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Year : 2000  |  Volume : 48  |  Issue : 3  |  Page : 171-94

Ischaemic optic neuropathy.

Ocular Vascular Division, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, USA

Correspondence Address:
S S Hayreh
Ocular Vascular Division, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City
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Source of Support: None, Conflict of Interest: None

PMID: 11217249

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Ischaemic optic neuropathy is of two types: anterior (AION) and posterior (PION), the first involving the optic nerve head (ONH) and the second, the rest of the optic nerve. Pathogenetically AION and PION are very different diseases. AION represents an acute ischaemic disorder of the ONH supplied by the posterior ciliary artery (PCA), while PION has no specific location in the posterior part of the optic nerve and does not represent an ischaemic disorder of any definite artery. The most important step towards a logical understanding of the underlying causes, clinical features, pathogenesis and rational management of AION, is to understand the basic scientific issues involved; these are discussed in some detail. AION clinically is of two types: (1) that due to giant cell arteritis (arteritic AION: A-AION) and (2) non-arteritic AION (NA-AION). NA-AION, the more common of the two, is one of the most prevalent and visually crippling diseases in the middle-aged and elderly, and is potentially bilateral. NA-AION is a multifactorial disease, with many risk factors collectively contributing to its development. Although there is no known treatment for NA-AION, reduction of risk factors is important in decreasing chances of involvement of the second eye and of further episodes. Our studies have suggested that nocturnal arterial hypotension is an important risk factor for the development and progression of NA-AION. The role of nocturnal arterial hypotension in the pathogenesis of NA-AION and management of nocturnal hypotension is discussed. Potent antihypertensive drugs, when used aggressively and/or given at bedtime, are emerging as an important risk factor for nocturnal hypotension, and there is some evidence that NA-AION may be occurring as an iatrogenic disease in some individuals. A-AION, by contrast, is an ocular emergency and requires immediate treatment with systemic corticosteroids to prevent further visual loss. The clinical parameters which help to differentiate the two types of AION, and their respective management are discussed.

Keywords: Blood Pressure, physiology, Circadian Rhythm, Diagnosis, Differential, Fluorescein Angiography, Fundus Oculi, Humans, Hypotension, complications, physiopathology,

How to cite this article:
Hayreh S S. Ischaemic optic neuropathy. Indian J Ophthalmol 2000;48:171

How to cite this URL:
Hayreh S S. Ischaemic optic neuropathy. Indian J Ophthalmol [serial online] 2000 [cited 2023 Sep 26];48:171. Available from: https://journals.lww.com/ijo/pages/default.aspx/text.asp?2000/48/3/171/14876

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Ischaemic optic neuropathy represents an acute ischaemic disorder of the optic nerve. The source and pattern of blood supply of the anterior part of the optic nerve (also called the optic nerve head, ONH) is very different from that of the posterior part. The ONH is almost entirely supplied by the posterior ciliary artery (PCA) circulation and the rest of optic nerve posterior to the ONH is supplied from several other sources. In view of that, pathogenetically, as well as clinically, ischaemic optic neuropathy is of two very distinct types: anterior ischemic optic neuropathy (AION) involving the ONH, and posterior ischaemic optic neuropathy (PION) involving a segment of the rest of the optic nerve posteriorly. [1, 2] The former is far more common than the latter. It is often not appreciated that AION is one of the most prevalent and visually crippling diseases in the middle aged and elderly, and is potentially bilateral.

In order to understand the various features of a clinical condition and its management, it is absolutely necessary to comprehend the various basic scientific issues involved, and the scientific basis of the disease process. Therefore, before describing the clinical characteristics of the two types of ischaemic optic neuropathy and their management, I will first discuss very briefly some of the basic issues about the optic nerve circulation, the pathogeneses of AION and PION, and the role of various factors in their development.

  Blood supply of the optic nerve Top

This has been discussed in detail elsewhere.[3-10] Based on the arterial blood supply the optic nerve is divided into anterior and posterior parts.

A. Arterial blood supply of the anterior part of the optic nerve (ONH) [Figure - 1]:

The ONH consists of, from front to back, (i) surface nerve fiber layer, (ii) prelaminar region, (iii) lamina cribrosa region, and (iv) retrolaminar region[11] [Figure:1a].

The surface nerve fiber layer

This is mostly supplied by the retinal arterioles. In the temporal region, however, in some eyes it may instead be supplied by the PCA circulation from the deeper prelaminar region. The cilioretinal artery (rarely a tiny ciliopapillary artery), when present, usually supplies the corresponding sector of the surface layer.

The prelaminar region

This is situated in front of the lamina cribrosa. It is supplied by centripetal branches from the peripapillary choroid. [7, 9, 10] [Figure - 2], [Figure - 3] The central retinal artery has no branches in this region.

The region of the lamina cribrosa

This is supplied by centripetal branches from the short PCAs, either directly or by the so-called arterial circle of Zinn and Haller, when that is present. Contrary to the prevalent impression, the circle of Zinn and Haller is not seen in every eye and, when seen, may be an incomplete circle. The central retinal artery gives off no branches in this region.

Retrolaminar region

This is the part of the ONH that lies immediately behind the lamina cribrosa. This part of the optic nerve is supplied by two vascular systems the peripheral centripetal and the axial centrifugal systems.

1. Peripheral centripetal vascular system

This is seen in all nerves and forms the major source of supply to this part. It is formed by recurrent pial branches arising from the peripapillary choroid and the circle of Zinn and Haller (when present, or the short PCAs instead). In addition, pial branches from the central retinal artery and other orbital arteries also supply this part. [4, 12, 13] The pial vessels give off centripetal branches, running in the septa of the nerve.

2. Axial centrifugal vascular system

This is not present in all eyes. When present, it is formed by inconstant branches arising from the intraneural part of the central retinal artery. [3, 12, 13]

From this description of the blood supply of the ONH it becomes obvious that the main source of blood supply to the ONH is the PCA circulation via the peripapillary choroid and the short PCAs (or the circle of Zinn and Haller). Our fluorescein angiographic studies have shown a sectoral blood supply in the ONH, which goes along with the overall segmental distribution of the PCA circulation;[14] this helps explain the segmental visual loss in AION.

B. Arterial blood supply of the posterior part of the optic nerve [Figure:1b]:

This part of the optic nerve has a peripheral and an axial vascular system.

1. Peripheral centripetal vascular system:

This is always present. It is formed by the pial vessels, which come from the collateral arteries arising directly from the ophthalmic artery and some of its intraorbital branches. [4, 6]

2. Axial centrifugal vascular system:

It is formed by branches of the central retinal artery, seen in 75% of cases, [3, 4, 12, 13] and the supply by the central retinal artery may extend 1-4 mm behind the site of penetration of the central retinal artery into the optic nerve and give rise to centrifugal branches.

