Does Intracranial Pressure Influence the Development of Glaucoma?

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory P. Van Stavern, MD Does Intracranial Pressure Influence the Development of Glaucoma? Michael S. Lee, MD, Timothy J. McCulley, MD, Andrew G. Lee, MD, Gregory P. Van Stavern, MD Introduction—Andrew Lee, MD and Gregory Van Stavern, MD Optic nerve damage can result from changes in both intraocular and intracranial pressure (ICP). Both are believed to cause damage to the optic nerve due to a change in the pressure gradient across the lamina for both. Recently, some investigators have proposed that ICP may directly contribute to the development and progression of glaucoma. Two authors debate this topic. Pro—Intracranial Pressure Influences the Development of Glaucoma Timothy J. McCulley, MD, Professor and Chair, Richard S. Ruiz, MD, Distinguished University Chair, Department of Ophthalmology, McGovern Medical School, The University of Texas, Houston Our understanding of the role ICP plays in the pathophysiology of glaucoma is evolving. The change in pressure across the lamina cribrosa (LC), or translaminar pressure gradient (TPG), has been proposed to be the primary factor, with intraocular pressure (IOP) being just 1 of 2 determinates, ICP being the other. Recent evidence near uniformly supports the assertion that ICP impacts the occurrence and severity of glaucoma. Cerebrospinal fluid (CSF) surrounds and fills cavities of the brain and spinal cord.1–5 ICP is most commonly measured through a lumbar puncture (LP) and described in units cmH2O. IOP is most commonly reported in units of mm Hg. One cmH2O is roughly equal to 0.74 mm Hg. Normal adult ICP is between 6.5 and 20 cmH2O (5 and 15 mm Hg).5 The significance of ICP measurements between 20 and 25 cmH2O (15 and 18 mm Hg) is unclear. ICP of . 25 cmH2O (18 mm Hg) is considered elevated. There are Department of Ophthalmology (MSL), University of Minnesota, Minneapolis, Minnesota; Department of Ophthalmology (TJM), University of Texas, Houston, Texas; Department of Ophthalmology (AGL), Houston Methodist, Houston, Texas; and Department of Ophthalmology and Visual Sciences (GPVS), Washington University in St. Louis, St. Louis, Missouri. The authors report no conflicts of interest. Address correspondence to Gregory P. Van Stavern, MD, Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St Louis, MO 63110; E-mail: [e-mail] Lee et al: J Neuro-Ophthalmol 2023; 43: 423-429 several physiologic or normal variations in ICP. For example, ICP changes with age, being lower in children, rising with adulthood, and then again declining with advancing age.6 ICP fluctuates slightly (i.e., CSF pulsation) with respiration and the cardiac cycle. It is believed that arterial pressure contributes directly to ICP. The balance between mean arterial pressure (MAP) and ICP is important; the difference between MAP and ICP determines cerebral perfusion pressure. Venous pressure is also relevant because elevations can result in a reduction in the rate of CSF resorption, leading to increased ICP. Body position may also affect ICP and its measurement.7,8 The numerous factors influencing ICP is relevant to the current discussion because instability or changes in TPG, in addition to the absolute or mean TPG, may contribute to glaucomatous optic nerve injury. It is well established that ICP can have a profound effect on the structure of the optic nerve. Edema of the optic disc is an accepted consequence of elevation in ICP, which is attributable to alterations in axoplasmic flow. There are numerous studies demonstrating structural changes of the lamina cribrosa, with alteration of the TPG, precisely documented with modern imaging techniques. Ophthalmodynamometry measures intraocular vasculature compressibility and is believed to be an indirect measure of ICP. Although the precision of ophthalmodynamometry may be debated, the correlation between compressibility of central retinal vein and ICP is well established.9 An even more easily appreciated effect of ICP on optic disc blood flow is the cessation of spontaneous venous pulsations (SVP) with elevation in ICP. Cessation is believed to occur when ICP, transmitted to the cavernous sinus and subsequently superior ophthalmic vein, rises above intraocular systolic pulse pressure.10,11 Therefore, it is plausible that local alterations in optic nerve structure, blood supply, or axonal 423 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point transport could result from changes in ICP, all of which have been considered as possible mechanisms central to the development of glaucoma. The theoretically reasonable mechanisms combined with clinical experience strongly support the assertion that the ICP is a determinant of the development of glaucomatous optic nerve injury. Lower ICP can be considered a risk factor for glaucoma, and conversely, high ICP is likely protective against the development