Discussion
In this study, we aimed to identify the possible risk factors for elevated optic disc cupping and elucidate the association between several brain lesions and optic disc cupping by analysis of an age/gender-stratified population.
As illustrated in table 2, we observed a higher proportion of basal ganglia lesions in the older age group. Conversely, there was a lower proportion of basal ganglia lesions in the younger age group. Thus, there appeared to be a significant positive relationship between a high grade of basal ganglia lesions and age. In addition, the grade of basal ganglia lesion was higher in men than in women after adjusting for age groups. All of the basal ganglia lesions consisted of lacunar infarctions which occur frequently in the basal ganglia, subcortical white matter and pons.19 Those with less than 200 µm diameter penetrating artery infarcts tended to be asymptomatic.20
Our stepwise multiple regression analysis findings revealed basal ganglia lesions to be the only determinant factor related to elevated VCDR after being adjusted for age and gender. This finding indicates that of the brain infarct lesions, only those in the basal ganglia were significantly associated with elevated VCDR.
In the final multivariate analysis, we observed that VCDR significantly increased with a high degree of basal ganglia lesions and a high IOP after being adjusted for age, gender, optic disc area, systolic blood pressure, diastolic blood pressure, BMI, CCT and a history of cataract surgery. The findings of a previous large epidemiological study showed that the most significant factor for elevated VCDR was high IOP,18 which is also believed to be the most significant factor for glaucoma.13 Thin CCT is reportedly a risk factor for glaucoma, as it has a significant influence on IOP measurement; that is, a thinner cornea has less resistance to corneal shape distortion against external pressure than a thick cornea, and thus leads to the projected IOP reading being less than the real IOP in a thin CCT.21 A previous study has reported that CCT is significantly thinner in normal-tension glaucoma (NTG), defined as a condition in which glaucomatous optic nerve and visual field changes exist within a normal range of IOP, than in POAG or normal subjects.22 In addition, BMI reportedly has a significantly positive correlation with IOP after adjustment for several parameters.23 Despite the correlation with IOP, a high BMI appears to protect against glaucoma, while a low BMI has been found to be a significant risk factor for elevated VCDR and glaucoma.
As for the possible mechanisms, we speculate that BMI and/or CSF pressure mediate the relationship between VCDR and degree of basal ganglia lesions, because BMI alone can probably not fully explain the increased incidence of glaucoma and elevated VCDR. Previous studies have reported a statistically significant correlation between elevated CSF pressure and higher BMI.10 24 A lower CSF pressure caused by low BMI might be a potential risk factor for glaucoma, especially NTG, due to the presence of a pressure gradient across the lamina cribrosa, which is a mesh-like structure in the sclera at the optic nerve head that separates the intraocular space from the CSF-filled subarachnoid space. The translaminar pressure gradient increases with elevated IOP and/or a low CSF pressure.
Recent research suggests a structural and functional relationship between the putamen (a part of the basal ganglia) and BMI. Lou et al reported enlargement in the bilateral putamen in obese and overweight Chinese adults,25 and the authors found that the bilateral putamen volume was positively correlated with both BMI and waist circumference. Obese women and adolescents reportedly show greater responses of the putamen in response to high-calorie food cues compared with their thin counterparts.26 These results provide indirect evidence that elevated VCDR is associated with a low CSF pressure caused by a low BMI, and demonstrate that a low BMI is also associated with a reduced size and lower response of the putamen.
A few neuropathological studies27 28 on human patients with POAG have assessed the brain degenerative changes by using voxel-based morphometry (VBM), a technique that provides the ability to perform automatic and external analysis for structural changes of the whole brain, as well as diffusion tensor imaging. In those studies, VBM and fractional anisotropy revealed a significant volume reduction, not only in optic pathways, including the optic nerve, lateral geniculate nucleus and visual cortex, but also in several brain areas such as the basal ganglia, including the putamen and caudate nucleus. In addition, their findings indicated that neurodegenerative changes beyond that of the optic pathway could be found in patients with POAG, though it remains unclear whether the higher brain cortex is affected or which other regions of the brain are affected in patients with POAG.
It should be noted that the pathophysiology of glaucoma has yet to be fully elucidated. Glaucoma is histologically characterised by RGC apoptosis,29 which is a process of programmed cell death in the absence of inflammation characterised by cell shrinkage, blebbing and DNA fragmentation.30 Major mediators of apoptosis include elevation of glutamate, local oxidative stress caused by elevated IOP, vascular dysregulation and systemic oxidative stress.31 The glutamate transporters excitatory amino acid carrier 1 (EAAC1; encoded by SLC1A1) (known as excitatory amino acid transporters 3 in humans) are highly enriched in the cortex, hippocampus and caudate–putamen, as well as RGCs.32 The RGCs of SLC1A1/EAAC1 knockout mice, known as a model of NTG, reportedly die in response to oxidative stress without elevated IOP and have a high expression of gamma-aminobutyric acid (GABA, a major inhibitory neurotransmitter synthesised from glutamate by glutamic acid decarboxylase in neurons) receptor β subunits.33 In that study, the authors reported that GABAA receptor agonist-induced RGC death is inhibited by bicuculline, a GABAA receptor antagonist. Their findings also showed that hydrogen peroxide-induced death of RGCs is reduced by GABAA receptor antagonist, and that the oxidative stress signalling activated by hydrogen peroxide is also inhibited. The authors concluded that GABAA receptors expressed on RGCs may play a major role in the death of RGCs induced by oxidative stress in glaucoma. Because it is highly expressed in the basal ganglia area of humans as well, the RGCs and basal ganglia may share the same neurodegenerative process from the local and systemic oxidative stress.
It should be noted that this study did have some potential limitations, such as the fact that only subjects from the general Japanese population were enrolled. However, this allowed us to have a higher power of analysis in a single race/ethnicity than in multiple races/ethnicities. On the other hand, considering the different prevalence distribution of glaucoma across races,2 similar considerations may not be applicable to other races/ethnicities. A population-based epidemiological study reported that the Japanese population seems to have a higher incidence rate of NTG.34 It is possible that the subject eyes enrolled in this study have a higher proportion of NTG than eyes in other ethnicities; however, NTG is a common form of POAG, and both share similar mechanisms.35 However, it should be noted that IOP may be a relatively lower risk factor in NTG than in POAG. Considering the proposed mechanism of a translaminar pressure gradient and difficulty of treatment for NTG, we believe there must be other factors that may contribute more in NTG, which led us to the finding of the relationship between VCDR and basal ganglia lesions. Moreover, we do believe that further hospital-based research studies comparing severe glaucoma cases diagnosed with both ocular morphological changes and the development of glaucomatous visual field defects that correspond with the loss of the area of the optic neuronal rim with a healthy control group are surely needed.
In conclusion, the findings in this illustrate that VCDR significantly increases with a high degree of basal ganglia lesions after being adjusted for age, gender, optic disc area, systolic blood pressure, diastolic blood pressure, BMI, CCT and a history of cataract surgery. In this study, we proposed some possible mechanisms to explain this relationship. However, since the detailed mechanism remains unclear, further studies are needed to elucidate how basal ganglia lesions affect optic nerve disc cupping, as well as whether they are a cofactor or causal factor of elevated VCDR. At present, the main treatment of glaucoma is limited to reduction of elevated IOP via the instillation of anti-glaucoma eye drops and/or surgery. It is comparatively difficult to reduce IOP in NTG due to the already normal IOP. These could be important findings that might help shed light on the growing body of evidence for mechanisms and treatments for glaucoma.