C. Inter-individual variation in the blood supply of the optic nerve head:

There is a general impression that the pattern of blood supply of the ONH is almost identical in all eyes, and that all ischaemic lesions can be explained by one standard vascular pattern. This fundamental error is responsible for a good deal of confusion. My multifaceted studies[8-10] have clearly shown that ONH blood supply shows a marked inter-individual variation, which is produced by the following factors:

1. Variation in the anatomical pattern of the arterial supply

The usual anatomical pattern is described above and shown in [Figure - 1]. However, there are tremendous variations in the anatomical pattern and some of the differences in the vascular anatomy reported in the literature[7] can be explained on this basis. In my anatomical study of the pattern in 100 human specimens, no two specimens had identical patterns, not even two eyes of the same individual. [10, 12, 13]

2. Variations in the pattern of PCA circulation

From the account of the arterial supply of the ONH given above, it is evident that the PCAs are the main source of blood supply to the ONH. The PCAs show marked inter-individual variation, which must profoundly influence the blood supply pattern of the ONH. I have reviewed the subject in detail elsewhere,[8-10] and the following is a very brief summary:

(a) Variations in number of PCAs supplying an eye: There may be 1-5, usually 2 or 3 PCAs. [6, 9, 15] The PCAs enter the eyeball usually medial and lateral to the optic nerve and hence are called medial and lateral PCAs.

(b) In vivo supply by the PCAs: My experimental [6, 9, 14, 16] and clinical [1, 8, 17-20] studies have demonstrated that the PCAs and their branches have a segmental distribution in vivo, in the choroid as well as in the ONH, The lateral and medial PCAs supply the corresponding parts of the choroid [Figure:4b]-[Figure - 7]; however, there is marked inter-individual variation in the area supplied by the PCAs in man, both in the choroid and in the ONH ([Figure:4b]-[Figure - 7]. [1, 8, 10, 16, 19-21] The medial PCA may supply the entire ONH [Figure:7b], or it may take no part in the blood supply of the ONH [Figure:7d]; or there may be any number of variations between these two extremes [Figure - 5]-[Figure - 7]. The lateral PCA supplies the area of the ONH not supplied by the medial PCA or vice versa. When there is more than one medial or lateral PCA, the area supplied by each may be only a sector. When the superior PCA is present, it accordingly supplies a superior sector. Therefore, the inter-individual variation in number and distribution by the various PCAs produces an extremely variable pattern of distribution by the PCAs in the ONH - this is very important to keep in mind while dealing with ischaemic disorders of the ONH.

(c) Watershed zones in the PCA distribution and their location: I have discussed the subject in detail elsewhere. [8, 10, 21] When a tissue is supplied by two or more end-arteries, the border between the territories of distribution of any two end-arteries is called a "watershed zone". The significance of the watershed zones is that in the event of a fall in the perfusion pressure in the vascular bed of one or more of the end-arteries, the watershed zone, being an area of comparatively poor vascularity, is most vulnerable to ischaemia. Since PCAs and their subdivisions are end-arteries in vivo, they have watershed zones between them [Figure - 3], [Figure - 7]. As discussed above, when there are two (medial and lateral) PCAs, the area of the choroid and ONH supplied by the two shows a marked inter-individual variation which results in wide variation in the location of the watershed zone between the two. [Figure - 7] illustrates some of the locations of the watershed zone between the medial and lateral PCAs in man seen by me. [8, l0, 14, 21] When there are three or more PCAs supplying an eye, the locations of the watershed zones vary according to the number of the PCAs and their locations, as shown diagrammatically in [Figure - 8].

The location of the watershed zone in relation to the ONH is an extremely important subject in any discussion of ischaemic disorders of the ONH. This is because in the event of fall of perfusion pressure in the PCAs or their branches, the part of the ONH located in the watershed zone becomes vulnerable to ischaemia, as shown by my studies. [8, 21]

(d) Difference in blood flow in various PCAs as well as short PCAs: Our clinical and experimental studies have indicated that the mean blood pressure (BP) in the various PCAs may be different in health and in disease.[8] In the event of a fall of perfusion pressure, the vascular bed supplied by one artery may be affected earlier and more than the others.

  Pathophysiology of factors controlling blood flow in the optic nerve head Top

The subject is discussed in detail elsewhere. [22, 23] The blood flow in the ONH is calculated by using the following formula:

Perfusion pressure = Mean BP minus intraocular pressure (IOP).

Mean BP = Diastolic BP + 1/3 (systolic minus diastolic BP).

From this formula, it is evident that the blood flow depends upon ( a) resistance to blood flow, ( b) BP and (c) IOP.

A. Resistance to blood flow

This depends upon the state and calibre of the vessels supplying the ONH, which in turn are influenced by the following:

1. Efficiency of autoregulation of the ONH blood flow

The goal of blood flow autoregulation in a tissue is to maintain a relatively constant blood flow during changes in perfusion pressure. Blood flow in the ONH is normally autoregulated. [9, 22, 23] Autoregulation in general operates only over a critical range of perfusion pressure so that with a rise or fall of perfusion pressure beyond the critical range, the autoregulation becomes ineffective and breaks down [Figure - 9]. Thus autoregulation does not protect the ONH all the time. Derangement of the autoregulation in the ONH may be produced by many known, and perhaps some unknown, systemic and local causes, including the aging process, arterial hypertension, diabetes mellitus, marked arterial hypotension from any cause, arteriosclerosis, atherosclerosis, and hypercholesterolemia. [24, 26]

Endothelial derived vasoactive agents are emerging as important factors in regulation of blood flow. There is evidence to suggest that damage to vascular endothelium occurs in arterial hypertension, arteriosclerosis, atherosclerosis, hypercholesterolemia, aging, diabetes mellitus, ischaemia and other so far unknown causes. [24, 25, 27] Of the various endothelial-derived vasoactive agents, nitric oxide (a vasodilator) and endothelin (a powerful vasoconstrictor) are important in our discussion because the lumen of the vessels depends upon the balance between the opposing actions of the two. Morphologic and functional alterations of endothelial cells reduce basal formation of nitric oxide.[27] Reduced formation of dilating agents by the endothelium may lead to unopposed vasoconstriction action of endothelin, causing vasoconsfriction and interfering with autoregulation.

The importance of blood flow autoregulation in the ONH is that when there is a reduction in the perfusion pressure, normal autoregulation protects the ONH from ischaemia but deranged autoregulation makes the ONH vulnerable to ischaemia.

2. Vascular changes in the arteries feeding the ONH circulation:

The main factor normally determining the vascular resistance to blood flow is thought to be the size of the lumen of the pre-capillary arterioles - the primary resistance vessels. Arterial changes altering the vascular resistance in internal carotid, ophthalmic and PCAs and/or smaller vessels in the ONH itself may be produced by vasospasm, arteriosclerosis, atherosclerosis, vasculitis, drug-induced vasoconstriction or dilatation, a host of other systemic and cardiovascular diseases, and abnormalities in production of endothelial-derived vasoactive agents.

3. Rheological properties of the blood:

These would be influenced by a large variety of haematologic disorders, particularly those causing increased blood viscosity.

B. Arterial blood pressure

This is an important component determining the blood flow in the ONH. Both arterial hypertension and hypotension can influence the ONH blood flow in a number of ways.

1. Arterial hypertension

Both essential and malignant hypertension can interfere with the ONH blood flow. [9, 28-31] Chronic arterial hypertension does this in many ways, including increased vascular resistance in the terminal arterioles (as a part of hypertensive process), secondary hypertensive vascular changes in ONH vessels, and by deranging blood flow autoregulation, as well as by causing the range of autoregulation to shift to higher levels to adapt to high BP. [29, 32] [Figure - 9] Such an adjustment, although it improves the patient's tolerance to high BP, it correspondingly decreases his tolerance to low BP.

2. Arterial hypotension

In an ONH, a fall of BP below a critical level of autoregulation would decrease its blood flow. Fall of BP in the ONH may be due to systemic or local hypotension.

