Glaucoma, a major ocular neuro-degenerative disease, is the leading cause of irreversible blindness in the world. Its prevalence was 76 million in 2020 worldwide, and the global burden is expected to increase up to 118.8 million in 2040. It is a multi-factorial disease with complex pathophysiology which ultimately leads to the apoptosis of retinal ganglion cells (RGCs) and optic nerve fibres. It causes an irreversible optic neuropathy with a characteristic pattern of visual loss. Mechanisms behind the accelerated rate of RGC damage can be multiple, which includes vascular dysregulation, oxidative stress, immune-inflammatory response, excitotoxicity, and mitochondrial impairment. IOP, increasing age, positive family history, and epigenetic and environmental factors are well recognized risk factors for glaucoma. Among these, the most important risk factor is elevated IOP. Hence, all current standard therapies primarily aim to lower eye pressure with a combination of topical anti-glaucoma medications, laser therapy, and surgical intervention. However, recent insight into newer dimensions underlying the pathophysiology of glaucoma suggests the role of various non-IOP-dependent factors. It has been reported that besides raised IOP, decreased ocular perfusion pressure (OPP) can lead to the death of RGCs and adjacent cells such as astrocytes and oligodendrocytes, initiating a vicious cycle of apoptosis cascade. This knowledge has incited interest in exploring factors that affect the OPP as additional therapeutic modality that might be called as alternative or complementary medicine in glaucoma management. This includes development of novel pharmacological agents as well as investigating non-pharmacological means such as lifestyle modifications with the capability of counteracting the degenerative process, maintaining optimal ocular blood flow, and providing neuro-protection. These additional mechanisms can work either independently in glaucoma suspects as preventive measures or complementary to the IOP-based treatments in confirmed glaucoma cases. It aims at preventing further degeneration of RGCs and other neuronal components and to arrest the progression of disease. Certain lifestyles such as eating habits, sleep preferences, habits of meditation, yoga postures, and other exercises are known to have an influence over the pathophysiological mechanisms underlying glaucoma development and progression. This aspect of the disease seems interesting and has recently gained interest with many published literature studies with conflicting opinion. A thorough literature search was performed in PubMed, Google Scholar, and Scopus for relevant articles published in English with key words such as glaucoma and lifestyle, optic neuropathy and nutritional supplements, exercise and optic neuropathy, exercise and IOP, diet and glaucoma, body weight and glaucoma, and sleep postures and IOP. Existing reports signify therapeutic potential in various lifestyle modifications in glaucoma patients. Furthermore, this area has tremendous research potential that needs to be explored and validated by well-planned randomized control trials (RCTs). In this review, we provide a summary of the current evidence on the effect of different lifestyles, dietary habits, and supplementations on the incidence and progression of glaucoma and their future prospects in the management of glaucoma.
RELATION OF DIET, DIETARY SUPPLEMENTS, AND GLAUCOMA
Essential nutrients and glaucoma
Different components of food such as carbohydrates, proteins, essential fats, vitamins, and minerals have been evaluated for their association with glaucoma in different study designs [Table 1]. Kang et al., in a prospective study on health professionals, demonstrated a lower risk of primary open-angle acute glaucoma (POAG) with diet rich in nitrate contents such as green leafy vegetables. Hanyuda and colleagues, in three cohort studies, showed that low-carbohydrate diets were not associated with the risk of POAG, but higher consumption of fat and protein from vegetable sources substituting for carbohydrates was associated with a lower risk of the POAG sub-type with initial paracentral VF loss. A cross-sectional study in elderly females concluded that higher intake of certain fruits and vegetables high in vitamins A and C and carotenoids may be associated with a decreased likelihood of glaucoma. However, another case control study showed that intake of fruit juice, low-salt diet consumption, and low-fat content meat can be beneficial for glaucoma suspects and POAG patients. In general, it has been found that dietary modifications such as restricting saturated fats, salt, and sugar recommended for a good cardio-vascular status are beneficial for ocular health as well.
Poly-unsaturated fatty acids and glaucoma
The role of poly-unsaturated fatty acids (PUFAs), particularly long omega-3 fatty acids (ω-3 PUFAs) in glaucoma, has recently been investigated. This is because patients with POAG have an abnormal blood fatty acid composition that is characterized by a reduction in eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and omega-3 fatty acids. In a survey conducted by the National Health and Nutrition Examination, it was found that increased daily dietary intake levels of EPA and DHA were associated with a lower likelihood of glaucomatous optic neuropathy, but high consumption of total PUFAs was associated with a higher risk of glaucoma. Hence, it was assumed that increasing the proportion of dietary ω-3 consumption levels while controlling overall daily PUFA intake may be protective against glaucoma by reducing oxidative stress and inflammation. Oral DHA or omega-3 supplement has finally been approved as adjunct therapeutics for reducing IOP in normotensive adults and pseudo-exfoliation glaucoma patients.
