Anterior Ischemic Optic Neuropathy:
Part II: a discussion for physicians
Sohan Singh Hayreh, MD, MS, PhD, DSc, FRCS, FRCOphth
Ocular Vascular Clinic
Department of Ophthalmology & Visual Sciences
Carver College of Medicine
University of Iowa
Iowa City, Iowa
Note: This is the second in a pair of articles about AION. Part one is an introduction suitable for patients and others unfamiliar with AION.
Ischemic optic neuropathy constitutes one of the major causes of blindness or seriously impaired vision among the middle-aged and elderly population, although no age is immune. Its pathogenesis, clinical features and management have been subjects of a good deal of controversy and confusion. I have conducted basic, experimental and clinical research on the blood supply of the optic nerve and on various aspects of ischemic optic neuropathy since 1955. Based on those studies and other published reports, I have discussed the entire subject of ischemic optic neuropathy at length in a recent review article published in the journal Progress in Retina and Eye Research . The following is an abbreviated version of that. For detailed information and bibliography, please consult the original paper. There is also a forthcoming book on AION by Sohan Singh Hayreh, it should be available in 2011.
Ischemic Optic Neuropathy
Ischemic optic neuropathy is due to acute ischemia of the optic nerve.
Based on the pattern of blood supply of the optic nerve, it can be divided into two distinct regions:
- The anterior part (optic nerve head) which is supplied primarily by the posterior ciliary artery circulation (Fig. 1A below).
- The posterior part which is supplied by multiple sources other than posterior ciliary artery circulation (Fig. 1B below).
Therefore, ischemic optic neuropathy is of two distinct types [17, 36, 74]:-
Anterior ischemic optic neuropathy (AION): This is due to acute ischemia of the optic nerve head. Etiologically and pathogenetically, AION is of two types:
- Arteritic AION (A-AION): This is due to giant cell arteritis.
- Non-arteritic AION (NA-AION): This type is not due to giant cell arteritis.
Posterior ischemic optic neurropathy (PION): [24, 60]: This is due to involvement of a part of the rest of the optic nerve. Etiologically and pathogenetically, PION is of 3 types:
- Arteritic PION due to giant cell arteritis,
- Non-arteritic PION due to causes other than giant cell arteritis,
- Surgical PION as a complication of a surgical procedure.
Abbreviations: A = arachnoid; C= choroid; CRA= central retinal artery; Col. Br.= Collateral branches; CRV= central retinal vein; D= dura; LC= lamina cribrosa; NFL= surface nerve fiber layer of the disc; OD= optic disc; ON= optic nerve; P= pia; PCA= posterior ciliary artery; PR and PLR= prelaminar region; R= retina; RA= retinal arteriole; S= sclera; SAS= subarachnoid space.
|Fig. 1: (enlarge the view) Schematic Representation Of Blood Supply of: (A) The Optic Nerve Head And (B) The Optic Nerve.|
Non-Arteritic Anterior Ischemic Optic Neuropathy (NA-AION)
NA-AION is the most common type of ischemic optic neuropathy, and has attracted the most controversy as to its pathogenesis and management.
PATHOGENESIS OF NA-AION
This is discussed at length elsewhere [36, 74]. Following is a brief account:
NA-AION is due to acute ischemia of the optic nerve head, whose main source of blood supply is from the posterior ciliary artery circulation (Fig. 1-A). Therefore, NA-AION represents an ischemic disorder of posterior ciliary artery circulation in the optic nerve head. Marked inter-individual variations in blood supply of the optic nerve head  and its blood flow  patterns profoundly influence the pathogenesis and clinical features of NA-AION.
Etiologically and pathogenetically NA-AION is of two types:
- Due to transient nonperfusion or hypoperfusion of the optic nerve head circulation: This is by far the commonest cause of NA-AION. There is almost a universally held belief among ophthalmologists and neurologists that NA-AION has a pathogenesis like that of a stroke which is a thromboembolic disorder; however, in the vast majority of NA-AION cases there is no evidence of that, as discussed at length elsewhere  - this is an extremely important fact to be borne in mind while managing NA-AION patients.
Naturally the question arises: what is the mechanism of transient nonperfusion or hypoperfusion of the optic nerve head circulation in NA-AION? It can be caused by a variety of factors. Available evidence indicates that in the vast majority of cases it is a transient fall of blood pressure, most commonly during sleep (nocturnal arterial hypotension - see below) or a nap during the day, or shock. A transient fall of perfusion pressure (perfusion pressure = mean blood pressure minus intraocular pressure) in the optic nerve head capillaries below the critical autoregulatory range (Fig. 2 below) in susceptible persons (see below), results in ischemia of the optic nerve head and development of NA-AION.
- Due to embolic lesions of the arteries/arterioles feeding the optic nerve head: This is only an occasional cause of NA-AION. Compared to the hypotensive type of NA-AION, the extent of optic nerve head damage in this type is usually massive, severe, and permanent (similar to that in A-AION – see below), depending upon the size of the artery involved and the area of the nerve supplied by the occluded artery.
Fig. 2: A diagrammatic representation of blood flow autoregulation range at different perfusion pressures in normal persons. Absent and present denote absence or presence of the autoregulation. (Reproduced with permission from Hayreh, 2009 
RISK FACTORS FOR DEVELOPMENT OF NA-AION:
All the available evidence indicates that NA-AION is multifactorial in nature. The various risk factors fall into two main categories:
Predisposing risk factors make a person susceptible to develop NA-AION but do not necessarily produce NA-AION on their own. These may be systemic or local in the eye and/or optic nerve head.
a. Systemic risk factors: Various studies have shown a significantly high prevalence of
- arterial hypertension, nocturnal arterial hypotension,
- diabetes mellitus,
- ischemic heart disease,
- atherosclerosis and arteriosclerosis in NA-AION patients compared to the general population.
- Other associated systemic diseases have also been reported, including
- sleep apnea,
- arterial hypotension due to a variety of causes,
- malignant arterial hypertension and
b. Ocular and optic nerve head risk factors: A significant association of NA-AION has been seen with a number of ocular and optic nerve head conditions. These include
- absent or small cup in the optic disc,
- angle closure glaucoma or other causes of markedly raised IOP,
- marked optic disc edema due to any cause,
- location of the watershed zone of the posterior ciliary arteries in relation to the optic disc,
- optic disc drusen and
- cataract extraction.
- Defective autoregulation of the optic nerve head may also play a role
The role of an absent or small cup in the pathogenesis of development of NA-AION: Since 1974, several studies have shown that in eyes with NA-AION there is a significantly higher prevalence of absent or small cup than in the general population [12, 72, 78]. This has resulted in a misconception in the ophthalmic community that a small or absent cup is actually the primary factor in the development of the disease; this has resulted in catchy terms like "disc at risk". The role of an absent or small cup in the pathogenesis of development of NA-AION is discussed in detail elsewhere [72, 78]. Briefly, it is evident that in the multifactorial scenario of pathogenesis of NA-AION, contrary to the prevalent impression, an absent or small cup is simply a secondary contributing factor, once the process of NA-AION has started, and not a primary.
Precipitating risk factor(s): In a person with predisposing risk factor already present, these risk factors act as the final insult ("last straw"), resulting in ischemia of the optic nerve head and NA-AION. Nocturnal arterial hypotension is the most important factor in this category. This is because studies have shown that patients with NA-AION and often also those with A-AION typically complain of discovering visual loss on waking in the morning. In NA-AION, 73% gave a definite history of discovering the visual loss on waking up in the morning or from a nap, or first opportunity in the day to use vision critically . The incidence may actually be much higher than 73% because among the remaining patients many were not certain when it had actually occurred. My 24-hour ambulatory blood pressure monitoring (Fig. 3 below) has shown development of marked nocturnal arterial hypotension in such patients. For example, the 24-hour ambulatory blood pressure monitoring pressure graph in figure 4 shows a steep drop in blood pressure on falling asleep at night and recovery to normal on waking in the morning. Studies have also shown that arterial hypertensives on oral hypotensive therapy have a significant association between progressive visual field deterioration in NA-AION and nocturnal hypotension [33, 46]. The fall of blood pressure during sleep is a physiological phenomenon, but it is influenced by many factors, including the various arterial hypotensive drugs taken for arterial hypertension or other cardiovascular disorders, particularly the number and amount of drugs taken and the time of day they are taken. When these drugs were taken at bedtime, they produced a far more marked degree of nocturnal hypotension than when taken in the morning, because they aggravate the naturally occurring fall of blood pressure during sleep (Fig. 5). There are, however, some patients who develop marked nocturnal hypotension even without any medication (presumably due to defective cardiovascular autoregulation), as can be seen in figure 4.
Conclusion: From this brief discussion, it becomes clear that development of NA-AION and the role of nocturnal hypotension in it, is highly complex. A whole host of systemic and local factors, acting in different combinations and to different extents may derange the optic nerve head circulation, with some making the optic nerve head susceptible to ischemia and others acting as the final insult. Nocturnal hypotension seems to be an important precipitating factor in the susceptible patient. It is the lack of in-depth understanding of the complex interrelationships that has resulted in controversy and confusion. The pathogenesis of NA-AION is complex but not, as often stated, unknown.
