Anterior ischemic optic neuropathy is a common acute clinical ophthalmology with complex etiology, various treatment methods, and varying efficacy reports. The authors have combined several clinical observations and studies over the years with domestic and international research advances to systematically discuss its diagnosis, etiology, treatment, prognosis, prevention, and research outlook.
Anterior ischemic optic neuropathy is a common eye disease with rapid onset, which can involve both eyes and cause severe damage to visual function. It is characterized by a sudden loss of visual acuity, fan-shaped or hemianopia (mainly at the upper and lower levels) and optic papillary edema. It occupies the front position among neurological eye diseases. The disease was reported by Hayreh SS et al [1] in 1971-1975 based on fluorescence imaging. Those caused by temporal arteritis are called arteritis anterior ischemic optic neuropathy, which is more common abroad and rarely reported in China. NAION has an incidence of 1.02:10,000-1:15,000 in the United States and was first reported as 1:16,000 per year in China by Xu Liang et al. The actual incidence may be even higher due to the vast geographical area of China, differences in dietary habits and physical fitness of the population, and the lack of awareness among ophthalmology clinicians.
Although the etiology of NAION is not well understood, some systemic and local factors are closely related to the pathogenesis of NAION, and the study of related factors is helpful to increase the understanding of the etiology and the choice of treatment options. With better understanding, early diagnosis and treatment can significantly reduce the blinding and disability rate of this disease. This article discusses NAION.
I. Clinical manifestations
1, the age of onset: foreign patients are mostly elderly, the average age of 60 years or more, in recent years there are reports of foreign patients aged less than 50 years. National people are mostly 40 to 82 years old, with an average of 49 or 53 years old, and few people under 35 years old. There is little difference in gender.
2, more than two eyes are involved, but often weeks to years apart. Some foreign studies suggest that 14% of the other eye develops within 5 years, and we have observed that 48% of the contralateral eye has no visual cup within 3 years.
3. The onset of the disease is rapid, occurring mostly in the morning, initially as a dark shadow above, below or regionally, and expanding to diffuse blurring in front of the eye for a few hours or days, with a loss of central vision. At the beginning of the disease, almost more than half of the patients have visual acuity over 0.6, and 23% of the patient population has visual acuity of 0.1 or less [7]. Domestically, 51% to 61% of patients were reported to have central visual acuity above 0.2, and some had low visual acuity or even index or light perception [8].
4, Optic papillar edema, which can present as whole optic papillar edema or regional edema, or can be regional at first and become total optic papillar edema after a few hours to days; initially the optic papillar edema rises <1D and can bulge 2-3D in a few days, and the optic papillar color is basally pale or relatively pale above, below, and regionally. There may be radiolucent hemorrhage at the edge of the optic papilla. After the edema of the optic papilla has subsided, the color of the optic papilla may become lighter regionally or completely, and part of it may show white atrophic changes.
5. Some patients may have discomfort before or at the onset of the disease with dullness and swelling of the affected forehead or brow arch, but no painful eye rotation. Most patients do not feel any discomfort.
6. Disease duration: foreign studies suggest that the natural course of the disease takes 6 months from onset to stabilization [9], and the edema subsides in an average of 7.9 weeks [10].
Second, auxiliary examination
1, visual field: showing relative or absolute defects in the quadrant, superior, and inferior visual fields connected to the physiological blind spot, with less severe vision loss in most cases.
2, fluorescein fundus angiography (FFA) seen in.
(1) Early phase of FFA in the presence of optic papilloedema shows: (1) delayed filling or relative hypofluorescence of the ischemic area and its adjacent choroid. (2) Late phase of contrast shows strong fluorescence due to compensatory, passive dilatation of non-ischemic areas and disc surface capillaries.
(2) FFA after resolution of optic papillary edema shows relative hypofluorescence in the ischemic area in the early phase of the contrast, or even low fluorescence in the entire optic papilla, and normal fluorescence or fluorescence staining in the late phase.
