossal [62]. The technique assumes that the direction of light impinging on erythrocytes is completely random and therefore the mean velocity of the erythrocytes and the blood volume is measured using arbitrary units (AU) [63].

The Heidelberg Retinal Flow meter (HRF) is a Scanning Laser Doppler Flow meter (SLDF) that combines laser Doppler flowmetry with scanning laser technology [64]. It provides a two-dimensional map of the perfusion within the retina and optic nerve head and it measures blood flux through the capillary beds of these areas. The Doppler shift in the reflected light is analyzed to determine blood velocity in the volume

19.4.3  Pulsatile Ocular Blood

Flow (POBF)

POBF quantifies the pulsatile portion of total OBF (i.e. retinal and choroidal blood flow) measured during systole­ . POBF represents the calculated change in ocular­ volume over time that is derived from pulsatile variation in IOP [65]. This method utilizes a pneumotonometer connected to a computer system to record the ocular pulse wave. Variations in IOP are also recorded and used to derive intraocular volume and blood volume changes using a preset equation. However, the calculation­ of POBF from the change in IOP is based upon a model eye assuming a standard ocular rigidity [66­ –68]. Additionally,­ this method is based on the assumptions that (a) the pulsatile ocular volume changes mainly reflect choroidal blood flow volume changes that are responsible for 90% of the OBF in each cardiac cycle, (b) that no retrograde blood flow occurs, and (c) that the outflow of blood is nonpulsatile. A recent study reported that POBF determinations are influenced by the pulsatile components of both the choroidal and retinal vasculature [69]. Reduced POBF measurements were reported in studies on NTG and POAG patients [65, 70, 71]. An initial decrease followed by an increase in POBF has been documented in patients with diabetes who subsequently develop diabetic retinopathy [72–74].