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 Table of Contents  
REVIEW ARTICLE
Year : 2014  |  Volume : 4  |  Issue : 1  |  Page : 9-16

Treatment of anterior ischemic optic neuropathy: Clues from the bench


Byers Eye Institute at Stanford, Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA

Date of Web Publication4-Mar-2014

Correspondence Address:
Yaping Joyce Liao
Department of Ophthalmology, Stanford University Medical Center, 2452 Watson Court, Palo Alto, CA 94303-5353
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.1016/j.tjo.2013.09.003

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  Abstract 


Anterior ischemic optic neuropathy (AION) is due to optic nerve head ischemia, and there is currently no effective treatment. Age is a significant risk factor for both arteritic and nonarteritic AION (NAION), although we do not fully understand the changes that occur in aging that lead to selective vulnerability of the optic nerve head. Arteritic AION, which is most often seen in the setting of giant cell arteritis, is caused by vasculitis and thromboembolism of the ophthalmic circulation leading to impaired perfusion of the short posterior ciliary artery and infarction of the optic nerve head. More commonly, AION is nonarteritic, and vision loss is typically altitudinal and noted most commonly upon awakening. NAION has been associated with a variety of risk factors, including disc-at-risk, vascular risk factors including diabetes, vasospasm and impaired autoregulation, nocturnal hypotension, and sleep apnea. This review summarizes the clinical presentation of non-arteritic AION and arteritic AION associated with giant cell arteritis and the current and future treatment approaches for human NAION based on lessons from photochemical thrombosis models of NAION.

Keywords: animal model, anterior ischemic optic neuropathy, giant cell arteritis, optic neuropathy, retinal ganglion cell


How to cite this article:
Liao YJ, Hwang JJ. Treatment of anterior ischemic optic neuropathy: Clues from the bench. Taiwan J Ophthalmol 2014;4:9-16

How to cite this URL:
Liao YJ, Hwang JJ. Treatment of anterior ischemic optic neuropathy: Clues from the bench. Taiwan J Ophthalmol [serial online] 2014 [cited 2022 Jan 26];4:9-16. Available from: https://www.e-tjo.org/text.asp?2014/4/1/9/203928




  1. Introduction Top


Anterior ischemic optic neuropathy (AION) is the most common acute optic neuropathy in adults older than 50 years old, and it typically leads to irreversible vision loss.[1],[2],[3],[4] AION is subdivided into arteritic and non-arteritic types. About 10% of patients with AION have the arteritic type, whereas the non-arteritic type (NAOIN) accounts for the majority of cases. AION is due to ischemia of the optic nerve head, which is a watershed zone and therefore vulnerable to changes related to vascular risk factors and compartment syndrome. The incipient event involves acute ischemia of the prelaminar, and, in particular, the laminar and retrolaminar optic nerves due to reduced perfusion in the circle of ZinneHaller, with the short posterior ciliary arteries thought to contribute most significantly.[4] The pathogenesis of arteritic AION is thought to arise from vasculitis leading to stenosis and thromboembolism involving the ophthalmic, central retinal artery, and especially the short posterior ciliary artery. Although the pathogenesis of NAION is not well understood, vascular, anatomic, and other risk factors are involved.[1],[3],[4] Some medications such as amiodarone, phosphodiesterase type 5 inhibitors such as sildenafil, and interferon-a have been associated with NAION. Age is a leading risk factor in both arteritic and nonarteritic AION as well as in glaucoma, suggesting that the process of normal aging may play a role in increasing the susceptibility of central axons.[5]

We are particularly interested in an AION animal model because: (1) AION is easily and well modeled in rodents using photochemical thrombosis to induce localized optic nerve head ischemia; (2) acute injury of the central nervous system is potentially better timed and more amenable to therapeutic intervention than a slowly progressive condition such as glaucoma; (3) there is currently no effective treatment for AION; and (4) ischemia plays a role in other optic neuropathies such as glaucoma and papilledema, so findings in AION are also potentially significant to other causes of retinal ganglion cell (RGC) loss.

