Cerebrospinal fluid pressure in ocular hypertension

Abstract

Background: To assess the lumbar cerebrospinal fluid pressure (CSF-P) in ocular hypertensive subjects with elevated intraocular pressure (IOP) but without development of glaucomatous optic nerve damage. Methods: The prospective interventional study included 17 patients with ocular hypertension and 71 subjects of a nonglaucomatous control group. All patients underwent a standardized ophthalmologic and neurological examination including measurement of lumbar CSF-P. In the ocular hypertensive group, the IOP was corrected for its dependence on central corneal thickness (IOPcorrected). The trans-lamina cribrosa pressure difference (Trans-LCPD) was calculated as IOPcorrected − CSF-P. Results: CSF-P was significantly (p < 0.001) higher in the ocular hypertensive group (16.0 ± 2.5 mmHg) than in the control group (12.9 ± 1.9 mmHg). CSF-P was significantly associated with IOPcorrected (p < 0.001; r = 0.82). In multivariate analysis, CSF-P was significantly correlated with IOPcorrected (p < 0.001) and marginally significantly with mean blood pressure (p = 0.05). Trans-LCPD was not associated significantly with blood pressure (p = 0.69). Conclusion: Some ocular hypertensive subjects with increased intraocular pressure measurements (after correction for their dependence on central corneal thickness) had an abnormally high lumbar cerebrospinal fluid pressure. Assuming that lumbar cerebrospinal fluid pressure correlated with orbital cerebrospinal fluid pressure, one may postulate that the elevated retro-lamina cribrosa pressure compensated for an increased intraocular pressure. The elevated retro-lamina cribrosa pressure may have led to a normal trans-laminar pressure difference in the eyes with elevated intraocular pressure, so that glaucomatous optic nerve damage did not develop. Intraocular pressure, cerebrospinal fluid pressure and arterial blood pressure were correlated with each other. Previous articles and studies by Volkov, Yablonsky, Berdahl and Ren have suggested that a low cerebrospinal fluid pressure may potentially play a role in the pathogenesis of glaucomatous optic neuropathy in patients with so-called normal-pressure glaucoma (Volkov 1976; Berdahl et al. 2008a,b; Ren et al. 2010). As a corollary, a recent retrospective investigation by Berdahl et al reported that ocular hypertensive subjects with elevated intraocular pressure but without glaucomatous optic nerve damage had an abnormally high cerebrospinal fluid pressure (Berdahl et al. 2008b). The abnormally high cerebrospinal fluid acting as a counterpressure across the lamina cribrosa may have compensated for the elevated intraocular pressure. The studies by Berdahl et al had, however, limitations; in particular, they consisted of a retrospective selection of a small subset of subjects (77 patients or 0.2% of the entire group of 31 787 patients; or 191 or 0.3% of 62 468 subjects). We therefore conducted the study described herein to prospectively measure the cerebrospinal fluid pressure in subjects diagnosed with ocular hypertension without signs of glaucomatous optic neuropathy. This clinical interventional investigation included an ocular hypertensive study group of subjects with elevated intraocular pressure higher than 21 mmHg as repeatedly measured by applanation tonometry, with a normal appearance of the optic nerve head and with a normal visual field, and the study included a control group. Diagnostic criteria for a normal appearance of the optic nerve head were a physiological shape of the neuroretinal rim, fulfilling the so-called inferior–superior–nasal–temporal rule with the smallest part of the rim located in the temporal 60°C of the optic disc (Jonas et al. 1988); no disc haemorrhages; a normal appearance of the retinal nerve fibre layer, usually with a slightly better detectability in the temporal inferior fundus region, followed by the temporal superior region, the nasal superior region and finally the nasal inferior region (Jonas & Schiro 1993); the lack of wedge-shaped localized retinal nerve fibre layer defects; and a normal appearance of the retinal arteries without signs of localized narrowing and a normal appearance of the arterial diameter (Jonas et al. 1989, 1999). All ocular hypertensive subjects underwent repeated intraocular pressure measurements, with some subjects participating in 24 -hr pressure profiles. During those profiles, intraocular pressure was measured at 10 am, 2 pm, 6 pm, 10 pm, 2 am, 5 am and 7 am. For the diagnosis of ocular hypertension, at least two intraocular pressure measurements corrected for their dependence on the central corneal thickness had to be higher than 21 mmHg. The intraocular pressure measurements obtained by Goldmann applanation tonometry were corrected for their dependence on the central corneal thickness according to the study by Kohlhaas and Pillunat (Kohlhaas et al. 2006) with an approximately 1-mmHg correction for every 25-μm deviation from a central corneal thickness of 550 μm. Central corneal thickness was measured for all ocular hypertensive patients