Introduction
Ischemic optic neuropathy refers to a group of conditions in which damage to the optic nerve is presumed to be secondary to ischemia of the optic nerve head (anterior ischemic optic neuropathy; AION) or retrobulbar optic nerve (posterior ischemic optic neuropathy; PION). It is clinically characterized by sudden painless loss of vision. By definition, AION presents with optic disc edema and PION without optic disc edema. AION is further subclassified as nonarteritic AION (NAION) and arteritic AION (AAION) based on the presumed underlying etiology of the latter being an inflammatory process most commonly caused by giant cell arteritis (GCA). NAION is considered to encompass diabetic papillopathy.
Nonarteritic ischemic optic neuropathy
NAION typically occurs in patients older than 50 years, with most being between 60 and 70 years. The incidence in Caucasian populations is about 2.3–10.3 patients per 100 000 over the age of 50 years. 2,3 NAION is uncommon in patients under 50 but does occur. 4 It occurs predominantly in Caucasians. The clinical features of NAION are summarized in Box 41.1 .
| Frequency | |
|---|---|
| Symptoms | |
| Painless loss of vision | Common |
| Pain on eye movement | 10% of patients |
| Simultaneous bilateral involvement | Uncommon |
| Positive visual phenomenon | Very rare |
| Signs | |
| Loss of visual acuity | Two-thirds have better than 20/200 visual acuity |
| Dyschromatopsia | Usually in proportion to visual acuity loss |
| Relative afferent pupillary defect | If unilateral involvement |
| Visual field defect | Inferior altitudinal most common |
| Hyperemic disc swelling | Sectorial or diffuse |
| Retinal exudates | Only reported in 7% |
Clinical course
Progressive NAION occurs in approximately 22–27% of patients and is defined as either stepwise, episodic decrements or steady decline of vision over weeks prior to eventual stabilization. Further decline in visual acuity after 1–2 months from initial onset is rare. The Ischemic Optic Neuropathy Decompression Trial (IONDT) reported up to 40% of patients showing an improvement of several lines of visual acuity. However, this apparent visual recovery may be an adaptation to the visual field defect or eccentric fixation. Younger patients with NAION (less than 50 years of age) have been reported to have better visual acuity outcomes.
Second eye involvement occurs in approximately 15–24% of patients within 5 years of the first eye being affected. There is thought to be an increased incidence in second eye involvement in patients with poor visual acuity in the first eye and diabetes. However, the IONDT did not report age, sex, smoking history, or aspirin use to alter the incidence of second eye involvement. It has been suggested that younger patients may have a higher risk of fellow eye involvement than older patients, with rates of up to 35% fellow eye involvement within a median of 7 months being reported. Other investigators have suggested that higher rates of both anemia and type 1 diabetes mellitus are significantly associated with decreased time to second eye involvement in younger patients. The recurrence rate of NAION in the same eye is approximately 3–8% with a median follow-up of 3 years from first onset.
A classic finding on the unaffected side is a small-diameter optic disc with small or absent optic cup: this is known as “disc at risk.” The optic disc swelling subsides between 6 and 12 weeks, with a median time of 8 weeks, after acute disc swelling, leaving a pale atrophic-appearing optic nerve head. The time to resolution of the disc edema has been shown to be longer in diabetics, but also longer in those who have milder visual loss. It seems that corticosteroid treatment may hasten the time to resolution of the disc swelling. Despite the retinal nerve fiber layer (RNFL) loss that occurs after NAION, excavation of the optic cup is rarely detected, as opposed to eyes with AAION, in which it is the most common end-stage appearance.
Investigations
The diagnosis of NAION is based on clinical history and examination and there are no specific tests to confirm the diagnosis. The differential diagnosis includes an extensive list of causes of unilateral optic disc swelling (rarely, bilateral). The three most important differential diagnoses to consider are AAION secondary to GCA, and optic neuritis ( Box 41.2 ). Figure 41.1 demonstrates the different appearance between the optic nerve head appearance in NAION and AAION.
