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Ophthalmology and Visual Sciences

Anterior Ischemic Optic Neuropathy:
Part 2. A discussion for physicians

Anterior Ischemic Optic Neuropathy:
Part 2. A discussion for physicians

Category(ies): Neuro-ophthalmology
Contributors: Sohan Singh Hayreh, MD, MS, PhD, DSc, FRCS, FRCOphth

Ocular Vascular Clinic
Department of Ophthalmology & Visual Sciences
University of Iowa Carver College of Medicine
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.


Introduction

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 [74]. 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.

Classification:

Based on the pattern of blood supply of the optic nerve, it can be divided into two distinct regions:

  1. The anterior part (optic nerve head) which is supplied primarily by the posterior ciliary artery circulation (Fig. 1A below).
  2. 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:

  1. Arteritic AION (A-AION): This is due to giant cell arteritis.
  2. 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:

  1. Arteritic PION due to giant cell arteritis,
  2. Non-arteritic PION due to causes other than giant cell arteritis,
  3. Surgical PION as a complication of a surgical procedure.
Schematic Representation Of Blood Supply of: (A) The Optic Nerve Head
Fig. 1a: Schematic Representation Of Blood Supply of: (A) The Optic Nerve Head. A Reproduced With Permission From Hayreh 1978 [16]. B Modified From Hayreh, S.S. 1974 [8].
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.
Schematic Representation Of Blood Supply of: (A) The Optic Nerve Head
Fig. 1b: Schematic Representation Of Blood Supply of: ((B) The Optic Nerve. A Reproduced With Permission From Hayreh 1978 [16]. B Modified From Hayreh, S.S. 1974 [8].
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.

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 [25] and its blood flow [51] patterns profoundly influence the pathogenesis and clinical features of NA-AION.

Etiologically and pathogenetically NA-AION is of two types:

  1. 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 [74] - 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.

  2. 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.

diagrammatic representation of blood flow autoregulation range at different perfusion pressures in normal persons
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 [74]

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.

  1. Systemic risk factors: Various studies have shown a significantly high prevalence of
    • arterial hypertension
    • nocturnal arterial hypotension
    • diabetes mellitus
    • ischemic heart disease
    • hyperlipidemia
    • atherosclerosis
    • arteriosclerosis
    • sleep apnea
    • arterial hypotension due to a variety of causes
    • malignant arterial hypertension
    • migraine.
  2. 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
    • 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 [41]. 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.

Diagrammatic representation of mean hourly systolic and diastolic blood pressures over a 24-hour period
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. [33])
Ambulatory BP and heart rate monitoring records (based on individual readings) over a 24-hour period
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 [46])
Two 24-hour ambulatory blood pressure monitoring records
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 [69])

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 [41]. 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 [62]. 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.

example of fields of vision plotted with a Goldmann Perimeter
Fig. 6a: Example of field of vision plotted with a Goldmann Perimeter [Using I2e (red), I4e (blue), V4e (purple)] (Reproduced with permission from Hayreh [29])
example of fields of vision plotted with a Goldmann Perimeter
Fig. 6a: Example of field of vision plotted with a Goldmann Perimeter [Using I2e (red), I4e (blue), V4e (purple)] (Reproduced with permission from Hayreh [29])

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 [71]. Visual acuity and visual fields showed improvement or further deterioration mainly up to 6 months, with no significant change after that [71]. 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 [66] (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 [66]. There is a characteristic evolutionary pattern of optic disc edema in NA-AION, as discussed elsewhere [66]. 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 [66]. 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.

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 [66] (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 [66]. There is a characteristic evolutionary pattern of optic disc edema in NA-AION, as discussed elsewhere [66]. 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 [66]. 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 [70].

fundus photograph showing optic disc edema and hyperemia during the acute phase of 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 [74])
fundus photograph showing optic disc edema and hyperemia, with a splinter hemorrhage
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 [74])
Fundus photographs of left eye of a 53-year-old man
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 [74])
Fundus photographs of left eye of a 53-year-old man
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 [17])
During early stage with optic disc edema with prominent blood vessels on the disc and many retinal hemorrhages
Fig. 11: Fundus photographs of right eye of a diabetic patient with nonarteritic AION showing (reproduced with permission from Hayreh et al [23]) A. During early stage with optic disc edema with prominent blood vessels on the disc and many retinal hemorrhages
During later stage with pale color (optic atrophy) and spontaneous resolution of prominent blood vessels on the optic disc as well as hemorrhages.
Fig. 11: Fundus photographs of right eye of a diabetic patient with nonarteritic AION showing (reproduced with permission from Hayreh et al [23]) 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 [25]. 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.