Vitamins, minerals, and glaucoma
Oxidative stress leading to apoptosis of RGCs is an established pathophysiology underlying glaucoma. Hence vitamins such as Vit A, C, and E, which are known to have anti-oxidative properties, have been hypothesized to provide neuro-protection by reducing the oxidative stress. Few epidemiologic studies and small randomized clinical trials have been conducted to explore the association of vitamins with glaucoma with conflicting results. Yuki and co-workers investigated the levels of anti-oxidant vitamins, A, B9, C, and E, and the anti-oxidative substance uric acid in the serum of Japanese patients with normal-tension glaucoma (NTG) and compared the results with normal controls. It was found that NTG patients had lower serum levels of vitamin C and increased levels of uric acid. Another survey by Wang et al. noted that neither supplementary consumption nor serum levels of vitamins A and E were associated with glaucoma prevalence, but supplementary consumption of vitamin C was associated with a decreased odds ratio of glaucoma; however, serum levels of vitamin C did not correlate with glaucoma prevalence. The use of multi-vitamins or supplements of vitamins C, E, and A in any dose or duration, analyzed by a large prospective cohort study, was unrelated to POAG risk. It has been shown in various recent studies that neuro-degenerative diseases such as Alzheimer dementia, Parkinson's disease, depression, and schizophrenia aggravate the progression or elevate the incidence of glaucoma. Since Vit D has been associated with such neuro-degenerative diseases, its role in IOP control has also been evaluated. Krefting et al., in a small, randomized controlled trial in healthy participants, found no associations between serum 25-hydroxyvitamin D [25(OH) D] levels and IOP. Even supplementation of vitamin D3 to participants with low levels of 25(OH) D did not affect the IOP. Hence, these results do not support the role of vitamin D in IOP regulation.
Engin et al. investigated the neuro-protective role of α-tocopherol and demonstrated enhanced ocular blood flow which was time- and dose-dependent. The additional vaso-regulatory effect of the antioxidant α-tocopherol on retina was via the protein kinase C pathway. Contrary to this, no statistically significant effect on the success rate of trabeculectomy was found when oral α-tocopherol was given post-operatively by Goldblum and co-workers. The supplement of nicotinic acid in the amide form in mice study shows protection against glaucoma, but in humans, the relation is yet to be explored. However, there are some studies showing a decreased serum level or reduced intake of retinol equivalents and vitamin B1 and increased intake of magnesium with an increased risk of OAG. Besides magnesium, some studies show an increased risk of glaucoma with a high level of calcium, iron, and selenium because of increased oxidative stress.
Herbal medicine and glaucoma
Herbal medicines containing flavonoids and polyphenols such as Ginkgo biloba (GBE), saffron, and anthocyanins are increasingly being used in glaucoma patients. They are thought to decrease the oxidative stress, enhance ocular perfusion, and provide neuro-protection as well. Although animal models have shown favorable outcomes in preventing RGC loss, human studies document conflicting results. A randomized, placebo-controlled, crossover study by Quaranta et al. reported statistically significant improvements in visual field indices in patients receiving GBE as compared to the placebo group. However, IOP was similar in the two groups. A randomized clinical trial by Park et al. reported that GBE significantly increases peri-papillary blood flow in patients with NTG compared to placebo. On the contrary, study conducted by Guo and colleagues reported improvements neither in visual field indices nor in contrast sensitivity in GBE-treated groups compared to placebo. Bonyadi et al. investigated the hypotensive effects of saffron extracts in clinically stable POAG patients receiving treatment with timolol and dorzolamide eye drops. The ocular hypotensive effect became evident after 3 weeks of therapy with oral aqueous saffron extract. Anthocyanins, a kind of polyphenols abundant in berries such as black currant, have anti-oxidant and anti-inflammatory effects. A randomized, placebo-controlled trial by Ohguro and co-workers demonstrated significantly decreased deterioration of visual field mean deviation and increased ocular blood flow of OAG patients with BCAC supplement compared to placebo-treated ones, but there was no change in IOP.