of glaucoma. Most relevant is categorizable in 2 groups: those that assess the correlation between ICP and glaucoma and those that look at the mechanical effect of alterations in the TPG and the structure of the optic nerve. Evidence dates to as early as 1979, when Yablonski et al12 conducted a study in cats. By cannulating the cisterna magna, they lowered the animals’ ICP to negative 5 mm Hg. In 1 eye, they also lowered the IOP to 0 mm Hg. Histologic findings consistent with glaucoma developed in the fellow eye with normal IOP. This strongly supports the notion that low ICP and, more specifically, the TPG are central to the development of glaucoma. In 2008, Berdahl et al13 compared ICP between patients with and without primary open-angle glaucoma (POAG). By reviewing the database at the Mayo clinic, 28 POAG patients were identified out of 37,786 patients who underwent LP. Forty-nine individuals without glaucoma comprised the control group. Mean CSF pressure was found to be lower in POAG patients (9.2 ± 0.77 mm Hg) than in control subjects (11.8 ± 0.71 mm Hg, P , 0.0001). In addition, their findings suggested that low ICP may contribute to the development of glaucoma in some patients with IOP that falls within normal range: patients with NTG had a mean ICP that was even lower than those with POAG (8.7 ± 1.16 mm Hg vs 9.1 ± 0.77 mm Hg, P , 0.01).14 These investigators also found that higher ICP may be protective in some patients with elevated IOP: mean ICP was higher in patient with OHT (12.6 ± 0.85 mm Hg) than in control subjects (10.6 ± 0.81 mm Hg, P , 0.05).14 All these differences persisted and remained statistically significant when the TPG was calculated (subtracting mean ICP from mean IOP) and compared between the groups. Subsequent reports support these findings. Ren et al15 prospectively assessed ICP in patients with POAG (n = 29), those with NTG (n = 14), and control subjects (n = 71). Their findings were like that of Berdahl et al: ICP was lowest in the NTG group (9.5 ± 2.2 mm Hg), intermediate in the POAG group (11.72.7 mm Hg), and highest in the control group (12.9 ± 1.9 mm Hg). The difference between TPG of glaucomatous and control patients was even greater: NTG (6.6 ± 3.6 mm Hg), POAG (12.5 ± 4.1 mm Hg), and control patients (1.4 ± 1.7 mm Hg). This study’s strengths include being prospective and using direct measurement of ICP through LP. One year later, the same group published a study correlating the degree of optic nerve damage with TPG.16 In 2014, Siaudvytyte et al17 published the results of an investigation that measured TPG in patients with POAG 424 (n = 9), those with NTG (n = 9), and healthy control subjects (n = 9). They also reported lower ICP in patients with NTG and POAG than in control subjects. More recently Siaudvytyte et al18 assessed TPG and neuroretinal rim area (NRA) in patient with POAG and NTG. They reported that TPG was higher in glaucoma patients and that there was a relative reduction of NRA in patients with higher TPG in the NTG group. Taken together, most data that correlate ICP and glaucoma come from 3 groups. The data from the Mayo Clinic is robust and, although retrospective, used a rigid well-defined study design.13,14 The data from the group in Beijing is impressive in that it is prospective and used direct measurement of ICP.15,16 The final group from Lithuania presents data in agreement.17,18 Another consideration is that the retrolaminar space may have lower pressure compared with other CSF compartments, with a larger TPG than that based on LP results.19,20 In 1 study, CT cisternography was used to assess CSF exchange between spaces in patients with NTG (n = 18) compared with control subjects (n = 4).19 “A difference in the concentration gradients between the contrast-loaded cerebrospinal fluid within the intracranial spaces and the subarachnoid space of the optic nerves in the group of NTG patients compared with control subjects,” indicative of a disturbance in CSF dynamics possibly explained by optic nerve compartmentation. They did not measure ICP in their patient cohorts. Further investigation into NTG and ICP, specifically the retrolaminar compartment pressure, will be helpful. Declining ICP likely in part explains the increased prevalence of glaucoma seen in the aging population. Mean ICP decreases with advanced age. Using the Mayo Clinic database, Fleischman et al21 identified more than 12,000 patients who had their ICP measured through LP. In adults from 20 to 49 years of age, mean ICP was found to be 11.6 mm Hg. ICP began to decline noticeably in the 50–54 years age-group, it was found to be 11.2 mm Hg (P , 0.001). This trend continued with further older age groups and correlated with the age-related increase in glaucoma incidence. This further supports the assertion that low ICP is a risk factor for glaucoma.22 Evidence also supports the assertion that high ICP may be protective against developing