Systemic hypotension: The most common causes of systemic arterial hypotension are nocturnal arterial hypotension during sleep [28, 30] and intensive antihypertensive medication; less common causes include massive haemorrhages, shock, renal haemodialysis, etc. [28, 33, 34] This is further discussed below.

Local ocular/ONH arterial hypotension: Instead of or in addition to the systemic arterial hypotension, there may be regional fall in the mean BP in the ocular blood vessels. This may be due to narrowing of the regional arteries, such as internal carotid, ophthalmic or one or more of the PCAs (supplying the ONH), or a fall of perfusion pressure locally in the peripapillary choroid.

C. Intraocular pressure

ONH blood flow depends upon the perfusion pressure, which is equal to mean BP minus IOP. Thus, there is an inverse relationship between IOP and perfusion pressure in the ONH. A much greater rise in IOP would be required to interfere significantly with the ONH blood flow in healthy persons (with normal BP and autoregulation) than in persons with arterial hypotension, defective autoregulation or other vascular risk factors. The role of IOP in the development of NA-AION is discussed below.

This, then, gives some idea of the great complexity of the blood flow in the ONH. In ischaemic disorders of the ONH, a whole host of systemic and local factors acting in different combinations and to different extents may derange the circulation in the ONH, with some making the ONH susceptible to ischaemia (predisposing risk factors) and others acting as the final insult (precipitating risk factors). One set of factors may be responsible for ONH ischaemia in one case and a totally different set in another, and so on. In such a scenario, a particular factor or a group of factors may be present in one case and not in another. Thus, according to the available evidence, [28, 34] ischaemic optic neuropathy is multifactorial in origin, particularly non-arteritic AION (NA-AION). Each patient with NA-AION may have a unique combination of systemic and local factors which together produce it; contrary to the popular belief, there is no single "silver bullet" that does it.[9]

  Pathogenesis of AION and the role of various factors in its development Top

This account is based essentially on my prospective clinical studies of over 1000 cases of this disorder, and on experimental studies in primates. [1, 8, 17-19, 28-46] The subject is discussed at length elsewhere.[22] AION is due to acute ischaemia of the ONH [1, 8, 18, 19, 38, 39] whose main source of blood supply, as mentioned above, is from the PCA circulation [Figure - 1]. Therefore, AION represents an ischaemic disorder of PCA circulation in the ONH. As discussed, the ONH varies markedly among individuals in its blood supply and blood flow patterns and those exercise profound influence on the pathogenesis and clinical features of AION.

A. Aetiological and pathogenetical classification of AION

Aetiologically and pathogenetically, AION cases can be broadly classified into two groups.[19]

1. AION due to thrombotic or embolic lesions of the arteries/arterioles feeding the ONH

(a) Thrombotic lesions: Occlusion of the PCAs [Figure - 4]-[Figure - 6] or their subdivisions is most commonly caused by giant cell arteritis [GCA (resulting in infarction of the ONH[47-50] and arteritic AION - A-AION)] and less commonly by other types of vasculitis (e.g., polyarteritis nodosa, systemic lupus erythematosus, and herpes zoster).

(b) Embolic lesions: Embolic occlusion of the PCAs or of the ONH arterioles seems to occur much less frequently than thrombotic occlusion, but this impression may be erroneous because of our inability to see the emboli in these vessels on ophthalmoscope compared to the ease with which they are seen in the retinal arterioles. Multiple emboli in the vessels of the anterior part of the optic nerve have been demonstrated histopathologically in NA AION.[51] Clinically I suspect embolic aetiology of NA-AION if I find the following:

  1. (i) Sudden onset of visual loss, definitely later on in the day, and not related to sleep or any other condition associated with arterial hypotension.

  2. (ii) The optic disc has a large cup.

  3. (iii) Evidence of occlusion of a PCA on fluorescein fundus angiography [Figure - 6] but no systemic symptoms or signs suggestive of GCA and a negative temporal artery biopsy for GCA.

In the thrombotic/embolic group, there is usually massive, severe, and permanent damage to the ONH, the extent of which depends on the size of the artery involved and the area of the nerve supplied by the occluded artery. [35, 47, 51]

2. AION due to transient non-perfusion or hypoperfusion of the nutrient vessels in the ONH

As discussed above, the blood flow in the ONH depends upon the perfusion pressure in its vessels. A transient non-perfusion or hypo-perfusion of the ONH can occur due to a transient fall of perfusion pressure in its vessels, which in turn in susceptible persons would produce NA-AION. It is extremely important to remember that in this mode of development of NA-AION there is no actual occlusion of the PCA. This is by far the most common type of AION and almost all NA-AION cases belong to this group.

A fall of the perfusion pressure below the critical level in the capillaries of the ONH may be caused either by a marked fall in mean BP (e.g., in shock, nocturnal hypotension[28-30, 43, 44] during sleep at night or a nap during the day, severe internal carotid artery and/or ophthalmic artery stenosis or occlusion, [41, 46] and other causes) or to a rise in the IOP,[37] or a combination of the two (e.g., in neovascular glaucoma associated with ocular ischaemia due to internal carotid artery and/or ophthalmic artery stenosis or occlusion [41, 46]). The ONH damage, which may be mild to marked, depends upon the severity and the duration of the transient ischaemia, but is usually less extensive and less severe than in thrombotic/embolic group. Since the ischaemia in the hypo-perfusion group is mostly due to transient non-perfusion without an organic block in the vessels, fluorescein fundus angiography may reveal minimal or no filling defect or delay in filling in the optic disc and/or peripapillary choroid [Figure - 2] and [Figure - 3], or choroidal watershed zone [Figure - 2], [Figure - 3], [Figure - 7]. In thrombotic/embolic group, by contrast, fluorescein angiography, during the first few days after the onset of AION, shows gross filling defects in the deep vessels of the optic disc and adjacent choroid, depending on the distribution pattern of the occluded artery [Figure:4b], [Figure - 5], and [Figure - 6].

B. Risk factors for development of NA-AION

All the available evidence indicates that NA-AION is multifactorial in nature and the risk factors fall into two main categories:

1. Predisposing Factors

These may be systemic or local in the eye and/or ONH (see below), and they make the ONH susceptible to ischemic disorders.

2. Precipitating Factor(s)

These act as the final insult, resulting in ischaemia of the ONH and NA-AION. Nocturnal arterial hypotension is an important factor in this category. [28, 30, 43-45]

C. Systemic diseases associated with NA-AION

Our study[34] showed that, compared with the prevalence reported in the general population, young (<45 years), middle-aged (45-64 years) and elderly (≥65 years) patients with NA-AION showed a significantly higher prevalence of arterial hypertension, diabetes mellitus, and gastro-intestinal ulcer. Also, middle-aged and elderly patients showed a significantly higher prevalence of ischaemic heart disease and thyroid disorders. Middle-aged patients exhibited significantly higher rates of chronic obstructive pulmonary disease and cerebrovascular disease. Following NA-AION, patients with both arterial hypertension and diabetes mellitus had a significantly higher incidence of cerebrovascular disease. The relevance of these systemic diseases to NA-AION is discussed at length elsewhere.[34]

In addition to these diseases, AION patients may also have a number of other systemic diseases which may directly or indirectly act as risk factors in the development of AION, [18, 34, 46-59] and these include the following:

1. Giant cell arteritis

This is the most important, though not the most common cause, of AION [47, 49, 54, 59] In every AION patient aged 55 years or older, GCA must be ruled out first.