Fig. 3: Diagrammatic representation of mean hourly systolic and diastolic blood pressures over a 24-hour period in persons with normal blood pressure (normotensive and those with high blood pressure (hypertensive). (Reproduced with permission from Hayreh et al. )
Fig. 4: Ambulatory BP and heart rate monitoring records (based on individual readings) over a 24-hour period, starting from about 11 a.m., in a 58-year old woman with bilateral NA-AION, and on no medication. The BP is perfectly normal during the waking hours but there is marked nocturnal arterial hypotension during sleep. (Reproduced with permission from Hayreh et al.1999 )
Fig. 5: Two 24-hour ambulatory blood pressure monitoring records (based on individual readings), starting at 10 a.m. , of a 63-year old woman taking Verapamil hydrochloride for migraine. Both records show normal blood pressure during the waking hours. The upper record, when she was taking Verapamil at bedtime, shows that during sleep there was a marked degree of nocturnal arterial hypotension (blood pressure falling as low as 80/30 mmHg). The lower record shows markedly less nocturnal hypotension on stopping the bedtime dose of Verapamil (lowest blood pressure 110/50 mmHg). (Reproduced with permission from Hayreh 2008 )
CLINICAL FEATURES OF CLASSICAL NA-AION
NA-AION is the most common type of ischemic optic neuropathy. It usually has classical symptoms and signs which make it easy to diagnose. The subject is discussed at length elsewhere [36, 74]. Following is a very brief account of the clinical features of NA-AION.
NA-AION is mostly a disease of the middle-aged and elderly, although no age is immune from it. In the vast majority, symptoms are typical. There is a sudden and painless deterioration of vision, usually discovered on waking in the morning . When there is progressive visual loss, the patients again usually notice it on waking in the morning. NA-AION patients often complain of loss of vision towards the nose and less commonly altitudinal loss. Later on, photophobia is a common complaint, particularly in bilateral cases.
Poor visual acuity is common with NA-AION, however, initial visual acuity was 20/20 in 33%, better than 20/40 in 51% in a study of 500 consecutive NA-AION eyes [71, 73]. This shows that the presence of normal visual acuity does not rule out NA-AION - a common mistake. In contrast to that, visual field defects are a universal occurrence. Therefore, perimetry is the most important and essential visual function test to evaluate the visual loss. These eyes can present with a variety of optic nerve related visual field defects; however, a combination of a relative inferior altitudinal defect with absolute inferior nasal defect is the most common pattern in NA-AION (Fig. 6-A). This contradicts the commonly held belief that inferior altitudinal visual field defect (Fig. 6-B) is typical of NA-AION. My studies have shown that in NA-AION the visual field plotted with manual kinetic perimetry (using Goldmann perimeter) compared to that by automated perimetry provides far superior information about type of visual field defect and the peripheral field, and for evaluating visual functional disability . This is because unfortunately, automated perimetry provides information on only up to about 24° - 30° in the periphery, whereas kinetic perimetry provides peripheral visual field information all the way to about 80° – 90° temporally, 70° inferiorly, 60° - 70° nasally and 50° - 60° superiorly.
Fig. 6: Two examples of fields of vision plotted with a Goldmann Perimeter [Using I2e (red), I4e (blue), V4e (purple)] (Reproduced with permission from Hayreh )
A. Right eye field of vision shows loss of inner and lower field of vision toward the nose.
B. Left eye field of vision shows loss of the entire lower half of field of vision.
Natural history of visual outcome in NA-AION: To evaluate whether a particular mode of treatment is beneficial or not, the first essential is to find out the natural history of a disease. It is not uncommon to find that natural history is credited as beneficial effect of a treatment. There are two prospective studies that have evaluated natural history of visual outcome in NA-AION [71, 79]; both arrived at the same conclusion. Both studies showed that in patients seen within 2 weeks of onset of visual loss and initial visual acuity of 20/70 or worse, there was spontaneous improvement of visual acuity in 41% - 43% and worsening in 15%-19% at 6 months. My study also evaluated visual fields with kinetic perimetry and that showed that 26% of those who were first seen <2 weeks of onset with moderate to severe visual field defect, showed improvement at 6 months . Visual acuity and visual fields showed improvement or further deterioration mainly up to 6 months, with no significant change after that . When NA-AION develops in the second eye, there is no correlation in the visual outcome in the two eyes.
Ophthalmic evaluation: At the onset of visual loss, there is always optic disc edema. There are several misconceptions about optic disc edema in NA-AION. The most common one is that in NA-AION the optic disc edema is always pale – that is not true at all initially, because the color of optic disc edema in NA-ION initially does not differ from optic disc edema due to other causes – in some cases there may even be hyperemia of the optic disc  (Figs. 7, 8, 9-B). A splinter hemorrhage at disc margin is common (Fig. 8). Optic disc edema starts to develop pallor about 2-3 weeks after the onset of NA-AION, and optic disc edema usually resolves spontaneously in about 2 months . There is a characteristic evolutionary pattern of optic disc edema in NA-AION, as discussed elsewhere . On resolution of optic disc edema, the distribution of optic disc pallor does not always correspond with the extent and location of visual and nerve fiber loss . In occasional cases, where NA-AION is due to embolism, the optic disc edema usually has a chalky white appearance unlike in the classical NA-AION.
In the fellow normal eye, optic disc usually shows either no cup or small cup (see "predisposing risk factors" above). This can be a helpful clue in the diagnosis of NA-AION in doubtful cases. If originally both eyes have a small disc cup, I have seen that in unilateral NAION, once the disc edema resolves, the cup in the involved eye may become slightly larger than the fellow eye because of loss of nerve fibers.
In diabetics, optic disc changes in NA-AION may have some characteristic diagnostic features. During the initial stages, the optic disc edema is usually (but not always) associated with characteristic prominent, dilated and frequently telangiectatic vessels over the disc, and much more numerous peripapillary retinal hemorrhages than in non-diabetics (Figs. 10-A, 11-A) [23, 70 ] These findings may easily be mistaken for proliferative diabetic retinopathy associated with optic disc neovascularization. When the optic disc edema resolves spontaneously, these prominent telangiectatic disc vessels and retinal hemorrhages also resolve spontaneously (Figs. 10-B, 11-B). The presence of these characteristic fundus changes in some diabetics with NA-AION has resulted in a good deal of controversy because it has been thought to be a separate clinical entity - described under different eponyms, the most common being "diabetic papillopathy", when in fact it is NA-AION .
Fig. 7: Left fundus photograph showing optic disc edema and hyperemia during the acute phase of NA-AION. (Reproduced with permission from Hayreh, 2009 )
Fig. 8: Right fundus photograph showing optic disc edema and hyperemia, with a splinter hemorrhage (arrow) during the acute phase of NA-AION. (Reproduced with permission from Hayreh, 2009 )
Fig. 9: Fundus photographs of left eye of a 53-year-old man. (A) Normal disc before developing NA-AION, (B) with optic disc edema during the active phase of NA-AION, and (C) after resolution of optic disc edema and development of optic disc pallor – more marked in temporal part than nasal part. (Reproduced with permission from Hayreh, 2009 )
Fig 10: Fundus photographs of the left eye, of a 19½ year-old white male juvenile diabetic. (A) shows massive optic disc edema with marked telangiectatic vessels on the optic disc, multiple punctate peripapillary and macular retinal hemorrhages, engorged retinal veins. (B) shows normal-looking optic disc, no abnormal vessels on the disc, and no retinal hemorrhages on resolution. (Reproduced with permission from Hayreh 1978 )
Fig. 11: Fundus photographs of right eye of a diabetic patient with nonarteritic AION showing (reproduced with permission from Hayreh et al )
A. During early stage with optic disc edema with prominent blood vessels on the disc and many retinal hemorrhages
B. During later stage with pale color (optic atrophy) and spontaneous resolution of prominent blood vessels on the optic disc as well as hemorrhages.
Other fundus changes: The presence of a few splinter hemorrhages on optic disc or immediate peripapillary region is common in association with the optic disc edema (Fig. 8); those resolve spontaneously with optic disc edema resolution. Diabetics tend to have more peripapillary retinal hemorrhages than non-diabetics [23, 70]. Occasionally, there may be mild serous retinal detachment between the optic disc and macula and that may even extend to macular region to produce macular edema (Fig. 12).
Fluorescein fundus angiographic findings: It is only when angiography is performed during the first few days after the onset of visual loss and during the very early arterial phase of dye filling in the fundus that demonstrates the tell-tale impaired circulation and its location in NA-AION. In my studies, there is almost invariably filling defect/delay in the prelaminar region and in the peripapillary choroid (Fig.13) and/or choroidal watershed zones (Figs. 14-A, B, D) at onset of NA-AION . In the occasional case, where NA-AION is due to embolism into the posterior ciliary artery, the part of the choroid supplied by the occluded posterior ciliary artery or short posterior ciliary artery does not fill (Fig. 15-A). In view of that, fluorescein angiography provides very useful information when patients are seen early, particularly in differentiation of NA-AION and A-AION; therefore, it is essential to perform that in all early cases. Late optic disc staining is a non-specific finding of optic disc edema, and has no diagnostic importance for NA-AION.