This review summarizes the state of our understanding in the clinical presentation and treatment of AION with particular emphasis on lesson learned from photochemical thrombosis animal models and their implications on designing future treatment modalities.


  2. Naion Top


2.1. Clinical presentation

NAION is the most common type of AION.[4] Historically, NAION was reported in Europe during the 19th century but was not recognized until the 1960s and 1970s.[1],[2],[6],[7] Patients typically present upon awakening with altitudinal visual field defects, relative afferent pupillary defects from unilateral involvement, optic disc edema, and narrowing of the peripapillary retinal arterioles [Figure 1]. Optical coherence tomography (OCT), which uses light interferometry to visualize in vivo retinal layers and anatomic changes, has revealed acute retinal nerve fiber layer swelling and thinning over a period of months.[8],[9],[10],[11] The macular ganglion cell complex (GCC), which measures the total thickness of the ganglion cell layer and the inner plexiform layer, estimates irreversible RGC loss over time.
Figure 1: An 89-year-old Caucasian woman presented upon awakening with left eye visual field loss due to non-arteritic anterior ischemic optic neuropathy. (A) Fundus photo of the left eye shows optic disc swelling, splinter hemorrhage, and narrowing of the peripapillary arterioles. (B) Fundus photo of the left eye 1 year after non-arteritic anterior ischemic optic neuropathy exhibits optic nerve pallor and narrowing and irregularity of the peripapillary arterioles. (C) Humphrey visual field study of the left eye reveals inferior greater than superior visual field loss. (D) Spectral-domain optical coherence tomography shows significant retinal nerve fiber layer thinning of the left eye (shown on the right). OD = right eye; OS = left eye.

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2.2. Incidence and risk factors

The incidence of NAION in the USA is 2.3–10.2/100,000 or 1500–6000 new cases/year. The most significant risk factors for NAION include: crowded disc (so-called disc-at-risk), diabetes, atherosclerosis, age, and sleep apnea. Arguably, the most modifiable risk factor after the diagnosis of NAION is sleep apnea. In one study of 635 patients (871 eyes or 925 episodes), 73% note vision loss soon after awakening.[12] This may be related to a combination of nocturnal hypoxemia and hypotension. Systemic hypotension from shock or certain type of prolonged surgery is significantly associated with AION.[13] Other reported risk factors include cataract or other ophthalmic surgeries,[14],[15] and the use of phosphodiesterase type 5 inhibitors.[16],[17],[18],[19]

2.3. Pathogenesis and treatment of human NAION

The pathogenesis of human NAION is unclear. Important players include vascular factors (diabetes, nocturnal hypotension, atherosclerosis, failure of autoregulation, increased resistance from relatively elevated IOP), hypoxemia (sleep apnea), and compartment syndrome (disc-at-risk, congenital optic nerve hypoplasia). There are relatively few research studies designed to perturb these factors to determine how they contribute to AION or how their alteration may impact outcome.

There are some data suggesting that inflammation may play a role in human NAION. In one valuable case of human autopsy obtained 20 days after the onset of vision loss from NAION, there was an accumulation of Iba1+/ED1+ cells or extrinsic macrophages in ischemic areas of the optic nerve and a presence of Iba1+/ED1− cells or intrinsic microglia in the area of ischemia and the penumbra.[20] Proinflammatory cytokines are involved in thrombotic events such as myocardial infarction and stroke, and they may play a rolefollowing AION. A study of 10 patients (12 eyes) showed that NAION is associated with elevated interleukin (IL)-8 but normal levels of IL-6 and tumor necrosis factor-α (TNF-α).[21] These markers have also been shown to be elevated in patients with central retinal artery occlusion.[22] Plasma levels of IL-6 and IL-8 are significantly elevated after central retinal artery occlusion, especially within 6 hours of onset.[22],[23] Although NAION patients typically have normal erythrocyte sedimentation rate, one study of 33 NAION patients reveals that NAION patients have slightly higher erythrocyte sedimentation rate on average than normal controls (p = 0.025), sometimes necessitating a temporal artery biopsy as part of the diagnostic evaluation.[24] NAION patients also have a higher level of highly sensitive C-reactive protein.[24] These findings in a small number of patients support the idea that inflammation plays a role after ischemia, and more studies are necessary to determine if biomarkers of inflammation are important in human NAION.