glaucoma. As mentioned previously, the study by Berdahl et al compared ICP in patients with OHT (n = 27) with a control group (n = 39).14 They found that the mean ICP was higher in patients with OHT (12.6 ± 0.85 vs 10.6 ± 0.81 mm Hg, P , 0.05). Ren et al16 published study results assessing 17 patients with OHT and 71 nonglaucomatous control subjects, who prospectively underwent LP. Again, IOP was reported to be significantly higher in the OHT group than in the control group (16.0 ± 2.5 mm Hg vs 12.9 ± 1.9 mm Hg, P , 0.001). This strongly suggests that a slight elevation in ICP balancing elevated IOP may be protective and at least, in part, explain why some patients with ocular hypertension do not progress to glaucoma. Another interesting finding, which further provides evidence that ICP may relate to glaucoma comes from Lee et al: J Neuro-Ophthalmol 2023; 43: 423-429 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point our study of patient with normal pressure hydrocephalus (NPH). NPH is a disorder in which patients accumulate or “fail to adequately drain” CSF despite normal ICP, which is often managed by placement of a CSF shunt, dropping ICP to low or subnormal levels. In 2009, Chang and Singh published the astute observation that the prevalence of glaucoma was higher in the NPH group (n = 72) than in an agematched control group (n = 72): 18.1% vs 5.6%, P = 0.02.23 Glaucoma in this patient group is likely a complication of the treatment (i.e., CSF shunting).23,24 By lowering ICP, we may be creating an unfavorably large TPG resulting in glaucomatous optic nerve damage. The LC divides the intraocular and CSF space and is the probable site of axonal injury in glaucoma. Positional changes of the LC would be expected to occur with alteration in the TPC regardless of whether IOP or ICP changed. Anterior movement is expected with decreasing IOP. Conversely, posterior displacement is expected with decreased ICP. This has been documented in a case report: enhanced-depth SD-OCT showed posterior movement of the LC with reduction in the retrolaminar pressure following optic nerve fenestration by 137 mm.25 Although LC movement with increased IOP has been described,26–28 displacement of the LC with a reduction in IOP has received more attention.29–34 Lee et al29,30 used enhanced depth imaging spectral-domain (SD) OCT to assess patients before and after trabeculectomy. They reported a significant reduction in mean LC depth following surgery to reduce IOP. Reis et al31 assessed changes in LC position and prelaminar tissue thickness (PTT). In 22 patients using SD-OCT, they demonstrated a mean anterior movement of LC (1.8 mm) and increase in PTT (1.7 ± 13.3 mm), with a mean of 4.7 ± 55 mm Hg decrease in IOP. Yoshikawa et al32 published similar results using 3dimensional (3D) swept-source optical coherence tomography (SS-OCT). Taken together, movement of the LC has been documented with alterations in the TPC, due to changes in both IOP and ICP. There are several additional studies, all with congruous findings.33,34 If or how displacement and/or movement of the LC leads to glaucomatous axonal loss has not been determined; however, there are several possible mechanisms. For example, Jonas et al35 noted that the LC to be thinner and presumably less stable in patients with glaucoma. Park et al33 compared LC displacement and PTT between patients with POAG and angle closure glaucoma. They found relatively more pronounced changes in patients with angle closure. Analogous to bone remodeling seen with intracranial hypotension, they suggest that this difference may reflect tissue remodeling that occurs with long-term deformation.36–38 This finding may prove important as the role that remodeling of the LC collagen matrix plays in glaucoma becomes better understood. It has also been suggested that instability or vacillations in the LC position, brought on by fluctuations in the TPG may be more damaging than stable displacement.39 ICP also is not stable and as noted above is responsive to a myriad of external factors, such as the cardiac and respiratory cycles, body position, time of day, and compartmentation. In 1 report, the magnitude of LC movement was found to be greater with variation in ICP as compared with an equal change in IOP.34 Perhaps, relatively low and/or fluctuant ICP (frequency and/or amplitude) will prove to be key factors in the development of glaucoma. In closing, published data are very suggestive that ICP is a risk factor for glaucoma. This may help explain the higher frequency of glaucoma seen in older populations. Low ICP may, in part, explain normal tension glaucoma (NTG). Evidence suggests that low ICP following CSF shunting is responsible for the increased incidence of glaucoma observed in patients with normal pressure hydrocephalus. Evidence suggests that high ICP is protective against glaucoma in patients with ocular hypertension. Structural alteration of