Fundus photograph (A) and OCT (B) of right eye with NA-AION and serous retinal detachment between the optic disc and the macula.
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 [74])
Fluorescein fundus angiogram of 2 eyes with NA-AION
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 [25] and (B) Hayreh 1996 [36].)
Fluorescein fundus angiograms of 4 eyes with AION showing different locations of the watershed zone (vertical dark bands) in relation to the optic disc.
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 [25]) Abbreviations: LPCA = lateral posterior ciliary artery; MPCA = medial posterior ciliary artery; WSZ = watershed zone
Fluorescein fundus angiograms of 3 eyes showing areas of supply by the occluded posterior ciliary artery and the patent posterior ciliary artery.
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 [25]) (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 [17]) (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 [17])

Bilateral NA-AION: The cumulative probability of the fellow eye developing NA-AION has varied among different studies: 25% within 3 years [80], 17% in 5 years [81] and 15% over 5 years [4]; however, different criteria were used to determine the probability, which may explain the differences. According to one study [4], 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 [70].

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 [53]. 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 [63] 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 [67]. 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.

Management of NA-AION

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 [79]. Following is a discussion of the currently advocated treatments.

Systemic Corticosteroid Therapy:

A recent large, prospective study [73],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:

  1. Most importantly, there is no scientific rationale for the use of corticosteroid therapy in NA-AION.
  2. There was no conventional randomization in this study.
  3. 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:

  1. Scientific rationale for visual improvement with corticosteroid therapy in NA-AION

    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[73].

    1. 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].
    2. 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]
    3. 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 [14]. 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 [41].
    4. 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 [14]. Foulds [95] 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 [95] 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) [66]. 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 [66] → 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.[74] 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.

  2. There was no conventional randomization in this study

    The reason was discussed in the original paper.[73] 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.[73]

    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,[73] there was no significant difference between the treated and untreated groups in the baseline demographic and clinical characteristics, as is evident from the following:

    1. 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.
    2. 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.

  3. The study was not collected in a masked fashion.

    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.[73]

    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.[73]

    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

  1. Aspirin

    This is discussed at length elsewhere [96]. 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 [74].

    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.[79] 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 [1] and another one based on 4 eyes claiming beneficial effect [83]; however, the claims of the latter study are not justified [68].

    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 [73]. 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 [84].

    Like intravitreal triamcinolone, there are problems following intravitreal injection of anti-VEGF drugs. This is discussed at length elsewhere.[93] 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.[93]

    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 [73]. 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:

  1. NA-AION or history of NA-AION in one eye
  2. active giant cell arteritis
  3. normal-tension glaucoma
  4. occlusion or severe stenosis of internal carotid artery
  5. low central retinal artery pressure
  6. 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 [22] 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"[64]. 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 [64]. 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 [63].

early stages optic disc edema involving the superior temporal part of the optic disc and prominent vessels
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.
elater stages: pale color (atrophy) in the upper half of the optic disc – more marked in the temporal than the nasal part
Fig. 16: Fundus photographs of right eye of a diabetic patient with non-arteritic AION showing: 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.

Misconceptions about NA-AION:

The subject of NA-AION is plagued with multiple misconceptions, resulting in controversy and confusion. Following are the major misconceptions.

  1. 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.
  2. 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.
  3. 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.
  4. That NA-AION is not seen in young persons. That has been proven to be a myth by two large studies.
  5. 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.
  6. 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.
  7. 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.
  8. 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%).
  9. That smoking is a risk factor for development of NA-AION. Two large prospective studies have shown that this is not true [65, 82].
  10. That aspirin reduces the risk of second eye involvement by NA-AION. As discussed above, two large studies have disproved this belief.
  11. 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 [75].

More information

More about fundus photography

More about fluorescein angiography

Blood tests and referrals to specialists in other areas: Blood tests which will be done immediately are the Erythrocyte Sedimentation Rate (ESR) and C-reactive protein (CRP). The results of these tests are available within a couple of hours. These two blood tests are extremely important to find out if a patient has giant cell arteritis. Both are usually abnormally high in giant cell arteritis.