by sonography (ultrasonic pachymeter SP-3000; Tomey Co. Nagoya, Japan). The visual field was assessed by computerized perimetry (Humphrey Field Analyzer; Zeiss Meditec AG, Jena, Germany). The ocular hypertensive study group consisted of subjects who primarily were seen in the ophthalmic department within the study period. They were invited consecutively to participate in the study, which eventually included all subjects who gave their consent. All subjects of the study group were referred to the neurological department to exclude any neurological disease. Examination there included magnetic resonance imaging of the brain and optic nerve and examination of the cerebrospinal fluid, including a lumbar pressure measurement. All of these ocular hypertensive subjects had an unremarkable neurological examination. As described in detail recently (Ren et al. (2010), the control group consisted of individuals primarily examined in the neurological department in the period from 2007 to 2008 for reasons such as peripheral neuropathy (n = 16 patients), unilateral anterior ischaemic optic neuropathy (n = 39), multiple sclerosis (n = 4) and unilateral optic neuritis (n = 12). There was generally a neurological reason, as decided by the neurologist, to perform a spinal tap and to measure the cerebrospinal fluid pressure in patients of the control group. Exclusion criteria were any factors or disorders that could influence intracranial pressure, such as pseudotumour cerebri, intracranial tumours, oral medication (including drugs such as carbonic anhydrase inhibitors), any cranial surgery or any lumbar puncture prior to inclusion in this study. For each subject of the control group, glaucoma and ocular hypertension were excluded by an examination performed by an ophthalmologist. This examination included gonioscopy to avoid the inclusion of subjects with occludable anterior chamber angles. For the subjects of the control group, the intraocular pressure was measured a few minutes before the lumbar puncture was performed. The lumbar puncture was performed at about the same day time for all study participants to avoid an effect of the circadian rhythm of intraocular pressure and cerebrospinal fluid pressure. The Medical Ethics Committee of the Beijing Tongren Hospital approved the study protocol, and all participants provided written informed consent, according to the Declaration of Helsinki. Based on theoretical considerations and findings in the literature, it was explained to the ocular hypertensive subjects that an abnormally high cerebrospinal fluid pressure may be involved in their situation. These patients were also told that the purpose of the lumbar puncture was primarily for scientific reasons, but that knowledge of an abnormally high cerebrospinal fluid pressure in their individual situation may also have the clinical consequence that the eventual development and diagnosis of glaucoma may become unlikely. All subjects in the control group underwent lumbar puncture for diagnostic reasons. Cerebrospinal fluid pressure was measured under local anaesthesia in a standardized manner at 2 pm in a lateral decubitus position, with the patient’s neck bent in full flexion and the knees bent in full flexion up to the chest (Gilland 1969). A standard spinal needle (20-gauge needle, 90 mm length) was inserted between lumbar vertebrae L3/L4 or L4/L5 and pushed in until a decrease in resistance indicated that the needle had passed the dura mater. The stylet from the spinal needle was withdrawn, a manometer was connected to the needle, and the opening pressure of the cerebrospinal fluid was measured. Taking the lumbar spinal fluid pressure measurement as surrogate for pressure in the orbital cerebrospinal fluid space, the trans-lamina cribrosa pressure difference was calculated as intraocular pressure minus cerebrospinal fluid pressure. For that calculation, the intraocular pressure measurement was taken on the same day that the lumbar puncture was performed. Because the intraocular pressure showed an intra-individual variation in the ocular hypertensive subjects, the single intraocular pressure measurements taken to calculate the trans-lamina cribrosa pressure difference were lower than 21 mmHg for some subjects. None of the study participants received any intraocular pressure–lowering therapy. It must be kept in mind that the term ‘trans-lamina cribrosa pressure difference’, as used in this manuscript, is from a terminological point of view partially incorrect, because it is the difference between lumbar spine cerebrospinal fluid pressure taken in the lateral decubitus position and intraocular pressure taken in a sitting position. Statistical analysis was performed using spss (SPSS for Windows, version 17.0, SPSS, Chicago, IL, USA); data are presented as mean ± standard deviation. General parameters of the study groups (Table 1) and the outcome parameters (intraocular pressure, cerebrospinal fluid pressure and their difference) (Table 2) were compared applying the Student’s t-test for unpaired samples or a nonparametric test (Mann–Whitney test). Finally, a