| NAION | AAION | Optic neuritis | |
|---|---|---|---|
| Age | Most commonly over 50 years | Most commonly over 60 years | 20–45 years |
| Disc appearance |
|
| ± Swelling |
| Other symptoms | None |
| Pain on eye movement |
| Laterality | Simultaneous rare, but sequential common | Simultaneous or within days of first eye involvement is not uncommon | Simultaneous uncommon |
| Associated features | Small disc with small cup:disc ratio in contralateral eye | Giant cell arteritis | Multiple sclerosis |
| Visual acuity | Majority better than 20/64 at presentation | Majority worse than 20/200 at presentation | Variable |
Neuroimaging
There are a few magnetic resonance imaging (MRI) studies evaluating small series of patients with NAION. Unlike patients with optic neuritis who had abnormal MRI in 97% of cases, patients with NAION only had an abnormal scan in 17%. There are more white-matter abnormalities in patients with NAION, suggesting that it is more likely in the setting of diffuse cerebrovascular small-vessel disease. Eyes with NAION have more white-matter hyperintensities, lower optic nerve volume, and magnetization transfer ratio of the chiasm than controls, likely reflecting axonal loss and demyelination.
Electrophysiology
Both arteritic and nonarteritic ION have been shown to result in amplitude reduction in pattern visual evoked potential (VEP) and flash VEP. This contrasts with demyelination in which there is delayed latency as well as reduced amplitude in the involved eye, and the uninvolved eye is commonly abnormal. The N95 component of the pattern electroretinogram (PERG) may be reduced in ischemic optic neuropathy, while the P50 component of the PERG is more frequently affected in NAION than demyelination.
Quantitative ocular imaging modalities
Quantitative techniques that measure the peripapillary RNFL thickness and/or optic disc morphology, such as optical coherence tomography (OCT, StratusOCT), scanning laser polarimetry (SLP), and confocal scanning laser ophthalmoscopy (Heidelberg Engineering retinal tomography; HRT) have been used to evaluate the optic disc and RNFL in NAION. Presently, these techniques do not assist in diagnosis or management but they may offer a quantitative measurement of ganglion cell loss in the pale optic disc and may be useful in the evaluation of patients with NAION after swelling of the optic disc has resolved.
Several studies have evaluated the correlation between RNFL thickness and visual field sensitivities using these modalities. It has been demonstrated that both SLP and OCT show strong correlations between RNFL thickness, and visual sensitivities. OCT has also demonstrated that some patients develop subretinal fluid following NAION. The resolution of the subretinal fluid may explain some of the visual recovery that has been documented to occur. The HRT has also been used to evaluate the morphology of the optic nerve head cup and disc and has shown that eyes that have had an episode of AAION show greater excavation than eyes with NAION. A possible explanation is that in AAION the ischemic insult is more severe compared to NAION and consequently leads to more tissue damage. Alternatively, it may be that excavation in eyes with NAION is more difficult to detect because of the previously small or absent physiologic cup and the development of optic disc pallor ( Figures 41.2–41.5 ).
Pathology
Histology
The histopathology from cases of NAION does not provide conclusive evidence of the underlying pathophysiology with no definite histopathologic documentation of the vasculopathy that produces NAION. The largest series of eyes with histological evidence of ischemic optic neuropathy is by Knox et al who collected 193 eyes over 47 years, although those cases of typical NAION were not analyzed separately. In these eyes, infarction was primarily located in the retrolaminar region of the optic nerve head with occasional extension to the laminar and prelaminar layers.
Of the few cases of clinically diagnosed NAION that have been studied histopathologically the majority have been atypical cases, including internal carotid occlusion, multiple embolic lesions, and severe blood loss. The short posterior ciliary arteries (SPCAs) were described in only one case, which was an atypical NAION associated with internal carotid artery occlusion and which demonstrated emboli within the vessels, central retinal artery (CRA), and pial vessels. 31–33
Histopathological data from NAION patients and experimentally induced anterior optic nerve ischemia demonstrate apoptosis of the retinal ganglion cells and oligodendrocytes, associated with axonal demyelination and wallerian degeneration.
In contrast, histopathological studies of AAION have demonstrated greatest signs of infarction of the optic nerve at or just posterior to the lamina cribrosa. A comparison of studies in which optic nerve tissue was obtained at various time points from the onset of loss of vision reveals progressive stages of retrolaminar liquefaction at 4 and 8 weeks and fibrosis at 4 months. These optic nerve findings are associated with loss of the retinal ganglion cell layer with preservation of the other retinal layers. It has been suggested that this absence of transsynaptic degeneration in the retina may be due to the fact that the longest histological specimen was 4 months following the AAION episode and such degeneration is estimated to take 2–3 years to develop. Anterograde degeneration with loss of axons and myelin in the chiasm was demonstrated to be present by 4 months. In AAION, the SPCAs have been shown to be infiltrated by chronic inflammatory cells producing segmental occlusion of multiple vessels.
