Glaucoma (glaucoma) is a clinically common blinding eye disease with an estimated 67 million patients worldwide, 6.7 million of whom eventually go blind. Primary closed-angle glaucoma is the most common type of glaucoma in the Asian population. According to a survey of the glaucoma population conducted by Hu et al. in China in 1989, it was projected that there were as many as 9.6 million glaucoma patients in the population over 40 years of age, and primary closed-angle glaucoma accounted for 70-80% of glaucoma patients , of whom 5.2 million were blind. Therefore, the treatment of primary glaucoma has become the focus of attention in the Chinese ophthalmology community. With the aging of the Chinese population and the increasing level of various forms of testing glaucoma patients may approach 20 million. Acupuncture is an important part of Chinese medicine, and according to ancient and modern literature, it plays an important role in lowering IOP in primary glaucoma and in the treatment of optic neuropathy in late glaucoma, as well as in psychosomatic factors in glaucoma patients. In this paper, the understanding of glaucoma in Chinese medicine, the pathogenesis of glaucoma and the treatment and mechanism of action of acupuncture on glaucoma are reviewed.
1. Definition of glaucoma.
More than a hundred years ago, glaucoma was defined as a disease of the eye caused by increased intraocular pressure. after Von Graefe discovered glaucomatous optic nerve changes and normal intraocular pressure glaucoma in 1857, the definition of glaucoma was no longer just a disease of elevated intraocular pressure, but was gradually enriched and improved. The modern definition of glaucoma is an eye disease that causes damage to the optic papilla, retinal nerve fiber layer defects, and visual field defects due to elevated intraocular pressure or/and relative ischemia of the optic nerve and retina. Together with a series of neurological, psychiatric, psychological and even vascular system symptoms that accompany glaucoma patients, glaucoma is actually a syndrome with predominantly ocular symptoms and signs. The formation of this definition illustrates the complexity and systemic nature of glaucoma.
2. Pathogenesis of glaucoma.
With the development of medicine, the study of the pathogenesis of glaucoma has gradually advanced. Modern research suggests that high intraocular pressure (mechanical theory), disorders of ocular blood circulation (vascular theory), apoptosis of ganglion cells, genetic inheritance and regulation play an important role in the mechanism of glaucoma disease damage.
2.1 Mechanical theory.
The mechanical theory suggests that elevated IOP causes the axonal flow of optic nerve cells to be blocked in the sieve plate area, and the ATP produced by mitochondria cannot be used by the axonal membrane, and the production and movement of axonal proteins are reduced, resulting in impaired normal cell metabolism and death. As the non-macular fibers enter the optic nerve close to the periphery, they are the first to be involved due to the higher pressure when the IOP rises, resulting in the typical glaucomatous visual field defect, where the periphery and Bjerrum’s area are damaged first. Epidemiological data show that 95% of the population has an IOP between 10 and 22 mmHg, and glaucoma can occur if the IOP continues to increase significantly. In patients with asymmetric pressure in both eyes, the higher the IOP, the more pronounced the visual field loss in the eye. Thus the mechanistic theory has been the basis of almost all glaucoma research and clinical treatment. However, as clinical studies have progressed, it has been found that some people with IOPs above the normal range do not develop optic papillary damage or visual field defects. Some people who have always had normal IOP, or whose increased IOP has been controlled in the normal range with surgery or medication, still develop optic papillary damage and visual field defects similar to glaucoma. As a result, there is a growing interest in non-intraocular pressure factors. One of the most highly regarded is the vascular theory, in which the pathogenesis of glaucomatous optic nerve damage is due, at least in part, to abnormal blood flow to the optic nerve and optic papilla.
2.2 Angiographic theory.
Laser Doppler velocimetry measurements of the optic papillary microcirculation showed that there was a significant difference between normal and decreased superficial optic papillary blood flow in patients with primary open angle glaucoma (POAG) and normal intraocular pressure glaucoma (NTG). In POAG patients, the maximum frequency shift was decreased by 40%. The erythrocyte viscosity was also found to be significantly higher in patients with POAG. Both of them support the involvement of the optic papilla microcirculation in POAG patients. Fundus fluorography showed significant abnormalities in retinal circulation in patients with POAG, with prolonged arteriovenous access time, slowed arterial staining velocity and macular microcirculation, while NTG showed slowed choroidal circulation. These studies suggest that alterations in blood circulation also play an important role in the mechanism of glaucoma injury, but this theory needs to be further investigated because it is very difficult to construct an animal experimental model of glaucoma ischemia.