3, indocyanine green choroidography (ICG): A clear correspondence exists between the fractionation of the fractional zone and the site of optic disc ischemia in patients with AION. early stage of ICGA has no fluorescence in the optic disc, late stage has no fluorescence in the ischemic area of the optic disc, and the non-ischemic area mainly shows inhomogeneous fluorescence [11]. The early regional hypofluorescence in choroidal imaging and the strong fluorescence in the ischemic area of the late optic papilla correspond to the regional hypofluorescence in the choroid.
4, Optical coherence tomography (OCT): peripapillary nerve fiber thickness showed variable manifestations in different disease stages, with the edematous stage showing diffuse peripapillary nerve fiber thickness thickening in all quadrants. We initially observed that the non-ischemic area of peri-optic disc nerve fiber thickness was greater than the ischemic area, and the cross scan showed edematous elevation, and the elevation in the non-ischemic area was more prominent.
III. Diagnosis and differential diagnosis
Diagnosis.
1.History:Sudden blurred vision and regional dark shadow.
2.Visual field:Fan-shaped, superior and inferior visual field defects connected with physiological blind spots.
3, Fundus: limited or complete optic papillary edema, color inconsistency, small optic disc in non-lesioned eyes, physiological cup narrowing.
Differential diagnosis.
1, optic nerve papillitis rapid onset, significant visual acuity loss, red edema of the optic papilla with hemorrhage and multiple exudates, macula often affected, visual field mainly clear central dark spot, FFA early optic disc without regional hypofluorescence, etc., not difficult to distinguish from the lack of disc.
Foster-Kennedy syndrome has something in common with lack of disc, that is, lack of disc can appear in both eyes before and after the onset of optic papillar edema in one eye and optic papillar atrophy in the other eye, optic nerve atrophy is caused by tumor compression under the frontal lobe, and optic papillar edema in the contralateral optic nerve due to successive intracranial pressure increase. It is easy to differentiate because of slow onset, visual field changes without NAION, and olfactory impairment.
3. Optic disc vasculitis (optic papilla type) is characterized by red edema of the optic papilla in the fundus of the eye, without obvious vision loss and visual field defects.
Etiology and pathogenesis
1, anatomical factors – optic cup narrowing (small optic disc shallow optic cup)
In 1994 and 1995, we measured and counted the optic disc cups of 139 eyes of NAION patients and 105 eyes of their contralateral eyes, compared with 222 eyes of normal people, and compared: NAION optic disc average The mean diameter of the optic disc in NAION eyes was 1.46 ± 0.15 mm and contralateral 1.45 ± 0.13 mm were smaller than the mean diameter of the optic disc in normal subjects 1.47 ± 0.11 mm, with statistically significant differences; 85.6% of the optic cups were not apparent in NAION eyes, 81.9% in contralateral eyes, and only 9% in normal subjects [14 15]. The role of the small cup-to-disc ratio in the pathogenesis of NAION was also revealed by Lu Lu et al.
In recent years, the authors also examined the optic disc diameters of 106 diseased eyes and 60 contralateral eyes after the edema of NAION had subsided by OCT to compare the optic cup depths with the normal population indexes, and the optic disc transverse diameters of 1.29 ± 0.19 mm in the diseased eyes and 1.32 ± 0.17 mm in the contralateral eyes were smaller than the mean optic disc transverse diameters of 1.40 ± 0.15 mm in normal subjects, and the optic disc longitudinal diameters of 1.54 ± 0.13 mm and 1.49±0.17 mm in the contralateral eye were smaller than the average longitudinal diameter of the normal human optic disc of 1.60±0.15 mm, both of which were statistically significant.
