**2. Anterior ischemic optic neuropathy (AION)**

Anterior ischemic optic neuropathy (AION) is a medical condition involving insufficient blood supply of the pial vessels originating from the choroidal vessels to the optic disk. AION is generally divided into two types: arteritic AION (or AAION) and nonarteritic AION (NAION) [1, 2].

We have to differentiate between two different etiologies, and therefore, workout prognosis and treatment possibilities are different.

#### **2.1. Nonarteritic ischemic optic neuropathy (NAION)**

NAION is the most common cause of sudden optic nerve-related vision loss. It is estimated that the incidence of NAION is about 8000/year in the USA and encountered for 90% of the optic neuropathies. NAION is mostly unilateral [3] and rare bilaterally. NAION is more frequent in Caucasians, no gender predisposition, and mean age at onset in most studies is from 57 to 65 years. No clinically effective treatment exists because little is known about its pathophysiology, and there are only few histopathological studies of the acute condition.

ophthalmologist or neurologist can make the differential diagnosis according the symptoms, the age of onset, and the gender. Young age group (15–45 years) for optic neuritis women gender and pain on eye movement are more typical for optic neuritis versus. Elderly patients (older than 50 years), painless loss of vision without gender predisposition are typical for ischemic optic neuropathy. Additionally, in a young patient, history of neurological symptoms such as parenthesis, limb weakness, and ataxia is suggestive of demyelinating optic neuritis. In an elderly patient (more than 60 years mostly 70–80 years) with signs of severe optic neuropathy and the presence of preceding transient visual loss, temporal pain, jaw claudication, fatigue, fever, anemia, weight loss and myalgia, an arteritic ischemic optic neuropathy

In children, a history of recent flu-like illness or vaccination days or weeks before vision loss

Transient visual obscurations, transient diplopia, and headache should raise the suspicion of

The use of any medications should be carefully noted, since some are either directly or indirectly toxic to the optic nerve. These include drugs as ethambutol, methanol, isoniazid, tobacco alcohol, and more. History of diabetes mellitus, systemic hypertension, hypercholesterolemia, coagulation deficit, and smoking is more common in patients with nonarteritic ischemic optic neuropathy (NAION). Patients who have history of malignancy may have infiltrative or para-neoplastic optic neuropathy. It is important to inquire into the patient's general health, eating, and social habits (drinking and smoking) in suspected nutritional optic neuropathy (complex B–vitamins). In addition, a detailed family history is inquired in diag-

This chapter addresses the major diseases neuropathies accompanied by rapid visual loss: nonarteritic and arteritic optic neuropathy, traumatic optic neuropathy, and optic neuritis.

Anterior ischemic optic neuropathy (AION) is a medical condition involving insufficient blood supply of the pial vessels originating from the choroidal vessels to the optic disk. AION is generally divided into two types: arteritic AION (or AAION) and nonarteritic AION

We have to differentiate between two different etiologies, and therefore, workout prognosis

NAION is the most common cause of sudden optic nerve-related vision loss. It is estimated that the incidence of NAION is about 8000/year in the USA and encountered for 90% of the optic neuropathies. NAION is mostly unilateral [3] and rare bilaterally. NAION is more

(AION) due to giant cell arteritis (GCA) should be suspected.

increased intra-cranial pressure.

34 Causes and Coping with Visual Impairment and Blindness

(NAION) [1, 2].

and treatment possibilities are different.

points to a para-infectious or postvaccinia optic neuritis, respectively.

nosing hereditary autosomal and mitochondrial optic neuropathies.

**2. Anterior ischemic optic neuropathy (AION)**

**2.1. Nonarteritic ischemic optic neuropathy (NAION)**

NAION [1, 2] typically presents suddenly upon awakening the painless patient notes seeing poorly in one eye. Vision in that eye is obscured by a dark shadow, often involving just the upper or lower half of vision. On examination, the patient is found with visual acuity reduction from 20/25 down to hand movement only, relative afferent pupillary defect (RAPD), swollen disk (segmental or diffuse) with splinter hemorrhages (see **Figure 1**), absent of large cup, and contralateral disk is small and crowded in 20–40% of the patents [4]. In approximately 6 months following the infarct visual acuity improves by 3 or more lines of vision on the Snellen chart in 42.7% of patients. In addition, vision had worsened by 3 lines or more in 12.4% of patients; some clinicians use the term "progressive ischemic optic neuropathy". Second eye involvement occurs in approximately 20% of patients with NAION within 5 years. Furthermore, most cases of NAION involve the loss of an altitudinal hemifield (**Figure 2**) (either the upper or mostly lower half of the visual field, but not both), and visual acuity remains almost normal or slightly reduced.