Numerous studies have suggested that no single theory, whether vascular or mechanical, can fully explain the pathogenesis of glaucoma. However, these studies have guided the direction of clinical treatment and provided a theoretical basis for the study of the mechanism of action of therapeutic approaches.
2.3 Apoptosis of optic ganglion cells and related factors.
Studies have shown that optic nerve damage is the pathological basis for vision loss in glaucoma patients. in 18 eyes of 17 cases of primary open-angle glaucoma, Kerrigan et al. observed positive TUNEL responses in the retinal ganglion cell layer in 10 eyes by the TUNEL method, while only 1 eye of 11 normal control eyes of age-, race-, and sex-matched whole-body healthy individuals was positive for glaucoma Quigley et al. used the TUNEL method to identify DNA fragments in the ganglion cells of experimental glaucoma. The results showed that the TUNEL-positive retinal ganglion cells were at least 10 times higher in monkey experimental glaucoma than in control eyes.
It has been shown in both human and experimental glaucoma that elevated intraocular pressure interferes with both cis- and retrograde axoplasmic flow transport, and that this axonal block, which is much less severe than optic nerve dissection, may be what prevents brain-derived nerve growth factor from flowing to retinal ganglion cells, thereby triggering apoptosis.
There are two theories for the cause of these apoptotic cells.
1) Local ischemia of the cells causes glutamate dehydrogenase-mediated toxic effects.
2) Pathological deprivation of neurotrophic factors. dkhissio et al. found a significant increase in glutamate levels in the vitreous humor of patients with glaucoma disease. And glutamate antagonists were able to prevent glutamate receptor-mediated death of RGCs. These findings strongly support that the death of retinal ganglion cells in glaucoma is apoptosis.
2.4 Genetic factors.
Primary glaucoma is a disease with a genetic predisposition, as evidenced by the high prevalence in glaucomatous relatives and studies of twins. About 20 causative genes and mutation loci have been identified for various types of glaucoma, such as GLC1A, GLA1B, GLA1C, 1GLAD, GLA1E in idiopathic open-angle glaucoma; GLC3A, GLC3B in asplastic glaucoma; chromosome 11 loci in small-eye, closed-angle glaucoma family lines, etc. The studies confirmed the genetic predisposition of IOP, cup-to-disc ratio, C-value, and IOP changes after topical glucocorticoid application. These molecular genetic studies not only provide new ideas in the treatment of glaucoma, but also can be used in the prevention of the disease.
2.5 Psychosomatic factors.
Modern research has also found that glaucoma is another important ocular psychosomatic disease, when a person is stimulated by the heart to produce a stress response, this psychophysiological stress can cause an increase in intraocular pressure, so that the atrial angle with narrow angles and other anatomical characteristics of the eye closes. According to the survey, about 73-80% of acute attacks of glaucoma are related to sudden changes in emotion, and excessive worry, depression, anger, nervousness, and overexcitement are all causative factors of this disease. Experimental evidence shows that mood swings can cause dysregulation of the vascular nerve regulation center, inhibition of parasympathetic nerves, hyperexcitation or enhancement of sympathetic nerves, as well as hormonal changes in blood pressure, heart rate, respiratory rhythm, muscle tone, cortisol, etc. Drastic mood changes can activate the activity of blood fibrinolytic enzymes, and these pathological changes play an important role in the pathogenesis of glaucoma.
In summary, it can be hypothesized that patients with a molecular genetic basis for the occurrence of glaucoma histopathology experience elevated IOP local mechanical damage and or local ischemia during psychophysiological stress, which induces the onset of acute signs and symptoms of glaucoma and further stimulates apoptosis of ganglion cells, ultimately leading to glaucomatous ocular damage. These studies confirm that glaucoma is the result of a synergistic effect of multiple factors, on the basis of which the question of how to target treatment is raised. This article focuses on the non-surgical treatment of glaucoma.