Fig. 12: Fundus photograph (A) and OCT (B) of right eye with NA-AION and serous retinal detachment between the optic disc and the macula. In (A) arrows indicate the presence of lipid deposits in the central part of the macula. (Reproduced with permission from Hayreh, 2009 )
Fig. 13: Fluorescein fundus angiogram of 2 eyes with NA-AION showing non-filling of temporal part of the peripapillary choroid (arrow) and adjacent optic disc and the choroidal watershed zone (arrow). (Reproduced with permission from (A) Hayreh 1985  and (B) Hayreh 1996 .)
Fig. 14: Fluorescein fundus angiograms of 4 eyes with AION showing different locations of the watershed zone (vertical dark bands) in relation to the optic disc. (A): Right eye with the watershed zone lying temporal to the optic disc. (B): Right eye with the watershed zone passing through the temporal part of the disc and adjacent temporal peripapillary choroid. (C): Left eye with the optic disc lying in the center of the watershed zone. (D): Left eye with the watershed zone passing through the nasal part of the disc and adjacent nasal peripapillary choroid. (Reproduced with permission from Hayreh 1985 ) Abbreviations: LPCA = lateral posterior ciliary artery; MPCA = medial posterior ciliary artery; WSZ = watershed zone
Fig. 15: Fluorescein fundus angiograms of 3 eyes showing areas of supply by the occluded posterior ciliary artery and the patent posterior ciliary artery. (A): Right eye with NA-AION (negative temporal artery biopsy for giant cell arteritis), showing normal filling of the area supplied by the lateral posterior ciliary artery (including the temporal half of optic disc) but no filling of the area supplied by the medial posterior ciliary artery (including the nasal half of optic disc). (Reproduced with permission from Hayreh 1985 ) (B): Right eye with A-AION, showing normal filling of the area supplied by the lateral posterior ciliary artery (including the temporal ¼ of the optic disc) but no filling of the area supplied by the medial posterior ciliary artery (including the nasal ¾ of the disc). (Reproduced with permission from Hayreh 1978 ) (C): Left eye with A-AION associated with cilioretinal artery occlusion, showing normal filling of the area supplied by the lateral posterior ciliary artery, but no filling of the choroid and entire optic disc supplied by the medial posterior ciliary artery or of the cilioretinal artery(arrow). (Reproduced with permission from Hayreh 1978 )
Bilateral NA-AION: The cumulative probability of the fellow eye developing NA-AION has varied among different studies: 25% within 3 years , 17% in 5 years  and 15% over 5 years ; however, different criteria were used to determine the probability, which may explain the differences. According to one study , the risk is greater in men, particularly young diabetic men. The risk of the second eye getting involved by NA-AION is significantly greater in diabetics than in nondiabetics .
Recurrence of NA-AION in the same eye: In a study of 829 NA-AION eyes, the overall cumulative percentage of recurrence of NA-AION in the same eye was about 6% at two years . The only significant association for recurrence of NA-AION was with nocturnal arterial hypotension. Thus, this study indicated that nocturnal diastolic arterial hypotension might be a risk factor for recurrence of NA-AION; however, since NA-AION is a multifactorial disease, other risk factors so far unknown may also play a role.
NA-AION and erectile dysfunction drugs: The subject is discussed at length elsewhere [61, 64]. Briefly, most patients who reported to have developed NA-AION following the use of these drugs are middle-aged or elderly men who generally already had various predisposing risk factors for NA-AION (see above). These drugs are mostly taken in the evening for sexual intercourse. They result in fall of blood pressure; when taken in the evening, as discussed above, there is high chance of them producing abnormal nocturnal arterial hypotension, which may be further aggravated if the person taking other arterial hypotensive drugs for arterial hypertension or other cardiovascular disorders. Like the vast majority of NA-AION patients, most of the patients reporting NA-AION following ingestion of these drugs discovered visual loss upon awakening in the morning. A critical review of all the reported cases shows a usually good temporal relationship between the ingestion of these drugs and onset of NA-AION. When all the above evidence is put together, it suggests that Viagra® (sildenafil) and other erectile dysfunction drugs can result in development of NA-AION in persons who already have predisposing risk factors.
Amiodarone and NA-AION: There is a universal belief that amiodarone causes optic neuropathy, called "amiodarone-induced optic neuropathy". However, various facts discussed elsewhere  show that this in fact is NA-AION. In the multifactorial scenario of NA-AION, it is the systemic cardiovascular risk factors rather than amiodarone that cause NA-AION.
Familial NA-AION: There are 5 reports in the literature representing 10 unrelated families in which more than one member developed NA-AION . We have shown that this rare entity of familial NA-AION is clinically similar to the classical non-familial NA-AION, with the exception that familial NA-AION occurred in younger patients and had much higher involvement of both eyes than the classical NA-AION. The role of genetic factors in familial NA-AION is not known.
This has been a highly controversial subject. Over the years, a number of treatments have been advocated, including optic nerve sheath decompression, aspirin, systemic corticosteroids, and intravitreal triamcinolone and vascular endothelial growth factor inhibitory drugs. Optic nerve sheath decompression was found to be not only of no benefit but also a harmful procedure . Following is a discussion of the currently advocated treatments.
Systemic Corticosteroid Therapy:
A recent large, prospective study ,reported its finding on the role of systemic corticosteroid therapy in NA-AION. In this "patient randomization" study, there were 696 eyes with NA-AION; of these cases, 51% voluntarily opted for systemic therapy while 49% opted for no treatment. There was no significant difference between the two groups in initial visual acuity and visual fields defects, and systemic diseases, except that patients who opted for treatment were slightly younger (59.2 vs. 62.0 years) and had a lower prevalence of arterial hypertension (34% vs. 43%). To determine if those factors influenced the visual outcome, they were accounted for in the statistical analysis by including them as covariates in the logistic regression model – they made no difference in visual outcome (age p=0.8; hypertension p=0.6).
Median follow-up was 3.8 years. At 6 months from onset of NA-AION, of the eyes with initial visual acuity 20/70 or worse and seen within 2 weeks of onset, there was visual acuity improvement in 70% (95% confidence interval (CI): 57.3%, 79.9%) in the treated group compared to 40.5% (95% CI: 29.2%, 52.9%) in the untreated group (odds ratio of improvement: 3.39; 95% CI:1.62, 7.11; p=0.001). Comparison of visual field defect at 6 months from onset of NA-AION, among those seen within 2 weeks of NA-AION onset with moderate to severe initial visual field defect, there was improvement in 40% (95% CI: 33.1%, 47.5%) of the treated group and 24.5% (95% CI: 17.7%, 32.9%) of the untreated group (odds ratio: 2.06, 95% CI: 1.24, 3.40; p=0.005). In both treated and untreated groups, the visual acuity and visual fields kept improving up to about 6 months from onset of NA-AION and very little thereafter.
Therefore, in NA-AION with no proven and effective treatment so far, this study suggested that treating these patients with systemic corticosteroids during the acute phase results in a significantly higher probability of improvement in visual acuity (p=0.001) and visual fields (p=0.005), compared to an untreated group. Both visual acuity and visual fields improved for up to 6 months after onset of NA-AION and no more after that.
Neuro-ophthalmologists and neurologists do not accept the findings of this study and are of opinion that corticosteroid therapy has no role in treatment of NA-AION. They have raised the following objections to this study:
Neuro-ophthalmologists and neurologists do not accept the findings of this study and are of opinion that corticosteroid therapy has no role in treatment of NA-AION. They have raised the following objections to this study:
- Most importantly, there is no scientific rationale for the use of corticosteroid therapy in NA-AION.
- There was no conventional randomization in this study.
- The study was not collected in a masked fashion.
The authors of this study have discussed all these objections at length in their paper. Following are the responses:
Naturally, the question arises, why did corticosteroid therapy help to improve the visual acuity and visual fields of NA-AION patients? This is discussed at length elsewhere.
- To comprehend that, one has to consider some of the relevant basic aspects of NA-AION.
---NA-AION is due to ischemia of the optic nerve head, which is primarily supplied by the posterior ciliary artery circulation [6, 52].
- Ischemia of axons in NA-AION results in axoplasmic flow stasis, which in turn causes axoplasmic accumulation and consequent axonal swelling in the optic nerve head; that manifests as opic swelling.[14, 16, 94]
- It has been shown that, in the majority of NA-AION eyes, the optic disc has a small cup or none at all [72, 78]. Thus, there is crowding of the nerve fibers as they pass through a restricted space in the rigid opening in Bruch's membrane and the small scleral canal. The importance of this factor is that the swollen axons in the restricted and unyielding space within the optic nerve head have to expand at the cost of other tissues in that restricted space. The only thing that they can compress to expand is the fine capillaries lying among them; that results in secondary vascular changes . A vicious circle may, therefore, be set up, in which compression of capillaries may further aggravate ischemia, particularly when perfusion pressure in them falls for any reason (as for example, during nocturnal arterial hypotension [33, 41, 47]). This is supported by the fact that in at least 73.3% of episodes of NA-AION, visual loss was discovered first upon awakening or a first opportunity to use vision critically after sleeping, because of fall of blood pressure during sleep .
- On fluorescein fundus angiography, the optic disc with edema in NA-AION always shows dye leaking from the capillaries in the optic nerve head and late staining. Fluorescein leakage may be due to two factors: (i) ischemic insult to the capillaries in the optic nerve head, and (ii) venous stasis produced by the capillary compression . Foulds  also pointed out that increased capillary permeability due to anoxic capillary damage was an important factor in development of optic disc edema in NA-AION.
