INTRODUCTION Normal intraocular pressure glaucoma is a clinical condition in which characteristic glaucomatous damage to the fundus and visual field occurs while the intraocular pressure remains normal. Although the IOP level remains in the statistically normal physiological range, the optic nerve undergoes the same pathological damage as in primary open-angle glaucoma [1]. The age of onset of NTG has tended to increase in recent years, and a survey conducted among Chinese in Singapore showed that the prevalence of glaucoma was 4, 8% in people over 60 years of age. Among them, 61% were NTG [2]. In this paper, we review the research status of the pathogenesis and treatment direction of NTG in recent years. 1, pathogenesis of normal intraocular pressure glaucoma Modern research on the pathogenesis of NTG focuses on three aspects: vascular factors, mechanical factors and autoimmune factors. 1.1 Mechanical factors Due to the histological differences in the sieve plate of the optic papilla and its developmental defects and degenerative changes, the upper and lower regions of the sieve plate are structurally weak and cannot withstand normal levels of IOP, causing blockage of axoplasmic flow transmission here, which in turn causes brain-derived neurological factor deprivation and initiates apoptosis of ganglion cells within the upper and lower arches, resulting in glaucomatous optic papillary depression and dysfunction. Thus, in NTG patients, the normalization of IOP is no longer based solely on the meaning of the normal range of general population statistics, but rather on the “individual tolerated IOP”. It has been shown that in NTG patients, lower target IOP levels (30% and more IOP reduction) can slow down the lesion and control long-term visual field damage [3].Nakagami et al [4] investigated visual field damage in 64 NTG patients treated with at least 4a of ocular IOP reduction and found that the likelihood of visual field stabilization after 76mo of IOP reduction was 56%. 1, 2 Vascular factors Ocular blood circulation is regulated by several factors, such as blood viscosity or coagulability, vasodilatory function, vascular self-regulatory mechanisms and perfusion pressure levels. When the perfusion pressure of the optic nerve is not sufficient to supply blood flow to the optic nerve, then optic nerve damage will occur. The impaired autoregulation of the optic nerve blood supply also increases the susceptibility of the optic papilla to pressure-induced ischemia. Lu Yunfeng et al [5] used extraocular negative pressure cup suction to induce IOP elevation in 8 normal subjects, 10 POAG patients and 7 NTG patients, and found that the decrease in blood flow to the optic papilla was more pronounced in NTG patients than in the normal and POAG groups when the IOP was elevated, and there was no significant increase in blood flow after the negative pressure suction was removed, suggesting that the vascular autoregulation in NTG patients was significantly impaired. Plange et al [6] also reported that the blood flow in the retrobulbar vessels of NTG patients was slowed down and under high pressure. And one study [7,8] hypothesized that the pathogenesis of optic nerve damage in NTG patients may be related to abnormal vascular permeability and damage/dysfunction of the vascular endothelium and vascular inflammatory processes by measured levels of plasma vascular endothelial growth factor, vWf factor, and plasma C-reactive protein levels. 1.3 Autoimmune factors Disturbances in autoimmune regulation may result in causing the patients themselves to alter certain components of the retina and nerve fibers and exhibit autoantigenicity, triggering autoimmune reactions that lead to damage to the optic nerve and retina.Yang et al [9] investigated and found that NTG patients had increased plasma expression of lymphocyte subsets (CD8, CD3) and antigens of HLA-DR, and Soluble interleukin-2 receptor (SIL-2R) titers were also elevated. a study by Tezel et al [10] also found increased immunostaining of heat stress proteins (HSP60 and HSP 27) in retinal cells of NTG patients. 2, Treatment of normal intraocular pressure glaucoma The current clinical treatment pathways for NTG are: (1) lowering IOP; (2) improving blood perfusion and microcirculation in the optic papilla; and (3) protecting the optic nerve. 2,1 Methods of IOP lowering 2,1,1 Surgical treatment Filtration surgery plays a great role in lowering IOP in NTG patients, but the surgery is limited to cases with progressive visual field and fundus damage. The use of filtration surgery that penetrates the entire sclera or the combination of adjuvant drugs such as pentafluorouracil (5-FU) or mitomycin C (MMC) can result in lower postoperative IOP, but the incidence of postoperative complications also increases. shigeeda et al [12] evaluated 23 patients with NTG who had markedly progressive preoperative visual field damage, and after trabeculectomy with the application of antimetabolic drugs for at least 5a After at least 5a of trabeculectomy with antimetabolites, IOP decreased by approximately 31% and visual field damage was slowed. Postoperative complications were found to be superficial anterior chamber (6 eyes), choroidal detachment (9 eyes), hypotensive macular degeneration (7 eyes), follicular leak (1 eye), cataract development (3 eyes), and follicular inflammation (2 eyes). Therefore the procedure should be approached with caution and postoperative review is mandatory to avoid serious postoperative complications. Argon laser trabeculoplasty has been suggested to reduce IOP in patients with NTG, but its effectiveness is not yet certain or limited. However, argon laser trabeculoplasty may be helpful in the treatment of NTG at least as an intermediate means between maximally tolerated medication and filtration surgery. 