The optic cup morphology was divided into four classes: class I optic cup was the bottom of the optic cup above the level of the peripapillary nerve fibers, without optic cup morphology; class II optic cup was the bottom of the optic cup located at the level of the peripapillary nerve fibers, without optic cup morphology; class III optic cup was the bottom of the optic cup located below the level of the peripapillary nerve fibers and above the choroidal connection, with optic cup morphology; class IV optic cup was the bottom of the optic cup located below the choroidal connection, with optic cup morphology [ After the edema of NAION subsided, 41 eyes (38.68%) of grade I, 32 eyes (30.19%) of grade II, 24 eyes (22.64%) of grade III, and 9 eyes (8.49%) of grade IV were found in 106 eyes with intraocular cups; 12 eyes (18.18%) of grade I, 21 eyes (31.82%) of grade II, and 27 eyes (31.82%) of grade III were found in 66 eyes contralateral to NAION with intraocular cups. (31.82%), 27 eyes of grade III (40.91%), and 6 eyes of grade IV (9.09%).
The mean cup morphology of the diseased and contralateral eyes differed significantly from that of the normal population: 0.54±0.22 mm for transverse scan, 0.53±0.24 mm for longitudinal scan, 0.27±0.14 mm for transverse cup depth, and 0.31±0.14 mm for longitudinal cup depth. It is noteworthy that patients with grade I and II optic cups have the possibility of recurrence after the edema has subsided, with recurrence in 8 of the 98 eyes that had developed (8.51%), and the site of recurrence was usually outside the area of the original ischemic zone. It can be seen that class I and II optic cups (no optic cup) have a high risk of NAION development.
2. Hemodynamic factors-impaired blood circulation
The degree of vascular filling of the optic papilla and its peripapillary choroid depends on the difference between ciliary vascular perfusion pressure and intraocular pressure; the greater the difference, the better the vascular and tissue perfusion. hayreh pointed out according to fundus angiography that when the difference between diastolic pressure and intraocular pressure is 10 mmHg (1.33 Kpa) or less, the optic papilla and choroidal vessels are not filled. The author performed a comparative analysis of blood pressure intraocular pressure in 111 patients with anterior ischemic optic neuropathy in 1993, and the systolic and diastolic pressure of the brachial artery in the NAION group was 123.33±17.7 mmHg (16.45±2.36 Kpa) and the diastolic pressure was 78.15±10.95 mmHg (10.42±1.46 Kpa), then the systolic and diastolic pressures of the ophthalmic artery were 65.02±9.52 mmHg (8.67±1.27 Kpa) and 35.18±5.1 mmHg (4.69±0.68 Kpa), respectively, which were significantly lower than Bailiartt’s criteria for normal ophthalmic artery pressure and lower than the 41.8 mmHg of the control group in this paper. the difference between diastolic and intraocular pressure of the ophthalmic artery in the control group was 17.25 mmHg (2.3 The difference between ophthalmic artery diastolic pressure and intraocular pressure was below 12.75 mmHg (1.7 Kpa), a higher value than Hayreh’s 10 mmHg (1.33 Kpa), which was proposed as a risk value for the development of AION.
The low pulse pressure difference of brachial blood pressure is important in the occurrence of NAION. In normal times, sufficient perfusion pressure can still be maintained because systolic blood pressure is significantly higher than intraocular pressure. During sleep, when systemic blood pressure is low, even if the diastolic pressure of the posterior ciliary artery is below the critical level, if the pulse pressure difference of brachial artery pressure is reduced, the perfusion pressure of the posterior ciliary artery, which feeds the optic papilla during systole, is relatively low, and the diameter of the posterior ciliary artery is very small in the optic nerve and is located in the connective tissue septum, which is not easily self-regulated; The risk of ischemia is higher if there is anemia, arteritis, or local vascular stenosis. In addition, the intraocular pressure of normal people is higher in the early morning, and the difference between the intraocular arterial pressure and intraocular pressure decreases, and if they get up more dramatically, they are prone to develop the disease due to their position. In hypertensive atherosclerosis, the wall of the ciliary artery thickens and the effective volume of the lumen decreases, so that the actual perfusion volume decreases despite the high pulse pressure.