Therefore, there are primary and secondary changes in the optic nerve head to produce optic disc edema in NA-AION - the primary change being ischemic axoplasmic flow stasis in the axons and the secondary vascular changes and fluid leakage.
Foulds  postulated that corticosteroid therapy in acute NA-AION reduces optic disc edema by reducing the capillary permeability. There is ample evidence that corticosteroids work in many non-inflammatory diseases. For example, a large number of studies have shown that corticosteroid therapy reduces macular edema due to various causes. It is due to reduction of capillary permeability and decrease of fluid leakage. As discussed above, fluorescein angiography shows leakage of fluorescein in the optic nerve head when the disc is edematous in NA-AION but not in normal or atrophic discs - a proof of increased capillary permeability in optic disc edema. A study investigated the effect of systemic corticosteroid therapy on optic disc edema in NA-AION, by comparing the rate of resolution of optic disc edema in the treated group (343 eyes) versus the untreated group (380 eyes) . It showed that those treated with corticosteroid therapy within 2 weeks after onset of NA-AION had significantly (p=0.0006) faster optic disc edema resolution than the untreated cases. This indicates reduction in capillary leakage, similar to that seen in macular edema with corticosteroid therapy.
Thus, from the above discussion, the scenario that emerges to explain the beneficial effect of corticosteroid therapy on visual outcome in NA-AION seems to be as follows. The faster resolution of optic disc edema with corticosteroid therapy compared to the untreated patients  → progressive decrease of compression of the capillaries in the optic nerve head → better blood flow in the capillaries → improved circulation in the optic nerve head → improved function of the surviving but not functioning hypoxic axons. There is a possibility that corticosteroids may have beneficial effects from some other unknown mechanisms; one of those mentioned has been inhibition of damage by free radicals.
A well-known neuro-ophthalmologist, while commenting on the role of corticosteroid therapy in NA-AION, stated: "Oral steroids in the setting of acute cerebral stroke are contraindicated". This statement is based on a serious misconception about pathogenesis of NA-AION. Cerebral stroke is a thromboembolic disorder, involving a large mass of tissue in the cerebrum. In contrast to that, NA-AION is a hypotensive disorder, involving a minute amount of tissue in the optic nerve head. To equate the two conditions is a fundamental mistake and responsible for confusion and controversy on various aspects of NA-AION, including its management.
The reason was discussed in the original paper. In early 1970s, I planned a large, multicenter randomized clinical trial to investigate systematically in a large cohort of NA-AION patients whether systemic corticosteroids improved visual outcome. Unfortunately, that clinical trial was not funded by the NIH, because of a firm belief (based on no scientifically valid data) among neuro-ophthalmologists that corticosteroid therapy has no role in NA-AION. Since no alternative treatment existed, I felt that it was crucial to find out whether corticosteroid therapy was actually beneficial, ineffective or conceivably harmful in NA-AION. Lacking funding, I decided on a "patient choice" study instead of the "conventional randomized study" – the next best choice. Every NA-AION patient seen in my clinic was given a free and informed "patient choice". The decision was left entirely up to the patient, to opt for corticosteroid therapy or no treatment, in consultation with their physicians or other sources. We had no in-put at all into their choice. I specifically told all patients that I really did not know whether the treatment was beneficial, ineffective or even harmful. I collected the data for 28 years, completely masked about visual outcomes and numbers of patients in each group. The study finally included 613 consecutive NAION patients (696 eyes) seen in my clinic.
What are the critical criteria for "conventional randomization"? It is to have comparable treated and untreated groups at baseline in demographic and clinical characteristics. In this study, there was no significant difference between the treated and untreated groups in the baseline demographic and clinical characteristics, as is evident from the following:
- Of the 696 eyes with NA-AION, 51% voluntarily opted for systemic corticosteroid therapy, and 49% opted for no treatment. Thus, the number of patients in the treated and untreated groups was similar.
- There was no significant difference between the two groups in visual acuity, visual fields and systemic diseases, except that patients who opted for treatment were slightly younger (59.2 vs. 62.0 years) and had a lower prevalence of arterial hypertension (34% vs. 43%).To determine if those factors influenced the visual outcome, they wereaccounted for in the statistical analysis by including them as covariates in the logistic regression model – they made no difference in visual outcome (age p=0.8; hypertension p=0.6).
Thus, this "patient choice" study fulfilled the most crucial criteria of any clinical trial, i.e. the treated and untreated groups were comparable in demographic and clinical characteristics. Therefore, the results of this study must be valid.
I expected this criticism from the start of the study. Therefore, all possible steps were taken in collecting all the data in a masked fashion, and during data analysis. These steps are discussed at length in the paper.
This discussion, answers all the objections raised by critics to this study. In fact, all this information is already provided in detail in the original paper.
Treatment protocol in this systemic corticosteroid therapy study
All patients were given initially 80 mg Prednisone daily for 2 weeks, then tapered down to 70 mg for 5 days, 60 mg for 5 days, then cut down by 5 mg every 5 days, to nothing.
Who, when and how to treat NA-AION patients with corticosteroid therapy?
The sooner the treatment is started, the better are the chances of visual improvement. That may be because the shorter the duration of axonal ischemia, the fewer axons are likely to be damaged permanently.
Secret of Corticosteroid Therapy Success
Over a period of almost five decades having treated several thousand patients with corticosteroid therapy for a variety of conditions, including giant cell arteritis, scleritis, uveitis, orbital myositis, retinal vasculitis and other conditions, I have found that the most effective way to use corticosteroid therapy is to hit hard at the beginning and then taper down. The major flaw in the way corticosteroid therapy has been given for NA-AION in some studies is "too small a dose, for too short a period". This timidity has led to the prevailing misconception that corticosteroid therapy does not help NA-AION
Other advocated therapies in NA-AION
This is discussed at length elsewhere . There is a common belief that NA-AION and cerebral stroke are similar in nature pathogenetically and in management. Under this misconception, aspirin is routinely advocated in NA-AION. Cerebral stroke is a thromboembolic disorder, involving a large mass of tissue in the cerebrum. By sharp contrast, NA-AION is a hypotensive disorder, involving a minute amount of tissue in the ONH. Thus, there is a fundamental difference between the two .
Two large studies have shown that aspirin has no long-term benefit of reducing the risk of NA-AION.[81, 82]. The fellow eye in NAION: report from the Ischemic Optic Neuropathy Decompression Trial Follow-Up Study. These findings are not surprising since NA-AION is not a thromboembolic disorder but a hypotensive disorder and aspirin has no effect on the blood pressure or nocturnal arterial hypotension.
2. Intravitreal Triamcinolone acetonide
There have recently been two contradictory reports on this therapy, one based on 3 patients showing no benefit  and another one based on 4 eyes claiming beneficial effect ; however, the claims of the latter study are not justified .
It is impossible to judge the effectiveness of intravitreal modes of treatment in studies containing only one to 4 eyes when 41% - 43% of NA-AION eyes show spontaneous visual acuity improvement. Most importantly, intravitreal injection in NA-AION eyes can be harmful. Optic nerve head circulation depends upon the perfusion pressure (mean blood pressure minus intraocular pressure). Intravitreal injection increases the volume in the eyeball, thereby resulting in a transient rise of intraocular pressure. In addition, there are many reports showing a substantial rise in intraocular pressure a few days or weeks after intravitreal triamcinolone. In NA-AION; with already precarious optic nerve head circulation, even a small rise in intraocular pressure for any reason can further compromise the circulation and result in further visual loss. Oral corticosteroid therapy for NA-AION by contrast, did not have that effect on intraocular pressure during a short-term treatment . Thus, one cannot equate oral and intravitreal corticosteroid therapy in NA-AION.
3. Intravitreal Bevacizumab (Avastin®):
There is an anecdotal case report claiming reduction of optic disc edema and visual improvement after an intravitreal injection of bevacizumab (Avastin®) 3 weeks after the onset of NA-AION in one eye .
Like intravitreal triamcinolone, there are problems following intravitreal injection of anti-VEGF drugs. This is discussed at length elsewhere. Briefly, following intravitreal injection of Avastin, a short term and a long term sustained rise of intraocular pressure has been documented. As discussed above, blood flow in the optic nerve head in NA-AION is already precariously poor. Any rise of IOP can be harmful in such circumstances. I recently reviewed a manuscript where the authors treated 3 eyes with anti-VEGF therapy within 2 days after the onset of NA-AION and found no improvement in visual acuity and visual fields. Moreover, there are 2 reports of development of NA-AION following intravitreal injection of Avastin in eyes with age-related macular degeneration, because of vascular problems in persons of that age group.
Thus, we have no evidence so far that intravitreal triamcinolone or anti-VEGF therapies have any beneficial effect. In fact, judging from the precarious circulation in the optic nerve head in NA-AION, these therapies, because of their associated rise in intraocular pressure, can be harmful.