the LC has been documented with changes in the TPG. Distortion and perhaps instability in LC structure likely contribute to the development of glaucoma. Other possible mechanisms include ICP-related alteration in axoplasm and blood flow, which hypothetically could be primary or secondary to observed structural changes. To date, published data strongly supports an association between ICP and glaucoma. Further investigation of the role ICP plays in glaucoma will enhance our understanding of the pathophysiology of glaucoma and ultimately may lead to new innovative therapeutic options. Con—Intracranial Pressure Does Not Influence the Development of Glaucoma Michael S. Lee, MD, Professor, Departments of Ophthalmology and Visual Neurosciences, Neurology, and Neurosurgery; Mackall-Scheie Research Chair in Ophthalmology; University of Minnesota When Drs. Lee and Van Stavern first approached me about writing the CON for this, I intended to politely decline, Lee et al: J Neuro-Ophthalmol 2023; 43: 423-429 because I could envision getting “posturized” by Dr. McCulley because of the groundswell of support for the PRO side in recent years. However, as I researched the topic myself, I realized that there are major holes in the theory that low ICP plays a role in glaucoma. The biggest problem with the entire hypothesis is measuring ICP accurately. As we all know, LP opening pressure (OP) is capricious, and one measurement often 425 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point does not reflect the true ICP throughout any given day. There have been many instances in my career where an obese young woman has symptoms of increased ICP, papilledema, a brain MRI and MRV consistent with idiopathic intracranial hypertension (IIH), and an OP that is normal or merely borderline. In those cases, I have chosen to treat them as presumed IIH with an inaccurate OP, and they respond accordingly. Unfortunately, with LP, the majority of patients will not have more than one. And, yet we use one measurement as the declaration of the true ICP. In an ironic twist, consider how many times one measures the IOP in a patient with glaucoma before calling it normal tension or not. If any of the IOPs are above 21 mm Hg, then we stop calling them NTG. However, they may have several other IOPs that fell in the normal range. Consider also that there are multiple ways to measure IOP such as tonopen, iCare, applanation tonometry, Schiotz tonometry, noncontact (air puff) tonometry, among others. Ophthalmologists do not generally consider these methods interchangeable. A survey of 577 neuroradiologists showed significant variability in the measurement of OP.40 The respondents described marked differences in needle gauge, spinal entry level, and prone vs lateral decubitus position. Even in the lateral decubitus position, some measured OP with legs bent, others with legs straight, and others allowed the patient to position the legs ad lib. Although most added the length of the needle to the manometer, 21% did not. Two-thirds measured OP when the meniscus stopped rising, whereas others after systolic/diastolic equilibration had occurred. However, when a clinician reports OP, they simply record a number rather than the details of patient positioning and how the OP was measured. This variability reduces our faith that a single OP from 2 different providers can truly be compared among patients with glaucoma vs control subjects even if performed in the same institution. With this in mind, let us address the articles that many have used to support the concept that low ICP plays a role in glaucoma. Studies Supporting the Pro Side and the Arguments Against Them: Humans Three articles from the Mayo Clinic have used similar methodology using many of the same patients. Each article identified patients who underwent LP with OP at a single institution during 3 time periods, which can generally be broken up into an early,13 middle,13,14 and late41 time period. Of those patients who had an LP, they compared the OP of those who did and did not have glaucoma. Below are some observations about these articles: 1. When they looked at the reasons for the LP in the middle group, headache was significantly more common in the control group.13 This headache group had a signif- 426 icantly higher ICP, which could explain why the control patients had a higher OP. As an aside, the late cohort with glaucoma did not have a lower OP than the control subjects.41 The authors argue that this was likely due to sample size. Interestingly, among the late cohort, there were 29 glaucoma patients and 48 control subjects,41 whereas there were 28 glaucoma patients and 49 control subjects in the middle cohort.13,14 I guess that 1 less control and 1 more glaucoma patient in the late group made the difference! All joking aside, in the late cohort, there was no difference in headache as the indication for LP. This may have explained the difference