Since human blood pressure fluctuates rather than remains fixed over 24 hours, the above observations do not provide a theoretical explanation for the favored time period affecting the onset of NAION. the relationship between 24-hour ambulatory blood pressure and nocturnal hypotension and NAION was studied by Landau K et al [20] in 1996 and Hayreh SS et al [21] in 1997. in 2002, we studied the relationship between NAION and 50 patients in each of the NAION and its sex- and age-matched control group without NAION, measured 24-hour blood pressure and heart rate, and plotted the change curve from night to day [22], and found that there was no significant difference in the comparison of blood pressure and heart rate during the day between the two groups, and blood pressure and heart rate were higher during the day than at night.
Blood pressure and heart rate were lower in the NAION group than in the control group at night, blood pressure from 2:00 to 7:00, especially diastolic blood pressure was lower in the NAION group than in the control group, heart rate was lower in the NAION group than in the control group from 2:00 to 5:00, and the rising curve of blood pressure from night to day showed a slow and fluctuating rising curve in the NAION group, while the control group showed a sharp and smooth rising curve. It can be seen that NAION patients have some kind of defect in blood pressure regulation, and the low point of blood pressure and heart rate from 2:00 to 7:00 may be the susceptible time for NAION to occur. 24h ambulatory blood pressure abnormal changes, hypotension, irregular use of antihypertensive drugs, hypertension but low perfusion pressure at a certain time, etc., in the slower heart rate, long heart beat interval, then posterior ciliary artery diastolic pressure is below the critical level for a time beyond its tolerance This leads to impaired blood circulation to the optic nerve, resulting in ischemia of the optic papilla and posterior sieve plate, and thus the onset of the disease.
3. Hemorheological factors – high blood viscosity
High blood viscosity is closely related to the occurrence of NAION. In 1998, we performed blood rheological examination and statistical processing on 39 patients (19 males and 20 females) with anterior ischemic optic neuropathy in the optic papillary edema stage and 20 males and 20 females in the same number of normal controls that could be matched [23]. The results showed that the items that were significantly higher in the patient group than in the control group were: erythrocyte pressure volume, fibrinogen, low-cut viscosity, aggregation index, and erythrocyte electrophoresis time. In 2005, 260 patients (120 men and 140 women) with anterior ischemic optic neuropathy were examined for cholesterol and triglycerides in plasma, and cholesterol and triglyceride levels were statistically compared with those of the normal population control group. The results showed that cholesterol and triglycerides were significantly higher in the lesion group than in the control group, cholesterol levels were higher in female patients than in male patients, and there was no difference in triglyceride levels between men and women [24].
4, Vascular endothelin factors
It is possible that various vasomodulators and other biomolecules are involved in NAION pathology and correlate with the degree of optic disc ischemia and the duration of the disease, which remains to be studied.ET-1 is one of the endothelin isoforms and is the most potent vasoconstrictor known.In 2005, we measured plasma by radioimmunoassay (RIA) in 41 patients with NAION and age-matched 15 non-lesioned controls ET-1 levels. Plasma ET-1 levels were compared and analyzed in NAION patients with different degrees of optic disc edema and different disease duration. The results showed that plasma ET-1 levels were higher in patients with NAION than in controls; plasma ET-1 levels were higher the more severe the degree of optic disc edema; plasma ET-1 levels gradually decreased with the prolongation of the disease course, indicating that changes in ET-1 concentrations were involved in the course of NAION [25].
5. Arterial stenosis – carotid, ophthalmic, and posterior ciliary short artery stenosis
Ultrasound Doppler or cerebral angiography (DSA) in patients with NAION shows the presence of carotid artery malformations, atheromatous plaques, intimal thickening, ophthalmic artery stenosis malformations, posterior ciliary short artery stenosis, and slower blood flow in the nasal posterior ciliary short artery and central retinal artery in patients in the acute phase.