2. Vasculitis

This may be due to systemic collagen vascular diseases (e.g., systemic lupus erythematosus and polyarteritis nodosa), Herpes zoster, and other causes.

3. Malignant arterial hypertension

Patients with renovascular malignant arterial hypertension, toxaemia of pregnancy and renal disease can develop NA-AION.[32]

4. Systemic arterial hypotension

The most important disease in this category is nocturnal arterial hypotension;[28-31,43-45] its role is discussed below.

5. Atherosclerosis and arteriosclerosis

As a part of generalized atherosclerosis and arteriosclerosis, the internal carotid artery, ophthalmic artery, PCAs and other nutrient arteries to the ONH may be involved and may contribute to the development of NA-AION. [46, 52, 53]

6. Massive or recurrent systemic haemorrhages

Development of NA-AION following massive or recurrent haemorrhages has been know for well over twenty centuries. These usually occur from the gastrointestinal tract or uterus, less frequently from other sources. [18, 33, 34] Such haemorrhages may or may not be associated with severe arterial hypotension.

7. Migraine and other vasospastic disorders

Patients with NA-AION may give a history of these disorders, particularly migraine.[34] It seems reasonable to assume that there is an association between NA-AION and vasospastic disorders. Our studies have shown that serotonin released by platelets at the site of atheromatous plaques in the atherosclerotic arteries can also produce vasospasm of the PCAs. [52, 53]

8. Haematologic disorders

NA-AION has been reported in patients with haematologic disorders, including sickle-cell trait, polycythaemia, thrombocytopenic purpura, leukaemia and various types of anaemia.[34]

9. Internal carotid artery disease

This can contribute to development of NA-AION either by embolism or by lowering the perfusion pressure because of marked stenosis. [41, 46]

10. Cardiac valvular disease

These include mitral valve disease (e.g., mitral prolapse), aortic valve disease, artificial heart valve, rheumatic heart disease, and other valvular diseases.[34] The most likely mechanism of development of NA-AION in them is microembolism to the ONH.

11. Defective cardiovascular autoregulation

Patients who develop orthostatic arterial hypotension would seem to have this disorder. It is known that diabetics have defective autoregulation.

12. "Type A" behavior pattern

I have seen a number of such persons with NA-AION complain that episodes of stress or agitation produced either temporary or permanent visual deterioration and even attribute the onset of NA-AION to such an episode.[34] A significantly high incidence of associated gastrointestinal ulcers and chronic obstructive pulmonary disease (secondary to smoking) with NA-AION in our study would further suggest that.[34]

13. Sleep apnoea

I have seen a number of patients with NA-AION give a history of sleep apnoea. Because of the well documented associated cardiovascular disorder with this condition, there is a possibility that it may act as a risk factor in the development and/or progression of NA-AION.

D. Role of nocturnal arterial hypotension in development of NA-AION

I have discussed this elsewhere.[28-31, 43-45] Typically patients with NA-AION and often those with A-AION complain of discovering visual loss on waking in the morning. In our series of 544 NA-AION cases, where the patients could give some information on the time of onset of visual loss, 73.3% gave a definite history of discovering the visual loss on waking up in the morning or from a nap, or early in the morning.[44] The incidence may actually be much higher than this because many others who became aware of visual loss later on in the day could not be certain when it had occurred.

We have so far investigated the BP pattern during sleep in about 500 patients with ONH ischaemic disorders, including NA-AION and giaucomatous optic neuropathy. [28, 30] The graph shown in [Figure - 10] shows an actual BP tracing in a patient with bilateral NA-AION over a 24-hour period, starting at 10 a.m. and continuing till 10 a.m. next day. There is a steep drop in BP on falling asleep at night and recovery to normal on waking in the morning. These studies also showed that arterial hypertensives on oral hypotensive therapy have a significant association between progressive visual field deterioration in NA-AION and nocturnal hypotension. [28, 30]

The fail of BP during sleep is a normal physiological phenomenon, but it is influenced by many factors, including drugs such as beta-blockers, calcium-channel blockers [Figure - 11], angiotensin converting enzyme inhibitors, Hytrin (terazosin hydrochloride - used in enlarged prostate to reduce nocturia), amitriptyline and other similar compounds, particularly the number and amount of drugs taken and the time of day they are taken. For example, 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 BP during sleep [Figure - 11]. Our study also showed the beta-blocker eye drops may also produce a significant nocturnal arterial hypotension.[60] 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 - 10], a BP tracing of a patient with bilateral NA-AION and progressive visual loss.

Our studies suggest that in an ONH already susceptible to ischaemic disorder, nocturnal hypotension may act as "the straw that breaks the camel's back". In a healthy ONH with normal autoregulation, a similar fall of BP during the night may have no deleterious effect at all. The very potent drugs, e.g., beta-blockers, calcium-channel blockers and angiotensin converting enzyme inhibitors, which are now available to treat hypertension, have begun to emerge as an important risk factor for arterial hypotension (particularly nocturnal hypotension), especially when used aggressively and/or given at bedtime. All these indicate that NA-AION may be occurring as an iatrogenic disease in some persons. A combination of arterial hypertension and associated nocturnal hypotension can play an important role in either the development or the progression of NA-AION, as discussed elsewhere.[31]

This brief discussion points to the great complexity of mechanisms of development of NA-AION and the role of nocturnal hypotension in it. A whole host of systemic and local factors acting in different combinations and to different extents may derange the ONH circulation, with some making the ONH susceptible to ischaemia and others acting as the final insult. Nocturnal hypotension seems to be an important precipitating factor in the susceptible patients.

E. Ocular conditions associated with NA-AION

A significant association of NA-AION with a number of ocular and ONH conditions has been shown. These conditions include:

1. Absent or small cup in the optic disc

Studies have shown that eyes with NA-AION have no cup or only a very small cup in the optic disc [35, 61] [Figure - 12]-[Figure - 15]. It is probable that overcrowding of the nerve fibers in a small scleral canal may be a precipitating factor in the production of NA-AION, although not the primary factor, as discussed elsewhere.[61] Briefly, the ONH in the prelaminar region is surrounded by a firm, non-yielding Bruch's membrane. When the axons swell (see later), they can expand only at the expense of capillaries in the ONH, so the capillaries are compressed, causing impaired blood flow. When BP falls during sleep due to nocturnal arterial hypotension, there may be little or no blood flow in the ONH capillaries, resulting in hypoxia or ischaemia of the axons. The patient discovers the visual loss upon waking. If the optic disc has a large enough cup, the axons have sufficient space to swell without significantly compressing the capillaries; thus the presence of a cup is a protective mechanism. The mechanism for development of NA-AION in eyes with absent cup proposed recently by Feldon[62] has no scientific basis and is highly misleading.[63]

2. Raised intraocular pressure

This reduces the perfusion pressure in the capillaries of the ONH and is an important risk factor in the production of NA-AION in susceptible individuals, e.g., in acute angle closure glaucoma, during the immediate postoperative period after cataract extraction,[37] in neovascular glaucoma with ocular ischaemia due to internal carotid artery and/or ophthalmic artery stenosis or occlusion, [41, 46] or in eyes with already low perfusion pressure in the vessels of the ONH. I have also seen patients who developed unilateral or bilateral NA-AION while undergoing prolonged orthopaedic back surgery, lying face down. In these patients, pressure on the eyeball and orbital oedema (both associated with elevated IOP), combined with arterial hypotension during general anaesthesia and haemorrhage, result in development of NA-AION, and they discover visual loss on waking from anaesthesia.