Many other blood studies may be needed to find out if there is anything else wrong with the patient, and may help in finding the reason for the development of AION, such as diabetes or collagen vascular disease. Cholesterol and/or triglyceride levels will be checked because high levels lead to "hardening of the arteries." The results of these blood studies may indicate a need for follow-up by a local physician or referral to a specialist in hematology.

Blood pressure will be taken to determine if the patient has high blood pressure (hypertension). A cardiologist or cardiovascular specialist may be consulted if it seems that the cause of AION is a blood clot from somewhere else in the body, or that the heart, carotid arteries, or generalized "hardening of the arteries" may be contributing to the ischemia in the eye. Our recent studies have shown that abnormal fall of blood pressure during sleep is a serious risk factor for AION in the vast majority [12, 14, 15, 52, 60]. This can be tested by recording the blood pressure every 10 to 20 minutes over a 24 hour period, with an ambulatory blood pressure monitor

Temporal artery biopsy: When the patient's symptoms, the eye examination, elevated ESR and CRP, and fluorescein angiography make it seem likely that he/she has giant cell arteritis, a temporal artery biopsy will be done. The temporal artery lies just under the skin on the side of the forehead, or temple. The area is anesthetized and a small cut made in the skin to expose the artery. About an inch of the artery is removed for examination and the area is sutured with several stitches (which will be removed in about a week). This sample of the artery is examined under a microscope by a pathologist to determine whether there is inflammation of the artery. It may take several days before this result is known; however, treatment for giant cell arteritis may be started immediately if there is a strong suspicion of giant cell arteritis, even before the biopsy is done, because of the very high risk of blindness if adequate treatment is not given soon enough. Starting treatment before the biopsy is done does not interfere with the results.