RELATION OF EXERCISE AND GLAUCOMA
Dynamic exercise and glaucoma
Physical exercises have an important role in maintaining health and well-being of an individual. Their benefits are well studied in a wide range of systemic and ocular diseases, including glaucoma. Lowering IOP, increasing ocular perfusion, and providing neuro-protection form the cornerstone of glaucoma management. The impacts of physical exercise on IOP, ocular perfusion, neuro-protection, and mental health in patients with glaucoma have extensively been investigated in the recent past. Existing literature reports a consistent decrease of IOP after dynamic exercises such as cycling, walking, jogging, and stepping with a wide range of variations from 0.56 mmHg to 5.6 mm Hg. The amount of IOP reduction depends upon the type, intensity, duration of the exercise, current general fitness of the patient, and existing ocular pathology. A meta-analysis by Roddy et al. suggests an almost double IOP reduction effect in sedentary persons compared to their active counterparts. Studies have been performed to find if there is any difference in dynamic exercise on glaucoma patients as compared to healthy individuals. Surprisingly, Qureshi et al have reported in 1995 that the magnitude and duration of exercise-induced IOP reduction could be more prominent in patients with glaucoma not receiving treatment, compared to normal subjects. A study by Yokota et al. in 1996 showed that self-reported habitual exercise of more than 30 minutes per week was associated with slower visual field progression in open-angle glaucoma patients. Exercise-induced IOP reduction in patients with glaucoma was independent of the use of anti-glaucoma agents. Yang et al. have reported that IOP reduction after dynamic exercise is more profound in myopic eyes as compared to emmetropic eyes, probably because of insufficient perfusion to the choroid and the retina that might result in a defective auto-regulatory response. Furthermore, the magnitude of IOP reduction increases with the intensity of exercise but not with the duration.
Although the underlying mechanism of IOP reduction remains uncertain, it has been postulated to be related to nitric oxide release. There is shifting of the blood flow to the muscles and the raising of plasma osmolality with blood lactate decreasing blood pH. The effect seemed to wear off shortly with time, and the IOP-lowering effect was only modest in most of the reports. The long-term effect of exercise on sustainability of IOP remains an area of research.
Certain forms of glaucoma such as pigment dispersion glaucoma (PDG) respond to the contrary where exercise may cause remarkable IOP elevation in exercise-induced iris concavity and enhanced pigment release. Likewise, certain types of dynamic exercise can adversely affect the ocular health. Several case reports exist that document activities such as swimming with goggles, scuba diving, and Bungee jumping, which can cause visual impairment and visual field defects because of either raised IOP or ocular barotrauma. This adverse effect is more prominent in glaucoma patients.
Isometric exercise and glaucoma
Exercises performed in static positions, such as weightlifting and hand gripping, are called isometric exercises. Although there is a decrease in IOP after dynamic exercise, the effect of isometric exercise on IOP is controversial. Castejon et al. have documented a rise in IOP after isometric exercise in both humans and animal studies. Vieira et al. reported this IOP elevation to be related to the Valsalva maneuver that increases the episcleral venous pressure. Discontinuation of the Valsalva maneuver could partly relieve the raised IOP. Another study by Rüfer et al. found that there was no influence of isometric exercise on IOP if a Valsalva maneuver was avoided.
Yoga is a popular exercise in India but practiced worldwide with great enthusiasm and anticipation as a viable alternative to conventional medical management for different ailments. Some of the Yoga positions can be regarded as isometric exercises. Yoga postures (yogasanas) that involve body inversion were found to have a severe impact on IOP. Baskaran et al. in 2006 demonstrated an immediate 2-fold increase (around 15 mmHg) in IOP while performing Sirsasana, which is a headstand posture. The IOP returned to near baseline level as soon as the sitting posture was resumed. Evidence suggests that the transient IOP elevation in Sirsasana contributes to disease progression in patients with glaucoma. The rise in IOP in four common head-down Yoga positions, namely, Adho Mukha Svanasana, Uttanasana, Halasana, and Viparita Karani, is well reported. The range of IOP elevation reported varies from 16% to 70% in both patients with POAG and normal subjects. Postulations behind this rise include an increase in choroidal thickness in addition to the increase in episcleral venous pressure. In the head-down position, there is an increase in intra-cranial cerebrospinal fluid pressure, which indirectly influences the choroid veins draining into superior ophthalmic vein and finally into intra-cranial cavernous sinus. Hence, these head-down postures might be a risk factor for glaucoma progression and should be avoided in people with or at high risk of glaucoma.
Exercise and ocular perfusion pressure
As per the recent insight into the pathophysiology of glaucoma, besides IOP, ocular perfusion pressure (OPP) also forms an important determinant of optic nerve health. Evidence from epidemiological surveys suggested that subjects with low OPP were more likely to develop glaucoma and suffer from disease progression. Published research studies are consistent with the fact that physical exercise remarkably induces OPP elevation. The association between OPP and ocular blood flow (OBF) to the posterior pole of the eye is complex because of the presence of auto-regulation, a mechanism that maintains constant blood flow despite changes in OPP. Auto-regulation occurs in both dynamic exercise and isometric exercise, resulting in the unparalleled elevation of OBF and OPP. Contrary to the different responses of IOP to dynamic exercise and isometric exercise, the OPP was elevated in both, although the increase was limited because of auto-regulatory response.
