Cerebrospinal Fluid Pressure and Glaucoma
Intracranial pressure may hold the key to understanding why IOP plays a major role in the development of glaucoma.
Glaucoma is not well understood. It is an optic neuropathy of unknown etiology that results in a characteristic pattern of visual field loss and changes to the optic nerve. Elevated IOP is a well-known risk factor for the development of glaucoma, but it is not always present, such as in cases of normal-tension glaucoma (NTG). Furthermore, an individual with high IOP may not develop glaucoma. For example, only a small percentage of people with ocular hypertension (OHT) ultimately develop glaucoma.1 The mechanism through which IOP contributes to optic nerve damage remains speculative despite immense research efforts.
In addition to IOP, the optic nerve is exposed to intracranial pressure (ICP) as it is surrounded by cerebrospinal fluid (CSF) in the subarachnoid space immediately posterior to the lamina cribrosa. Because the lamina cribrosa separates these two pressurized regions,2 the decrease in pressure that occurs across the lamina cribrosa (IOP - ICP) is known as the translaminar pressure difference. The average IOP is 16 mm Hg, and the average ICP is 12 mm Hg, resulting in a small, posteriorly directed pressure difference across the lamina.3 If this disparity became larger due either to an elevation in IOP or a reduction in ICP, the imbalance could result in glaucomatous changes.
WHAT IS PRESSURE?
The term intraocular pressure is a misnomer. IOP is typically considered to be the pressure inside the eye, but this is mostly incorrect. A better term would be transcorneal pressure difference. Applanation tonometry applies a force outside the eye that equals the force inside the eye (across the cornea) according to the Imbert-Fick principle. This measurement (IOP) is unrelated, however, to the absolute pressure in the eye, because absolute pressure varies significantly with the barometric pressure that is experienced simultaneously by all tissues of the body. Interestingly, the absolute pressure in the eye is of little significance, whereas the transcorneal pressure difference (IOP) does matter in glaucoma. This makes sense when one considers that it is differences in pressure that generate forces. The pressure difference across the cornea (IOP) may be important as a surrogate for the pressure difference across the optic nerve head (IOP - ICP). Instead of comparing the pressure inside the eye to atmospheric pressure outside the eye, as with IOP, perhaps clinicians should compare the pressure inside the eye to the ICP.
A DISRUPTION OF HOMEOSTASIS
Aqueous humor and CSF represent the two circulating fluids of the nervous system, and they share many similarities. Both are produced by carbonic anhydrase-catalyzed reactions and generally represent an ultrafiltrate of blood. In the normal state, the similarity in average IOP and ICP results in a small translaminar pressure difference. Increasing that difference alters the homeostatic balance and generates great posteriorly directed force at the level of the lamina cribrosa, resulting in glaucoma (Figure 1). ICP can affect the optic nerve in diseases such as pseudotumor cerebri, in which the ICP becomes higher than the IOP, resulting in a swelling of the optic nerve head. Similar swelling occurs in ocular hypotony, where the translaminar pressure difference is altered not by elevated ICP but low IOP. Either way, the optic nerve swells secondary to an alteration of the translaminar pressure difference.
If the balance between IOP and ICP is the critical factor, then patients with OHT who do not develop glaucoma may be protected by an elevated ICP, whereas patients with NTG may develop glaucoma because of an abnormally low ICP.
MECHANISM OF ACTION OF GLAUCOMATOUS OPTIC NEUROPATHY
A higher translaminar pressure difference may lead to abnormal function and nerve damage due to changes in axonal transport, deformation of the lamina cribrosa, altered blood flow, or a combination thereof. Clearly, in glaucoma, axonal transport is reduced at the lamina cribrosa,4-8 which is thinner and posteriorly bowed in these diseased eyes.9-11 The thinness of the lamina cribrosa may be a critical factor in the optic nerve's susceptibility to the translaminar pressure difference. A thinner lamina cribrosa would necessitate a higher translaminar pressure gradient (the pressure difference across a specific distance) and create a steeper path that retrograde axonal transport must traverse—much like swimming up a waterfall. Recent data indicate that the lamina thickens (but is still posteriorly displaced) at the earliest detectable stage of experimental glaucoma in monkeys.12,13 This response may represent the body's efforts to protect itself from a high pressure difference.
Ocular blood flow may be inseparably intertwined with ICP. Both IOP and ICP appear to be affected by blood pressure.14 If systemic hypotension results in decreased CSF production and a lower ICP, the risk of glaucoma would presumably increase, which might explain why nocturnal hypotension appears to be a risk factor for NTG. On a smaller scale, differences in IOP and ICP occurring at the optic nerve head may lead to localized areas of decreased blood flow and, ultimately, glaucomatous damage.
My colleagues and I retrospectively reviewed the charts of 62,468 patients who had lumbar punctures at the Mayo Clinic over a 20-year period and identified 189 who met our inclusion criteria, including a complete eye examination by an ophthalmologist.15,16 The ICP was significantly lower in patients with primary open-angle glaucoma (POAG) and NTG and was significantly higher in those with OHT when compared to that of individuals without glaucoma (Figure 2). For perspective, the 3- to 4-mm Hg difference in ICP between patients with and without glaucoma is similar to the difference in IOP between patients with POAG and controls in large population-based studies.17,18 Additionally, a difference of 4 mm Hg in IOP can mean the difference between stability and glaucomatous progression.14,19,20 The apparently small divergence between groups therefore may have large implications.
Many factors continue to limit physicians' understanding of ICP's role in glaucoma. Positional changes affect both ICP and IOP, leading to alterations in the translaminar pressure difference,21-26 and the orbital tissue pressure may transmit forces that influence the retrolaminar CSF pressure.27,28 "Snapshot" measurements of the IOP and ICP may not accurately represent the long-term variations in pressure that are probably more important in a chronic disease like glaucoma. Animal models, mathematical models, and prospective studies should help to clarify the mechanisms of glaucoma.
A pressure imbalance between the two circulating fluids of the nervous system may be the cause of glaucomatous damage to the optic nerve. The ICP is lower than normal in POAG and NTG and elevated in OHT. These findings suggest that an elevated ICP in OHT may counterbalance the high IOP, thus potentially preventing or slowing glaucomatous damage to the optic nerve. Conversely, a reduced ICP in patients with NTG may increase their risk of developing glaucoma.
John Berdahl, MD, is a clinician and researcher with Vance Thompson Vision and Sanford Health in Sioux Falls, South Dakota. He performs collaborative research with the Mayo Clinic in Rochester, Minnesota. Dr. Berdahl may be reached at email@example.com.