ABSTRACT. Factors other than intraocular pressure (IOP) elevation must be involved in initiation and progression of glaucoma. An additional element in disease causation may be ischemia in the retina and optic nerve head. Ischemic damage to neurons in the CNS is similar mechanistically and histopathologically to changes seen in glaucoma. Further, glaucoma patients with normal IOP show clear evidence for cerebral and ocular ischemia. Aging and atherosclerosis reduce the ability of the eye to autoregulate blood flow when ocular perfusion pressure changes: the dependence of blood flow on perfusion pressure links ischemia to IOP. Consequently, neuroprotective treatments for glaucoma should be designed to both reduce IOP and improve ocular nutrient delivery.
Although elevation of the intraocular pressure (IOP) is clearly a major risk factor for the development and progression of glaucoma, therapeutic reduction of the IOP provides neither improved visual function nor stabilization of the disease process in many patients (Rossetti et al. 1993; Chauhan 1995). The failure of ocular pressure lowering to prevent disease progression, the association of glaucomatous optic nerve head damage with normal pressure in many patients, and racial variations in disease incidence independent of IOP (Tielsch et al. 1991), point to the critical role that other factors must play in the development of this disease (Flammer et al. 1999).
One candidate for an additional glaucoma risk factor, independent from, yet interacting with IOP, is blood flow insufficiency. Ischemia fulfills many of the criteria for a causative element for this illness:
1)Ischemic cellular damage mimics pathologic changes seen in glaucoma
2)Glaucoma patients with normal IOP show signs of ocular and cerebral ischemia
3)Increases in IOP worsen ischemia, linking the known and hypothetical risk factors, and potentially contributing to the increased risk for glaucoma in persons with elevated IOP
While each of these topics will be addressed in turn, the third point is the primary topic for this review: the simultaneous management of both ocular blood flow and the IOP. This relationship will be considered with special attention to the potential role that carbonic anhydrase inhibitors may play in simultaneous management of both risk factors in older persons with compromised vascular autoregulatory capacity.
Ischemic cellular damage mimics pathologic changes seen in glaucoma
While the pathogenesis of primary open angle glaucoma (POAG) remains unknown, understanding of the disease process may be gained through models which demonstrate mechanisms of apoptotic neuronal cell death. In human glaucoma and in animal models of the disease, retinal ganglion cells primarily die via apoptosis (Quigley et al. 1995; Pease et al. 2000). Elevated intraocular pressure in the rat dilates these cells, leads to abnormal intracellular accumulation of tyrosine kinase receptor B, and blocks delivery of brain-derived neurotrophic factor, suggesting that neurotrophin deprivation causes retinal ganglion cell apoptosis in glaucoma (Pease et al. 2000). While the genetic factors that regulate these processes remain to be fully elucidated (Nickells 1999), a similar pathway apparently leads to ischemia-induced death of cells in the central nervous system (Endres et al. 2000). In mice lacking both alleles for neurotrophin-4 or deficient in a single allele for brain-derived neurotrophic factor, infarct size after occlusion of the middle cerebral artery is increased, suggesting that expression of neurotrophin-4 and brain-derived neurotrophic factor, and hence the tyrosine kinase B receptor, are essential for protection against ischemic injury (Endres et al. 2000). Further, brain cells resistant to hypoxic-ischemic insult are those highest in endogenous expression of brain-derived neurotrophic factor (Walton et al. 1999). Similarly, blocking brain-derived neurotrophic factor with the tyrosine kinase receptor B-Fc fusion protein causes greater neuronal loss in the forebrain during ischemia (Larsson et al. 1999), although the neuronal loss was selective, striking CA4 pyramidal neurons while sparing CA1 neurons (Larsson et al. 1999). A similar, linked pathway involves glutamate release and the activation of N-methyl-D-aspartate receptors (Gross et al. 2000; Osborne et al. 1999; Sucher et al. 1997). Using calcium influx as second messenger, this pathway is toxic to retinal ganglion cells in part via induction of oxygen radicals (Osborne et al. 1999). Glutamate toxicity can be provoked by either IOP elevation or ischemia in susceptible cells (Osborne et al. 1999; Fig. 1). A third related mechanism may involve astroglial production of toxic levels of nitric oxide during ischemia: nitric oxide synthase inhibition increases retinal ganglion cell survival during anoxia or after administration of glutamate (Morgan et al. 1999). These results taken together suggest that neuronal apoptosis, provoked by either IOP elevation or by ischemia, may proceed along a common pathway, and that certain neurons, such as retinal ganglion cells, may be particularly susceptible to damage (Pease et al. 2000; Nickells 1999; Endres et al. 2000; Walton et al. 1999; Larsson et al. 1999; Fig. 1). Clearly, if IOP elevation potentates retinal and optic nerve head ischemia, this would accelerate retinal ganglion cell apoptosis with both factors acting in concert to cause cell death (Pease et al. 2000; Larsson et al. 1999). Finally, in animal models, endothelin-1 induced ischemia generates glaucoma-like optic neuropathy despite normal IOP, a histopathologic result consistent with the possibility that ischemia may play a significant role in glaucoma development in some patients (Cioffi & Sullivan 1999; Haefliger et al. 1999; Oku et al. 1999).