2,1,2 Pharmacological treatment ① β-adrenergic receptor blockers: 5g/L Timolol, 10-20g/L Carteolol, 5g/L Levobunolol, Betagan Betagan, 5g/L Betaxolol, etc. are currently used. The first three are non-selective β-adrenergic receptor blockers, and Betagan is a selective β1-adrenergic receptor blocker with Ca2+ antagonism, which can significantly increase ocular blood flow. tomita et al [15] investigated 62 NTG patients with more than 3a disease, and found that timolol alone can lower IOP by 13%-15%, and has a protective effect on visual field. However, at the same time, Chen et al [16] also found that the mean pressure indices of the central retinal artery and the long posterior ciliary artery decreased significantly after 12 wk of 20 g/L melphalan in 12 NTG patients, suggesting that treatment with 20 g/L melphalan may increase vascular resistance in NTG patients, which may be attributed to its intrinsic sympathomimetic activity. Therefore, in NTG patients, non-selective β-adrenergic receptor blockers may affect blood flow, and their drug selection and dosing schedule need to be carefully considered. ②Adrenomimetic drugs. Nowadays, 10-20g/L epinephrine, 1g/L Dipivefrin, 2-5g/L Brimonidine tartrate (Alphagan), etc. are mostly used. Dipivefrin, as an adrenergic precursor drug, is hydrolyzed to adrenaline after entering the eye and exerts its pharmacological effects. Brimonidine tartrate, a selective α2-adrenoceptor agonist, inhibits atrial aqueous production and increases scleral-uveal atrial outflow, and has neuroprotective effects. Gandolfi et al [18] also found that 16 NTG patients treated with 2 g/L alfagen for 30 d had a mean IOP reduction of about 18% and 4 had a 30% IOP reduction compared to the pre-treatment period. They all concluded that alfagen had a significant IOP-lowering effect on NTG patients in the short term. (iii) Prostaglandin analogs. Such as 0,05g/L latanoprost, 1,5g/L uroprostone, 0,3g/L bemiprost, 0,04g/L travoprost, etc. Otori et al [19] treated 30 patients with POAG, 1 with high IOP and 21 with NTG with 1,5g/L uroprostone and 0,05g/L latanoprost for 4wk, respectively, and found that the mean IOP after treatment decrease was 16, 6% and 28, 9%, respectively. Similarly Ang et al [20] investigated 76 patients with NTG treated with 0,05g/L latanoprost (mean treatment 11mo) and the mean daytime IOP reduction was 17%, the highest daytime IOP reduction was 19%, and 10% of patients had a 30% IOP reduction. It has also been demonstrated [21,22] that after treatment with 0,05 g/L latanoprost in NTG patients, the IOP reduction was accompanied by an increase in ocular perfusion pressure and an improvement in optic disc perfusion. Prostaglandins can effectively lower IOP and increase ocular perfusion and improve ocular blood flow, which is more therapeutic for NTG patients with multiple pathogenesis. ④Carbonic anhydrase inhibitors: such as acetazolamide, 2-3 g/L brinzolamide, 20 g/L dorzolamide, etc. Klemm et al [22] found a 20% decrease in IOP in 8 NTG patients treated with 3-5 wk of piperidine. Harris et al [23] gave 4 wk of dutilamide to 20 NTG patients and also found a significant decrease in IOP without altering ocular perfusion pressure but significantly reduced the arteriovenous traffic time in the temporal retina. and noted that its hypotensive effect was most pronounced at 2 wk post-treatment [24]. Recently Zeitz et al [25] also demonstrated that duceramide accelerates choroidal artery blood flow in NTG patients at the end of cardiac systole. This shows that topical carbonic anhydrase inhibitors have good IOP-lowering effects, improve optic nerve blood flow and reduce systemic side effects, and have synergistic effects in combination with other antihypertensive drugs, and their clinical applications are gradually increasing. 2.2 Methods to improve blood perfusion to the optic papilla 2.2.1 Calcium antagonists Calcium channel blockers inhibit the inward flow of extracellular calcium ions by blocking calcium channels, causing peripheral vasodilation. These include nifedipine, nimodipine, nifedipine, and lomepizine [26]. It has been shown in numerous studies that systemic application of calcium channel inhibitors can increase optic disc blood flow velocity, prevent the progression of visual field defects and improve optic nerve papillary blood flow in NTG patients.Yamamoto et al [27] treated 25 NTG patients with nivadipine 2 mg orally (2 times/d) and found a significant increase in central retinal artery and long posterior ciliary artery blood flow at end diastole after 4 wk increased, while the resistance index was significantly reduced. Recent investigations [28,29] suggest that lomepizine, which protects neuronal cells against retinal neurotoxicity and improves ocular blood circulation with minimal side effects, has clinical possibilities for the treatment of NTG-induced neuronal damage. Although calcium channel blockers can increase the blood flow rate of the optic disc in NTG patients, thereby improving the oxygen supply to the optic nerve and protecting the optic nerve and visual function, they have a high incidence of hypotensive side effects and are not tolerated by some patients. 