For over a century glaucoma was conceptualized as a disease characterized by high intraocular pressure (IOP) that causes the optic nerve to deteriorate. Clinicians and researchers long focused on glaucoma as an “inside the eye” disease. Over time, the definition of glaucoma has evolved into an optic neuropathy consisting of characteristic visual field loss and characteristic optic nerve changes, with the most important and only clear modifiable risk factor being intraocular pressure (IOP). However, that definition certainly does not encompass the underlying pathophysiology of glaucoma, which is far from fully understood.
Increasing data suggest that cerebrospinal fluid pressure (CSFP) may play an important role in the pathogenesis of glaucoma.1–4 Low CSFP may place a patient at risk for glaucoma while elevated CSFP may protect against it. The eye is an extension of the central nervous system and the majority of the optic nerve is bathed in CSF. Factors outside the eye, including CSFP, may play an important role in causation of the disease. Assuming that CSFP plays a role in glaucoma, we will discuss our understanding of systemic parameters that can affect it.
SYSTEMIC ASSOCIATIONS OF CSF PRESSURE
Before delving into systemic parameters that affect CSFP, it is worth considering the similarities between CSF and the aqueous humor. The aqueous humor and the CSF are strikingly similar in chemical composition. Both are clear fluids with low protein content, which protect and nourish the surrounding structures. Average IOP and average CSFP are quite similar, the average IOP being about 15 mmHg and the average CSFP about 11 mmHg.2 In population-based studies,5–9 that pressure, body mass index (BMI) and central corneal thickness correlate positively with IOP, while age correlates negatively.10 If CSFP and IOP were meant to remain in homeostatic balance, one could hypothesize that similar correlations could be found in CSFP.
Numerous studies have attempted to demonstrate a correlation between IOP and CSFP, primarily in order to use IOP as a noninvasive way to detect elevated CSFP. Although some studies have found IOP to correlate loosely with CSFP, the only prospective masked study found little correlation.11–13 Experimental studies of rodents have shown that CSF production decreases with age. These data are corroborated by a large retrospective study that showed a significant decline in CSFP that begins near the age of 65.14
Recent data indicate that elevated BMI may be protective against glaucoma, while low BMI may place a patient at risk for glaucoma. Pasquale et al10 showed that women with an elevated BMI are protected from glaucoma despite their high IOP. They suggested that perhaps a hormone found in fat offered neural protection against glaucoma. However, we and others have suggested that an elevated CSFP may be found in the context of an elevated BMI and may protect against glaucoma. Asrani et al15 have recently demonstrated that a low BMI places patients at risk for normal-tension glaucoma. Prospective and retrospective studies have confirmed that increased BMI does lead to increased CSFP (Fig. 1).16
Other studies have explored whether or not hypotension or nocturnal hypotension is a risk factor for glaucoma. Some studies have shown that blood pressure correlates positively with CSFP and others have shown no correlation. This is a particularly difficult parameter to investigate because of the widespread use of antihypertensive medications that may not only alter the blood pressure/CSFP relationship but may also directly affect CSFP. Further prospective investigation of the relationship between IOP, blood pressure, and CSFP will likely help our understanding of these mechanisms.
Some models have shown a lack of a diurnal variation in CSFP. However, large retrospective studies have shown a diurnal variation in which CSFP during the evening may rise by 1 mmHg.17 Numerous medications affect CSFP. Osmotic agents such as mannitol lower it, as do carbonic anhydrase inhibitors and diuretics. A number of medications, such as tetracyclines, retinoids and others have idiosyncratic effects on CSFP as evidenced by inciting idiopathic intracranial hypertension. Low pressure headache syndrome is a fairly recently described phenomenon in which spontaneous CSFP leaks can lead to headache. This has yet to be investigated in combination with glaucoma to determine if patients with low CSFP have a higher incidence of glaucoma.
In summary, CSFP appears to increase at night and correlate positively with BMI. Age and female sex appear to correlate negatively with CSFP and more data are required to determine the relationship between IOP, CSFP and blood pressure. Additionally, the role of medications in the increase or decrease of CSFP needs to be elucidated. Emerging data continue to confirm that CSFP plays an important role in the pathogenesis of glaucoma, offering the potential to redefine our basic understanding of this disease. It also potentially provides entirely new therapeutic targets to treat glaucoma. By manipulating the IOP/CSFP gradient, optic nerve damage could be slowed or halted.
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