With a relative lack of understanding of disease mechanisms, it is no surprise that there is no effective treatment for NAION. One area of controversy in the treatment of NAION is the use of corticosteroids in acute NAION. On the one hand, there is some evidence that inflammation plays a role in human AION (see above), and the idea of decreasing swelling and minimizing worsening of compartment syndrome seems sound. On the other hand, the efficacies of corticosteroids are not spectacular, probably at least partly because they are given too late. Also, corticosteroids have known side effects, and we cannot rule out that corticosteroids may suppress some inflammatory responses that are beneficial. The lack of clinical trial data means we may never know if corticosteroids work or not.

Although anti-VEGF therapy has been shown to inhibit inflammatory molecules and reduce edema, there is a potential concern of inducing further vascular compromise in an eye that is already at a critical or threshold level of perfusion.[25] Regarding these therapeutic options, there is no well-designed study or clinical trial that shows a significant benefit, and treatment is at the discretion of the physician.

There has been a small number of clinical trials involving treatment of human NAION, including the ischemic optic neuropathy decompression trial, which shows no benefit in surgical treatment of the compartment syndrome.[26],[27] Atkins et al[25] provides an excellent review on the key approaches in the treatment of human NAION and therapeutic interventions addressing vasoactive mechanisms, potential thrombosis, decreasing optic disc edema, decompression, neuroprotection, and others.


  3. Arteritic AION and giant cell arteritis Top


Arteritic AION is an ophthalmic emergency because it is associated with a significant risk of bilateral involvement and rapid progression of vision loss.[28] The risk of bilaterality in patients with arteritic AION is 1.9 times that of NAION patients.[29] In arteritic AION, there is typically a significant decrease in visual acuity, altitudinal or generalized visual field loss, pallid optic disc edema, narrowing of the peripapillary arterioles, and sometimes choroidal or retinal ischemia [Figure 2]. Arteritic AION is most commonly associated with giant cell arteritis, also known as temporal arteritis. Giant cell arteritis is a systemic vasculitis syndrome leading to stenosis and thromboembolism affecting the medium and large arteries, especially the temporal, cervical, vertebral, and coronary arteries, as well as the aorta and its branches. In arteritic AION, doppler studies have shown significantly reduced central retinal and short posterior ciliary arterial mean flow velocities.[30] Depending on the location of stenosis or occlusion, there can be high velocity, turbulent, or reversal of flow within the ophthalmicartery. Ophthalmic manifestations of giant cell arteritis include AION, central retinal artery occlusion, choroidal and submacular choroidal ischemia, posterior ischemic optic neuropathy, ocular ischemic syndrome, and anterior segment ischemia. Cerebral artery involvement can lead to stroke, and ischemia of the orbit, cranial nerves 3, 4, 6, or brainstem can lead to binocular diplopia.
Figure 2: A 77-year-old Caucasian man presented with amaurosis fugax followed by persistent superior vision loss in the left eye due to arteritic anterior ischemic optic neuropathy. (A) Fundus photo of the left eye within days of the onset with inferior pallid optic disc edema. There is a ribbon of whitening just superior to the disc due to nerve fiber layer ischemia. (B) Fluorescein angiography of the left eye within days of the onset shows choroidal hypoperfusion most notably in the temporal periphery. (C) Fundus photo of the left eye 8 years prior to anterior ischemic optic neuropathy, which is shown for comparison. (D) Humphrey visual field of the left eye showing superior visual field loss.