Reduction of risk factors:
The usual advice given by ophthalmologist and neurologists to NA-AION patients is that nothing can be done. Having dealt with more than a thousand patients with NA-AION and having investigated various aspects of NA-AION over the years, I find that is an inadequate and incorrect response. Firstly, because, as discussed above, systemic corticosteroid therapy during the early, acute stage of the disease has shown to be beneficial in visual outcome in a significant number of patients . Secondly, as discussed above, NA- AION is a multifactorial disease and many risk factors contribute to it. The correct strategy is to try to reduce as many risk factors (discussed above) as possible to reduce the risk of NA-AION in the second eye or any further episode in the same eye.
As discussed above, nocturnal arterial hypotension is a major risk factor in NA-AION patients who already have predisposing risk factors. Since the 1960s many highly potent drugs with arterial hypotensive effect have emerged to treat arterial hypertension, other cardiovascular diseases, benign prostatic hyperplasia and other diseases; those drugs are currently widely used. It may not be coincidental that the incidence of NA-AION has progressively increased since the 1960s, so that it has now become a common visually disabling disease. This strongly suggests that NA-AION may be emerging as an iatrogenic disease, stemming from the aggressive use of the very potent arterial hypotensive agents now available. In view of this, management of nocturnal arterial hypotension seems to be an important step both in the management of NA-AION and in the prevention of its development in the second eye. Therefore, I strongly recommend that when a patient is at risk of developing ocular and optic nerve head ischemic and vascular disorders, or has the following:
- NA-AION or history of NA-AION in one eye,
- active giant cell arteritis,
- normal-tension glaucoma,
- occlusion or severe stenosis of internal carotid artery,
- low central retinal artery pressure or
- chronic optic disc edema due to any cause, the treating physician should be made aware of the potential risks of intensive arterial hypotensive therapy, particularly giving that drug in the evening.
INCIPIENT NON-ARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY
In 1981, I reported  that "symptomless optic disc edema precedes the visual loss and may be the earliest sign of AION (NA-AION)". More recently, based on a detailed study of symptomless optic disc edema, I described this as a distinct clinical entity under the name of "incipient nonarteritic anterior ischemic optic neuropathy". This clinical entity initially presents with asymptomatic optic disc edema and no visual loss attributable to NA-AION. Available evidence indicates that it represents the earliest, asymptomatic clinical stage in the evolution of the NA-AION disease process; therefore, it shares most clinical features with classical NA-AION except for the visual loss.
CLINICAL FEATURES of incipient NA-AION
These have been described in a recent study . At initial visit, there is optic disc edema without any visual loss attributable to NA-AION (Fig. 16-A). In that study, incipient NA-AION progressed to classical NA-AION (after a median time of 5.8 weeks) in 25%, and 20% developed classical NA-AION after resolution of a first episode of incipient NA-AION. Patients with incipient NA-AION had a greater prevalence of diabetes mellitus than classical NA-AION; therefore, this has often been misdiagnosed as "diabetic papillopathy" or "diabetic papillitis", which has created confusion and controversy. Similarly, incipient NA-AION progressing to classical NA-AION has also been misdiagnosed as "amiodarone-induced optic neuropathy" in patients who happen to be on amiodarone therapy for cardiovascular disorders .
Fig. 16: Fundus photographs of right eye of a diabetic patient with non-arteritic AION showing:
A. During early stages optic disc edema involving the superior temporal part of the optic disc and prominent vessels in that region.
B. During the later stages: pale color (atrophy) in the upper half of the optic disc – more marked in the temporal than the nasal part, and spontaneous resolution of the prominent blood vessels on the optic disc.
Management of incipient NA-AION:
When a patient presents with asymptomatic optic disc edema, incipient NA-AION must be borne in mind as a strong possibility for those who have had classical NA-AION in the fellow eye, for diabetics of all ages, and for those with high risk factors for NA-AION. This can avoid unnecessary and expensive investigations.
To reduce the risk of progression of incipient to classical NA-AION, immediate steps should be taken to try to eliminate risk factors for development of NA-AION. These include nocturnal arterial hypotension, elevated intraocular pressure and evaluation for sleep apnea.
The subject of NA-AION is plagued with multiple misconceptions, resulting in controversy and confusion. Following are the major misconceptions.
- That NA-AION and cerebral stroke are similar in nature. As discussed above, cerebral stroke is a thromboembolic disorder whereas NA-AION is primarily hypotensive disorder.
- That absence of optic disc cup is the main cause of development of NA-AION. As discussed above, an absent or small cup is simply a secondary contributing factor, once the process of NA-AION has started, and not a primary factor.
- That there is no spontaneous visual improvement in NA-AION. Two large prospective natural history studies have shown that visual acuity improves spontaneously in 41% - 43% of the eyes.
- That NA-AION is not seen in young persons. That has been proven to be a myth by two large studies.
- That all eyes with NA-AION initially have pale optic disc edema. Disc pallor actually starts to develop only 2 to 3 weeks after the onset of visual loss; before that there is no pale optic disc edema.
- That inferior altitudinal defect is the classical diagnostic visual field defect in NA-AION. As discussed above, the most common defect in NA-AION eyes is the inferior nasal field defect.
- That all eyes with NA-AION have poor visual acuity at onset. As discussed above, in eyes seen within 2 weeks of onset, 33% had 20/20 or better visual acuity.
- That steroid therapy has no role in the management of NA-AION. As discussed above, in a study of 696 NA-AION eyes (364 treated versus 332 controls) the treated group showed significantly more visual acuity improvement than the control group (70% versus 41%).
- That smoking is a risk factor for development of NA-AION. Two large prospective studies have shown that this is not true [65, 82].
- That aspirin reduces the risk of second eye involvement by NA-AION. As discussed above, two large studies have disproved this belief.
- That all patients with NA-AION should be investigated for thrombophilia. As discussed above, NA-AION is not a thromboembolic disorder in the vast majority of cases .
Arteritic Anterior Ischemic Optic Neuropathy (A-AION)
A-AION is almost invariably due to giant cell arteritis, although rarely other types of vasculitis may also cause it. A-AION in one or both eyes is the most common cause of visual loss in giant cell arteritis.
Giant cell arteritis is the primary cause of A-AION. Other rare causes include other types of vasculitis, e.g. , polyarteritis nodosa, systemic lupus erythematosus, and herpes zoster.
Giant cell arteritis is a systemic vasculitis, and it preferentially involves medium-sized and large arteries. In the eye, giant cell arteritis has a special predilection to involve the posterior ciliary artery, resulting in its thrombotic occlusion. Since the posterior ciliary artery is the main source of blood supply to the optic nerve head[6, 35, 52], occlusion of the posterior ciliary artery (Figs. 15-B,C) results in infarction of a segment or the entire optic nerve head, depending upon the area of the optic nerve head supplied by the occluded posterior ciliary artery . That results in development of A-AION and in massive visual loss.
CLINICAL FEATURES of A-AION
Age, gender and race: Giant cell arteritis, which is by far the most common cause of A-AION, is a disease of late middle-aged and elderly person and is almost 3 times more common in women than in men . There is evidence that giant cell arteritis is far more common among Caucasians than other races; however, some cases have been reported from China, India, Thailand, Israel, among Arabs, Hispanics (Mexican) and African Americans . These racial differences suggest a genetic predisposition to giant cell arteritis.
Symptoms: Transient visual loss (amaurosis fugax) is an important visual symptom and an ominous sign of impending visual loss in giant cell arteritis. It may be brought about by stooping or induced by postural hypotension. Most patients with giant cell arteritis develop visual loss suddenly without any warning. The incidence of bilateral involvement depends upon how early the patient is seen, when the diagnosis is made, and how aggressively systemic corticosteroid therapy is used – the longer the time interval from the onset of visual symptoms in one eye without adequate steroid therapy, the higher the risk of second eye involvement. Other uncommon ocular symptoms include diplopia and ocular pain . I have seen a rare patient with giant cell arteritis suffering from euphoria and even denying any visual loss.
Giant cell arteritis patients usually present with systemic symptoms, including anorexia, weight loss, jaw claudication, headache, scalp tenderness, abnormal temporal artery, neck pain, myalgia, malaise and anemia. A study , based on 363 patients who had temporal artery biopsy, showed that systemic symptoms exhibiting a significant association with a positive temporal artery biopsy for giant cell arteritis were jaw claudication (odds 9.0 times, p<0.0001), neck pain (odds 3.4 times, p=0.0003), and anorexia (p=0.0005), with no other systemic symptoms exhibiting significant difference from those with a negative biopsy . Most interestingly, that study showed that 21% of patients with visual loss due to giant cell arteritis had occult giant cell arteritis, i.e. no systemic symptoms whatsoever, with a positive temporal artery biopsy and visual loss . This is an extremely important clinical entity because there is almost a universal belief that all patients with giant cell arteritis always have systemic symptoms; that has resulted in missing giant cell arteritis, with tragic consequence of blindness. Thus one in 5 patients with giant cell arteritis is at risk of going blind without any systemic symptoms of giant cell arteritis at all.
Visual acuity: Although usually there is a marked deterioration of visual acuity in giant cell arteritis, almost normal visual acuity does not rule it out, and it is usually due to A-AION .
Visual Fields: Compared to NA-AION, the visual defects are much more extensive and severe in A-AION.
Anterior segment of the eye: Usually it is normal except for relative afferent pupillary defect in unilateral A-AION cases. In an occasional case, there may be signs of anterior segment ischemia, with ocular hypotony, and/or marked exudation in the anterior chamber  (erroneously diagnosed as anterior uveitis).