6, hemorrhagic shock, eye surgery that increases intraocular pressure, such as retinal detachment annuloplasty, vitrectomy, cataract surgery, etc.
7.Other non-direct risk factors
Hypertension, atherosclerosis, diabetes and other such diseases are important causes of cardiovascular events, although patients with cardiovascular obstruction have an increased chance of NAION, but they are not causally linked to NAION, but they have the same risk factors and therefore this type of disease can be regarded as the cause of NAION. There is also a small number of patients with NAION who have isolated or no close association in the pathogenesis of the disease.
V. Treatment and prognosis
The key to treatment is the rapid reduction of optic papillary edema. If the ischemic area and adjacent tissues are edematous due to ischemia, visual impairment can occur when the optic nerve fibers in the non-ischemic area become functionally impaired due to edema. If the impairment factors are relieved or the edema is removed in a timely manner, the optic function is restored and its central visual acuity and visual field impairment are reversible; if the impairment persists, which in turn leads to RNFL deficiency, the visual field deficiency is irreversible. Most of the nerve fibers in the ischemic area are irreversible in terms of degeneration and necrosis, while some of the nerve fibers in the ischemic area that are not completely necrotic lose their function due to edema, and if the edema rapidly subsides, some nerve fibers still recover their visual function to varying degrees, which is also illustrated by the fact that some patients change from absolute visual field defects to relative defects in the ischemic area in clinical practice. Therefore, continuous treatment and follow-up observation of patients according to different conditions are necessary.
(1) Glucocorticoids (steroids)
Advantages: Glucocorticoids are effective in reducing edema and have an inhibitory effect on the expression of endothelin-1. Disadvantages: NAION patients have different degrees of primary diseases (hypertension, hyperlipidemia, diabetes, etc.), the high dose and long-term use of hormones will aggravate the patient’s primary disease, but not conducive to the recovery of NAION edema; NAION is a gradual characteristic recovery process, short-term application of hormones is useful for edema subsidence, we advocate early short-term application.
(2) Vasodilators
Disadvantages: Due to the narrow physiological structure of the optic papilla, the patient’s optic disc will be in a crowded state due to vasodilation during NAION edema, resulting in further edema due to blocked axoplasmic transport and worsening of the disease, so it is recommended to use with caution during edema [26].
(3) Dehydrating agents
Advantages: increase intravascular colloid osmotic pressure, dehydration, diuresis, reduce intracranial pressure, accelerate the absorption and decompensation of edema Disadvantages: clinical use found that some patients have a tendency to aggravate edema during the use of drugs , and also has side effects on renal function, such as high blood viscosity people with abnormal renal function should not be used.
(4) Improving cellular energy metabolism – calf blood deprotein extract
Advantages: enhance cellular uptake and utilization of oxygen and glucose, shift the anaerobic metabolism of glucose to aerobic metabolism, increase the synthesis of energy substance ATP, promote and improve blood flow, and facilitate the recovery of neurological function, which is effective in the period of NAION edema [26 27]. Disadvantages: it is expensive and unaffordable for some patients.
(5) Hyperbaric chamber is an adjuvant treatment that has a positive effect on accelerating edema absorption. The mechanism is that under specific hyperbaric oxygen conditions, the edematous optic papillae are under sufficient oxygen, the blood circulation of the optic papillae tissue is reduced and the blood vessels are constricted, which relieves the crowded optic disc and blocks the vicious cycle, which is conducive to edema absorption. However, patients with concomitant hypertension must take vasodilators before entering the chamber after controlling the blood pressure and stabilizing it.
(6) Optic nerve sheath decompression has proven to be ineffective and is rarely used.
(7) Plant neuromodulators Compound camptothecin can accelerate the restoration of the normal level of vasoactive substances in the ischemic area. However, further research is needed to determine when it is more effective during the edema or edema subsidence period.