Selected References

  1. Singh (Hayreh) S, Dass R (1960) The central artery of the retina. I. Origin and course. The British journal of ophthalmology 44: 193-212
  2. Singh (Hayreh) S, Dass R (1960) The central artery of the retina. II. A study of its distribution and anastomoses. The British journal of ophthalmology 44: 280-299
  3. Hayreh SS (1962) The Ophthalmic Artery: III. Branches. The British journal of ophthalmology 46: 212-247
  4. Hayreh SS (1963) The blood supply and vascular disorders of the optic nerve. An Inst Barraquer 4: 7-109
  5. Hayreh SS (1963) The Central Artery of the Retina. Its Role in the Blood Supply of the Optic Nerve. The British journal of ophthalmology 47: 651-663
  6. Hayreh SS (1969) Blood supply of the optic nerve head and its role in optic atrophy, glaucoma, and oedema of the optic disc. The British journal of ophthalmology 53: 721-748
  7. Hayreh SS, Baines JA (1972) Occlusion of the posterior ciliary artery. 3. Effects on the optic nerve head. The British journal of ophthalmology 56: 754-764
  8. Hayreh SS (1974) Anatomy and physiology of the optic nerve head. Transactions - American Academy of Ophthalmology and Otolaryngology 78: OP240-254
  9. Hayreh SS (1974) Anterior ischaemic optic neuropathy. I. Terminology and pathogenesis. The British journal of ophthalmology 58: 955-963
  10. Hayreh SS (1974) Anterior ischaemic optic neuropathy. II. Fundus on ophthalmoscopy and fluorescein angiography. The British journal of ophthalmology 58: 964-980
  11. Hayreh SS (1974) Anterior ischaemic optic neuropathy. III. Treatment, prophylaxis, and differential diagnosis. The British journal of ophthalmology 58: 981-989
  12. Hayreh SS (1974) Pathogenesis of cupping of the optic disc. The British journal of ophthalmology 58: 863-876
  13. Hayreh SS (1975) Anterior ischemic optic neuropathy. Springer-Verlag, Heidelberg
  14. Hayreh SS (1977) Optic disc edema in raised intracranial pressure. V. Pathogenesis. Archives of ophthalmology 95: 1553-1565
  15. Hayreh SS (1977) Optic disc edema in raised intracranial pressure. VI. Associated visual disturbances and their pathogenesis. Archives of ophthalmology 95: 1566-1579
  16. Hayreh SS (1978) Fluids in the anterior part of the optic nerve in health and disease. Survey of Ophthalmology 23: 1-25
  17. Hayreh SS (1978) Ischemic optic neuropathy. International Ophthalmology 1: 9-18
  18. Hayreh SS (1978) Structure and blood supply of the optic nerve. In: Heilmann K, Richardson KT (eds) Glaucoma: Conceptions of a Disease Pathogenesis, Diagnosis, and Therapy. Thieme, Stuttgart, pp. 78-96.
  19. Hayreh SS, Podhajsky PA (1979) Visual field defects in anterior ischemic optic neuropathy. Documenta Ophthalmologica Proceedings Series 19: 53-71
  20. Hayreh SS (1980) Anterior ischemic optic neuropathy. IV. Occurrence after cataract extraction. Archives of ophthalmology 98: 1410-1416
  21. Hayreh SS (1981) Anterior ischemic optic neuropathy. Archives of Neurology 38: 675-678
  22. Hayreh SS (1981) Anterior ischemic optic neuropathy. V. Optic disc edema an early sign. Archives of ophthalmology 99: 1030-1040
  23. Hayreh SS, Zahoruk RM (1981) Anterior ischemic optic neuropathy. VI. In juvenile diabetics. Ophthalmologica 182: 13-28
  24. Hayreh SS (1981) Posterior ischemic optic neuropathy. Ophthalmologica 182: 29-41
  25. Hayreh SS (1985) Inter-individual variation in blood supply of the optic nerve head. Its importance in various ischemic disorders of the optic nerve head, and glaucoma, low-tension glaucoma and allied disorders. Documenta ophthalmologica 59: 217-246
  26. Hayreh SS (1986) Anterior ischemic optic neuropathy. Japanese Journal of Clinical Ophthalmology 40: 581-587
  27. Hayreh SS, Servais GE, Virdi PS (1986) Fundus lesions in malignant hypertension. V. Hypertensive optic neuropathy. Ophthalmology 93: 74-87
  28. Hayreh SS (1987) Anterior ischemic optic neuropathy. VIII. Clinical features and pathogenesis of post-hemorrhagic amaurosis. Ophthalmology 94: 1488-1502
  29. Hayreh SS (1990) Anterior ischaemic optic neuropathy. Differentiation of arteritic from non-arteritic type and its management. Eye (London, England) 4: 25-41
  30. Hayreh SS (1990) In vivo choroidal circulation and its watershed zones. Eye (London, England) 4: 273-289
  31. Hayreh SS (1990) The role of optic nerve sheath fenestration in management of anterior ischemic optic neuropathy. Archives of ophthalmology 108: 1063-1065
  32. Hayreh SS (1991) Ophthalmic features of giant cell arteritis. Baillieres Clinical Rheumatology 5: 431-459
  33. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL (1994) Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. American journal of ophthalmology 117: 603-624
  34. Hayreh SS, Joos KM, Podhajsky PA, Long CR (1994) Systemic diseases associated with nonarteritic anterior ischemic optic neuropathy. American journal of ophthalmology 118: 766-780
  35. Hayreh SS (1995) The 1994 Von Sallman Lecture. The optic nerve head circulation in health and disease. Experimental eye research 61: 259-272
  36. Hayreh SS (1996) Acute ischemic disorders of the optic nerve: pathogenesis, clinical manifestations and management. Ophthalmology Clinics of North America 9: 407-442
  37. Hayreh SS (1996) Anteriore ischamische Optikusneuropathie. Stellenwert der nachtlichen arteriellen Hypotonie. [Anterior ischemic optic neuropathy: Role of nocturnal arterial hypotension]. Klinische Monatsblatter fur Augenheilkunde 208: aA12-17
