Glaucoma is a group of diseases characterized by optic disc cupping and visual field defects due to loss of retinal ganglion cells (RGCs). The most widely recognized modifiable risk factor is intraocular pressure (IOP), but not all cases of high IOP develop glaucoma, and normal-tension glaucoma (NTG) occurs even when IOP is within the normal range 3).
In normal-tension glaucoma, IOP remains within the statistically normal range, but higher IOP is associated with faster progression of optic neuropathy, and IOP-lowering treatment can slow progression 3). However, many cases do not respond to IOP-lowering therapy, suggesting involvement of mechanisms other than IOP. Recently, it has been thought that not only IOP but also intracranial pressure (ICP) contributes to the pressure load at the optic nerve head.
The mechanical strain created by IOP levels affects axonal function at the lamina cribrosa (LC) 1). The physical response of the optic nerve head depends on IOP level, collagen fiber structure of the lamina cribrosa, morphology of the optic nerve head, and biomechanical properties of the three-dimensional load-bearing structure.
QWhy does glaucoma develop even with normal intraocular pressure?
A
Multiple factors are involved in the onset of normal-tension glaucoma. First, the pressure load on the optic nerve head is determined not only by intraocular pressure but also by the difference from intracranial pressure (TLPG); therefore, in patients with low ICP, the relative pressure load on the optic nerve increases even with normal IOP. Second, IOP-independent factors such as structural vulnerability of the optic disc, circulatory disorders, neurotrophic factor depletion, and oxidative stress are involved. Third, due to diurnal IOP fluctuations and measurement errors, IOP may be normal during examination but elevated at other times.
2. Lamina Cribrosa and Translaminar Pressure Gradient
The lamina cribrosa is a mesh-like structure located in the posterior sclera, serving as a passage for optic nerve fibers to exit the eye. Anteriorly, it faces the intraocular space; posteriorly, it is surrounded by the meninges and the optic nerve. The cerebrospinal fluid in the subarachnoid space surrounding the optic nerve is continuous with the subarachnoid space surrounding the brain and spinal cord.
RGC axons pass through the pores of the lamina cribrosa, where they are exposed to mechanical forces from IOP1). The lamina cribrosa is considered the primary site of axonal damage in glaucoma, and both anterograde and retrograde axonal transport are impaired in mouse, rat, monkey, and human glaucoma1).
The translaminar pressure gradient (TLPG) generated between IOP and ICP at the level of the lamina cribrosa is considered a major determinant of optic nerve damage. In humans, TLPG is estimated to average 20–33 mmHg/mm.
The optic nerve head is exposed to two mechanical stresses 1). First, the hoop stress of the peripapillary sclera due to IOP; second, the stress from the translaminar gradient between IOP and the lower optic nerve tissue pressure 1). The capillaries, astrocytes, and axons of the lamina cribrosa are subjected to unique biomechanical influences not present in the retina or myelinated optic nerve.
Fleishman and Berdahl proposed the “cerebrospinal fluid (CSF) theory of glaucoma.” The balance between IOP and ICP determines TLPG; when TLPG increases due to decreased ICP or increased IOP, damage to the lamina cribrosa occurs, leading to increased anterior lamina cribrosa surface depth (ASLC depth) and optic disc cupping2).
The reverse effect of this theory can be observed in idiopathic intracranial hypertension (IIH) and ocular hypotension. In IIH, elevated ICP leads to a dominant forward force, causing optic disc swelling. It has been suggested that patients with IIH may tend to have high intraocular pressure to compensate for the elevated ICP.
Another hypothesis proposes a mechanism where low ICP or high IOP reduces or blocks CSF flow into the optic nerve. Animal and human studies have shown decreased CSF inflow into the optic nerve in glaucoma and normal-tension glaucoma.
4. Evidence Supporting Low Intracranial Pressure and Glaucoma
Diagnostic lumbar puncture studies: A retrospective study reported that ICP in patients with primary open-angle glaucoma was significantly lower than in age-matched controls. Mean ICP was 11.2 mmHg in primary open-angle glaucoma vs. 11.8 mmHg in controls (p<0.0001). In normal-tension glaucoma patients, it was even lower at 8.7 mmHg2).
Prospective ICP studies: ICP in normal-tension glaucoma (9.5 mmHg) was shown to be significantly lower than in primary open-angle glaucoma (11.7 mmHg) and normal controls (12.9 mmHg).
Tissue clearance pressure studies: Primary open-angle glaucoma was demonstrated to have significantly higher TLPG. In normal-tension glaucoma, higher TLPG was associated with reduced neuroretinal rim area.
Animal Experiments and Additional Evidence
Mechanical stress studies: CSF pressure is reported to be a major determinant of posterior lamina cribrosa pressure, and the effect of changing CSF pressure is biomechanically equivalent to changing intraocular pressure.