3. Modern conservative treatment of glaucoma.
The in-depth study of the pathogenesis has pointed out the direction for the treatment of glaucoma. Reconciliation of intraocular pressure and the ability of the optic nerve papillae to tolerate intraocular pressure has become the core of treatment. Therefore, the research of drugs to lower IOP, improve blood circulation in the eye and block the expression of retinal ganglion cell regulation has become a hot spot. There are five main classes of modern IOP-lowering drugs: cholinergic receptor drugs, β-adrenergic antagonists, prostaglandins, α2-adrenergic stimulants, and topical carbonic anhydrase inhibitors. These drugs mainly reduce atrial aqueous production and increase atrial aqueous drainage, thus lowering IOP and reducing damage to the optic nerve. Among the drugs that improve ocular blood circulation, calcium channel blockers have been found to improve the ocular blood supply and play a role in optic nerve protection. In optic nerve protection therapy, Martinou et al. expressed the apoptosis suppressor gene bcl-2 in a transgenic mouse line, resulting in a 50% increase in the number of retinal ganglion cells, accompanied by a thickening of the inner plexiform layer. However, this therapy is currently difficult to apply to the clinic. Modern studies have confirmed that exogenous neurotrophic factors, such as brain-derived neurotrophic factor, ciliary nerve growth factor and basic fibroblast growth factor, promote retinal ganglion cell survival in vitro in culture and in vivo. Antioxidants, free radical scavengers, and nitric oxide synthase inhibitors enhance the effects of brain-derived nerve growth factor on retinal ganglion cells with axonal damage.
According to the pathogenesis of glaucoma, the three aspects of lowering IOP, improving ocular circulation and protecting retinal ganglion cells have become the center of modern treatment for glaucoma, and the medication should take into account the effects of these three aspects, however, there are still many unsolved problems, such as the side effects of IOP-lowering drugs and the route of administration of neurotrophic factors, which still plague clinicians.
4. Awareness of glaucoma in Chinese medicine.
4.1 The origin of the Chinese medical name of glaucoma.
According to the symptoms and clinical manifestations of glaucoma, it belongs to the category of five winds (green wind, green wind, yellow wind, black wind), thunder head wind and partial head wind in Chinese medicine. The naming of the five winds of internal cataracts also reflects the progression of the disease, “review of the Yao letter”: “green wind internal cataracts, but still see themselves, but than the usual light is faint hazy day into, urgent treatment, lest become green …… green wind internal cataracts, the gas color green … …This disease is specifically talking about the pupil god gas color cloudy and unclear, its color like yellow clouds of cage cui glaze, like indigo of the combined vine yellow, is a serious disease of green wind, a long time will become yellow wind ……”. Ming Dynasty “Long Shu Bodhisattva eye theory” in the record, “if the eye first sense of the patient, head slightly rotated, frontal angle partial pain, even the orbital bone, and nose forehead when the pain, eye astringent, between the flowers, eye pain, is the main wind between the labor heat …… ancient formula are green blind …… “The first time this disease occurs, the head is spinning, the two forehead angles are involved, the pupils are painful even in the nose, or sometimes the red and white flowers start …… or vomit ……”. According to the manifestation of the disease, green wind endophthalmos is similar to open-angle glaucoma in Western medicine, while green wind endophthalmos is similar to closed-angle glaucoma.
4.2 Etiology and pathogenesis.
It is because the phlegm and dampness attacked and injured the real qi, and the god’s anointing was depleted, so the color changed. The long depression is heat, heat is the wind of liver wood evil, so the pupil scattered, the more scattered more yellow ……”. The medical zongjinjian: “Although there are five wind, the cause of the disease is two: one is the external cause, must be due to head wind, the pain led to the eye attack on the brain ……; one is the internal cause, must be due to internal injuries to the internal organs, the essence can not be injected into the eye …… “. Modern Chinese medicine mostly believes that the disease is wind-heat of liver and gallbladder, phlegm and fire on the congestion, spleen and stomach deficiency and cold, liver depression and fire, Yin deficiency and Yang hyperactivity of wind and fire and phlegm, attacking and rushing to the eyes, so that the qi is not normal, qi and blood is not harmonized, the meridians are not favorable, the xuanfu is closed, and the Shen Shui is stagnant, resulting in this disease.
4.3 Ancient acupuncture treatment.
Acupuncture has been used in China for thousands of years and has been widely accepted worldwide, but its therapeutic mechanism is not yet well understood. According to modern research acupuncture has a significant role in lowering IOP to improve circulation and gene regulation, and it is almost without side effects. These advantages suggest that acupuncture has great promise in the treatment of glaucoma. The treatment of glaucoma with acupuncture and the related mechanism of action are reviewed here.
The history of “acupuncture point treatment” is very long, as early as the early Western Han Dynasty, “Nei Jing” proposed that “pain is Yu”. Acupuncture was first used to treat eye diseases in Su Wen? The theory of mu stabbing “evil guest in the foot Yang F pulse, people eye pain from the inner canthus, stab the outer ankle half inch below each of the two, left stab the right, right stab the left, such as the line of ten miles and self”. The Book of Rites? In the Book of Rites, it is stated that “In ancient times, the stone was used as a proverb, so it was used to stab the disease.” In the treatment of this disease, such as the “Medical formula class collection? Long Shu Bodhisattva eye theory”, “the first awareness that the urgent treatment, first take soup pills, will rest cautious protection, acupuncture according to the treatment of …… and acupuncture Qiu Hui, Xie Xi points, often lead to another wind Qi down ……”. The “standard of evidence and treatment? Miscellaneous diseases? Seven orifices door” said, “the pupil is scattered large …… what internal obstruction, or needle or medicine is not lost to collect the pupil God of regret”. These records as proof of the application of acupuncture in glaucoma is after hundreds of years of clinical verification.