Neuro-protection and physical exercise
Limited but consistent evidence of neuro-protection from exercise in animal models has been found in various retinal degenerative diseases, although the type and protocol of exercise were inconsistent and not comparable in those studies. Possible underlying mechanisms of exercise-induced neuro-protection include up-regulating neurotrophin expression, such as brain-derived neurotrophic factor (BDNF), enhancing mitochondrial functions and reducing inflammation.
Mental health in glaucoma and exercise
The role of exercise in mental health has been widely studied. An increase in physical activity is directly correlated with a decrease in anxiety and depression by De Moor et al. A recent study by Lim and colleagues from Singapore has reported the incidence of anxiety and depression in patients with glaucoma to be as high as 64% and 30%. The mental disorders not only have a negative impact on the quality of life of patients but also promote disease progression. Mental stress was found to increase IOP and induce insomnia by Marc et al. Surprisingly, the use of zolpidem, a drug to treat insomnia, was found to increase the risk of glaucoma development. Contrary to this, mindful meditation reduces stress, decreases IOP, and promotes ocular health.
In addition to preventing RGC loss via IOP control and increasing ocular perfusion, exercise may be beneficial in enhancing the overall well-being of patients with glaucoma and thus improving their quality of life.
BODY MASS INDEX AND GLAUCOMA
Although obesity has been associated with higher IOP, contrastingly, Lin et al. have reported association of a lower BMI, especially in women in the 40−49 age range, to a higher incidence of NTG. It has been observed that female patients with a lower BMI developed more paracentral visual defects compared to patients with a higher BMI. The impact of sudden weight loss on IOP, especially through bariatric surgery, was investigated in some studies. Lam and co-workers reported that each 10 unit decrease in BMI correlates with a 2.4 mm Hg decrease in IOP.
CAFFEINE, ALCOHOL, CANNABINOIDS, SMOKING, AND GLAUCOMA
Caffeine, a methylxanthine alkaloid, consumed worldwide in different beverages, has been reported to cause a transient rise in the IOP and OPP levels in both healthy individuals and glaucoma patients. This action is basically attributed to increased intra-cellular levels of cyclic AMP and increased hydrostatic pressure, which cause aqueous humor over-production. Further raised cyclic AMP results into decreased outflow by the relaxation of smooth muscle tone.
Relationship between alcohol intake and glaucoma is not yet clear. Some studies show no association between the two, whereas few cohort studies have reported a positive relationship between alcohol intake and an increase in IOP. These mixed findings may be attributed to individual differences in alcohol metabolism that can affect IOP and the ganglion cell complex.
Tobacco consumption, in general, is potentially detrimental for health. Although nicotine potentially increases blood flow, its effect on optic nerve blood flow remains conflicting. Some studies have reported the neuro-protective effect of nicotine on the retina, preventing glutamate-induced excitotoxicity in RGC. On the other hand, it has vasospastic properties as well, which may cause glaucomatous nerve damage by decreasing blood flow. The difference in results can be attributed to multiple mechanisms of action of nicotine. Almost all studies have shown a decrease in IOP with topical, inhaled, or intravenous cannabinoids with strong evidence of neuro-protection in animal studies. Both increases and decreases of IOP have been reported as a function of the mode of administration and of the precise cannabinoids used.
Sleep posture and glaucoma
Change in body posture causes change in IOP and OPP. Studies conducted to investigate the effects of different sleeping positions of the head and body in healthy subjects reported an elevation of IOP as compared with the sitting position. Postural change from supine to lateral decubitus or prone with the head turn position increased the IOP of the dependent eyes without significant alteration in OPP. Although in pigment dispersion glaucoma, lateral and prone sleeping positions usually result in significant elevations of IOP, it was unrelated to the dependency status. In general, use of specially designed pillows and bed-head elevation up to 30 degrees are recommendations to avoid IOP rise while sleeping.
ELECTRONIC GADGETS AND GLAUCOMA
Mobile devices (i.e., smartphones) have become an integral part of daily living in today's era. Published research reports that reading and writing on smartphones cause a significant increase in IOP. The elevation was faster and greater under low-light conditions. The exact underlying ocular dynamics for these IOP changes during and after smartphone work are unclear. However, the mechanism postulated for this change relates to the phenomena of accommodation and convergence with external ocular muscle (EOM) contraction. In addition to this, psycho-physiological stress-associated dry eye and neck-flexion posture also contributes for a rise in IOP.
Modifications in the lifestyle do seem to have a positive impact on the health of the optic nerve. It includes our physical activity, exercises, eating habits, and even addictions to smoking, alcohol, or use of electronic gadgets [Table 2]. They have the potential to modulate the IOP and OPP and hence can be explored as an alternative or complementary medicine to the existing plan of glaucoma management. Although some of the existing pieces of evidence are contradicting and insufficient to make strong recommendations, they need to be validated by well-structured randomized trials.
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