Are intracranial pressure fluctuations important in glaucoma?

Authors: Peter Wostyna, Veva De Grootb, Kurt Audenaertc and Peter Paul De Deynd, e

Glaucoma is one of the leading causes of irreversible blindness. Primary open-angle glaucoma (POAG), the most common type, is a progressive optic neuropathy with characteristic structural changes in the optic nerve head and functional changes in the visual field. Mechanical and vascular theories for the pathogenesis of glaucomatous optic neuropathy have been proposed. Elevated intraocular pressure (IOP) is a strong risk factor, although a subset of POAG patients has normal IOP and is designated normal tension glaucoma (NTG). Clearly, factors other than IOP are likely to be involved in retinal ganglion cell death in glaucoma. An intriguing finding of recent studies is that intracranial pressure (ICP) is lower in patients with POAG and NTG when compared with nonglaucomatous control subjects. It has been suggested that the relationship between IOP and ICP may play a fundamental role in the development of glaucoma. A decreased ICP could result in an increased trans-lamina cribrosa pressure difference (IOP minus ICP) and lead to glaucomatous damage. In the present paper, we raise the question of whether ICP fluctuations also may be important in glaucoma. The effect of ICP fluctuation might be comparable to that of IOP fluctuation, which has been recognized as an independent risk factor for glaucoma progression.

a Department of Psychiatry, PC Sint-Amandus, Reigerlostraat 10, 8730 Beernem, Belgium
b Department of Ophthalmology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Antwerp, Belgium
c Department of Psychiatry, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium
d Department of Neurology and Memory Clinic, Middelheim General Hospital (ZNA), Lindendreef 1, 2020 Antwerp, Belgium
e Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium

Highlights

The cerebrospinal fluid pressure is lower in patients with glaucoma. This could result in an abnormally high trans-lamina cribrosa pressure difference. Repeated mechanical stress is more harmful than steady stress. Fluctuations of the cerebrospinal fluid pressure may be important in glaucoma.

Introduction

Glaucoma is one of the leading causes of irreversible blindness . Primary open-angle glaucoma (POAG), the most common type, is a progressive optic neuropathy with characteristic structural changes in the optic nerve head and functional changes in the visual field and . Although elevated intraocular pressure (IOP) remains one of the most important risk factors for POAG, it was reported that approximately 20–90% of patients with POAG, with percentages seeming to vary according to race, have normal IOP measurements, a condition known as normal tension glaucoma (NTG) , , , , and . In addition, many patients with POAG are still undergoing progressive visual field loss and/or optic disc cupping despite normalization of IOP with pressure-lowering treatment strategies and . Clearly, factors other than IOP are likely to be involved in the optic neuropathy of POAG . Furthermore, not all subjects with elevated IOP have glaucoma. Patients in whom the optic nerve and visual field show no signs of glaucomatous damage but the IOP is above the normal range are classified as having ocular hypertension (OHT). Only a small percentage of such patients may convert to POAG . The precise mechanisms by which elevated IOP may lead to optic nerve damage are still unclear. Mechanical and vascular theories for the pathogenesis of glaucomatous optic neuropathy (GON) have been presented , and . According to the mechanical theory, GON may be a direct consequence of increased IOP leading to regions of high shear stress and strain in the lamina cribrosa , and . At this site, increased IOP may result in mechanical forces on retinal ganglion cell axons with subsequent cell injury , and . The vascular theory considers GON as a consequence of insufficient blood supply due to either elevated IOP or other risk factors reducing ocular blood flow and .
An intriguing finding of recent studies is that intracranial pressure (ICP) is lower in patients with POAG and NTG when compared with nonglaucomatous control subjects , and . It has been suggested that the relationship between IOP and ICP may play a fundamental role in the development of glaucoma . A decreased ICP could result in an increased trans-lamina cribrosa pressure difference (IOP minus ICP) and lead to glaucomatous damage . A higher trans-lamina cribrosa pressure difference may lead to abnormal function and potential optic nerve damage due to changes in axonal transport, deformation of the lamina cribrosa, altered blood flow, or a combination of them all . In the present paper, we raise the question of whether ICP fluctuations also may be important in glaucoma. The effect of ICP fluctuation might be comparable to that of IOP fluctuation, which has been proposed as an independent risk factor for glaucoma progression .

