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Editors Selection IGR 15-4

Response

Comment by Rand Allingham & John Berdahl on:

20979 Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma, Berdahl JP; Allingham RR; Johnson DH, Ophthalmology, 2008; 115: 763-768

See also comment(s) by Jonathan Crowston • William Morgan • Jost Jonas • Louis Pasquale • Keith Martin • Kuldev Singh •

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We are very pleased to have our article chosen for discussion in IGR's glaucoma dialogue section and thankful to the experts for their clear and insightful commentary. The positive comments about the potential impact of low cerebrospinal fluid (CSF) pressure in glaucoma are quite encouraging. Most of the major criticisms of our study revolve around its retrospective design. We readily acknowledge that many biases could be present despite our best efforts to minimize them. We identified over 30,000 patients who had lumbar puncture (LP) and cross referenced that list with those diagnosed with glaucoma-ultimately identifying only 28 subjects who met all inclusion criteria. The large number of LPs reported allows other investigators to estimate number of LPs needed to identify an adequate study group. Importantly, the LPs included children and young adults who are much less likely to be diagnosed with glaucoma. Indications for LP were generally similar between groups; and regardless of indication for LP the glaucoma group had lower CSF pressure. Subjects using topical anti-glaucoma medications did not appear to have lower CSF pressure when compared to glaucoma subjects not taking topical anti-glaucoma medications (i.e., subjects with filtering surgery). Although the numbers are small, this suggests that anti-glaucoma drops did not lower CSF pressure. Importantly, IOP measurements and CSF pressure measurements were not taken simultaneously. Although the vast majority of LPs were performed within one year of the most recent eye exam, the large time interval means that either IOP or CSF pressure could have changed during that interval. Additionally, a 'moment in time' measurement may not reflect CSF pressure (or IOP) over time. It would have been ideal to use average IOP or untreated IOP in calculations; however this data was present only in a minority of patients. Since relatively few subjects met all inclusion criteria, multivariable analysis may have been unable to detect important associations such as CSF pressure and antihypertensive medications or visual field severity. Many factors could alter CSF pressure in the retrolaminar subarachnoid space. Although CSF pressure measured by lumbar puncture may not represent the true retrolaminar CSF pressure, it is the most accessible measurement available and the only surrogate available for our retrospective study. Obtaining simultaneous IOP and CSF pressure measurements in a standard position would be the optimal method to determine the translaminar pressure difference. Furthermore, 'normal' CSF pressure is usually expressed as a range of values.

Although CSF pressure measured by lumbar puncture may not represent the true retrolaminar CSF pressure, it is the most accessible measurement available and the only surrogate available for our retrospective study

Although both groups had a mean ICP within the 'normal' range, the control group had a mean CSF toward the upper end of normal. This demonstrates the importance of establishing a comparable control group, and avoiding the use of historical controls. The overarching concern is that our control group may not be representative of the 'normal population'. One important consideration may be age. Although, age did not appear to be an independent predictor of CSF pressure in our data, most historically 'normal' values for ICP have been ascertained in young presumably healthy volunteers. This 'normal' data may not be comparable to our more aged glaucoma population. However, we do not have CSF pressure data on normal or young subjects at the Mayo Clinic who were outside of our control group. Examining this information would be helpful to determine if bias was introduced by our approach in selecting a control group.

Although all subjects were examined by a fully-trained ophthalmologist, the cup-to-disk ratio is a notoriously incomplete characterization of the optic nerve, so caution should be used interpreting the relationship between cup-to-disk ratio and CSF pressure. Structural properties of the lamina cribrosa such as thickness, rigidity, and elasticity likely play an important role in optic nerve cupping. The translaminar pressure gradient (IOP-CSF pressure/thickness of the lamina cribrosa) may actually a key determinant of optic nerve cupping.

Our results imply that CSF pressure may be an important component in the pathogenesis of glaucoma. We agree that studies using animal models where IOP and CSF pressures can be manipulated will be essential to better elucidate disease mechanisms. As stated by the experts, there is a clear need for a reliable non-invasive method for measuring CSF pressure. In the meantime, the ethical issues surrounding a prospective study of CSF pressure in humans (especially in a normal control group) for whom no known treatment can be offered is clearly problematic, so other innovative approaches to study this finding will be essential.

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