5, acupuncture on the treatment of glaucoma and the mechanism of action of the study:.
5.1 Lowering IOP.
According to the studies in recent decades, there are more clinical studies on acupuncture for glaucoma, and these documents reflect that the effect of acupuncture on lowering IOP is very obvious. As early as 1968, Huang Shuren treated 46 eyes of primary glaucoma by using acupuncture at the Xingma point, and the IOP of 36 eyes decreased by 12.15 mmHg on average within a short period of time, with an efficiency of 78.26%. Liu Yan et al. performed acupuncture in 40 cases of 79 eyes with non-high IOP and observed the immediate effect before and after treatment. The acupuncture points were mainly Fengchi, Sun, Zhanzhu, Hougu, Hegu and Baihui, and IOP was measured 5 minutes before and after acupuncture to exclude the effects of time, medication and life activities on IOP. 49 eyes showed a significant decrease in IOP compared with that before acupuncture. The author observed clinically that acupuncture can reduce IOP, but it is closely related to the selection of acupuncture points, acupuncture technique, glaucoma type and the emotional state of the patient, emotional relaxation, light acupuncture technique or stay acupuncture and open-angle glaucoma patients after acupuncture usually more obvious, and vice versa, IOP decrease less, unchanged, and there are a few patients with elevated IOP.
5.2 Improvement of ocular circulation.
Currently, using color Doppler and ocular hemogram, it is found that acupuncture can improve the retrobulbar and local blood flow status in glaucoma patients. Jiang Jun established a rabbit eye model with high IOP using a modified colemenDJ method, and acupuncture points such as eye-mind (affected), xingma (double) and sanyinjiao (double) were applied. After acupuncture treatment, the high IOP in the model rabbits was significantly reduced, with an average decrease of 56%. Histopathological examination showed that the retinal edema gradually subsided, the vascular texture became clearer, and the optic papilla changed from pale to orange, suggesting a significant enhancement of retinal blood flow. Biochemical and light and electron microscopic observations suggested that the acupuncture group could promote the adjustment and repair of retinal tissue structure and ultrastructure.
5.3 Neuroprotection.
Tai Haoqing used New Zealand white rabbits to replicate the high IOP model and performed acupuncture to lower IOP. The IOP before and after modeling and acupuncture were observed, and the retinal succinate dehydrogenase (SDHase) and ATPase activities were detected, and the results suggested that acupuncture therapy could significantly reduce high IOP without significant effects on normal IOP, and the efficacy was longer lasting; acupuncture therapy could also significantly enhance the retinal SDHase and ATPase The acupuncture therapy also significantly enhanced the activity of retinal SDH enzymes and ATPases, accelerated the repair of damaged retina, and thus achieved the purpose of treating glaucoma. Sun Kexing et al. used 48 rabbits from New Zealand to create a model of acute hypertensive rabbits by instilling physiological saline into the anterior chamber, and the rabbits in the treatment group were treated with daily electroacupuncture.
These studies suggest that acupuncture has an important role in lowering IOP, improving ocular circulation, and protecting the optic nerve. Since the mechanism of action of acupuncture is still unclear, clinical studies are usually conducted on factors related to a particular disease. In fact, from the pathological point of view, many diseases have similarities in their development, and through the synthesis of acupuncture in the study of diseases with similar pathological basis as glaucoma, it will be beneficial to the in-depth study of acupuncture and glaucoma.