multivariate analysis was carried out to assess any correlation between all three pressure parameters and systemic blood pressure. The study included 17 subjects with ocular hypertension and 71 subjects of a control group (Table 1). The study groups did not vary significantly in gender, systolic and diastolic blood pressure, and body height or body mass index (Table 1). The ocular hypertensive subjects were significantly (p = 0.004) younger than the subjects of the control group. The central corneal thickness measured in the study group was 581 ± 27 μm (median: 592 μm; range: 538–625 μm) and was significantly higher than the mean central corneal thickness (556 ± 33 μm) measured in a recent population-based study on the same ethnic group (Zhang et al. 2008). Intraocular pressure measured on the same day that the lumbar puncture was performed was significantly higher (p < 0.001) in the ocular hypertensive study group than in the control group (Table 2). In a similar manner, the cerebrospinal fluid pressure was significantly higher (p < 0.001) in the study group than in the control group (Table 2) (Fig. 1). As the difference between the study group and the control group was higher in intraocular pressure than in cerebrospinal fluid pressure, the difference in the trans-lamina cribrosa pressure difference was significantly (p < 0.001) higher in the study group than in the control group (Table 2) (Fig. 2). Lumbar cerebrospinal fluid pressure in subjects with ocular hypertension and control subjects. Boxplots showing the distribution of cerebrospinal fluid pressure as measured by lumbar puncture in ocular hypertensive patients of the study group and subjects in the control group. The boxplots show the median, interquartile range, 95% percentile, outliers and extreme values. The difference between the groups was statistically significant (p < 0.001). Trans-lamina cribrosa pressure difference in subjects with ocular hypertension and control subjects. Boxplots showing distribution of the trans-lamina cribrosa pressure difference (intraocular pressure minus cerebrospinal fluid pressure) in ocular hypertensive patients and subjects in the control group. The difference between groups was statistically significant (p < 0.001). Boxplots show the median, interquartile range, 95% percentile, outliers and extreme values. Cerebrospinal fluid pressure was not significantly associated with age in the study group (p = 0.63) nor in the control group (p = 0.16). In a similar manner, intraocular pressure and the trans-lamina cribrosa pressure difference were not significantly associated with age in the study group (p = 0.90 and p = 0.39, respectively) nor in the control group (p = 0.44 and p = 0.67, respectively). Cerebrospinal fluid pressure was significantly associated with intraocular pressure in the study group (p < 0.001; correlation coefficient r = 0.81) and in the control group (p < 0.001; correlation coefficient r = 0.76) (Fig. 3). Association between lumbar cerebrospinal fluid pressure measurements and intraocular pressure. Scatterplot showing distribution of cerebrospinal fluid pressure measurements (determined by lumbar puncture) and intraocular pressure in ocular hypertensive subjects of the study group and nonglaucomatous subjects of the control group. The correlation was statistically significant (p < 0.001; r = 0.82; equation of the regression line: cerebrospinal fluid pressure (mmHg) = 0.46 × intraocular pressure (mmHg) + 6.2 mmHg). Combining both groups, cerebrospinal fluid pressure showed a tendency to increase with increasing mean arterial blood pressure (p = 0.11). Performing a multivariate analysis and including all three pressure parameters revealed that cerebrospinal fluid pressure was significantly correlated with intraocular pressure (p < 0.001) and marginally significantly with mean blood pressure (p = 0.05). Also in that multivariate analysis, cerebrospinal fluid pressure was not significantly associated with age (p = 0.64). The trans-lamina cribrosa pressure difference was not associated significantly with blood pressure (p = 0.69). The results suggest that the cerebrospinal fluid pressure as measured by lumbar puncture was significantly higher in subjects with ocular hypertension than in subjects of a nonglaucomatous control group (Fig. 1). Because the difference between the study group and the control group was higher in intraocular pressure than in cerebrospinal fluid pressure, the difference in the trans-lamina cribrosa pressure difference was significantly (p < 0.001) higher in the study group than in the control group (Table 2) (Fig. 2). In multivariate analysis, cerebrospinal fluid pressure was significantly correlated with intraocular pressure (p < 0.001) and (marginally significantly) with blood pressure (p = 0.05). The trans-lamina cribrosa pressure difference was not significantly associated with the blood pressure (p = 0.69). The finding of a high cerebrospinal fluid pressure in the subjects with ocular hypertension agrees with a recent retrospective highly selective study of Berdahl et al. (2008b), in which