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3.1. Incidence, geography, risk factors, and treatment of giant cell arteritis

The most important risk factors for giant cell arteritis include age,[31] female sex, HLA-DR4 major histocompatibility haplotype, and Caucasian ethnic origin.[32],[33] Geographically, giant cell arteritis is most commonly found in Scandinavia and Iceland, where the incidence can be as high as 20.4 and 27/100,000 for those older than 50 years.[34] African Americans and Asians have relatively lower risk of giant cell arteritis.[34],[35],[36],[37] In one Japanese study of 690 cases by questionnaire, the prevalence of giant cell arteritis was 1.47/100,000 people older than 50 years.[34],[35],[38] In a study of 38 patients with biopsy-proven giant cell arteritis, 2.6% (one) is Asian compared with 82% (31) Caucasian.[37] Once confirmed on biopsy, the mainstay of treatment for giant cell arteritis is long-term corticosteroid therapy with consideration of steroid-sparing agents, typically for months to years.[32],[39]


  4. Animal models of AION Top


4.1. Photochemical thrombosis model of AION

The best animal model for AION is the photochemical thrombosis model.[40] It is not arteritic, and it utilizes laser as a low energy, focused light source to induce optic nerve head ischemia immediately following intravenous tail vein injection of rose bengal.[41] Rose bengal is a derivative of fluorescein dye. When the laser light shines on the optic disc immediately following dye injection, platelet aggregation, and thrombosis of the arterioles that supply the optic discs occur, with relative sparing of the more superficial larger caliber central retinal vessels.[41] Since the first photochemical thrombosis model of AION in rats in 2003,[41] this model has been successfully used in rats,[41],[42],[43],[44] mice,[11],[45],[46],[47] and primates.[20],[48]

4.2. Differences between human and experimental AION

The photochemical thrombosis model is superior to the vascular occlusion model of posterior ciliary artery, optic nerve crush, optic nerve transection, retinal ischemia, N-methyl-D-aspartate-induced retinal ganglion cell excitotoxicity, and glaucoma or other optic neuropathy models because the mechanism is ischemic, the area involved is localized, and the technique is easy to perform rapidly and consistently in different species and across various laboratories. Direct comparison of murine AION and optic nerve crush reveal that AION leads to relatively less severe RGC loss compared with the optic crush model.[46]

Although this model is the best we have, the photochemical thrombosis model is still limited in many ways, because: (1) this model involves global optic disc ischemia and human NAION is often partial; (2) there are species differences in blood supply to the optic nerve head[49]; (3) in the animal model, ischemia is induced from the front of the eye in a transpupillary fashion, whereas human AION is a result of ischemia in the post-laminar or laminar region; (4) there is no evidence that human NAION is caused by thrombosis; (5) many animals used do not have a rigid lamina or the same anatomic factors that would contribute to compartment syndrome; and (6) animals used for the study are typically young adults rather than age-equivalent to 50-year-old humans.

4.3. Issues with mouse as an animal model

Other than the imperfection of animal models, there are also several issues specific to the use of mouse as an animal model. Although the explosion of available transgenic and knockout mice makes mouse an attractive animal in vision research in general, there are reports that describe retinal problems identified in seemingly normal mice.[50] In a study of over 450 mice from different genetic backgrounds including C57BL/6J, BALB/cJ, and transgenic or knockout mouse strains, the authors use fundus photography, confocal laser scanning ophthalmoscopy, and OCT to document abnormal eye findings. These include retinal drusen, vascular malformations, hyaloid vessel remnants, retinal pigment epithelium abnormalities, and cataracts. The frequency of abnormalities ranged from 1.5% in C57BL/6J mice to 100% in BALB/cJ mice in in 2–4-month-old mice. Exclusion of the BALB/cJ mice leads to average incidence of 5.7% or about one in every 20 mice. The presence of retinal drusens and cataract are more common in mice that are older than 1 year (M.A. Shariati and Y.J. Liao, unpublished observation), which is the equivalent of human age 42.5 years. In the study by Bell et al,[50] the incidence of retinal abnormalities increases from 1.5% in 2–4-month-old mice to 5.9% in 6–14-month-old in the C57BL/6J strain.