2.2.2 Other drugs Certain drugs that improve systemic blood circulation, such as ginkgo biloba extract (GBE) and brovincamine, are being studied for their therapeutic effects on NTG. The main effects of Ginkgo biloba extract are to reduce blood viscosity, antagonize platelet-activating factor receptors, increase neuronal tolerance to hypoxia, modulate neurotransmitters and prevent free radical damage to cell membranes.Quaranta et al [30] conducted a placebo-controlled, prospective randomized double-blind crossover trial in 27 NTG patients with bilateral visual field defects and found that with Ginkgo biloba extract treatment resulted in a significant improvement in visual field. However, long-term maintenance medication is required, and its duration of action and optimal dosing regimen for NTG patients need to be further investigated. Koseki et al[31] investigated 52 NTG patients with low IOP treated with oral bromovorin for 2a and found that it slowed down the development of long-term visual field damage in NTG patients. However, these studies are still limited to the experimental stage, and their clinical application needs to be further investigated. 2,2,3 Other preventive and curative measures Actively treat organic vascular diseases affecting blood circulation that NTG patients suffer from, such as diabetes, hypertension, hypotension, elevated lipids, peripheral vascular disease, etc.; relieve vasospasm, avoid triggers that cause vasospasm (cold, nicotine, tension, etc.) and drugs that cause vasoconstriction; adjust emotions and maintain a good psychological state, etc. Through these measures, to some extent Through these measures, the deterioration of the disease may be avoided to a certain extent. 2.3 Neuroprotective therapy Glaucoma optic nerve protection therapy is a treatment method to block or delay primary and/or secondary damage to ganglion cells. Current research in this field includes gene therapy, glutamate antagonists, calcium channel blockers, free radical scavengers, NO synthase inhibitors, β-blockers, α2 adrenergic agonists, and vaccination [32,33]. It reduces the damage to retinal ganglion cells by various primary and/or secondary pathogenic factors along with other means including IOP-lowering drugs. However, a great deal of research has been conducted in glaucoma optic neuroprotective therapy, mostly at the animal experimental stage, and further studies are needed to determine whether the drugs found are truly optic neuroprotective without significant side effects. Wang et al [34] conducted a multicenter, randomized, double-blind clinical study and found that the rate of visual field damage was significantly reduced in glaucoma patients treated with lanchin, and this effect was proportional to the duration of drug administration. Guo Wenyi et al [35] found a stabilizing effect on glaucomatous visual field damage in 48 eyes of 29 glaucoma patients, after treatment with methylcobalamin injection and oral administration. And Qiu Yandong et al [36] found that in patients with glaucomatous optic nerve atrophy, the use of compound camptothecin paratemporal artery injection slowed the progression of the disease and improved some visual functions. In conclusion, although some reports suggest that the natural course of untreated NTG is highly variable, with some disease progressing significantly while others may be quiescent, the development of NTG lesions is still considered by most to be a combination of several mechanisms, still requiring the reduction of IOP by more than 30% as much as possible to achieve the target IOP level in NTG patients, reduce the damage to the optic nerve caused by IOP, and protection of visual function. At the same time, because optic nerve atrophy continues to develop in some NTG patients after IOP control and progressive visual field loss, increasing ocular blood flow and protecting the optic nerve have also become a hot topic of research. The application of calcium channel antagonists is beneficial to improve blood circulation in NTG patients. The dual role of prostaglandin analogs, which possess significant IOP-lowering effects while improving optic nerve blood flow, is gaining attention for the protection of visual function in NTG patients. At the same time, the research on optic nerve protection therapy is also getting more and more advanced. A large number of Chinese herbal extracts, such as lanzanine, chuanxiongzin, compound camptothecin, and sanguinarine, have been applied in the treatment of glaucoma optic nerve protection. There will be a better prospect to protect the visual function of NTG patients and improve the quality of life of NTG patients through the comprehensive treatment of lowering IOP, improving blood circulation and neuroprotection.