3. Marked optic disc oedema

When this is seen with raised intracranial pressure or other causes, transient visual loss may be the presenting or a prominent feature;[36] the attacks may be brought about by any factor that lowers the perfusion pressure in the ONH, for example, a change of posture, sudden movement, stooping or rubbing the eyes, The transient obscuration may progress to complete blindness because of development of NA-AION. The mechanism of development of NA-AION in these cases is discussed in detail elsewhere.[36]

4. Location of the watershed zone of the PCAs in relation to the ONH

In the event of a fall in perfusion pressure in the choroidal vascular bed supplied by the PCAs, the part of the optic disc located in the watershed zone is more susceptible to ischaemia than the rest[21] [Figure - 3], [Figure - 7]. If the optic disc is situated away from the watershed zone, it remains relatively safe. However, if the entire disc lies on the watershed zone [Figure:7c], it is most vulnerable to ischaemic damage.

5. Vascular disorders in the nutrient vessels of the ONH

Defective autoregulation, vasospasm, arteriosclerosis, atherosclerosis, disorders of ophthalmic artery and/or PCAs, and many other conditions may make the ONH susceptible to ischaemic disorders. [9, 52, 53]

F. Bilateral NA-AION and the factors influencing its incidence

We discussed this subject based on our studies on about 450 patients with NA-AION.[64] [Figure - 16] shows cumulative incidence rates (Kaplan-Meier estimates) of developing bilateral AION in A-AION and NA-AION. It shows that in NA-AION the risk of second eye involvement is about 25% on a follow-up of about 3 years. In GCA, 95% of the patients with bilateral A-AION had already developed it in the second eye by the time they were seen by us and were not on adequate systemic corticosteroid therapy, and a few developed it in the second eye within the first 3-4 days of the therapy; none developed AION thereafter; that is why the curve for A-AION ends at 6.1 months. This shows that systemic corticosteroid therapy is most effective in the prevention of development of A-AION in GCA. In NA-AION, the risk of developing NA-AION faster in the second eye is significantly greater in: (a) young (<45 years old) diabetics than older diabetics or persons with other systemic diseases, (b) in men than in women, and (c) in younger than older persons.

G. Neural ischaemia not an "all or none phenomenon"

The concept that ischaemia always produces infarction is simply not correct. There is a wide range of ischaemia, varying from mild subclinical hypoxia to severe ischaemia; the subject is discussed elsewhere. [42, 65]

  Clinical features of Anterior Ischaemic Optic Neuropathy Top

I have described these in detail elsewhere.[17-20, 22, 58, 59] Patients with AION usually present with classical symptoms and signs, so much so that it is one of the easiest diagnoses to make in ophthalmology. Following is a very brief account of the clinical features of AION.

A. Clinical classification

Clinically based on aetiology, AION is of two types, A-AION due to GCA and NA-AION due to other causes.[20] Since GCA is a prime ocular emergency, because of the imminent danger of bilateral total blindness, it is imperative to diagnose GCA at the earliest possible moment to prevent any further visual loss. Our studies have demonstrated that with proper and immediate treatment, visual loss in GCA is almost entirely preventable. In every AION patient over 55 years, the first important step should be to rule out GCA.

B. Clinical features

1. Age

In our study of 406 patients with NA-AION, the age range was 11-91 years (mean age 60±14 and median 61 years) and 43 (10.5%) of the 406 patients were young (<45 years).[34] Thus, the prevalent impression that NA-AION is a disease of the elderly only and does not occur in young persons is not correct. No age is immune from NA-AION and many of the young patients tend to be diabetic. On the other hand, A-AION, like GCA, is almost always seen in persons aged older than 55 years[57-59, 66, 67]

2. Gender distribution

Of the 406 patients with NA-AION in our study, 60% were men and 40% women.[34] In our 170 patients with GCA, 28% were men and 72% women[58] - this difference in gender distribution in GCA has clinical importance.

3. Ocular Symptoms

There is a sudden and painless deterioration of vision, usually discovered on waking in the morning. [43, 44] In eyes where the visual field defect bisects the fixation point, the patient may complain of intermittent blurred vision because of unconscious shifting fixation between the seeing and the blind areas near the fixation [Figure - 17]. When there is progressive visual loss, the patient usually notices further loss on waking in the morning. In my series of about 1000 patients with NA-AION, I never saw simultaneous bilateral onset of AION, except in cases with severe arterial hypotension (e.g., during cardio-pulmonary or extensive surgery with massive blood loss, back surgery, haemodialysis). Apparent "simultaneous" loss of vision in both eyes almost always occurred when the patient was unaware of the prior visual loss in the first eye until the second eye became involved, at a later stage.

In patients with GCA, amaurosis fugax is a very important presenting symptom and they may also complain of diplopia. [55, 57, 58, 68] I have seen a rare patient with GCA experiencing euphoria[55] and even denying any visual loss. Later on most of the patients with AION complain of photophobia, particularly those who have had bilateral AION.

4. Visual Acuity

This may vary from better than 6/6 to no light perception, so that normal visual acuity does not rule out AION Table.

5. Visual Fields

Perimetry usually shows relative or absolute visual field defects which may be sectoral, altitudinal, central scotoma or other optic disc related types[40] [Figure - 17]. The most common visual field defect in NA-AION is the inferior nasal sectoral defect which may be relative [Figure:17a] or absolute [Figure:17b]; next most common is the relative [Figure:17f], [Figure:17g] or absolute inferior altitudinal [Figure:17d], [Figure:17e] and/or central scotoma [Figure:17d], [Figure:17e], and less common are other optic disc related field defects [Figure:17c], [Figure:17h]-[Figure:17k].[40] Perimetry (particularly done with a Goldmann perimeter) is the most important visual function test to evaluate the visual loss in AION. While the disc has oedema, the visual fields may improve or deteriorate further,[40] but once the disc oedema has resolved completely, the visual field defects tend to stabilize.

6. Ophthalmoscopy

(a) In NA-AION: Initially, the optic disc is oedematous [Figure - 12]-[Figure - 14], [Figure:15a] which may be more marked in one part of the disc than the other.[17-19, 22] Frequently there are splinter haemorrhages at the disc margin [Figure - 12]-[Figure - 14]. Gradually the optic disc develops pallor and the oedema starts to resolve. The prevalent impression that optic disc in NA-AION is a pale oedema is not correct, because if the patient is seen at the onset of NA-AION, then the oedema is not pale [Figure - 12]-[Figure - 14], [Figure:15a] and does not differ from oedema due to other causes; however, if a patient is seen a couple of weeks after the onset, the pallor starts to develop. Within 2-3 months the optic disc oedema resolves spontaneously and is replaced by sectoral or generalized pallor of the optic disc [Figure:15b]. Thus, my studies have shown that the optic disc changes in NA-AION go through an evolutionary process during the first 2-3 months and the findings depend upon the stage at which a particular eye is seen. The evolutionary changes in the optic disc follow the following pattern: initially the ischaemic part of the disc has oedema with the rest of the disc being normal or showing much less oedema \?\ after a few days the entire disc may show generalized oedema \?\ still later the optic disc in the original ischaemic part starts to develop pallor and the oedema starts to regress there so that the uninvolved part may have more oedema than the ischaemic part \?\ then the involved part has pallor but is not oedematous any more while the rest of the disc may show mild oedema and even some pallor \?\ gradually the optic disc oedema resolves and the entire disc or only the ischaemic region may show pallor which may be more marked in the ischaemic part. This evolutionary pattern of presence and severity of oedema and pallor of the optic disc in NA-AION has resulted in a good deal of confusion and misunderstanding about the optic disc changes in NA-AION. Frequently there is little or no relationship between the extent and severity of optic disc pallor and the severity of visual loss. In non-diabetics, should the optic disc oedema not resolve spontaneously within 3-4 months, that indicates that the diagnosis of NA-AION may not be correct and requires complete re-evaluation of the situation. In NA-AION, the fellow normal optic disc typically shows either no cup or only a very small cup.[61]