Another report identifies an inbred Rd8 mutation in the Crb1 gene in homozygous forms in C57BL/6N mice from many common commercial vendors.[51] This mutation results in retinal degeneration with many retinal drusen, and is not present in the C57BL/6J substrain, which is found to have relatively low incidence of eye abnormalities.[50] The Rd8 mutation is present in ES cells derived from C57BL/6N, so it is present in transgenic and knockout mice made using C57BL/6N embryos or C57BL/6N-derived ES cells.[51]

There are several ways to avoid experimental complications due to these issues: (1) use genetic strains that do not have known mutation; (2) perform in vivo imaging of the mouse at baseline to screen for issues prior to experimental intervention; and (3) use a relatively larger number of animals so elimination of data due to experimentally unrelated issues does not result in problems with statistical analysis. Finally, the use of mouse to study short-term changes in the retina, especially changes related to RGCs or the optic nerve may be relatively spared from these complications.


  5. Results of experimental AION studies Top


Despite the caveats of the photochemical thrombosis model of AION, this model has been highly valuable in studying the acute and chronic changes following optic nerve head ischemia. There is evidence that, following experimental AION, there is a complex set of likely simultaneous events involving changes in the RGC cell body, axons, optic nerve oligodendrocytes, local and extrinsic microglia, and the inflammatory cascade.

5.1. Within hours and a few days after AION

5.1.1. Capillary drop out

Immediately after experimental AION, there is visible whitening of the optic disc consistent with ischemia. Using India ink intracardiac perfusion, several reports show that there is loss of the fine capillaries within the disc.[41],[44],[45] Interestingly, one study uses FITCBSA perfusion and confocal imaging to show that there is minimal optic disc capillary dropout at 4 hours after ischemia and more dramatic loss at 1 day, suggesting the therapeutic window may be longer than 3 hours, which is typical of gray matter ischemia, but less than 24 hours.[52]

5.1.2. Optic disc leakage

One day after AION, fluorescein angiography in rodent AION and ICG angiography in primate AION reveal there is prominent staining of the optic disc due to leakage of the peripapillary vessels,[11],[41],[43],[45] which is similar to what has been seen in human NAION.[53] The breakdown of the nerve-blood barrier following AION has also been demonstrated on a cellular level. One day after rodent AION, there is diffuse immunoglobulin (Ig)G staining of the optic nerve head from the breakdown of the nerve-blood barrier and extravasation of serum protein.[52] This leaky blood-nerve barrier is well demonstrated using exogenous IgG or different molecular weight size dyes.[52] Although this optic disc leakage resolves within days in the rodent AION, in the primate AION, optic disc staining on Indocyanine green (ICG) angiography lasts for 2 weeks, suggesting that there may be persistent inflammation and edema, which can theoretically continue to cause further damage.[20],[48] Similar to the more prolonged inflammation and swelling seen in primate AION, a human pathologic study 20 days after AION reveals there is persistent evidence of inflammation.[20],[48] There is certainly amble evidence in serial human OCT studies after AION that the optic disc swelling takes weeks to resolve.[8],[9],[10]

5.1.3. Optic nerve head swelling

One day after experimental AION, the optic nerve head is swollen,[11],[41],[43],[44],[45],[48] and there is often subretinal fluid spillover in the peripapillary potential space (YJ Liao, unpublished data). This phenomenon has been reported in human NAION.[54] OCT 12° circular scan [also known as retinal nerve fiber layer (RNFL) scan] and measurement of the ganglion cell complex (GCC) which includes the nerve fiber layer, ganglion cell layer, and the inner plexiform layer, reveal that there is about 30% swelling of the GCC 1 day after AION compared with control eyes. There is also swelling of the outer retina at 1 day, probably from a combination of bystander effects and wrinkling of the nuclear layers due to a displacement from the swollen optic nerve.[11] This swelling may be a combination of vasogenic edema from the breakdown of nerve-blood barrier and cytotoxic edema. There is histologic evidence of axonal swelling in the optic nerve using electron microscopy.[41],[45] Axonal transport is significantly disrupted within 1 day after occlusion of the short temporal posterior ciliary artery[55] and after experimental AION (J. Ma, Y.J. Liao, unpublished data). This disruption contributes to optic nerve head swelling, but, more significantly, it also means there is a severe impairment of anterograde and retrograde transport of neurotrophic factors and other important survival cues. Functionally, at 1–2 days after AION, visual evoked potential amplitudes are already significantly diminished at 1 day .[41],[44],[47]