ocular hypertensive subjects had significantly higher cerebrospinal fluid pressure measurements than a control group. The findings suggest that the elevated cerebrospinal fluid pressure may have acted as a counterpressure across the lamina cribrosa to compensate for the elevated intraocular pressure. As a corollary and in contrast to the protective role of an elevated cerebrospinal fluid pressure may play in eyes with ocular hypertension, two recent studies suggested that an abnormally low cerebrospinal fluid pressure may play a role in the pathogenesis of glaucomatous optic nerve damage in patients with normal intraocular pressure (Berdahl et al. 2008a; Jonas 2010; Ren et al. 2010). The findings also agree with an experimental study by Yablonski et al. (1979). They decreased the intracranial pressure in cats to 5 cm H2O below the atmospheric pressure by canulation of the cisterna magna. The intraocular pressure of one eye was reduced to slightly above atmospheric pressure by canulation of the anterior chamber. After 3 weeks, the optic nerve heads of the eyes in which intraocular pressure was unaltered showed typical features of glaucomatous optic neuropathy. In contrast, in the eyes in which the intraocular pressure was also lowered, no changes occurred. The results of the present study suggesting a potential role of the cerebrospinal fluid pressure for the physiology and pathophysiology of the optic nerve head may also agree with a recent study on the prevalence of glaucomatous optic nerve damage in patients with normal-pressure hydrocephalus Chang & Singh 2009). In their retrospective case–control study, Chang and Singh examined the medical records of 72 patients with normal-pressure hydrocephalus and 72 age-matched controls with hydrocephalus. They found that the prevalence of glaucoma in normal-pressure hydrocephalus group was significantly (p = 0.02) higher than in the control group (18.1% versus 5.6%). Interestingly, however, the trans-lamina cribrosa pressure difference was significantly higher in the ocular hypertensive study group than in the control group, although the subjects of the study group did not have detected glaucomatous optic nerve damage. There may be several reasons. One reason may be that the correction of the intraocular pressure measurements for their dependence on the central corneal thickness was not sufficient, so that in reality the intraocular pressure in the study group was lower than assumed. Another, more likely reason may be that some of the eyes of the ocular hypertensive study group may undetectedly have been preglaucomatous so that the abnormally high trans-lamina cribrosa pressure difference may eventually have led to glaucomatous optic nerve damage. If that holds true, those ocular hypertensive subjects with an elevated trans-lamina cribrosa pressure difference were in need of antiglaucomatous treatment with lowering of the intraocular pressure. In that case, the measurement of the cerebrospinal fluid pressure in the ocular hypertensive subjects was helpful to differentiate between the subjects of the study group who were in need of treatment and who were not. Another reason why the elevated trans-lamina cribrosa pressure difference in some ocular hypertensive subjects did not lead to a glaucomatous optic nerve damage may have been structural and biomechanical differences in the optic nerve head anatomy. The finding of an elevated cerebrospinal fluid pressure in the ocular hypertensive subjects and of a low cerebrospinal fluid pressure in patients with normal (intraocular) pressure confirms previous anatomical and biomechanical optic nerve head studies, in which the potential role of the cerebrospinal fluid pressure as trans-lamina cribrosa counterpressure against the intraocular pressure was discussed (Jonas et al. 1992, 2003; Morgan et al. 1995, 2002; Burgoyne et al. 2005). The cerebrospinal fluid pressure and the intraocular pressure were strongly correlated with each other (Fig. 3). It confirms recent population-based studies in which intraocular pressure was related with systemic arterial blood pressure (Mitchell et al. 2005; Xu et al. 2007). This association was confirmed in the multivariate analysis, in which blood pressure as additional pressure parameter was added. There have been contradicting reports about a correlation between cerebrospinal fluid pressure and intraocular pressure in patients with an acutely elevated cerebrospinal fluid pressure (Lashutka et al. 2004; Sajjadi et al. 2006; Han et al. 2008). It is questionable, however, whether the emergency situation of an acutely elevated brain pressure can give information about a potentially physiological relationship between cerebrospinal fluid pressure and intraocular pressure under normal conditions. The correlation between the pressure parameters of all three fluid-filled the cerebrospinal fluid pressure, the blood pressure and the intraocular pressure, may suggest a systemic all three of It may why arterial hypertension, although associated with ocular hypertension, however, is not associated with glaucoma in population-based