In diabetics, in NA-AION during the initial stages, the optic disc oedema is usually associated with prominent, dilated and frequently telangiectatic vessels over the disc, and much more numerous peripapillary retinal haemorrhages than in non-diabetics [Figure:18a], [Figure - 19]. These findings may easily be mistaken for proliferative diabetic retinopathy associated with optic disc neovascularization and wrongly treated with panretinal photocoagulation.[42] When the optic disc oedema resolves, these prominent telangiectatic disc vessels and retinal haemorrhages resolve spontaneously [Figure:18b]; this resolution may erroneously be attributed to beneficial effect of panretinal photocoagulation! Because of these fundus changes, NA-AION in diabetics has mistakenly been described as a separate entity (described under different eponyms), not related to NA-AION; this has resulted in unnecessary confusion on the subject.[42] Optic disc oedema in some diabetics may last much longer than in non-diabetics.

(b) In-AION: In 69% of the A-AION eyes, unlike NA-AION the optic disc swelling has a characteristic chalky white appearance [17, 18, 58] [Figure:4a], [Figure:20a], [Figure:20c]. The evolutionary pattern of the optic disc changes in A-AION is similar to that of NA-AION. However, when optic disc oedema has resolved, almost all optic discs with A-AION finally develop cupping that is indistinguishable from glaucomatous optic disc cupping [Figure:20b], [Figure:20d], except that in A-AION the neuroretinal rim is pale, but not so in glaucomatous cupping. [17, 18, 35, 38] Also unlike NA-AION, the fellow optic disc in A-AION has a normal cup[61] [Figure:20c]

7. Fluorescein fundus angiography

In NA-AION, during the very early stages of the disease, there may be filling defects in the optic disc, peripapillary choroid and/or choroidal watershed zones [Figure - 2], [Figure - 3], [Figure - 7]. In A-AION, by contrast, there is almost always evidence of PCA occlusion with absence of choroidal and optic disc filling in its distribution [Figure:4b], [Figure - 5]. In a rare patient with NA-AION due to embolic occlusion of the PCA, similarly the entire area supplied by a PCA also shows filling defect [Figure - 6]. During the late phase of angiography, the disc stains with fluorescein, which is a non-specific finding for any type of optic disc oedema.

8. Incipient NA-AION

In my studies I found a small group of eyes with NA-AION that were initially totally asymptomatic, having optic disc oedema with no demonstrable visual function loss, subjectively or objectively, either on visual acuity testing or visual field plotting, indicating that asymptomatic optic disc oedema is an early sign of NA-AION.[65] During the past 20 years I have collected about 50 such patients. This condition was diagnosed on a routine eye examination during regular follow-up visits of patients with NA-AION in the fellow eye, or sometimes when examined for an unrelated eye condition, usually diabetic retinopathy.

C. Differential diagnosis of arteritic from non-arteritic AION

I have discussed this in detail elsewhere. [20, 59] Very briefly, over the years, I have found the following parameters highly suggestive of A-AION:

1. Systemic manifestations

Typically the patient is 55 years or older, more often a woman than a man, and complains of vague aches and pains, malaise, anorexia, "flu"-like symptoms, weight loss, fever of unknown origin, headaches, scalp tenderness, neck pain, jaw claudication, anaemia or other vague systemic symptoms; the patient feels tired, sleepy and generally unwell. [57, 66, 67] Paulley and Hughes[69] admirably summarized the symptoms when they stated, "When elderly people begin to fail mentally and physically, this disorder should be one of the first to be considered". In our study [66, 67] in 106 patients with positive temporal artery biopsy for GCA, the odds of a positive result were: 9.0 times greater with jaw claudication, 3.4 times greater with neck pain, and 2.0 times greater for age 75 years or more. However, in our study[59] 21% of the patients with positive temporal artery biopsy for GCA were perfectly fit and healthy and had absolutely no systemic symptoms or signs of GCA whatsoever, and this type of GCA is called occult GCA; this indicates that occult GCA is fairly common - a very important fact to be borne in mind when dealing with AION. The systemic symptoms are absent in NA-AION.

2. Visual symptoms

Amaurosis fugax is an important early visual symptom in GCA and precedes visual loss;[58] if a patient with AION gives a history of amaurosis fugax before the visual loss, it is highly suggestive of GCA. This is not the case in NA-AION.

3. Erythrocyte sedimentation rate (ESR) and C-Reactive Protein (CRP)

If the ESR is very high, it is fairly suggestive of this disease. But in our study we have seen patients with ESR as low as 4-5 mm who have a positive temporal artery biopsy for GCA; hence "normal" ESR does not rule out arteritis.[66] In our study we found that in 95% of the population normal ESR is anything up to 35 mm; generally higher in women than men.

For over a decade now we have used CRP in GCA cases regularly and find it a highly useful test in diagnosing and monitoring the activity of GCA. It generally runs parallel with ESR; however, in some cases there is elevation of ESR but not of CRP. Our studies showed that CRP is a more reliable parameter than ESR, and the combination of ESR and CRP together gives the best specificity (97%) for detection of GCA.[66]

4. Early and massive visual loss

In our study, 54% of patients with A-AION had initial visual acuity of counting fingers to no light perception as compared to 26% in the NA- AION group, and only light or no light perception in 29% and 4% respectively Table. [40, 58] This shows that early, massive visual loss is extremely suggestive of A-AION. However, in our series, about 21% of eyes with A-AION had 6/12 or better vision.

5. Chalky white swollen optic disc

In 69% of the A-AION eyes, the optic disc swelling has a characteristic chalky white appearance [17, 18, 58] [Figure:4a], [Figure - 20]. It is almost diagnostic of this condition. In the rest, however, the appearance of disc swelling is no different from that in NA-AION. On resolution of optic disc oedema in A-AION, the optic disc in the vast majority develops cupping [Figure:20b], [Figure:20d] indistinguishable from that of glaucomatous cupping except for the pale neuroretinal rim. [17, 18, 35, 58]

6. AION associated with cilioretinal artery occlusion

If an eye with fresh AION has optic disc edema and associated cilioretinal artery occlusion [17, 18, 20, 58] [Figure - 4], [Figure:20c], it is almost diagnostic of A-AION, because both are manifestations of PCA occlusion, the most common ocular artery involved in GCA. I have not encountered this combination in NA-AION.