5.1.4. Loss of oligodendrocytes

Damage of the optic nerve oligodendrocytes and RGC axons occurs within days, prior to a significant loss of RGCs.[45],[46] These changes extend anterogradely toward the optic chiasm and the brain.[45],[46] Apoptosis of the oligodendrocytes as seen by TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) stain is observed as early as a few days after AION and progresses over days.[45],[46] Demyelination is seen simultaneous by Luxol-fast blue stain of the optic nerve and transmission electron microscopy.[45],[46]

5.1.5. Inflammatory response

In rodent AION, there is evidence of an early postischemia inflammatory response. There is microglial activation as measured by the density of Iba-1+ cells at the optic nerve head.[47],[48] In primates, AION, the Iba-1+ cells are located at the prelaminar and laminar region but also at the postlaminar optic nerve. In primate AION, this inflammatory phenomenon lasts for 2 weeks, which raises the question of their role in the vicious cycle of further axonal loss due to bystander effect.[20],[48] Other than microglial activation, there is also an upregulation of proinflammatory cytokines including plasma and optic nerve IL-6, TNF-α, and macrophage inflammatory protein-2.[56]

5.1.6. Limited early RGC loss

Within days after AION, there is relatively little RGC death, and few cells in the ganglion cell layer stain positive for TUNEL.[46] However, there is already evidence of diffuse RGC stress as evident by c-fos-LacZ expression in a transgenic animal, which may correlate with cell death chronically.[57]

5.2. First week after AION

OCT shows that the optic nerve head swelling improves at 4–5 days after AION.[11],[41] However, this is just the beginning of axonopathy and RGC loss. Within the first week after AION, there is axonal edema and collapse in the optic nerve axons.[41] Primate models of AION show that there is tissue edema and hemorrhage for up to 1 week postischemia, consistent with reperfusion injury. This swelling increases within the first week and persists for 2–3 weeks,[48] and edema may result in compression of initially spared axons, causing secondary axonal defects.

5.3. Chronic AION

5.3.1. RGC axonal loss

Within weeks after AION, there is pallor and atrophy of the optic nerve head.[41] OCT study shows about 30% thinning of the GCC.[11] Optic nerve axons are lost in a variable pattern and range from 25% to 60% in murine AION. The central optic nerve axons are more severely affected than the periphery,[41],[45],[46],[57] due to the way AION is induced. Oligodendrocyte number also decreases significantly.[46]

5.3.2. RGC loss via apoptosis

RGC layer cells, which include RGCs and displaced amacrine cells, are lost.[41],[43],[44] Consistent with the loss of RGCs, the expression of Brn3, a marker for RGCs, decreases,[41] RGC loss peaks at 2–3 weeks after AION and is thought to be via apoptosis through activation of the caspase pathway.[42],[45],[57],[58],[59]

5.3.3. Three-week therapeutic window in experimental AION

We know from AION animal studies that RGCs are irreversibly lost 3 weeks after AION, so this is the upper end of the therapeutic window for all treatment of experimental AION except for cell replacement therapy with stem cells. In both animals and humans, there is also evidence of anterograde degeneration in chronic AION, which can be trans-synaptic. This means that both the RGCs and target neurons can be removed with surgical precision, posing serious obstacles for cell-based therapy.[60] This means that even if we can reconstitute RGCs in the retina and send the axons down the right way, there may be no retinoptic target neurons to make connections, so early therapeutic intervention likely means better therapeutic outcome.