Glaucoma patients with normal IOP show signs of ocular and cerebral ischemia
Two magnetic resonance imaging studies find evidence for pan-cerebral ischemia in normal-tension glaucoma (NTG) patients. In one of these studies, patients suffering from NTG revealed confluent deep white matter lesions (Stroman et al. 1995). Such lesions are most often found in concert with a reduction in total cerebral perfusion and with impairments in cognitive function (Herholz et al. 1990; Boone et al. 1992). A second study found atrophy of the corpus callosum and evidence for increased numbers of cerebral infarcts in normal-tension glaucoma (Ong et al. 1995). The close association of glaucoma with advancing age suggests that this illness could represent one aspect of accelerated central nervous system aging (Ong et al. 1995). Evidence for diffuse, generalized cerebral ischemia in normal-tension glaucoma supports the hypothesis that the illness may represent a chronic, non-episodic form of anterior ischemic optic neuropathy (Hayreh 1975). These studies are at the level of pilot studies. A better view of the frequency of cerebral hemodynamic deficiencies, and the strength of their link to glaucoma and advancing age, will require epidemiology work which includes measurements in a large number of elderly normal subjects.
There are other, more circumstantial lines of evidence linking normal-tension glaucoma with vascular insufficiency. The first is the association of NTG with migraine (Wang et al. 1997; Curseifen et al. 2000), the latter illness presumably involving dysregulation of the cerebral vasculature (Bednarczyk et al. 1998). Second, several experiments have found abnormal peripheral vascular responsiveness in NTG patients, suggesting that defects in systemic vascular control may be linked to development of glaucomatous optic neuropathy (Gass et al. 1997; O’Brien & Butt 1999). These microvascular abnormalities manifest themselves as excessive responsiveness to endothelin-1 mediated vasoconstriction, implying that endothelin-1 may be involved in glaucoma pathogenesis (Gass et al. 1997). The increased levels of endothelin-1 found in aqueous humor and blood in some reports supports the possibility that elevated levels of this vasoconstrictor may contribute to glaucoma development in some patients (Cellini et al. 1997; Hollo et al. 1998; Noske et al. 1997; Tezel et al. 1997). Third, administration of vasodilators can normalize retrobulbar flow velocities in NTG patients, indicating that for some patients vascular deficiencies in glaucoma may be reversible (Harris et al. 1994).
Increases in IOP worsen ischemia, linking the known and hypothetical risk factors, and potentially contributing to the increased risk for glaucoma in persons with elevated IOP
In vitro models of retinal ischemic-reperfusion injury routinely use acute, severe IOP elevation to provoke apoptosis and to study cell resistance and susceptibility to injury (Ju et al. 2000; Katai & Yoshimura 1999). However, the relationship between IOP within ranges typically seen in NTG and primary open-angle glaucoma (POAG) and ocular blood flow remains incompletely defined.