Extraocular motility disorders: When present, this results in diplopia.
Optic disc changes: Optic disc edema, compared to NA-AION, usually has a diagnostic appearance in A-AION, i.e. chalky white color [10, 13, 17, 43] (seen in 69% ) (Figs. 17, 18, 19-B, 20-A). When optic disc edema resolves, the optic disc in the vast majority shows cupping indistinguishable from that seen in glaucomatous optic neuropathy (Fig. 19-C) [10, 13, 17, 43], except that the disc rim is pale whereas it is of normal color in glaucomatous optic neuropathy. By contrast, in NA-AION no such cupping of the optic disc is seen [10, 13, 17, 43].
Fig. 17: Fundus photograph of right eye with A-AION showing chalky white optic disc edema during the initial stages. (Reproduced with permission from Hayreh, )
Fig. 18: Fundus photograph of right eye with arteritic AION showing during the early phase the typical white optic disc edema. (Reproduced with permission from Hayreh )
Fig. 19: ) Fundus photographs of right eye with A-AION: (A) Before developing A-AION, (B) one week after developing A-AION with chalky white optic disc edema and (C) 4 months later showing optic disc cupping with a cup/disc ratio of 0.8 (note no cup inA). (Reproduced with permission from Hayreh, )
Fig. 20: Fundus photograph (A) and fluorescein fundus angiogram (B) of right eye with A-AION and cilioretinal artery occlusion during the initial stages. (A) Fundus photograph shows chalky white optic disc edema with retinal infarct in the distribution of occluded cilioretinal artery. (B) Fluorescein fundus angiogram shows evidence of occlusion of the medial posterior ciliary artery and no filling of the cilioretinal artery. (Reproduced with permission from Hayreh, )
Other fundus changes: These were as follows in a series of 123 eyes .
- Retinal cotton wool spots: These were seen in one third of the eyes with visual loss.
- Central retinal artery occlusion: This was seen in 14%. They are almost invariably combined with posterior ciliary artery occlusion – the latter detected only on fluorescein fundus angiography. This is because in some cases the central retinal artery and posterior ciliary artery arise by a common trunk from the ophthalmic artery(Fig. 21) [1-3]; in such cases, if arteritis involves the common trunk and causes its thrombosis and occlusion, that results in occlusion of both the posterior ciliary artery (manifesting as A-AION) and the central retinal artery [10, 43]. Thus, in all eyes with central retinal artery occlusion in persons aged 50 and over, it is essential to rule out giant cell arteritis, to prevent catastrophic visual loss - which is preventable with adequate corticosteroid therapy (see below).
- Cilioretinal artery occlusion: The posterior ciliary artery supplies the optic nerve head as well as the cilioretinal artery, when that artery is present. Occlusion of the posterior ciliary artery by giant cell arteritis results in simultaneous development of both A-AION and cilioretinal artery occlusion (Figs. 15-C, 20) [10, 13, 17, 29, 43]. These eyes present with a classical, diagnostic clinical picture of giant cell arteritis, i.e. a combination of chalky white optic disc edema, retinal infarct in the region of the occluded cilioretinal artery and posterior ciliary artery occlusion on fluorescein angiography (Fig. 20). Occlusion of the cilioretinal artery in giant cell arteritis has erroneously been diagnosed as "branch retinal artery occlusion", but the so-called "branch retinal arteries" are in fact arterioles, and giant cell arteritis is a disease of the medium-sized and large arteries and not of the arterioles. I have seen patients with cilioretinal artery occlusion erroneously diagnosed by ophthalmologists as ordinary branch retinal artery occlusion and left untreated, resulting in catastrophic visual loss in both eyes, which could have been prevented, if a correct diagnosis had been made and the possibility of giant cell arteritis as one of its causes had been borne in mind.
- Choroidal ischemic lesions: Occlusion of the posterior ciliary artery by giant cell arteritis may also result in development of choroidal ischemic lesions, which are usually located in the midperipheral region of the fundus and frequently are triangular in shape, with their base toward the equator and apex toward the posterior pole (Fig. 22) .
- Ocular ischemia: Giant cell arteritis rarely may cause thrombosis and occlusion of the ophthalmic artery, which may result in development of ocular ischemia.
Fluorescein fundus angiographic findings: As discussed above, thrombosis and occlusion of the posterior ciliary artery is the main lesion in giant cell arteritis. This is very well demonstrated by fluorescein fundus angiography, provided it is performed soon after the visual loss (Figs. 15-B,C, 20B). Thus, fluorescein fundus angiography during the early stages constitutes a critical diagnostic test for A-AION.
Laboratory investigations: Markedly elevated acute-phase responses, i.e. , erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are the most important immediate diagnostic tests in the diagnosis of A-AION and its differentiation from NA-AION [40, 58]. Although high ESR is traditionally emphasized as a sine qua non for diagnosis of giant cell arteritis, there are numerous reports of "normal" or "low" ESR in patients with positive temporal artery biopsy for giant cell arteritis [40, 58]. In our series, we had some patients with ESR as low 4-5 mm/hr with positive biopsy [40, 58]. Thus, the rule is normal ESR does not rule out giant cell arteritis. CRP, on the other hand, emerged from our study as a much more reliable test to diagnose giant cell arteritis [40, 58]. A combination of ESR with CRP gave the very best specificity (97%) for detection of giant cell arteritis. We always use both tests in all our patients, for diagnosis of giant cell arteritis and monitoring of steroid therapy. Other hematological tests which can help in the diagnosis of giant cell arteritis include the presence of thrombocytosis, anemia, elevated white blood cell count and low hemoglobin and hematocrit levels . In conclusion, the combined information provided by ESR, CRP, platelet and white blood cell count and hemoglobin and hematocrit levels is highly useful in diagnosis of giant cell arteritis, although none of them is individually 100% sensitive and specific.
Fig. 21: Photograph of inferior surface of the intraorbital part of the optic nerve (ON) and adjacent eyeball (EB) showing ophthalmic artery (OA) with its lateral (LPCA) and medial (MPCA) posterior ciliary arteries and central retinal artery (CRA). Note a common trunk of origin of MPCA and CRA from the ophthalmic artery. (click on image for enlargement) (Reproduced with permission from Hayreh, 2009 )
Fig. 22: A composite fundus photograph of left eye of a patient with giant cell arteritis and A-AION. Note optic atrophy and cupping with extensive peripheral chorioretinal lesions. (Reproduced with permission from Hayreh, 2009 )
Management of A-AION
Management of A-AION is actually management of giant cell arteritis. Kearns  rightly stressed that giant cell arteritis "ranks as the prime medical emergency in ophthalmology, there being no other disease in which prevention of blindness depends so much on prompt recognition and early treatment. " A-AION is the most common cause of visual loss in giant cell arteritis. Therefore, to prevent blindness in giant cell arteritis, two things are crucial: (a) early diagnosis of giant cell arteritis and (b) immediate and adequate steroid therapy. My studies on giant cell arteritis have revealed that there is a difference of perspective between rheumatologists and ophthalmologists. For ophthalmologists giant cell arteritis is a blinding disease with tragic consequences, whereas rheumatologists see mainly a disease with rheumatologic complaints, not very serious. This difference in perspective on giant cell arteritis has resulted in the controversy about its diagnosis as well as management. This subject is discussed at length elsewhere . The 5 criteria advocated by the American College of Rheumatologists  for diagnosis of giant cell arteritis are likely to result in some false-negative or false-positive diagnoses of giant cell arteritis, risking visual loss.
Our study , using positive temporal artery biopsy as the definite diagnostic criterion for giant cell arteritis, showed that the odds of a positive biopsy were 9 times greater with jaw claudication (p<0.0001), 3.4 times with neck pain (p=0.0085), 2.0 times with ESR (Westergren) 47-107 mm/hr relative to those with ESR <47 mm/hr (p=0.0454), and 3.2 times with CRP >2.45 mg/dl compared to CRP <2.45 mg/dl (p=0.0208), and 2.0 times when the patients were aged >75 years as compared to those <75 years (p=0.0105). Among the other systemic signs and symptoms, the only significant one was anorexia/weight loss (p=0.0005); the rest showed no significant difference from those with negative biopsy. So the set of clinical criteria most strongly suggestive of giant cell arteritis are ♦jaw claudication, ♦CRP >2.45 mg/dl (normal value for CRP in our hematology laboratory is <0.5 mg/dl), ♦neck pain and ♦ESR > 47 mm/hr, in that order. CRP was more sensitive (100%) than ESR (92%), and a combination of ESR with CRP gave the best specificity (97%) for detection of giant cell arteritis. As discussed above, a "normal ESR" does not rule out giant cell arteritis. Notably, in our study 21% of patients with temporal artery biopsy confirmed giant cell arteritis and with visual loss had no systemic symptoms or signs of giant cell arteritis whatsoever, at any stage (i.e. occult giant cell arteritis) .
To get reliable information about giant cell arteritis from temporal artery biopsy, we have found that the following steps are essential. (a) The biopsy specimen must be at least one inch long; (b) All biopsy specimens must be examined by serial sectioning. (In one of our cases, only one of 300 sections showed evidence of giant cell arteritis.) (c) If there is a high index of suspicion of giant cell arteritis, but biopsy is negative on one side, it should be done on the second side, which was positive in 9% in our series .