Pathophysiology
Fluoroscein angiography and indocyanine green
Fluoroscein angiography provides evidence suggesting that pathophysiology of NAION involves a primary circulatory abnormality of the optic nerve head. Delayed onset of filling not seen in controls or cases of disc swelling due to causes other than NAION was demonstrated in the majority of patients (76%) with NAION during the acute phase. This suggests that the delay in filling is not related to mechanical obstruction potentially caused by disc swelling. Furthermore, these studies have shown that there is no consistent delayed filling in the choroidal vasculature in NAION (unlike AAION), suggesting that the vasculopathy lies within the distribution of the paraoptic branches of the SPCA after their branching from the choroidal branches rather than in the short ciliary arteries themselves.
The concept of the “watershed zone” in the pathophysiology of NAION is that the prominent dilation of the overlying optic disc vasculature that comes from the retinal circulation is analogous to the “luxury perfusion” that is seen at the junction of perfused and nonperfused areas of cerebral infarctions. However, the overlying vasculature of the optic disc that comes from the retinal circulation shows variable filling patterns ranging from impaired filling to prominent dilation. Furthermore, delayed filling of the watershed zone has been identified to occur equally frequently in normal eyes as in NAION eyes with no correlation between optic disc and choroidal filling. Indocyanine green angiography angiographic studies have also shown optic disc blood flow impairment in a pattern, suggesting SPCA occlusion but no abnormality in the choroidal circulation in NAION (unlike AAION).
Flow studies
With current technology, evidence for impaired vascular flow in NAION remains unsubstantiated. Several flow study instruments and techniques have been employed but all are limited in their ability to measure the blood volume in the branches’ posterior ciliary arteries that supply the optic nerve. Both stationary (laser Doppler flowmetry) and scanning (Heidelberg retinal flowmeter) laser imaging methods have been used to measure surface blood flow derived from the retinal arterial circulation, but have not been able to measure the deeper layers from the SPCA which supply the optic disc. Scanning laser Doppler flowmetry technique measures only the blood flow on the surface of the optic nerve in the nerve fiber layer which is supplied by the CRA. 41 Carotid duplex studies are limited because they measure velocity rather than volume, and are not able to measure flow in the paraoptic branches which supply the optic disc.
Single-point flowmetry instruments or similar systems may allow sampling of volume in the laminar layer of the optic nerve. Using such a system in rhesus monkey eyes after manipulation of ciliary and retinal circulations, it was found that flow measurements were decreased with occlusion of the CRA, but not the posterior cerebral artery. Other studies have considered flow velocity as a surrogate for volume and demonstrated changes in flow velocity in SPCA and the ophthalmic artery in NAION.
Experimental ischemia of the optic nerve
Over the past years various models of optic nerve injury have been developed to investigate axonal injury to optic nerves. These include complete optic nerve transaction, partial transaction, optic nerve crush, and partial crush. Ischemic optic neuropathy has been modeled by infusion of endothelin-1 (ET-1) around the optic nerve head, although this produces more chronic ischemia. 44 An ischemic optic nerve model to produce rodent AION (rAION) injury may be produced by intravenous injection of rose Bengal dye followed by argon green laser application to the retinal arteries overlying the optic nerve. The laser causes the rose Bengal to release superoxide free radicals that can then cause vascular occlusion. 45
Ischemic optic nerve injury can also be modelled in experimental animals by occluding the posterior ciliary arteries 46 or infusing vasoconstrictor ET-1 into the perineural space. 47 Since ET-1 has been reported to cause reduced blood flow in the optic nerve head and apoptotic death of retinal ganglion cells it is considered a valid model for optic nerve ischemia. Recent studies have indicated that ET-1 causes reactive astrocytosis and interferes with the anterograde axonal transport. These various animal models have been widely used in studies which aimed to find out which neuroprotective agents increase retinal ganglion cell survival.
Etiology
The etiology of NAION is believed to be multifactorial, although the mechanism of neural damage is generally considered to be ischemic.