studies et al. 2009). of study be it whether the lumbar cerebrospinal fluid pressure is related to the cerebrospinal fluid pressure in the the optic One to in mind that it is the difference between the retro-lamina pressure and the intraocular pressure, which the pressure difference across the lamina which was the of study in its to show a relationship between trans-lamina pressure difference and We however, the difference between the intraocular pressure in a sitting position and the cerebrospinal fluid pressure measured in the lateral decubitus position and it the ‘trans-lamina pressure In a recent study on patients with et al. that lumbar cerebrospinal fluid pressure measurements correlated with intracranial cerebrospinal fluid pressure measurements in patients with cerebrospinal fluid with a regression coefficient of A study by et al showed that the cerebrospinal fluid pressure at eye is at the same as the sitting or was on between and mmHg The same patients had a lumbar cerebrospinal fluid pressure of mmHg in the lateral decubitus position. The study suggested that on the intracranial cerebrospinal fluid pressure at eye by an of mmHg as a subject changes its position from the lateral decubitus to the sitting or et al. 2007). one may have to the difference between optic nerve pressure and intracranial pressure, which is may be by orbital and one the difference between the retro-lamina pressure and the optic nerve pressure, which may be by the mater. These considerations have also been in a recent by Morgan et al. to the lumbar for measurement of the cerebrospinal fluid pressure is potentially a (Jonas 2003; Jonas & Jonas & potential of study is the of the control group including patients who were primarily examined in the neurological department for neurological associated with an increased cerebrospinal fluid pressure were generally one exclude the that some of these patients had an abnormally high cerebrospinal fluid pressure. a previous study on and showed a mean lumbar cerebrospinal fluid pressure of ± mmHg et al. was lower than the mean lumbar cerebrospinal fluid pressure measured in the subjects of the control group of study (12.9 ± 1.9 mmHg). the of the previous study increase the calculated trans-laminar pressure difference from ± mmHg to about ± mmHg in the control group. it decrease the difference in the trans-laminar pressure difference between the ocular hypertensive group ± 2.5 mmHg) and the control group ± mmHg). It better that the abnormally high cerebrospinal fluid pressure in the ocular hypertensive group could the lack of glaucomatous optic nerve damage in the eyes with elevated intraocular pressure. these potential in the selection of the subjects of the control group, however, in view of the potential of a lumbar did not to measure the cerebrospinal fluid pressure in normal subjects without any medical for a spinal of study may be the of ocular As discussed it may be that some subjects of the ocular hypertensive study group had glaucoma or were to It may why the trans-lamina cribrosa pressure difference was significantly higher in the study group than in the control group, the that the cerebrospinal fluid pressure was higher in the study group than in the control group. the mean age was significantly younger in the ocular hypertensive study group than in the control group, which may have an of the lower of the cerebrospinal fluid pressure in the control group. The cerebrospinal fluid pressure however, statistically of age in the control group (p = and in the study group (p = It may therefore be that the age difference between study group and control group was a reason for the difference in cerebrospinal fluid pressure. In the study by et al. had not a significant difference in cerebrospinal fluid pressure between subjects and subjects. studies on ocular hypertensive patients generally the of a regression to the in the that a single intraocular pressure was above normal and led to the inclusion of the subject in the ocular hypertensive group. The patients of the ocular hypertensive group in study, however, showed elevated intraocular pressure measurements at several including at the and the intraocular pressure A regression to the mean in study be a unlikely. it questionable, the intraocular pressure measurements be for their dependence on the central corneal Finally, one to that study to be to be a study. In view of against the of a low cerebrospinal fluid pressure as one of the several for glaucomatous optic as out and by and et al. one to In an abnormally high cerebrospinal fluid pressure as increased counterpressure to an elevated intraocular pressure across the lamina cribrosa may play a role in the of glaucomatous optic nerve damage in eyes with ocular It is to similar studies on patients with pressure in which an abnormally low cerebrospinal fluid pressure was detected (Volkov 1976; Berdahl et al. 2008a,b; Ren et al. 2010). Interestingly, the pressure in all three fluid-filled was associated with each the cerebrospinal fluid pressure, the intraocular pressure and the mean arterial blood pressure.