  38. Hayreh SS (1996) Duke-elder lecture. Systemic arterial blood pressure and the eye. Eye (London, England) 10: 5-28
  39. Hayreh SS (1997) Anterior ischemic optic neuropathy. Clinical neuroscience 4: 251-263
  40. Hayreh SS, Podhajsky PA, Raman R, Zimmerman B (1997) Giant cell arteritis: validity and reliability of various diagnostic criteria. American journal of ophthalmology 123: 285-296
  41. Hayreh SS, Podhajsky PA, Zimmerman B (1997) Nonarteritic anterior ischemic optic neuropathy: time of onset of visual loss. American journal of ophthalmology 124: 641-647
  42. Hayreh SS, Podhajsky PA, Zimmerman B (1998) Occult giant cell arteritis: ocular manifestations. American journal of ophthalmology 125: 521-526
  43. Hayreh SS, Podhajsky PA, Zimmerman B (1998) Ocular manifestations of giant cell arteritis. American journal of ophthalmology 125: 509-520
  44. Hayreh SS, Podhajsky P, Zimmerman MB (1999) Beta-blocker eyedrops and nocturnal arterial hypotension. American journal of ophthalmology 128: 301-309
  45. Hayreh SS (1999) Retinal and optic nerve head ischemic disorders and atherosclerosis: role of serotonin. Progress in retinal and eye research 18: 191-221
  46. Hayreh SS, Podhajsky P, Zimmerman MB (1999) Role of nocturnal arterial hypotension in optic nerve head ischemic disorders. Ophthalmologica 213: 76-96
  47. Hayreh SS (1999) Role of nocturnal arterial hypotension in the development of ocular manifestations of systemic arterial hypertension. Current opinion in ophthalmology 10: 474-482
  48. Hayreh SS (2000) Does Levodopa improve visual function in NAION? Ophthalmology 107: 1434-1438
  49. Hayreh SS (2000) Ischaemic optic neuropathy. Indian journal of ophthalmology 48: 171-194
  50. Hayreh SS (2000) Steroid therapy for visual loss in patients with giant-cell arteritis. Lancet 355: 1572-1573
  51. Hayreh SS (2001) Blood flow in the optic nerve head and factors that may influence it. Progress in retinal and eye research 20: 595-624
  52. Hayreh SS (2001) The blood supply of the optic nerve head and the evaluation of it - myth and reality. Progress in retinal and eye research 20: 563-593
  53. Hayreh SS, Podhajsky PA, Zimmerman B (2001) Ipsilateral recurrence of nonarteritic anterior ischemic optic neuropathy. American journal of ophthalmology 132: 734-742
  54. Hayreh SS, Jonas JB (2001) Optic disc morphology after arteritic anterior ischemic optic neuropathy. Ophthalmology 108: 1586-1594
  55. Hayreh SS (2002) Diabetic papillopathy and nonarteritic anterior ischemic optic neuropathy. Survey of Ophthalmology 47: 600-602
  56. Hayreh SS, Zimmerman B, Kardon RH (2002) Visual improvement with corticosteroid therapy in giant cell arteritis. Report of a large study and review of literature. Acta ophthalmologica Scandinavica 80: 355-367
  57. Hayreh SS (2002) Neuropatías Ópticas Isquémicas. In: Arruga J, Sánchez B (eds) Neuropatías Ópticas: Diagnóstico Y Tratamiento LXXVIII Ponencia Oficial Soc Espãn Oftalmol. Soc Espãn Oftalmol, pp. 207-237.
  58. Hayreh SS, Zimmerman B (2003) Management of giant cell arteritis. Our 27-year clinical study: new light on old controversies. Ophthalmologica J 217: 239-259
  59. Hayreh SS, Zimmerman B (2003) Visual deterioration in giant cell arteritis patients while on high doses of corticosteroid therapy. Ophthalmology 110: 1204-1215
  60. Hayreh SS (2004) Posterior ischaemic optic neuropathy: clinical features, pathogenesis, and management. Eye (London, England) 18: 1188-1206
  61. Hayreh SS (2005) Erectile dysfunction drugs and non-arteritic anterior ischemic optic neuropathy: is there a cause and effect relationship? Journal of Neuro-Ophthalmology 25: 295-298
  62. Hayreh SS, Zimmerman B (2005) Visual field abnormalities in nonarteritic anterior ischemic optic neuropathy: their pattern and prevalence at initial examination. Archives of ophthalmology 123: 1554-1562
  63. Hayreh SS (2006) Amiodarone, erectile dysfunction drugs, and non-arteritic ischemic optic neuropathy. Journal of Neuro-Ophthalmology 26: 154-155
  64. Hayreh SS, Zimmerman MB (2007) Incipient nonarteritic anterior ischemic optic neuropathy. Ophthalmology 114: 1763-1772
  65. Hayreh SS, Jonas JB, Zimmerman MB (2007) Nonarteritic anterior ischemic optic neuropathy and tobacco smoking. Ophthalmology 114: 804-809
  66. . Hayreh SS, Zimmerman MB (2007) Optic disc edema in non-arteritic anterior ischemic optic neuropathy. Graefes Archive for Clinical and Experimental Ophthalmology 245: 1107-1121
  67. Hayreh SS, Fingert JH, Stone E, Jacobson DM (2008) Familial non-arteritic anterior ischemic optic neuropathy. Graefes Archive for Clinical and Experimental Ophthalmology 246: 1295-1305
  68. Hayreh SS (2008) Intravitreal triamcinolone for nonarteritic anterior ischemic optic neuropathy. Journal of Neuro-Ophthalmology 28: 77-78
  69. Hayreh SS (2008) Non-arteritic anterior ischemic optic neuropathy and phosphodiesterase-5 inhibitors. The British journal of ophthalmology 92: 1577-1580
  70. Hayreh SS, Zimmerman MB (2008) Nonarteritic anterior ischemic optic neuropathy: clinical characteristics in diabetic patients versus nondiabetic patients. Ophthalmology 115: 1818-1825
  71. Hayreh SS, Zimmerman MB (2008) Nonarteritic anterior ischemic optic neuropathy: Natural history of visual outcome. Ophthalmology 115: 298-305
  72. Hayreh SS, Zimmerman MB (2008) Nonarteritic anterior ischemic optic neuropathy: refractive error and its relationship to cup/disc ratio. Ophthalmology 115: 2275-2281