7. Evidence of PCA occlusion on fluorescein fundus angiography

PCAs are the ocular arteries most often involved in GCA. [8, 17-21, 58] If angiography is performed during the first few days after the onset of AION and shows that one half of the choroid (usually the nasal half) does not fill (because of complete occlusion of the corresponding PCA by thrombotic occlusion of the artery, [Figure:4b], [Figure - 5] [8, 17, 21,58] it is extremely suggestive of A-AION. However, later, with the establishment of collateral circulation, this information may be lost. In NA-AION, in our study, non-filling of a PCA on fluorescein angiography was seen only extremely rarely when there was embolic occlusion of the PCA. [8, 21]

8. Temporal artery biopsy

This is the single most reliable test to establish the diagnosis and must be done in every case without exception. We have discussed elsewhere its role in the diagnosis of GCA.[66]

In conclusion, although none of these 8 criteria is individually infallible and present in one hundred percent of A-AION cases, the collective information provided by the various parameters is extremely helpful in diagnosis of A-AION and GCA. To confirm the diagnosis finally, temporal artery biopsy must be performed.

D. Management of AION

In the management of any disease and to evaluate any therapy for a disease, the first essential rule is that the treatment must have a scientific basis.[70] Treatments without scientific bases have not only proven useless but also at times even dangerous.[70] Based on the available scientific information on AION (discussed above), I would like to discuss the logical treatment options available for the two types of AION.

In the management of AION, the first, most important step in all patients aged 55 and over is to rule out GCA because that is an ocular emergency; patients with GCA are in danger of bilateral total blindness - which is almost always preventable. Kearns[71] rightly stressed that GCA "ranks as the prime medical emergency in ophthalmology, there being no other disease in which the prevention of blindness depends so much on prompt recognition and early treatment." Since GCA is a well-known masquerader, its early diagnosis is the key to correct management of patients and prevention of its dreaded complications.

1. Management of A-AION and GCA

I have discussed my regimen of treatment in these cases in detail elsewhere. [20, 57, 58] If there is a reasonable index of suspicion of GCA, it is essential to start high doses of systemic corticosteroid, immediately, as an emergency measure. Do not wait for the temporal artery biopsy because by the time the biopsy is done and its result available, the patient could have lost further vision irreversibly, in one or both eyes. Temporal artery biopsy should be done as soon as possible but not necessarily that very day; starting the treatment does not interfere with the biopsy results. If the biopsy result and other evidence indicate that the patient does not have GCA, the drug can be stopped.

The only proven and effective treatment for GCA is systemic corticosteroids. I usually start with 80 - 120 mg of oral prednisone daily. There are, however, instances where I give 3-4 intravenous megadoses (equivalent to one gram of prednisone) as an intravenous drip, every 6-8 hours, and then switch to oral administration. My indications for the intravenous megadose steroids include: (a) development of amaurosis fugax in a patient with GCA, (b) complete loss of vision in one eye, and (c) early signs of second eye involvement, such as amaurosis fugax, visual field defect, optic disc oedema and sluggish retinal circulation. I always explain to the patient that the primary objective of this aggressive treatment is to prevent any further visual loss and that, despite some claims of visual recovery made in the literature, [57, 72] I have only very rarely seen any significant visual recovery in my large series, once an eye has lost vision. [20, 73] It is also important to stress to the patient that the treatment is essentially suppressive and not curative and may be required for the rest of his/her life.

The only parameter which helps in determining when and how fast to taper steroids is the level of ESR and CRP - no other parameter is reliable. Therefore, I perform both ESR and CRP at every visit and guide my therapy entirely by their levels. Initially, levels of ESR [Figure - 21] and CRP keep going down - CRP much faster than ESR. Until their levels have stabilized, which in my experience takes about 10-14 days at the high dose, tapering down of steroids is not indicated. If the steroids are prematurely tapered, the disease can immediately flare up again, and is reflected by a rise in ESR and CRP levels. The lowest level of ESR and CRP achieved provides a guideline for future management. The guiding principal in tapering down the steroids and finding the maintenance dose is to keep the lowest levels of ESR and CRP with the lowest possible dose of prednisone. To determine the maintenance dose is an extremely long and laborious process, because these patients show marked inter-individual variation in the maintenance dose required and the time it takes to reach that goal. No generalization is possible and there is no formula or any other way to predict the maintenance dose required by a particular patient - it can be determined only by trial and error. I have seen patients in whom steroids can be tapered fairly rapidly, to a very low maintenance dosage (as little as I mg prednisone daily) but at the same time I have patients who took many months or even years before the optimum lowest maintenance dosage was achieved, and that may be as high as 40 mg prednisone daily - any attempt to go lower than that dosage may cause rise of both ESR and CRP. These patients usually require steroid therapy for almost rest of their life; on a follow-up of these patients for up to 20 years, I have found the concept that GCA burns itself out after 9-12 months completely false. Overall, management of GCA is very taxing and laborious both for the patient and the physician, and it requires the trust and good cooperation of all, including the patient's local physician, because of the systemic side-effects of the prolonged steroid therapy. Alternate day steroid therapy, incidentally, has no role in the management of GCA at any stage.

2. Management of NA-AION

Unlike A-AION and GCA, there is no established treatment for NA-AION. I have found that "a disease which has no treatment has many treatments"; it becomes a graveyard of promising and then discarded treatments, some of which are even harmful.[70] A number of treatments have been tried, including the following, without much success:

(a) Optic nerve sheath decompression

Sergott et al.[74] in 1989 claimed: "Optic nerve sheath decompression improves visual loss due to progressive NAION (NA-AION), a disorder without any previously effective therapy". Based on my various studies on different basic aspects of the subject (some of these discussed above), I questioned their claims of improvement of visual function with that procedure, because there was no scientific rationale for doing optic nerve sheath decompression in NA-AION; I further added that the procedure can be harmful.[75] After the report by Sergott et al.[74] and a few other anecdotal reports, [76, 77] the procedure gained world-wide favor because of wide publicity in the ophthalmic and lay media claiming this as the treatment of choice in these cases. Hence it was practiced extensively not only in "progressive" but also in all types of NA-AION. Subsequently a multicenter clinical trial conducted by the National Institutes of Health[78] established that this procedure is "not effective" and "not an appropriate treatment for NA-AION" and "may be harmful" because 23.9% of the eyes with the optic nerve sheath decompression suffered further visual loss as compared to only 12.4% when left alone. This study also showed that 42.7% of cases showed improvement in visual acuity spontaneously, without any procedure. A recent report,[79] on visual acuity data after 24 month follow-up of 258 patients with NA-AION enrolled in the National Institutes of Health clinical trial,[78] confirmed that visual acuity was no better in patients who had optic nerve sheath decompression than those who were followed without surgery.

(b) Systemic corticosteroid therapy

A number of reports suggest that systemic corticosteroids given during the very early stages of the disease may help to improve the visual function in some patients. [40, 80] In my experience this therapy does not help the majority; however, I have found definite evidence of significant visual improvement with steroids in a small group of patients, particularly those with incipient NA-AION, treated early.

(c) Aspirin

It has been claimed that aspirin prevents the development of NA-AION in the fellow eye.[81] I have been conducting a study for many years by giving aspirin (usually 325 mg daily) to a random group of these patients after their initial episode. Our data analysis suggested no long-term benefit of aspirin in reducing the risk of NA-AION in the fellow eye.[82] This is not surprising. As discussed above, NA-AION is neither a thrombotic nor an embolic disorder in the vast majority and most common precipitating factor is the nocturnal arterial hypotension which is not influenced by aspirin. However, in patients where I suspect NA-AION to be embolic in origin (see above), and there is evidence of any embolic source in the heart and/or carotid arteries, I do recommend the use of aspirin to minimize the risk of further embolism.