  6. Potential treatment for AION based on animal studies Top


The current state of treatment of patients with NAION includes a multipronged approach to minimize further damage by correcting nocturnal hypotension, treatment of sleep apnea, stopping drugs with possible association with AION, and consideration of corticosteroid treatment or hyperbaric oxygen treatment. In the long term, patients should address their vascular risk factors such as diabetes, hypertension, and hyperlipidemia. The photochemical thrombosis model has been useful to narrow down the therapeutic window of intervention, which is at maximum up to 3 weeks in the rodent, because the majority of RGCs are lost,[41] and there is stable thinning of the retina.[11] However, most treatment modalities probably do not have such a generous window, and all therapeutic options are likely to be more effective if instituted as early as possible.

Based on all studies to date and collective wisdom of research on thromboembolic diseases, many different classes of drugs have been tested, although typically not in a rigorous clinical trials format.[25] Factors that contribute to this slow progress include: (1) lack of understanding of the pathogenic mechanisms of human AION and what interventions will make the most impact and when; (2) difficulties of translating our findings in animal studies to humans; (3) inability to address major risk factors such as disc anatomy and age; (4) the relative rarity of AION and low number of patients who present for medical attention in time; and (5) a short therapeutic window.

Based on animal studies, there are two obvious future directions: targeting the anti-inflammatory pathways and promoting survival of the remaining axons and RGCs. However, the likelihood of success will remain unclear as long as human AION continues to be an enigma.

6.1. Anti-inflammatory molecules

Several drugs have shown that modulation of the inflammatory cascade leads to the successful treatment of experimental AION. This is a logical choice and treatments targeting these pathways that have been tried include systemic corticosteroids, intravitreal triamcinolone, and intravitreal anti-VEGF therapy. However, we know that the optic nerve is actually relatively resilient to swelling or compartment syndrome alone, such as from papilledema or optic disc drusen, and inflammatory or infectious optic neuropathies often do not necessarily lead to blindness. The tipping point is probably not isolated inflammation and accompanying vasogenic edema. It is likely to be inflammation, which leads to rapidly worsening compartment syndrome, and the concurrent phenomena of impaired vascular autoregulation, ischemia-induced stasis of axoplasmic flow, that results in intra-axonal swelling, impaired axonal transport, loss of neurotrophic support, stasis of intracellular organelles, disruption of microtubules, and, finally, irreversible damage causing retrograde RGC degeneration.[8],[61] The goal of antiinflammatory treatment is to extend the therapeutic window in conjunction with an effective axonor neuroprotective option, and it should be given as early as possible.

6.1.1. QPI-1007

QPI-1007 is a synthetic small interference RNA that is designed to inhibit the expression of caspase 2, which is activated following retinal ischemia. According to its maker, QPI-1007 has significantly enhanced RGC survival in three different animal models. It was used in a phase I clinical trial to assess the safety of intravitreal injection and treatment following NAION, which is now closed.

6.1.2. PGJ2

Prostaglandin J2 (PGJ2) dampens inflammatory responses and has been found to be neuroprotective after stroke. Single, intravenous injection of PGJ2 following rodent AION leads to increased survival of Brn3+ RGCs 30 days later.[52] This treatment is efficacious when given either immediately or 5 hours later. PGJ2 is thought to decrease proinflammatory responses, and PGJ2 treatment has been associated with dampening of NFκB activity, including suppression of IL-1 and TNFα expression.[52] Consistent with this idea, PGJ2 treatment is associated with a reduction of optic disc swelling on OCT, which may enhance capillary perfusion.[52]

6.1.3. Alpha-B crystallin

Alpha-B crystallin is a small heat shock protein, like other α crystallins, which have been shown to act as molecular chaperones similar to Hsp70 and GroE,[62] and it has been shown to be important in central nervous system inflammation.[63] Alpha-B crystallin has been shown to be efficacious in the treatment of the experimental model of multiple sclerosis and optic neuritis.[64] Treatment with intravenous αB-crystallin leads to a significant rescue of the oligodendrocytes and improvement in visual evoked potential latencies but did not salvage the RGCs.[47] This drug appears to be protective toward oligodendrocytes and RGC axons and may be useful as part of a cocktail of treatment for AION.

