Berdahl, John P. MD
Department of Ophthalmology, Vance Thompson Vision, Sioux Falls, SD
Disclosure: The author declares no conflict of interest.
Low cerebrospinal fluid (CSF) pressure has recently been implicated in the pathogenesis of glaucoma. Although little data currently exists, various systemic parameters may affect CSF pressure. CSF pressure increases with increased body mass index (BMI), which corroborates recent studies that have demonstrated elevated BMI may be protective of glaucoma. CSF pressure decreases with age, while the incidence of glaucoma increases with age. Blood pressure has been reported to influence CSF pressure in some studies but not others. Women appear to have a slightly lower CSF pressure than men and CSF pressure shows diurnal fluctuation, as do blood pressure and intraocular pressure. Additionally, postural changes likely alter CSF pressure near the optic nerve. Finally, many factors that may affect CSF pressure (such as medications, genetics, race, and others) have yet to be studied conclusively.
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.
1. Berdahl JP, Allingham RR, Johnson DH .Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma.Ophthalmology. 2008; 115:763–768.
2. Berdahl JP, Fautsch MP, Stinnett SS, et al .Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study.Invest Ophthalmol Vis Sci. 2008; 49:5412–5418.
3. Ren R, Jonas JB, Tian G, et al .Cerebrospinal fluid pressure in glaucoma. A prospective study.Ophthalmology. 2010; 159:259–266.
4. Ren R, Zhang X, Wang N, et al .Cerebrospinal fluid pressure in ocular hypertension.Acta Ophthalmol. 2011; 89:142–148.
5. Mitchell P, Lee AJ, Wang JJ, et al .Intraocular pressure over the clinical range of blood pressure: Blue Mountains Eye Study findings.Am J Ophthalmol. 2005; 140:131–132.
6. Klein BE, Klein R, Linton KL .Intraocular pressure in an American community. The Beaver Dam Eye Study.Invest Ophthalmol Vis Sci. 1992; 33:2224–2228.
7. Varma R, Ying-Lai M, Francis BA, et al .Prevalence of open-angle glaucoma and ocular hypertension in Latinos: the Los Angeles Latino Eye Study.Ophthalmology. 2004; 111:1439–1448.
8. Nangia V, Bhojwani K, Matin A, et al .Intraocular pressure and arterial blood pressure: the Central India Eye and Medical Study.Arch Ophthalmol. 2009; 127:339–340.
9. Xu L, Wang H, Wang Y, et al .Intraocular pressure correlated with arterial blood pressure: the Beijing Eye Study.Am J Ophthalmol. 2007; 144:461–462.
10. Pasquale LR, Willett WC, Rosner BA, et al .Anthropometric measures and their relation to incident primary open-angle glaucoma.Ophthalmology. 2010; 117:1521–1529.
11. Han Y, McCulley TJ, Horton JC .No correlation between intraocular pressure and intracranial pressure.Ann Neurol. 2008; 64:221–224.
12. Kirk T, Jones K, Miller S, et al .Measurement of intraocular and intracranial pressure: is there a relationship? Ann Neurol. 2011; 70:323–326.
13. Sajjadi SA, Harirchian MH, Sheikhbahaei N, et al .The relation between intracranial and intraocular pressures: study of 50 patients.Ann Neurol. 2006; 59:867–870.
14. Preston JE .Ageing choroid plexus-cerebrospinal fluid system.Microsc Res Tech. 2001; 52:31–37.
15. Asrani S, Samuels B, Thakur M, et al .Clinical profiles of primary open angle glaucoma versus normal tension glaucoma patients: a pilot study.Curr Eye Res. 2011; 36:429–435.
16. Ren R, Wang N, Zhang X, et al .Cerebrospinal fluid pressure correlated with body mass index.Graefes Arch Clin Exp Ophthalmol. 2012; 250:445–446.
17. Lin JS, Liu JH .Circadian variations in intracranial pressure and translaminar pressure difference in Sprague-Dawley rats.Invest Ophthalmol Vis Sci. 2010; 51:5739–5743.