Differentiation of A-AION from NA-AION:
When a patient is diagnosed to have AION, the first crucial step in patients aged 50 and over is to identify immediately whether it is arteritic or non-arteritic. Collective information provided by the following criteria helps to differentiate the two types of AION reliably.
- Systemic symptoms of giant cell arteritis: These are discussed in detail above. However, 21% with occult giant cell arteritis have no systemic symptoms of any kind, ever, and visual loss is the sole complaint. Patients with NA-AION have no systemic symptoms of giant cell arteritis.
- Visual symptoms: As discussed above, amaurosis fugax is highly suggestive of A-AION and is extremely rare in NA-AION.
- Hematologic abnormalities: Immediate evaluation of ESR and CRP is vital in all patients aged 50 and over. As discussed above, elevated ESR and CRP, particularly CRP, is helpful in the diagnosis of giant cell arteritis. Patients with NA-AION do not show any of these abnormalities, except when a patient has some other intercurrent systemic disease.
- Early massive visual loss: This is extremely suggestive of A-AION. However, the presence of perfectly normal visual acuity does not rule out A-AION (see above).
- Chalky white optic disc edema (Figs. 17, 18, 19-B, 20-A): This is almost diagnostic of A-AIONand is seen in 69% of A-AION eyes. In NA-AION, chalky white optic disc edema occurs only very rarely with embolic occlusion of the posterior ciliary artery.
- A-AION associated with cilioretinal artery occlusion (Fig. 20): This is almost diagnostic of A-AION.
- Evidence of posterior ciliary artery occlusion on fluorescein fundus angiography (Figs. 15-B,C, 20-B): If angiography is performed during the first few days after the onset of A-AION, and the choroid supplied by one or more of the posterior ciliary artery does not fill, this once again is almost diagnostic of A-AION. However, later on, this information may be lost.
- Temporal artery biopsy: This finally establishes the diagnosis and its role has been discussed above
Steroid therapy in giant cell arteritis to prevent blindness
A detailed discussion of this is extremely important in the interest of prevention of visual loss due to giant cell arteritis. This is a highly controversial subject; especially since all the available information is from the rheumatological literature. As mentioned above, there is a differing perspective on giant cell arteritis between rheumatologists and ophthalmologists, which has influenced their recommendations on steroid therapy – the regimen advocated by the former primarily concerns managing benign rheumatologic symptoms and signs, whereas the latter confronts the probability of blindness . Moreover, I have found that rheumatologists often tend not to differentiate between polymyalgia rheumatica and giant cell arteritis in their management. A regimen of steroid therapy, which is adequate to control rheumatologic symptoms and signs and polymyalgia rheumatica, is often totally inadequate to prevent blindness associated with giant cell arteritis. With this in view, I did a 27-year prospective study  on steroid therapy in giant cell arteritis, to find a regimen that would prevent visual loss. That study showed marked differences between the rheumatologic and ophthalmic steroid therapy regimens. In the light of information from that study, the following are my guidelines to prevent visual loss.
- If there is a reasonable index of suspicion of giant cell arteritis, as judged from systemic symptoms, high ESR and CRP (particularly high CRP) and sudden visual loss from A-AION or central retinal artery occlusion, high doses of systemic corticosteroid therapy, must be started IMMEDIATELY, as an EMERGENCY MEASURE. The physician should not wait for the result of the temporal artery biopsy because by the time it is available, the patient may have lost further vision irreversibly, in one or both eyes. Every minute counts; it is unwarranted to take chances of losing vision by starting with a small dose; once vision is lost, a subsequent higher dose will not restore it. In my study, the median starting oral Prednisone dose was 80 mg/day, with 40% of patients on >100 mg/day.
- A high-dose steroid therapy must be maintained until both the ESR and CRP settle down to a stable level which usually takes 2-3 weeks – CRP usually settles much earlier than the ESR (Fig. 23).
- After that, gradual tapering down of steroid therapy should be started. Recently, Salvarani and colleagues  stated that 2–4 weeks after the start of initial dose, "the dose can be gradually reduced each week or every 2 weeks by a maximum of 10% of the total daily dose." In sharp contrast to that, my study  showed this to be a dangerous formula to prevent blindness. According to my study, a titration of the steroid dosage with the levels of ESR and CRP is the only safe and reliable method for tapering down and follow-up of steroid therapy. Using clinical symptoms and signs of giant cell arteritis as a guide (as recommended by rheumatologists) is a dangerous practice to prevent blindness . In my experience of managing several hundred giant cell arteritis patients during the past four decades, I have never had any giant cell arteritis patient who developed systemic symptoms even when his ESR and CRP went up significantly after steroid therapy was reduced; ESR and CRP are far more sensitive and reliable than systemic symptoms for managing steroid therapy to prevent visual loss. The relapses of giant cell arteritis frequently mentioned in the rheumatologic literature are the result of using inadequate criteria to monitor and manage steroid therapy and/or inadequate dose of corticosteroids; relapses put the patient at risk of going blind.
- Patients with giant cell arteritis show marked interindividual variation in the dosage of corticosteroids they require, their response to steroid therapy, and their therapeutic and tapering regimens of steroid therapy, so that therapy must always be individualized. No generalization is possible; no "one size fits all. "
- Salvarani and colleagues  recommended that "The necessary duration of glucocorticosteroid therapy is variable, but in most cases it can be discontinued within 1–2 years. " This recommendation is based on the widespread but mistaken belief among rheumatologists that giant cell arteritis is a self-limiting disease and burns itself out within 1-2 years. However, findings of my study  showed that the statement by Salvarani and colleagues  and other rheumatologists is not valid as regards preventing visual loss. In my study, the median follow-up was 2.43 years, and in many cases 20 years or more. I had some patients who went blind after their local rheumatologist stopped steroid therapy after a year or two, as suggested by Salvarani and colleagues . In addition, repeat temporal artery biopsy has shown evidence of active giant cell arteritis after as many as 9 years of steroid therapy . To keep giant cell arteritis under sufficient control and prevent blindness, my study showed that the vast majority of these patients require a lifelong low, maintenance dose of corticosteroids, which were found to have no systemic side-effects. In that study, the median time to reach the lowest maintenance dose of prednisone (at which the ESR and CRP stayed low and stable) was 48.7 months, and the median lowest Prednisone dose achieved was 7 mg/day (interquartile range of 1 to 16 mg/day). In the study, only 10 (7 without visual loss, 3 with visual loss) of 145 patients were able to stop the therapy completely and maintain stable ESR and CRP levels without visual loss.
- This study found no evidence that intravenous mega-dose steroid therapy was more effective than oral therapy in improving vision  or preventing visual deterioration  due to giant cell arteritis. My current recommendation for intravenous steroid therapy is to give initially one intravenous mega dose (equivalent to one gram of prednisone) followed by high-dose (80-120 mg) oral prednisone in any patient who presents with: (i) a history of amaurosis fugax, (ii) complete or marked loss of vision in one eye or (iii) early signs of involvement of the second eye.
Fig. 23: Graphs of (A) C-reactive protein levels and (B) erythrocyte sedimentation rates (ESR) of 6 patients with giant cell arteritis, showing their initial responses to high dose steroid therapy. (Reproduced with permission from Hayreh and Zimmerman )
Risk/benefit ratio of steroid therapy in giant cell arteritis patents:The concept that systemic steroid therapy is dangerous and must be given in the lowest possible dose and for the minimum period is over-stated in the rheumatologic literature. No doubt, chronic steroid therapy carries a high risk of variable side-effects, but most of them are either tolerable or easily manageable once the patient is fully aware of the alternative, i.e. the risk of going blind in one or both eyes. Most importantly, once a patient is made aware of the choice between side-effects of steroid therapy versus the risk of going blind (fear of going blind is next to fear of death), he/she will always choose the therapy, even at the risk of a certain amount of side-effects – I have yet to find a single patient in more than 40 years of dealing with giant cell arteritis patients who opted against steroid therapy and took the risk of going blind.
To reiterate: in my experience of dealing with several hundred giant cell arteritis patients for about four decades, I have found that if they are treated promptly and aggressively with an adequate dose of corticosteroids, and reduction of steroid therapy is regulated by using ESR and CRP as the only criteria, not a single patient suffered any further visual loss 5 days after starting adequate steroid therapy – that is testimony to the effectiveness of my steroid therapy regimen.
Visual prognosis with adequate steroid therapy:
In my study of steroid therapy in giant cell arteritis, in spite of start of high dose steroid therapy or even intravenous steroid therapy, only 4% of giant cell arteritis patients with visual loss showed any visual improvement , and during the first 5 days from the start of the therapy 4% developed further visual loss but there was no further visual loss after 5 days .
- That to diagnose giant cell arteritis, the patient must have systemic symptoms and signs of giant cell arteritis. A study showed that 21% of giant cell arteritis patients have no systemic symptoms and signs whatsoever and the only presenting sign is visual loss, i.e., occult giant cell arteritis.
- That to diagnose giant cell arteritis, the patient must have elevated ESR. As discussed above, it has been shown that normal ESR does not rule out giant cell arteritis.
- That steroid therapy can be tapered according to a set regimen [50, 56, 59, 73, 76]. As discussed above, it has been shown that there is marked inter-individual variation in the tapering regimen of steroid therapy and no "one size fits all".