6.2. Neuroprotection

The key events leading to RGC degeneration have been most intensely studied in animal models of glaucoma, although glaucomatous optic neuropathy occurs at a much slower time scale. Obstruction in axonal transport has been shown to be an early event in the neuronal degeneration of the optic nerve.[65],[66],[67] Quigley et al[68] show that the transport of brain-derived neurotrophic factor (BDNF), a trophic factor for RGCs, and its receptor tropomyosinreceptor kinase receptor B (TrkB), is impaired after acute elevation of intraocular pressure in rats, leading to loss of RGCs. These are all worthy considerations although we do not know what are the most critical issues when there is acute ischemia. There are several endogenous neuroprotective molecules that are upregulated after AION, including heat shock proteins 70, 84, and 86[41],[45] and small heat shock protein αB-crystallin.[47] These heat shock proteins are postulated to act as molecular chaperones that have been shown to be protective in a variety of different conditions. There is no evidence that a further increase of the level of expression beyond the endogenous response will help. We would be better off to identify what factors if missing, lead to increased vulnerability, or if certain factors promote axonal or neuroprotection.

6.2.1. Brimonidine

Brimonidine is an a2 agonist that has been shown to lower intraocular pressure and is often used to treat glaucoma. Brimonidine given intraperitoneally and by eye drop following experimental AION improves survival of RGCs.[69] In another study, brimonidine treatment prior to AION is correlated with more surviving axons and RGCs, however, brimonidine treatment 14 days after AION has no significant benefit.[58] Although brimonidine has been postulated to be neuroprotective, the efficacy is relatively modest. Brimonidine has been shown to increase BDNF level, suggesting it may work by improving neurotrophic support.[70] Lowering of the intraocular pressure is also theoretically beneficial because it may improve perfusion to the eye by lowering resistance.

6.2.2. TrkB receptor activation

Retrogradely transported neurotrophins such as BDNF and its receptor TrkB are particularly important in the survival of retinal ganglion cells during development and following injury.[5],[71],[72] When axonal transport is disrupted in optic nerve head ischemia, exogenous neurotrophic support may significantly impact RGC survival.[72] Part of the glaucoma pathogenesis and possibly that of AION is that there is disruption of the retrogradely transported BDNF and abnormal accumulation of TrkB receptor at the optic nerve head.[67],[71] Other than intravitreal BDNF, which has a very short half-life, another way to activate the TrkB receptor is to use monoclonal antibodies that can mimic the action of BDNF.[73],[74] Another option that has potentially fewer immunologic issues and is less expensive is the use of small molecule pharmacophores, which have nanomolar affinity for the TrkB receptor[75] and can cross the blood-nerve barrier. There are also published reports of using gene therapy or stem cell therapy as a chronic source of BDNF.[76],[77]


  7. Summary and future studies Top


Through studies using experimental models of AION, we are learning about molecular and cellular events that occur at the retina, optic nerve head, and the posterior optic nerve within hours, days, and weeks after ischemia. There are several potential therapeutic approaches involving targeting of the inflammatory cascade and promoting survival of the retinal ganglion cell axons and cell bodies. Successful treatment of human AION may not be possible without a better understanding of the incipient events leading to irreversible vision loss, and this must be done with more human and animal studies. Effective therapy should be given as early as possible, possibly within hours of onset, and, ultimately, a therapeutic cocktail that targets different aspects of the disease may be most effective. Our current drug development pipeline is failing conditions such as AION, and efforts to collaborate and perform rigorous testing of effective therapies will not happen until we realize that we need to revolutionize the system.

Acknowledgments

We thank Gun Ho Lee and M. Ali Shariati for their helpful comments. Y.J.L. was supported by the Career Award in Biomedical Sciences from the Burroughs Wellcome Foundation, the Weston Havens Foundation Grant, and the Center for Biomedical Imaging at Stanford grant.

Conflicts of interest: The authors declare that they have no financial or nonfinancial conflicts of interest related to the subject matter or materials discussed in the manuscript.



 
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