Crowded disc
The presence of a “disc at risk” is the most conclusive association with NAION. Small optic disc with a small cup-to-disc (C/D) ratio or absence of the cup is a well-recognized risk factor for NAION, with approximately 97% of eyes demonstrating small optic discs with small or absent optic cups. It is thought that this anatomical variant causes structural crowding of the axons at the level of the cribriform plate and places the optic nerve at risk for a compartment syndrome-like phenomenon.
Diseases associated with atherosclerosis
Significant controversy exists between the association of NAION and athereosclerotic risk factors and the relationship remains uncertain. Some studies have demonstrated an association between NAION and other cardiovascular diseases such as stroke and ischemic heart disease using general population studies as controls, although this finding has been inconsistent.
Hypertension
Systemic hypertension has been reported in 34–47% of patients, although in most studies this was compared to population-matched data. Hence, systemic hypertension as a risk factor for NAION remains unsubstantiated.
Diabetes
Diabetes has been shown to be associated with NAION at all ages, with a prevalence of 24% in the IONDT study.
Cerebrovascular or cardiovascular events
Studies have reported mixed findings on the prevalence of ischemic heart disease or cerebrovascular accident amongst patients with NAION.
Hypercholesterolemia
Various studies have attempted to investigate whether elevated cholesterol and lipids are associated with NAION but have had conflicting reports. NAION occurring at a younger age has also been reported in patients with hyperlipidemia.
Hypercoagulable states
Many prothrombotic states have been reported in patients with NAION, including hyperhomocysteinemia, and prothrombotic risk factors, such as lupus anticoagulant, anticardiolipin antibodies, prothrombotic polymorphisms, and deficiencies of protein C, S, and antithrombin III, heterozygous factor V Leiden mutation, and MTHFR mutations in case series but not larger studies. The presence of elevated homocysteine levels in NAION has been shown to be present in some studies, but not others.
Sleep apnea
Several studies have reported links between NAION and obstructive sleep apnea syndrome (SAS). The risk ratio for a NAION patient to have sleep apnea has been determined to be between 2.6 and 4.9 compared to the general population. Furthermore, sleep apnea was 1.5–2-fold more frequent than the rate of the other identified risk factors typically associated with NAION (hypertension, diabetes). However, the mechanism of this association is unclear. It is postulated that vascular changes such as acute surges in blood pressure, increased intracranial pressure, or nocturnal hypoxemia from repetitive apneic spells may contribute to local ischemia or hypoxia at the optic disc level. It has been suggested that continuous positive airway pressure may prevent NAION but it has been documented to occur in patients receiving such therapy.
Smoking
Smoking as a risk factor for NAION also remains unsubstantiated.
Medications
Phosphodiesterase inhibitor 5 (PDE5)
Several cases of NAION have been reported since 2005 in users of these agents. Following a series of case reports, the World Health Organization and Food and Drug Administration have labeled the association between use of PDE5 inhibitors and risk of NAION as “possibly” causal. Evidence is primarily in the form of case reports, including a rechallenge case report and a large managed-care database study. It has been hypothesized that PDE5 inhibitors may accentuate the physiological nocturnal hypotension enough to decrease the perfusion pressure in the posterior ciliary arteries, resulting in ischemia to an optic nerve head and setting off the cascade of a compartment syndrome, which is thought to occur in a small, crowded optic nerve. Alternatively, activation of the nitric oxide–cyclic guanosine monophosphate (GMP) pathway may reduce optic nerve head perfusion or disrupt autoregulation.
Interferon-α
Interferon-α has been associated with the development of bilateral, sequential NAION which has been shown not only to have a temporal association, but also to recur following rechallenge. There is variable improvement on cessation of the medication. Although the mechanism is unknown, the deposition of immune complexes within the optic disc circulation has been suggested.
Amiodarone
Amiodarone produces bilateral insidious visual loss with optic disc swelling that may persist for months despite withdrawal of the drug. The exact cause of the optic neuropathy is not known. Lipid inclusions characteristic of amiodarone have been found in one optic nerve studied histopathologically. Decreased vision is insidious in onset and is slowly progressive as long as the drug is taken. Optic disc swelling is bilateral and the decreased visual acuity is not usually worse than 20/200. The ingestion of the drug in the presence of bilateral optic disc edema is grounds for suspecting this diagnosis ( Box 41.3 ).