- That steroid therapy can be regulated by using clinical symptoms and signs of giant cell arteritis. That is not valid to prevent visual loss. The only reliable method is to use ESR and CRP as the guideline.
- That steroid therapy can be stopped after 1-2 years because the disease burns itself out. That is not only not true at all but a dangerous practice. A vast majority of patients require life-long steroid therapy to prevent visual loss.
Posterior Ischemic Optic Neuropathy
I first described this clinical entity in 1981 . Since then, many reports have appeared, but they are all anecdotal in nature, except for three series – 14 cases by Isayama et al. , 72 by Sadda et al.  and 42 by me more recently . This shows that PION is much less common than AION; this may be due to combination of various factors . Since the diagnosis of PION, and especially non-arteritic PION, is usually hard to make with certainty, it is difficult to ascertain its true incidence. When I first described this as a distinct clinical entity , I stressed that it is a diagnosis of exclusion. It should be made only after all other possibilities have been carefully ruled out, e.g. , macular and retinal lesions, NA-AION, retrobulbar optic neuritis, compressive optic neuropathy, other optic disc and optic nerve lesions, neurological lesions, hysteria, even malingering, and a host of other lesions.
Etiologically, PION can be classified into three types: (1) arteritic PION (A-PION) due to giant cell arteritis, (2) non-arteritic PION (NA-PION) due to causes other than giant cell arteritis, and (3) surgical PION as a complication of a surgical procedure. Incidence of various types of PION reported in the 3 large series varies widely.
This is discussed at length elsewhere . Briefly, it is as follows.
Fig. 24: Diagrammatic representation of blood supply of the various parts of the optic nerve, and location of the Circle of Haller and Zinn (CZ), as seen from above. (Reproduced with permission from Hayreh 1963 )
Ant. Sup. Hyp. Art. = anterior superior hypophyseal artery; CAR = central retinal artery; Col. Br. = Collateral branches; CZ = circle of Zinn and Haller; ICA = internal carotid artery; LPCA = lateral posterior ciliary artery; Med. Mus. = medial muscular artery; MPCA = medial posterior ciliary artery; OA = ophthalmic artery; Rec. Br. CZ = recurrent pial branches from peripapillary choroid/CZ.
Non-arteritic PION: An association between NA-PION and a variety of systemic diseases has been reported in the literature. The common diseases include arterial hypertension, diabetes mellitus, arteriosclerosis, atherosclerosis, and marked arterial hypotension, and there have been anecdotal case reports of PION associated with many other diseases. The pathogenesis of NA-PION, like NA-AION, is multifactorial in nature, with a variety of systemic diseases, other vascular risk factors and/or local risk factors predisposing an optic nerve to develop PION; defective autoregulation of the optic nerve may also play a role. Finally, some precipitating risk factor acts as the "last straw" to produce PION.
Surgical PION: This clinical entity has also been called postoperative  or perioperative  PION. I have used the term "surgical PION" because it is more inclusive. surgical PION usually tends to cause bilateral massive visual loss or even complete blindness, which is usually permanent; therefore, it has great medicolegal importance. A large number of surgical PION cases have been reported in the literature (mostly anecdotal), almost invariably associated with prolonged systemic surgical procedures, for a variety of conditions .
The pathogenesis of surgical PION is discussed at length elsewhere . Briefly, it is multifactorial in nature. The main factors include severe and prolonged arterial hypotension (due to prolonged general anesthesia, surgical trauma and massive blood loss), hemodilution from administration of a large amount of intravenous fluids to compensate for the blood loss, orbital and periorbital edema, chemosis and anemia, and rarely even direct orbital compression by prone position.
CLINICAL FEATURES of PION
Age and gender: PION, like NA-AION, is seen mostly in the middle-aged and elderly population but no age is immune to it.
Symptoms: Clinically, patients with A-PION and NA-PION typically present with acute, painless visual loss in one or both eyes, sometimes discovered upon waking up in the morning. In some eyes, it may initially be progressive. Patients with surgical PION discover visual loss as soon as they are alert postoperatively, which may be several days after surgery. surgical PION usually tends to cause bilateral massive visual loss or even complete blindness, which is usually permanent.
Visual acuity: This depends upon the type of PION. In my  series, in NA-PION, it was 20/20 to 20/25 in 17%, better than 20/40 in 20%, 20/200 or worse in 69%; in A-PION 29%, 43%, 50% respectively; and in surgical PION only light perception.
Visual Fields: A wide variety of optic nerve related visual field defects have been reported in PION; their type varies with the type of PION. In my study , the most common visual field defect was central visual loss, alone or in combination with other types of visual field defects (Fig. 25). Central visual field defect was present in 84% in NA-PION, 69% in A-PION. A small number of PION eyes show the reverse pattern, i.e. , the central field was normal with marked loss of peripheral fields (Fig. 26). Pathogenesis of various types of visual field defects seen in PION is discussed elsewhere .
Fig. 25: Four visual fields showing varying sizes and densities of central scotoma and other field defects, with normal peripheral visual fields in non-arteritic PION. (Reproduced with permission from Hayreh 2004 )
Fig. 26: Visual fields of (A) right and (B) left eyes with arteritic PION, showing markedly constricted central visual fields, with complete loss of peripheral fields in both eyes. (Reproduced with permission from Hayreh 2004 )
Ophthalmic evaluation: Initially, apart from relative afferent pupillary defect in unilateral PION, the anterior segment, intraocular pressure, and optic disc and fundus are normal on ophthalmoscopy and fluorescein fundus angiography. The disc develops pallor generally within 6-8 weeks, usually more marked in the temporal part. Rarely the optic disc may develop cupping in NA-PION . The criteria to differentiate arteritic from nonarteritic PION are basically the same as those for arteritic and non-arteritic AION discussed above, except that the optic disc and fundus are initially normal in both types in PION.
A combination of the following findings is highly suggestive of PION: (a) sudden onset of visual deterioration, with or without deterioration of central visual acuity, (b) optic nerve-related visual field defects in the involved eye, (c) presence of a relative afferent pupillary defect in the involved eye in patients with a perfectly normal fellow eye, (d) optic disc and fundus initially normal on ophthalmoscopy and fluorescein fundus angiography, (e) no other ocular, orbital or neurological abnormality to explain the visual loss, and (f) development of optic disc pallor, usually within 6-8 weeks. The diagnosis of surgical PION, on the other hand, is relatively straightforward; dramatic visual loss noticed as soon as the patient is alert enough after a major surgical procedure, with the above clinical findings. As I stressed in my original paper  on PION, it is a diagnosis of exclusion.
This depends upon the type of PION. In all cases other than surgical PION, as in AION, the most important first step in persons aged 50 years or older is always to rule out giant cell arteritis [29, 42].
Arteritic PION: Management is similar to that of A-AION discussed above. There is usually no visual improvement with systemic steroid therapy.
Non-arteritic PION: The role of systemic steroid therapy in PION was evaluated in my study . That showed that the eyes of patients treated with high dose systemic steroid therapy during the very early stages of the disease showed significant improvement in visual acuity and visual field, compared to untreated eyes. In addition, the magnitude of visual acuity and visual field improvement was much greater in the treated group than the untreated group. Thus, it is clear that aggressive systemic steroid therapy has a beneficial effect on visual function during the very early stages of the disease. However, spontaneous improvement in visual acuity and visual field may also occur to some extent in some eyes without steroid therapy.
In the management of these patients, since systemic risk factors may play a part in the development of NA-PION, one should try to reduce as many risk factors as possible, to reduce the risk of second eye involvement.
Surgical PION: Basically, the management amounts to prophylactic measures to prevent development, because once the visual loss occurs, it is usually bilateral, severe and irreversible. No treatment has been found to be effective to recover or improve the lost vision. Prophylactic measures during surgery include avoiding: arterial hypotension, excessive fluid replacement and hemodilution, pressure on the eyeball and orbit, and dependent position of the head, as well as shortening the duration of surgery to the minimum. Since systemic cardiovascular risk factors may predispose a patient to a higher risk of developing surgical PION, it may be advisable to consider those factors in the decision to perform surgery.
This varies with the type of PION. Eyes with NA-PION treated with high dose steroid therapy at onset showed significantly greater visual improvement than untreated patients . Patients with A-PION, if treated urgently and aggressively with high dose steroid therapy, showed no improvement in vision but also showed no further visual loss. Patients with surgical PION usually suffer severe, often bilateral and irreversible visual loss; this does not respond to steroid therapy [60, 91].
It is now clear that ischemic optic neuropathy is not one disease but a spectrum of several different types, each with its own etiology, pathogenesis and management. Each must be considered a separate clinical entity. Overall, they constitute one of the major causes of blindness or seriously impaired vision, yet there is marked confusion and controversy on their pathogeneses, clinical features and especially their management. This is because the subject is plagued by misconceptions about many fundamental aspects, discussed in this review.
Acknowledgements: I am grateful to many persons who have contributed in one way or another to the various studies on ischemic optic neuropathy over the years. The extraordinary biostatistical expertise of Professor Bridget Zimmerman has been crucial in statistical data analysis. I am grateful to Mrs. Patricia Duffel for her invaluable help in the preparation of this website.