  73. Hayreh SS, Zimmerman MB (2008) Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Graefes Archive for Clinical and Experimental Ophthalmology 246: 1029-1046
  74. Hayreh SS (2009) Ischemic optic neuropathy. Progress in retinal and eye research 28: 34-62
  75. Hayreh SS (2009) Non-arteritic anterior ischemic optic neuropathy and thrombophilia. Graefes Archive for Clinical and Experimental Ophthalmology 247: 577-581
  76. Hayreh SS (2010)Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Surv Ophthalmol. 55(4):399-400.
  77. Hayreh SS (2009). A Primate Model of Nonarteritic Anterior Ischemic Optic Neuropathy [electronic letter].Invest Ophthalmol Vis Sci. Available from www.iovs.org/cgi/eletters/49/7/2985#7919.
  78. Beck RW, Servais GE, Hayreh SS (1987) Anterior ischemic optic neuropathy. IX. Cup-to-disc ratio and its role in pathogenesis. Ophthalmology 94: 1503-1508
  79. The Ischemic Optic Neuropathy Decompression Trial Research Group (1995) Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. JAMA 273: 625-632
  80. Beri M, Klugman MR, Kohler JA, Hayreh SS (1987) Anterior ischemic optic neuropathy. VII. Incidence of bilaterality and various influencing factors. Ophthalmology 94: 1020-1028
  81. Beck RW, Hayreh SS, Podhajsky PA, Tan ES, Moke PS (1997) Aspirin therapy in nonarteritic anterior ischemic optic neuropathy. American journal of ophthalmology 123: 212-217
  82. Newman NJ, Scherer R, Langenberg P, Kelman S, Feldon S, Kaufman D, Dickersin K (2002) The fellow eye in NAION: report from the ischemic optic neuropathy decompression trial follow-up study. American journal of ophthalmology 134: 317-328
  83. Jonas JB, Spandau UH, Harder B, Sauder G (2007) Intravitreal triamcinolone acetonide for treatment of acute nonarteritic anterior ischemic optic neuropathy. Graefes Archive for Clinical and Experimental Ophthalmology 245: 749-750
  84. Bennett JL, Thomas S, Olson JL, Mandava N (2007) Treatment of nonarteritic anterior ischemic optic neuropathy with intravitreal bevacizumab. Journal of Neuro-Ophthalmology 27: 238-240
  85. Fineman MS, Savino PJ, Federman JL, Eagle RC, Jr. (1996) Branch retinal artery occlusion as the initial sign of giant cell arteritis. American journal of ophthalmology 122: 428-430
  86. Costello F, Zimmerman MB, Podhajsky PA, Hayreh SS (2004) Role of thrombocytosis in diagnosis of giant cell arteritis and differentiation of arteritic from non-arteritic anterior ischemic optic neuropathy. Eur J Ophthalmology 14: 245-257
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  89. Salvarani C, Cantini F, Hunder GG (2008) Polymyalgia rheumatica and giant-cell arteritis. Lancet 372: 234-245
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  91. Sadda SR, Nee M, Miller NR, Biousse V, Newman NJ, Kouzis A (2001) Clinical spectrum of posterior ischemic optic neuropathy. American journal of ophthalmology 132: 743-750
  92. Roth S, Barach P (2001) Postoperative visual loss: still no answers--yet. Anesthesiology 95: 575-577
  93. Hayreh SS (2009) Management of non-arteritic anterior ischemic optic neuropathy. Graefes Archives for Clinical and Experimental Ophthalmology 247:1595-1600
  94. McLeod D, Marshall J, Kohner EM (1980) Role of axoplasmic transport in the pathophysiology of ischaemic disc swelling. British Journal of Ophthalmology 64:247-261
  95. Foulds WS (1970) Visual disturbances in systemic disorders: optic neuropathy and systemic disease. Transactions of the Ophthalmological Society of the United Kingdom 89:125-146
  96. Hayreh SS (2010). The role of aspirin in non-arteritic anterior ischaemic optic neuropathy. Neuro-ophthalmology 34:1-5
  97. Hayreh SS (2009). Pathogenesis of nonarteritic anterior ischemic optic neuropathy. Arch Ophthalmol 127(8):1082-1083.
  98. Hayreh SS (2010). Role of steroid therapy in nonarteritic anterior ischemic optic neuropathy. . Journal of Neuro-ophthalmology 30(4):388-389.
  99. Hayreh SS (2011). Management of ischemic optic neuropathies. Indian Journal of Ophthalmology 59(2):123-136.
  100. Hayreh SS (2011). Treatment of non-arteritic anterior ischaemic optic neuropathy. British Journal of Ophthalmology 95(11):1617-1618.
  101. Hayreh SS (2012). Non-arteritic anterior ischemic optic neuropathy versus cerebral ischemic stroke. Graefes Archives for Clinical and Experimental Ophthalmology 250(9):1255-1260.
  102. Hayreh SS (2013). Ischemic optic neuropathies - where are we now? Graefes Archives for Clinical and Experimental Ophthalmology 251(8):1873-1884.
  103. Hayreh SS (2013). Treatment of non-arteritic anterior ischemic optic neuropathy with high-dose systemic corticosteroid therapy. Graefes Archives for Clinical and Experimental Ophthalmology 251(3):1029-1030.
  104. Hayreh SS (2015). Re: Parsa et al.: Nonarteritic anterior ischemic optic neuropathy (NAION): a misnomer. Rearranging pieces of a puzzle to reveal a nonischemic papillopathy caused by vitreous separation (Ophthalmology 2015;122:439-42). Ophthalmology 122(12):e75-76.
  105. Hayreh SS, Zimmerman MB (2013). Bilateral nonarteritic anterior ischemic optic neuropathy: comparison of visual outcome in the two eyes. Journal of Neuro-ophthalmology 33(4):338-343.
  106. Hayreh SS, Zimmerman MB (2014). Amaurosis fugax in ocular vascular occlusive disorders: prevalence and pathogeneses. Retina 34(1):115-122.
  107. Jonas JB., Hayreh SS, Tao Y, Papastathopoulos KI, Rensch F (2012). Optic nerve head change in non-arteritic anterior ischemic optic neuropathy and its influence on visual outcome. PLoS One 7(5):e37499.