in OP. 2. All of the glaucoma patients were diagnosed by a glaucoma specialist, whereas the control subjects were not. The control subjects were anyone who had an eye examination within a year of the LP. It is possible that some of these control patients had early or preclinical glaucoma, but they did not undergo the same level of scrutiny (corneal thickness, visual field, OCT).13 3. Many of the patients with glaucoma were excluded because they did not have their OP measured. The authors do not comment on why some patients had their OP measured and others did not, which could introduce bias.13 4. There is very little information on how the LP was performed, and it seems unlikely that all were uniformly measured over a 34-year period. It is not clear that the control subjects underwent LP around the same time period as the glaucoma patients, and techniques likely changed.13,14,41 5. The OP was normal in both groups with a difference in means ranging from 2 to 3.8 mm Hg. This may be statistically different, but the question is whether this is clinically significant or not. Is this degree of ICP difference really enough to cause glaucoma? Ren et al15 prospectively performed LPs on 43 glaucoma patients and 71 control subjects. Glaucoma patients were asked if they would be willing to have an LP for scientific knowledge. If they agreed, then they were sent to neurology to rule out neurologic disease, obtain a brain MRI, and then undergo LP. Control subjects were seen in neurology and underwent LP for a diagnostic purpose. All LPs were measured at 2 PM and measured with the patient in the lateral decubitus position with the neck in full flexion and the knees bent in full flexion up to the chest. These groups were very different with respect to the reason for the LP, which could easily have affected the OP results. Glaucoma patients volunteered for the LP, whereas the control subjects may have experienced greater anxiety and thus higher OPs not knowing if they harbored a neurologic illness or not. Siaudvytyte et al17 measured ICP using a transcranial Doppler and found that the ICP was lower in a group of Lee et al: J Neuro-Ophthalmol 2023; 43: 423-429 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point NTG patients compared with control subjects. Their findings were not statistically significant, and the Doppler likely does not precisely measure ICP. Gallina et al42 looked at patients with normal pressure hydrocephalus (NPH) who had undergone a ventriculoperitoneal shunt (VPS) 6 months or more prior. They found that 9 of the 22 had NTG when these patients did not have a diagnosis of NTG before the VPS. They concluded that VPS in NPH causes NTG. There are 2 main concerns with this study. First, these patients may have harbored NTG preoperatively but had not been diagnosed. Some have suggested that patients with NPH without shunting are more likely to have NTG.22 Second, the authors diagnose NTG as IOP of ,21 mm Hg, central corneal thickness of $520 mm, cup/disc of .0.5 associated with a mean deviation of , 22 dB and pattern SD .2 dB. These criteria are not likely adequate to make the diagnosis of NTG and may overestimate the diagnosis. A normal individual with a 0.6 cup-to-disc ratio and normal IOP undergoing automated perimetry for the first time could easily fail those perimetric outcomes and receive a diagnosis of NTG based on Gallina criteria. Animals Yablonski showed that cat eyes developed glaucoma-like changes when ICP was lowered. When the IOP was lowered concomitantly with ICP, the glaucomatous pathology did not occur. However, these data were never published in the peer-reviewed literature and have only appeared in meeting abstracts (Yablonski ME, et al. IOVS 1978; 17: ARVO Abstract 6; Yablonski ME, et al. IOVS 1979; 18: ARVO Abstract 8) Yang et al43 inserted lumboperitoneal shunt in 9 primates. The shunt was opened fully in 4 (mean ICP 2.0 ± 0.8 mm Hg) and was kept closed in 5 (9.2 ± 2.6 mm Hg). The retinal nerve fiber layer (RNFL) was significantly thinner at 1 year (89.4 vs 100.9 mm). This study represents an extreme difference in ICP, which is not apt to occur naturally in humans. Most studies in humans show a difference in OP of ,2 mm Hg. This study does not point to glaucoma but maybe very low ICP, as the cause of the RNFL loss. Studies Supporting the CON Side Meanwhile, there have been a few articles that did not find low ICP among patients with glaucoma.22,44,45 Lindén et al44 prospectively measured ICP using LP in patients with NTG and healthy control subjects. Thirteen patients with NTG and 11 healthy volunteers were identified and invited to participate in the study. The authors also added 40 healthy subjects who had undergone LP with OP for another previous study. They found that OP was no different between the 2 groups (10.3 ± 2.7 vs 11.3± 2.2 mm Hg, P = 0.24). Igarashi et al performed LPs on 20 patients with normal pressure hydrocephalus22: 