Data establishing the breadth and stability of the autoregulatory ranges for optic nerve and retinal blood flow in young, healthy individuals cannot, however, be extrapolated to older persons who may also suffer from vascular illness, sleep or medication-related blood pressure reductions, or other changes rendering the eye more susceptible to ischemia. For example, aging per se is a major element in glaucoma risk, yet those factors responsible for the close association of age with disease incidence have not yet been defined (Fafowara & Osuntokun 1997; Harris et al. 2000). While aging is associated with modest elevation of the IOP, senescence is also linked to progressive declines in cerebral and ocular perfusion (Klein et al. 1992; Harris et al. 2000; Nomura et al. 1999). Reduced baseline blood flow suggests that autoregulation may not function in old age as it does in youth, a possibility supported by data from old, atherosclerotic monkeys. In these animals, retinal anaerobic metabolism during ocular hypertension is sharply increased (Hayreh et al. 1994). In similar studies in rats, young, healthy animals display robust choroidal hyperperfusion after ocular hypertension-induced ischemia, but in older rats variable responses occur that may include minimal hyperperfusion or even a no-reflow phenomenon (Matsuura & Kawai 1998). These findings taken together suggest that aging per se can markedly alter the ocular blood flow response to IOP elevations (Matsuura & Kawai 1998), and raise the possibility that aging and/or atherosclerotic vascular changes may render some persons susceptible to ischemia-induced optic nerve head damage (Hayreh et al. 1994).
Emerging evidence supports this hypothesis linking aging, reduced ocular autoregulatory capacity, and ischemia. In POAG and NTG patients, optic nerve head and retinal perfusion are chronically reduced (Michelson et al. 1998; Chung et al. 1999; Grunwald et al. 1999). These reductions in optic nerve head blood flow are greater in persons with lower arterial blood pressure, such that within a group of POAG patients, optic nerve head blood flow directly correlates with mean arterial pressure (Grunwald et al. 1999). Consequently, any reduction in ocular perfusion pressure (via changes in arterial pressure or IOP) will reduce optic nerve head blood flow (Grunwald et al. 1999). In short, glaucoma patients, unlike healthy, young persons, may be characterized not by ocular blood flow autoregulation, but instead by dysfunction of both IOP and ocular blood flow (Flammer et al. 1999; Fig. 2). In the laboratory, some of these patients may be identified by cold pressor testing, hypercapnia stress testing, or other non-clinical techniques. In the future, vascular testing for a characteristic vasospastic response will become part of the examination regime of the glaucoma specialist, but not until the role of ischemia in the disease is better understood, and a proven medical treatment for vasospastic glaucoma subjects is identified.
Clinical management of both blood flow and IOP in glaucoma: implications for treatment
Evidence for the simultaneous clinical management of both IOP and blood flow in patients with glaucoma, in tandem with data showing that both high pressure and ischemia provoke apoptosis in CNS neurons, implies that therapy for glaucoma consider both pressor and vascular factors (Flammer et al. 1999). In this regard, any medical or surgical intervention that lowers IOP should directly benefit the retinal ganglion cells mechanically, and indirectly benefit these cells by relieving ischemia. Ideally, however, medical intervention would reduce IOP, provide additional local vasodilation, and also offer direct neuroprotection. While no single drug currently can boast all of these benefits, it is useful to consider the actions of a single class of medications in terms of this hypothetical framework for medical treatment.
One group of drugs currently used widely in glaucoma therapy are the carbonic anhydrase inhibitors. These drugs reduce IOP, thereby relieving mechanical forces on retinal ganglion cells and increasing ocular perfusion pressure. In addition, systemic carbonic anhydrase inhibition remains a standard method for cerebral vasodilation (Ringelstein et al. 1992). Given the emerging evidence that cerebral ischemia may contribute to normal-tension glaucoma (Stroman et al. 1995; Ong et al. 1995), interventions that can additionally target vascular insufficiency may have special utility in treatment of this form of the disease.
Systemic carbonic anhydrase inhibitors have been used for nearly half a century to lower ocular tension (Becker 1954). However, the protean side effects of systemic carbonic anhydrase inhibitors (chief among them fatigue, diarrhea, nausea, numbness, and loss of appetite) limit their usefulness and have stimulated the search for a viable topical agent (Maren 1987). In humans, carbonic anhydrase I and II are present in the corneal endothelium and in the lens, whereas carbonic anhydrase II is present in the ciliary process and in the retina (Maren 1987, Matsui 1996). More than 99% of the carbonic anhydrase in the ciliary body must be inhibited for physiologically-relevant IOP reductions to occur (Maren 1967). Dorzolamide, a topical carbonic anhydrase II blocker, penetrates to the posterior segment of the eye, significantly lowering IOP in glaucoma patients (Sugrue 2000) with many fewer side effects than systemic acetazolamide (Sugrue 2000; Ponticello et al. 1998). It appears that dorzolamide has a pharmacological effect in the fundus. In a comparison with betaxolol in NTG patients, both drugs lowered IOP equally, but only dorzolamide significantly hastened retinal hemodynamics (Harris 2000).