6. Research on related acupuncture mechanisms.
6.1 Acupuncture and apoptosis.
In the rat middle cerebral artery blockage and reperfusion model, a single electroacupuncture or cumulative electroacupuncture after ischemia can increase the expression of brain-derived neurotrophic factor (BDNF) in the rat cortex. Acupuncture also maintained the neurotrophic factor at high levels in rabbits with disconnected upper buccal branch of facial nerve at all times. In the shuttle test, the dopamine content of the cerebral cortex was reduced and the striatal pentazocine/5-hydroxyindoleacetic acid ratio was increased in rats with electroacupuncture at Baihui and Yin Tang points. Xu Nenggui et al. observed the effects of electroacupuncture on cerebral blood flow, superoxide dismutase, monoamine neurotransmitters, malondialdehyde, excitatory amino acids and brain tissue water content in the ischemic area, using focal cerebral ischemia caused by coagulation of the middle cerebral artery in rats as a model. It is suggested that electroacupuncture can increase cerebral blood flow, superoxide dismutase activity and central monoamine neurotransmitters, and decrease malondialdehyde, glutamate, aspartate and water content of brain tissue, thus protecting neuronal damage secondary to cerebral ischemia. Zhang Xuezhao et al. observed the effect of acupuncture on BDNF gene expression in the hippocampus of ischemia-reperfused rats, using electroacupuncture to stimulate Baihui, Kidney Yu, and Foot Sanli points, and using RT-PCR to detect BDNF mRNA. Li Min et al. studied the effect of acupuncture on the expression of p53 and bcl-2 genes in aging-modeled rats established by D-galactose injection, and found that electroacupuncture significantly improved the symptoms of affected rats; p53 gene expression was down-regulated; bcl-2 gene expression was not affected by D-galactose modelling and electroacupuncture. Acupuncture also downregulated the expression of Bax in the penumbra region of the middle cerebral artery obstruction-reperfusion model and relatively decreased the Bax/Bcl-2 ratio.
The above studies suggest that acupuncture increases the expression of nerve growth factor and inhibits the expression of pro-apoptotic genes. Embryologically and histologically, through the homology of the optic nerve with the brain, we can speculate that acupuncture can play the same role in the apoptotic mechanism of glaucoma, which is to be further experimentally confirmed by our ophthalmic researchers.
6.2 Acupuncture and psycho-spirituality.
Acupuncture also has a significant role in the treatment of psychiatric disorders. In 1995, Cassisi randomly divided 42 patients with fibromyalgia into three treatment groups: acupuncture alone, antidepressant alone, and acupuncture combined with antidepressant, and the combined group showed significant improvement in pain, sleep, and depressive symptoms. Luo and Chun et al. observed essentially the same efficacy of electroacupuncture and fluoxetine in the treatment of major depressive disorder. Tang Shengxiu used acupuncture to treat depressive neurosis and found a decrease in cortisol in patients. These studies suggest that acupuncture can also take into account the factors of glaucoma systemic disease for treatment.
6.3 Other.
Using functional MRI, Cho et al. observed that acupuncture stimulation of the xingma acupuncture point resulted in a response in the visual cortex. This study may suggest the rationale for acupuncture to promote recovery of vision in glaucoma and other eye diseases.
7. Outlook.
In conclusion, acupuncture is effective in the treatment of glaucoma. Acupuncture can lower IOP, improve ocular circulation and protect the optic nerve in glaucoma patients, and may also inhibit apoptosis in the optic ganglion cells of the disease, while there is clear scope for acupuncture to play a role in the psychological factors of glaucoma. Therefore, acupuncture may have a therapeutic effect on all five major pathological factors related to glaucoma, which is unmatched by any treatment method. Nowadays, the role of surgery and western medicine in the treatment of glaucoma is extremely important, and acupuncture cannot replace the therapeutic effect of surgery and IOP-lowering eye medication, but its synergistic and complementary role in the disease is very clear, especially for patients whose IOP has been controlled normally after glaucoma surgery, but whose visual field continues to shrink, the therapeutic advantage of acupuncture is very obvious.
The clinical efficacy of acupuncture in reducing high IOP and relieving clinical symptoms has been recognized by a wide range of clinicians. The current problem is that most clinical studies are limited to the observation of the immediate efficacy, and the long-term efficacy has rarely been reported; the inconsistency of treatment standards, the single test standard, and the non-objective test methods have brought difficulties to the evaluation of clinical efficacy and the wide promotion and application of acupuncture. Moreover, the mechanistic research joints on acupuncture for lowering IOP and treating optic nerve damage in late glaucoma are very weak, which have hindered the further development of acupuncture in glaucoma treatment. From the literature, the research potential of acupuncture in the field of ophthalmology has not been widely exploited. As the level of medical and scientific research technology improves, standardization of acupuncture treatment and objectification of mechanistic research will become the focus of researchers’ attention.
As an important part of traditional Chinese culture, acupuncture has been enjoying a high reputation in the Chinese medical community and the world. The efficacy of acupuncture and moxibustion is recognized worldwide, and the small side effects are significantly better than other therapies, which cannot be replaced by any other therapies at present, and we as modern physicians should not only inherit but also carry forward the essence of Chinese medicine to benefit patients all over the world.