Presentation of the hypothesis

The cerebrospinal fluid pressure is lower in patients with glaucoma

Recent research findings suggest the potential pathogenic role of an abnormally low cerebrospinal fluid pressure (CSFP) in the development of POAG and NTG. In a retrospective case-control study, Berdahl et al. reported the intriguing new observation that mean CSFP was 33% lower in a group of 28 patients with POAG than in a control group of 49 nonglaucomatous patients (9.2 ± 2.9 vs. 13.0 ± 4.2 mm Hg or 124 ± 39 vs. 177 ± 57 mm H2O; P < 0.00005). Subjects were considered to have POAG if they were diagnosed with POAG by a glaucoma specialist, had characteristic optic nerve changes, and had visual field loss consistent with glaucoma . The criteria did not include IOP, because POAG occurs across the entire spectrum of IOP and . Linear regression analysis showed that cup-to-disc ratio correlated independently with IOP (P < 0.0001), CSFP (P < 0.0001), and the trans-lamina cribrosa pressure difference (P < 0.0001) . Multivariate analysis demonstrated that larger cup-to-disc ratio (P < 0.0001) was associated with lower CSFP . The authors noted that their observation supports the concept that an abnormal high trans-lamina cribrosa pressure difference, whether the result of elevated IOP, reduced CSFP, or both, plays an important role in glaucomatous optic nerve damage . The lamina cribrosa forms the bottom of the optic cup in the optic nerve head and acts as a pressure barrier between the intraocular pressure space and the retrobulbar CSF pressure space and . Normally, the IOP ranges from 10 to 21 mm Hg, whereas the CSFP ranges from 5 to 15 mm Hg . From a mechanical perspective, a similar posteriorly directed force is caused by either a lower pressure on the CSF side of the lamina or a higher pressure on the intraocular side .
In another study with similar design, Berdahl et al. compared CSFP measurements in 57 subjects with POAG, 11 subjects with NTG (a subset of POAG), and 27 subjects with OHT with 105 age-matched control subjects without glaucoma (66 in the age-matched control group for comparison with POAG and the NTG subset and 39 in the age-matched control group for comparison with the OHT group). The CSFP was significantly lower in POAG compared with age-matched control subjects without glaucoma (9.1 ± 0.77 vs. 11.8 ± 0.71 mm Hg; P < 0.0001). The subjects with NTG also had a lower CSFP compared with the control subjects (8.7 ± 1.16 vs. 11.8 ± 0.71 mm Hg; P < 0.01). Furthermore, the CSFP was higher in OHT than in age-matched control subjects (12.6 ± 0.85 vs. 10.6 ± 0.81 mm Hg; P < 0.05). The authors concluded that a reduced CSFP may play an important role in the development of POAG and NTG . Conversely, the elevated CSFP in OHT may counterbalance the elevated IOP, potentially preventing or slowing glaucomatous optic nerve damage in this patient population .
The findings of Berdahl and colleagues were recently confirmed by a prospective study which compared CSFP in open-angle glaucoma patients and nonglaucomatous control subjects . The study included 43 patients with open-angle glaucoma differentiated into 14 patients with normal-pressure glaucoma and 29 patients with high-pressure glaucoma, and 71 control subjects . The CSFP was significantly lower (P = 0.013) in the normal-pressure glaucoma group (9.5 ± 2.2 mm Hg) than in the high-pressure glaucoma group (11.7 ± 2.7 mm Hg), in which it was significantly (P < 0.001) lower than in the control group (12.9 ± 1.9 mm Hg). The trans-lamina cribrosa pressure difference was significantly (P < 0.001) higher in the high-pressure glaucoma group (12.5 ± 4.1 mm Hg) than in the normal-pressure glaucoma group (6.6 ± 3.6 mm Hg), in which it was significantly (P < 0.001) higher than in the control group (1.4 ± 1.7 mm Hg). The extent of glaucomatous visual field loss was positively correlated with the height of IOP, negatively correlated with the height of CSFP, and positively correlated with the height of the trans-lamina cribrosa pressure difference . The authors concluded that a low CSFP in patients with normal IOP could lead to glaucomatous damage.