Experimental ICP manipulation: It has been experimentally demonstrated that lowering ICP in animal eyes induces glaucomatous cupping and axonal swelling, and that simultaneously lowering IOP counteracts these changes.
Association with aging: ICP decreases with age. This fact may partially explain the higher prevalence of glaucoma in older individuals.
However, some studies show conflicting results. There are reports of no significant difference in ICP between normal-tension glaucoma patients and normal controls, and reports that ICP is significantly higher in ocular hypertension patients than in normal eyes2), suggesting that ICP may have a protective effect on the optic nerve.
QHow is intracranial pressure measured?
A
Currently, ICP is mainly measured by lumbar puncture. Although lumbar puncture is invasive, it has been shown to accurately reflect ICP. Non-invasive ICP measurement methods are also being explored, but they have not proven as reliable or accurate as lumbar puncture. Additionally, the variability of ICP due to posture and diurnal fluctuations is similar to the ICP difference (a few mmHg) between glaucoma and non-glaucoma patients, which may affect the reliability of studies.
Chang and Singh retrospectively evaluated the prevalence of glaucoma in patients with normal pressure hydrocephalus (NPH). The prevalence of glaucoma in NPH patients was 18.1%, significantly higher (about three times) than the age-matched control group (5.6%) (p=0.02). It has been hypothesized that NPH patients may have increased neurological vulnerability to pressure-related damage.
Another theory suggests that ventriculoperitoneal (VP) shunt surgery, which some NPH patients undergo, lowers ICP and increases TLPG, leading to glaucomatous damage. Among NPH patients who had VP shunt surgery more than 6 months prior, some developed new-onset normal-tension glaucoma after shunt placement. Low ICP exposure duration has also been shown to be a significant risk factor for glaucoma development, with follow-up studies reporting that 50% of the cohort developed normal-tension glaucoma after shunt placement.
The lamina cribrosa is a primary site of RGC axonal damage 1). The following mechanisms leading to RGC death have been proposed 1).
Axonal transport impairment: Blockage of retrograde axonal transport at the lamina cribrosa disrupts the supply of neurotrophic factors, inducing apoptosis1). During normal development, RGCs that fail to reach appropriate target neurons undergo apoptotic cell death, and this programmed cell death is recapitulated in glaucoma1).
Mitochondrial dysfunction: Unmyelinated fibers in the lamina cribrosa have high energy demands, and dysfunction of axonal mitochondria may contribute to damage 1).
Mechanosensitive channels: RGC cell membranes contain mechanosensitive channels such as TRPV1 that sense intraocular pressure fluctuations 1). TRPV1 has been shown to be involved in RGC death induced by experimental intraocular pressure elevation 1).
The “biomechanical theory of the optic nerve head” posits that intraocular pressure-related stress and strain on connective tissue have pathophysiological effects on connective tissue, axons, and glial cells. Intraocular pressure-independent factors (ischemia, inflammation, autoimmunity, biological changes in astrocytes) may also interact with intraocular pressure-dependent factors to influence optic neuropathy.
In patients with idiopathic intracranial hypotension (IIH), the ASLC depth is significantly greater than in controls. This finding demonstrates that TLPG is a determinant of lamina cribrosa structure, and that low ICP with high TLPG leads to increased lamina cribrosa depth similar to glaucoma. Swept-source OCT and enhanced depth imaging techniques allow assessment of ASLC depth and TLPG.
Evaluation of TLPG and ICP may become a tool for assessing glaucoma patients in the future, but several unresolved issues remain.
Effect of the orbital septum: It is unclear whether ICP assessed by lumbar puncture reflects the presence of the orbital septum, which restricts fluid flow within the orbit.
Unresolved fluid dynamics: The role of postural changes and patient activity in ICP evaluation has not been sufficiently defined.
Lack of established optimal measurement method: It has not been established whether invasive (lumbar puncture) or non-invasive measurement methods are optimal.
Clinically, it is important to look for signs of glaucoma in patients presenting with symptoms of low ICP such as positional headache. The physiological balance between intraocular pressure and ICP is essential for the health of RGCs and their axons, and dysregulation of this process may play a key role in the pathogenesis of glaucoma.
Pitha I, Du L, Nguyen TD, Quigley H. 眼圧 and glaucoma damage: The essential role of optic nerve head and retinal mechanosensors. Prog Retin Eye Res. 2024;99:101232.
American Academy of Ophthalmology. Primary Open-Angle Glaucoma Preferred Practice Pattern. 2024.
日本緑内障学会. 緑内障診療ガイドライン(第5版). 日眼会誌. 2022.
Copy the article text and paste it into your preferred AI assistant.
Article copied to clipboard
Open an AI assistant below and paste the copied text into the chat box.