Recent books by Dr. Sohan Singh Hayreh

Hayreh SS (2011). Ischemic Optic Neuropathies: Springer. 456 pages. ISBN: 978-3642118494

Hayreh SS (2015). Ocular Vascular Occlusive Disorders: Springer. 851 pages. ISBN: 978-3319127804


Quiz


Select your current training level: (optional)

Question 1

What is NOT a typical symptom of IIH?

The correct answer is "No of the above, all are typical of IIH"

The symptoms most commonly reported by IIH patients followed by their frequency are:

  • headache (94%)
  • transient visual obscurations or blurring (68%)
  • pulse synchronous tinnitus or "wooshing noise" in the ear (58%)
  • pain behind the eye (44%)
  • double vision (38%)
  • visual loss (30%)
  • pain with eye movement (22%)
Question 2

Does a diagnosis of IIH require a high spinal fluid pressure (measured during a spinal tap)?

The correct answer is "True"

The diagnosis of IIH is made by identifying the typical symptoms of the disease along with documentation of a high spinal fluid pressure (measured during a spinal tap). The neurologic examination is normal except for the presence of swollen optic nerves called papilledema (seen by examining the back of the eye).

Question 3

Based on the diagnosis of IIH iwth mild visual loss, which treatment strategy would be most appropriate?

The correct answer is

  • Low Na+ diet
  • 10% weight loss
  • Acetazolamide

Answer: low sodium diet, wieght loss and acetazolamide