(8) IOP-lowering drugs have a positive effect on preventing the onset of disease.
(9) Application of neurorestorative agents The following are commonly used: . Cytophosphorylcholine, cerebroprotein hydrolysate, ganglioside, disodium cytidine triphosphate, nerve growth factor, etc. The best time to apply them is after the basic subsidence of optic papillary edema.
(10) Other therapies
The occurrence of NAION is closely related to systemic diseases such as hypertension and diabetes, as well as physiological and pathological states such as hemodynamics, local anatomy (small optic disc, narrow optic cup), high blood viscosity, and low ocular perfusion pressure. For this multifactorial disease, it is often difficult to achieve satisfactory results with the use of one or several drugs alone. According to the characteristics of the patient’s condition, active treatment of primary diseases, such as adjustment of blood glucose, blood pressure, lipids; carrier oxygen, hyperbaric oxygen to improve the hemodynamic shear rate, and the use of diphenhydramine are the basis for better results. Therefore, systemic basal therapy is performed along with local treatment.
We had selected different drugs for the treatment of NAION, fibrin-lowering enzymes can reduce high fibrinogen and high blood viscosity, the effect of selecting fibrin-lowering enzymes combined with ultraviolet glucose irradiation method (light quantum oxygen delivery) is more significant for the improvement of high blood viscosity in patients with NAION, the selection of sodium bis-alginate combined with ultraviolet glucose irradiation method is significant for the improvement of abnormal blood rheology in patients with NAION, in addition to the pharmacological effect of the selected drugs. There is no doubt that light quantum oxygen-carrying therapy can significantly increase the efficacy, and this combined method is convenient, safe, and has the characteristics of multiplying results with half the effort. In 105 patients with NAION, after combined treatment with different drugs, the blood viscosity was reduced and the abnormal blood rheology indexes were significantly improved. The recovery of visual acuity in the group of patients with improved blood rheology indexes was significantly better than that in the group of patients without improved blood rheology indexes.
VI. Prognosis
The extent, degree, edema and duration of optic disc ischemia are closely related to the recovery of visual function. The prognosis of patients with severe and extensive optic disc ischemia is poor; the prognosis of patients with prolonged and severe edema is poor; and the central vision of patients with damaged disc bundles is poor. If the disc bundle is not ischemic but the peripheral pressure edema, most of the visual acuity is better after the edema is removed, which is the misconception that some domestic literature reports the recovery of central visual acuity as the judgment of the efficacy. The prognosis is also determined by the reasonableness of the treatment strategy.
VII. Prevention
1. Those with small optic papillae, defective or narrow optic cups in the normal population should be the target of AION monitoring.
2. People with low blood pressure and high intraocular pressure (medium to high myopia because of the thin scleral wall and low scleral hardness, the intraocular pressure is in the normal range but actually higher), i.e., the difference between the diastolic pressure of the ophthalmic artery and the intraocular pressure is close to 12.75 mmHg, are at high risk of AION, and should be highly alert if there are anatomical factors in item 1. According to the 24-hour continuous ambulatory blood pressure monitoring value, choose the lowest diastolic blood pressure, the lowest pulse pressure difference and the slowest heart rate, and control the IOP at the corresponding lower level by medication, rather than mechanically administering IOP-lowering drugs in the usual way. According to the individual 24-hour blood pressure characteristics to adjust the dose of blood pressure-lowering drugs, dosage form (a combination of long- and short-acting), the time to take drugs, as well as adjust the type of IOP-lowering drugs and the time to order drugs is important for the prevention of AION.
3, blood viscosity, regular testing of blood rheology, blood lipids, blood fibrinogen, etc., according to the results of selective taking the appropriate drugs.
VIII. Outlook
With the progress of clinical and basic research, the pathogenesis of NAION will become clearer and clearer, especially the successful establishment of animal models of NAION similar to humans will advance the basic and drug treatment of NAION, we look forward to fruitful research.