11 with NTG and 9 without NTG. They found that the OP of the patients with NTG was higher than the non-NTG patients (10.8 ± 2.9 mm Hg compared with 8.3 ± 1.4 mm Hg [P = 0.0425]). It is not clear if NPH plays a role in NTG or not, but it is quite interesting that the OP was significantly higher in the NTG group. Pircher et al45 retrospectively identified 38 patients with progressive NTG who had also undergone LP with OP. The LP was performed as part of computer-assisted cisternography by the same neuroradiologist. The mean OP was 11.6 ± 3.7 mm Hg. This did not show a lower OP compared with previous retrospective or prospective studies. Unfortunately, they did not have a control group of patients without glaucoma with which to compare. Summary Low ICP could play a role in the development of glaucoma, but definitive proof remains lacking. Some circumstantial evidence exists, but many of the studies supporting this notion demonstrate concerns as discussed above. In the absence of an effective means to measure ICP accurately and repeatedly, the reader must come to the conclusion that low ICP does not play a role in the development of glaucoma (yet). Rebuttal—Dr. Mcculley In response to Dr Lee’s argument against ICP influencing the development of glaucoma, I will start by stating that his assertions are well founded, and for the most part, I am in agreement. There are animal studies, which if accurate, substantiate that at extremes, ICP can be impactful, either causative of glaucoma when low or protective against glaucoma when high. Dr Lee is correct that there are very few studies of this nature, and it would be difficult to state that this relationship has been established with certainty. Regarding Lee et al: J Neuro-Ophthalmol 2023; 43: 423-429 studies in humans, this too is limited, and each report has its own shortcomings. However, given that the majority of published data to date have found correlations between ICP and glaucoma, a causal relationship seems more likely than not. Many questions remain. Most notably, although extreme alterations in ICP probably influence the development of glaucoma, whether fluctuations or variations in ICP within the “normal” population have a meaningful impact is more easily debated: we are in need of further investigation. That 427 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point said, extremes do exist within our patient population, where ICP deserves consideration. The most glaring example is in patients who have undergone CSF shunting procedures. I would like to draw attention to patients with NPH, who are at an increased risk of glaucoma, seemingly related to CSF shunting procedures. Such patients should be monitored more closely for the development of glaucoma. In closing, there is mounting evidence that glaucoma severity is influenced by ICP. It remains unclear to what degree ICP plays a role in glaucoma development. I look forward to future investigations which will surely shed light on the relationship between ICP and glaucoma and may lead to new and innovative therapeutic options. Rebuttal—Dr. Michael Lee Dr. McCulley makes a strong argument that ICP influences the development of glaucoma. I have already discussed in my opening statement the problems with the studies by Berdahl, Ren, Yablonski, and Siaudvytyte that he references, and I will not rehash them here. In the second paragraph of his opening statement, my colleague explicitly identifies many of the ways in which the ICP can vary, which supports my main assertion that what a problem we have with the measurement of ICP. I want to emphasize that we should not and cannot place our faith in one OP as the sole measure of one’s CSF pressure throughout the day. When we obtain an eye pressure or blood pressure that will change our clinical approach, we almost always remeasure it to make sure it is truly abnormal. Why would we do this with OP? Ideally, a mechanism to repeatedly measure the CSF pressure among individuals and determine who develops glaucoma based on their average CSF pressure would help answer this question. Conclusion—Drs. Andrew Lee and Van Stavern The precise underlying mechanism of glaucoma remains uncertain, and ICP is an attractive option as a contributing factor because it is objective and measurable. Dr. McCulley discusses the pathophysiologic rationale for such a relationship, whereas Dr. Lee emphasizes the uncertainties regarding precision and accuracy of intracranial pressure measurement. If intracranial pressure plays a role, it may vary from individual to individual, with the impact dependent on intrinsic anatomic and physiologic risk factors. Further study is needed, particularly (as noted), a more precise way to accurately measure intracranial pressure, particularly over longer time intervals. REFERENCES 9. Koch FL. Ophthalmodynamometry. Arch Ophthalmol. 1945;34:234–247. 10. 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