Pulsatile mechanical stress is more damaging

It has also been shown that pulsatile mechanical load has a more dramatic effect on cell physiology than steady mechanical load , and . Indeed, both in vivo and in vitro, there is evidence that repeated mechanical stress on neurons is more harmful than steady stress . The response of neurons to deformation is known to be dependent on both the magnitude and rate of mechanical strain and . It is believed that injury occurs more readily at high strain rate . Strain rate associated with glaucoma is expected to be much lower than that associated with head injury . During glaucoma, diurnal variations in IOP give rise to cyclic variations in stress and strain in the cells in the optic disc . Although conflicting data exist and , there are several studies concluding that IOP fluctuations are more strongly correlated to progression of visual field damage than the level of mean IOP and .
In vitro, in neuron-like cells, Edwards et al. showed that during cyclical shear stress, which might mimic cell exposure conditions associated with diurnal variations in IOP or repetitive strain injury, the strain rate increased by over an order of magnitude from the first to all subsequent cycles, suggesting that the cell and/or its polymer network became more elastic upon cyclic shear stress application. The authors measured the degree of cytoskeletal polymerization before and after exposure of cells to cyclic shear stress and found that the fraction of polymerized tubulin in the cell relative to total tubulin decreased by a factor of 2 after six cycles of shear stress . This study also demonstrated that the extent of injury, as indicated by the fraction of cells with fragmented DNA, was three times higher for cyclic shear stress than for steady shear stress. This might be related to the change in strain rate and/or cytoskeletal reorganization associated with cyclic stress .
In an earlier study, Triyoso and Good showed that application of pulsatile shear stress to a neuron-like cell in vitro induces G protein activation, nitric oxide synthase activation, new protein synthesis, entry of calcium into the cell, and DNA fragmentation without lactate dehydrogenase release immediately after injury.

Fluctuations of the cerebrospinal fluid pressure may be a risk factor

Given the theory that IOP fluctuation is an independent risk factor for ganglion cell damage , it seems reasonable to speculate that the resulting translaminar pressure difference fluctuation may play an important role in the pathogenesis of glaucoma. If this is the case, the question arises whether fluctuations in ICP may result in similar translaminar pressure difference fluctuations, ultimately leading to glaucomatous damage. Interestingly, a recent study found that the prevalence of glaucomatous disease in patients with normal pressure hydrocephalus (NPH) was 18.1%, which was much higher than that of the age-matched non-NPH controls with hydrocephalus (5.6%) . It is generally assumed that NPH is a disorder of decreased CSF absorption . During the initial stage of the disease, intracerebroventricular pressure may increase, thereby leading to ventricular enlargement with stretching of the periventricular parenchyma . As the ventricles enlarge, cerebrospinal fluid pressure returns to normal so that it is within the normal range at lumbar puncture . However, the name of this condition is misleading because continuous ICP monitoring demonstrates intermittently raised ICP in association with B-waves . B-waves are slow and rhythmic oscillations in ICP with a period of 0.5–2 min . Given that ICP rises and falls during B-waves, our group recently hypothesized that such ICP fluctuations may result in significant fluctuations of the translaminar pressure difference . This could exert repetitive shear stress on the lamina cribrosa and ganglion cell axons, leading to glaucomatous damage. Periodic ICP fluctuations may also exist in non-NPH glaucoma patients. Indeed, ICP is not a static pressure and varies with respiration, with cardiac pulsation and during Valsalva maneuvers such as when straining or coughing and . Whereas the existence of a circadian (24-h) variation in IOP is well known, a circadian rhythm of ICP is less clear, with only a few reports in the literature . However, given that most individuals sleep in the supine position and are upright during the day, it is important to note that ICP varies according to changes in body position . In a standing position, the ICP falls and can be negative (lower than the atmospheric pressure) . Based on the above, one may, therefore, postulate that large fluctuations in ICP may be a risk factor for glaucoma progression. However, under certain conditions, ICP fluctuations may be accompanied by corresponding fluctuations of IOP. For example, the IOP also significantly increases during the Valsalva maneuver . Furthermore, IOP is significantly influenced by body position with higher readings found in the supine relative to the upright position and . It could be argued that if IOP changes simultaneously with ICP, then the trans-lamina cribrosa pressure difference would remain unchanged. However, more likely is the situation where both IOP and ICP change, but to different degrees and on different periodicity. Even assuming that the ICP fluctuations result in translaminar pressure difference fluctuations, the question remains whether such pressure difference fluctuations could be harmful to the optic nerve fibers.

Conclusions

In conclusion, the hypothesis of the present article is that large fluctuations in ICP may be an independent risk factor for glaucoma progression. It should be stressed that at this stage the present hypothesis remains unproven and speculative. Further study will be necessary to determine the possible role of ICP fluctuations in glaucoma. If confirmed, this hypothesis could provide new important insights into the pathogenesis of glaucoma.

Conflict of interest

None declared.

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Source: Science Direct