While it is clear that carbonic anhydrase inhibitors are vasodilators, the mechanisms that link enzyme inhibition to vascular smooth muscle relaxation are not understood. In healthy humans, systemic treatment with acetazolamide increases ocular fundus pulsations and mean flow velocity in the middle cerebral and ophthalmic arteries (Kiss et al. 1999). The mechanism for these changes is independent of nitric oxide, since administration of a nitric oxide synthase inhibitor or L-arginine have no effect on the response (Kiss et al. 1999). Comparing acetazolamide- with CO2-induced vasodilation suggests that similar biochemical cascades may be involved (Taki et al. 1999). Nitric oxide is not a factor in CO2-induced cerebral vasodilation (McPherson et al. 1995); instead, indomethacin abolishes hypercapnic vasodilation, while prostacylin analogues relax cerebral vessels, increasing cGMP and cAMP, much as does elevated CO2 (Parfenova et al. 1994). These results suggest that cyclic nucleotides are involved in hypercapnic vasodilation, via a prostanoid-dependent mechanism (Parfenova et al. 1994). At the receptor level, CO2-induced cerebrovascular relaxation appears to be mediated via glibenclamide-sensitive potassium channels (Faraci et al. 1994). Taken together, these findings suggest that carbonic anhydrase inhibition may relax resistance vessels by inducing vasodilator prostanoids and activating glibenclamide-sensitive potassium channels.
Two studies find that dorzolamide lowers IOP without changing retinal or optic nerve head perfusion in healthy persons (Grunwald et al. 1997; Pillunat et al. 1999). A third study using fluorescein angiography to quantify retinal hemodynamics, as opposed to a laser Doppler device, found hastened arteriovenous passage times in normal subjects (Harris et al. 1996). Dorzolamide also increases retinal arteriovenous dye transit rate in conjunction with IOP reductions in glaucoma patients (Sugrue 2000; Harris et al. In Press). In POAG and NTG, the topical medication also reduces resistance indices in the central retinal and posterior ciliary arteries, suggesting that choroidal and retinal vascular resistance and IOP may be reduced in tandem (Martinez et al. 1999; Tural et al. 2000).
An improvement in ocular blood flow, in order to be clinically significant, must be accompanied by measurable improvements in either oxygen delivery or visual function in the eyes of glaucoma patients. In anesthetized animals, oxygen tension immediately anterior to the optic disc is increased during intravenous administration of either acetazolamide or dorzolamide (Stefansson et al. 1999). In normal tension glaucoma subjects, central visual function measured by contrast sensitivity is significantly increased after four weeks of dorzolamide treatment (Harris et al. 1999). Long term testing on dorzolamide’s effect on the visual field is underway. These promising results suggest that topical dorzolamide could chronically increase blood flow to and oxygen tension within the optic nerve head in glaucoma patients, potentially improving visual function.
The diminished ability of the aging, atherosclerotic eye to autoregulate blood flow magnifies the risk for ischemic damage under conditions that reduce ocular perfusion pressure. Without autoregulation, any rise in ocular tension reduces nutrient delivery, with both elevated IOP and reduced tissue perfusion potentially contributing to retinal ganglion cell apoptosis. Therapies developed from this concept of the simultaneous clinical management of IOP and blood flow should target both mechanical and vascular factors, recognizing that both may play important and interacting roles in disease onset and progression.
Supported by Research to Prevent Blindness, and by NIH grant EY 10801 (Dr Harris).
Corresponding author: Alon Harris, PhD Rotary 134 Department of Ophthalmology Indiana University School of Medicine Indianapolis, IN 46202-5175 Tel: 317 278 2566 Fax: 317 278 1007 e-mail: email@example.com