(d) Other advocated treatments

Johnson et al, [83, 84] have recently claimed beneficial effects from the use of levodopa in NA-AION. Based on my studies on the various aspects of AION, its pathogenesis and ONH circulation, I[85] find no scientific rationale for this treatment in NA-AION and find no valid reason why this drug should help in improvement[84] or recovery of vision,[83] claimed by the authors.

Very recently it has also been proposed by some that the use of Brimonidine eye drops may have neuro-protective effect in NA-AION. In this connection, one needs to know some fundamental facts on the subject, and these include the following:

First, based on my studies, I find that any medication applied topically to the eye can have no direct entry to the ONH or retina (in spite of claims made to the contrary) except by minute absorption into the systemic circulation, as has been shown with beta-blocker eye drops.[60]

Second, the only remote theoretical possibility that Brimonidine could have any beneficial effect on NA-AION would be if it lowers the IOP enough to improve the perfusion pressure significantly (see above) in the surviving axons in the ONH. However, my studies showed that attempts to lower the IOP with systemic diamox (acetazolamide) and other ocular hypotensive drops in NA-AION did not make any appreciable difference when the IOP was normal; ocular hypotensive drugs did not lower the IOP far enough to improve ONH perfusion.

Third, in most NA-AION eyes the chance of axons surviving is remote, and once the axons are dead, nothing is going to restore their integrity and reestablish visual function.

Fourth, perhaps most importantly, it seems many proponents and promoters of the beneficial effects of "neuro-protective" drugs in NA-AION and glaucomatous optic neuropathy attribute their effectiveness to their protective effect on the retinal ganglion cells. However, the basic fact is that in both NA-AION and glaucomatous optic neuropathy the primary process is destruction of axons, and the damage occurs in the ONH and NOT in the retinal ganglion cells; the retinal ganglion cell damage is simply secondary to death of the axons. To me, claimed attempts to protect the ganglion cells is like pouring nutrition on a plant when it has already been cut off from its roots.

In view of all these facts, I find no scientific rationale at all for the use of Brimonidine eye drops (as a "neuro-protective" agent) in NA-AION to preserve or improve vision.

It is unfortunate that advocating such treatments gives false hope to desperate patients as happened with optic nerve sheath decompression.

(e) Reduction of risk factors

Patients with NA-AION are almost invariably told by their ophthalmologists and neurologists that there is nothing they can do for them. This is not true. I believe that reduction of risk factors for NA-AION is perhaps the most important aspect in the management of this disease. As discussed above, NA-AION is a multifactorial disease and many risk factors contribute to its development. I advise patients to reduce as many risk factors as possible, to avoid the risk of developing any further episode of NA-AION. As discussed above, our studies have demonstrated that nocturnal arterial hypotension is a significant risk factor and NA-AION may be emerging as an iatrogenic disease because of physicians' aggressive use of the very potent arterial hypotensive agents now available for treatment of arterial hypertension or other cardiovascular conditions. 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. I therefore strongly recommend that when a patient is at risk of developing NA-AION or has a history of NA-AION in one eye, the treating physician should be made aware of the potential risks of intensive arterial hypotensive therapy, particularly in the evening. Some of the patients may simply have "white coat hypertension" and may be put at risk unnecessarily.[28]

  Posterior ischaemic optic neuropathy (PION) Top

PION is due to acute ischaemia of the posterior part of the optic nerve, involving a localized segment.[85] Since this part of the optic nerve is supplied by multiple branches arising from many orbital arteries and the ophthalmic artery [Figure - 1], PION, in sharp contrast to NA-AION, does not represent an ischaemic disorder of any one known artery and does not have any specific location in the posterior part of the optic nerve. Any localized segment or part of the posterior optic nerve may be involved.

Clinically, during the acute phase, it presents with acute, painless visual loss in one eye, and optic nerve related visual field defects. The optic nerve fibers rearrange themselves as they travel posteriorly in the optic nerve; for example, the macular fibers lie in the temporal part of the ONH but lie in the central part of the optic nerve posteriorly.[86] This implies that segmental ischaemia in the ONH is likely to produce a visual field defect of a different type from that produced by segmental ischaemia in the posterior part of the optic nerve. Since the site of ischaemia is farther back in the optic nerve, the optic disc and rest of fundus are normal during the acute phase, both on ophthalmoscopy and on fluorescein fundus angiography, as is the case in retrobulbar optic neuritis. However, later on ischaemic degeneration of the optic nerve fibers would produce descending optic atrophy - the location and severity of which would depend upon the fibers involved. Therefore, within 2-3 months the optic disc develops pallor.

PION has been reported with GCA and systemic lupus erythematosus. [58, 86] It can also develop with other conditions, e.g., atherosclerosis, arteriosclerosis, collagen vascular disease, malignant arterial hypertension, diabetes mellitus, thromboembolic disorders, internal carotid artery disease, haematologic disorders, sphenoidal sinusitis, radiation, orbital compression, etc.

Since the diagnosis of PION is usually hard to make with certainty, it is difficult to ascertain its true incidence. When I first described this as a disease entity, I stressed that a diagnosis of PION is a diagnosis of exclusion.[86] That is, 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, migraine, hysteria, even malingering, and a host of other lesions. It can be said, however, that a combination of the following findings is highly suggestive of this condition: sudden onset of uniocular visual disturbance, with or without deterioration of central visual acuity; optic nerve-related visual field defects in the involved eye; normal optic disc and fundus on ophthalmoscopy and fluorescein fundus angiography; and absence of other fundus abnormality at onset, but the patient develops optic atrophy 2-3 months later.

Management of PION depends upon the cause. In persons aged 55 years or older, always rule out GCA first, as in NA-AION.[58] I have found high doses of systemic steroids helpful in a number of cases; however, some of them had collagen vascular diseases.[87]

  References Top

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Hayreh SS. The central artery of the retina - its role in the blood supply of the optic nerve. Br J Ophthalmol 1963;47:651-63.  Back to cited text no. 3
Hayreh SS. Blood supply and vascular disorders of the optic nerve. An Inst Barraquer 1963;4:7-109.  Back to cited text no. 4
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Hayreh SS. Structure and blood supply of the optic nerve. In: Heilmann K, Richardson KT (eds):, Glaucoma. Conceptions of a Disease. Pathogenesis, Diagnosis and Therapy. Stuttgart, Thieme, 1978, pp.78-96.  Back to cited text no. 7
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Hayreh SS. Blood supply of the optic nerve head - A 'reality check'. In Pillunat LE, Anderson DR, Greve EL, Harris A. eds. Update on Ocular blood flow in glaucoma. The Hague: Kugler, 1999:1-29.  Back to cited text no. 10
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  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7], [Figure - 8], [Figure - 9], [Figure - 10], [Figure - 11], [Figure - 12], [Figure - 13], [Figure - 14], [Figure - 15], [Figure - 16], [Figure - 17], [Figure - 18], [Figure - 19], [Figure - 20], [Figure - 21], [Figure - 22], [Figure - 23]

  [Table - 1]

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