**Figure 2** shows a few cases of NAION, which involve almost total loss of vision. The mechanism of injury for NAION is used to be controversial. Experts have come to a consensus that most cases involve two main risk factors. The first is a predisposition in the form of a type of optic disk shape named crowded disk [4, 5] or "disk at risk," where the cup/disk ratio is low (0.0–0.1), and secondly, cardiovascular risk factors as diabetes mellitus, hypertension, hypercholesterolemia, and coagulation deficits. Laboratory examinations at the presentation to differentiate between NAION and AAION include (erythrocyte sedimentation rate [ESR] that should be less than 40 mm/h) and C-reactive protein (CRP). It is advised to draw complete blood count and serum chemistry especially glucose, serum cholesterol and triglycerides, coagulophatic state, antitrombin III antiphospholipid antibody, and serum fibrinogen. Analysis of brain MRI suggests an increasing number of ischemic white matter lesions.

**Figure 1.** Disk appearance in nonarteritic ischemic optic neuropathy.

Additional risk factor such as obstructive sleep apnea, migraine, and hyperhomocysteinemia, smoking and optic disk drusen [6]. Ipsilateral carotid disease does not seem to be a risk factor for NAION. Association between cerebral and cardiac vascular disease seems to be very circumstantial. Drugs associated with NAION are amiodarone, phosphodiesterase-5 inhibitors such as sildenafil [7], and interferon-a.

*2.2.1. Ischemic optic neuropathy decompression trial (IONDT)*

patients with NAION and visual acuity of 20/64 or worse.

was used by the research group and measured by technicians.

for NAION is not effective and may be harmful [14].

*2.2.2. Bevacizumab (Avastin®) trial*

*2.2.2.1. Methods*

OCT thickness.

*2.2.2.2. Results*

119 patients had been randomized to surgery, with 6 months of follow-up.

The trial was done to assess the safety and efficacy of optic nerve decompression surgery compared with careful follow-up alone in patients with nonarteritic anterior ischemic optic neuropathy (NAION). The ischemic optic neuropathy decompression trial (IONDT) is a randomized, single-masked, multicenter trial and was carried out in 1994. Study was done by 244

Visual Loss in Neuro-Ophthalmology http://dx.doi.org/10.5772/intechopen.80682 37

First group of 125 patients had been randomized to careful follow-up, and second group with

Patients in the surgery group received optic nerve decompression surgery and follow-up ophthalmologic examinations; those in the careful follow-up group received ophthalmologic examinations at the same times as the surgery group. A parameter of gain and loss of three or more lines of visual acuity on the New York Lighthouse chart at 6 months after randomization

Results showed that patients assigned to surgery did no better when compared with patients assigned to careful follow-up regarding improved visual acuity of three or more lines at 6 months: 32.6% of the surgery group improved compared with 42.7% of the careful followup group. According to the results, IONDT indicates that optic nerve decompression surgery

Intravitreal bevacizumab for the treatment of NAION neuropathy: a prospective trial [15].

In this non-randomized controlled clinical trial, 1.25-mg intravitreal Bevacizumab was compared with natural history [15]. Twenty-five patients were enrolled (17 with treatment and 8 controls). Patients were examined at baseline, 1, 3, and 6 months with a full neuro-ophthalmic exam, automated perimetry, and optic nerve optical coherence tomography (OCT) measurements. The primary outcome measure was change in mean deviation on Humphrey visual field testing. Secondary outcome measures were changed in visual acuity and optic nerve

(A) There was no significant effect of treatment on the primary outcome measure of mean deviation score (P = 0.4). (B) There was no effect of group assignment on the secondary outcome measures of change in mean Early Treatment Diabetic Retinopathy Study (ETDRS) let-

Results show optic disc in NAION the results, there was no difference between Bevacizumab and natural history for change in visual acuity, visual field, or optic nerve OCT thickness [15].

ters (P = 0.33). (C) No change in nerve fiber layer thickness on OCT (P = 0.11).

Most experts throughout the world believe that there is no accepted treatment to reverse the damage. However, a recent large study by Hayreh has shown that if patients are treated with large doses of corticosteroid therapy during the early stages of NAION, in eyes with initial visual acuity of 20/70 or worse, seen within 2 weeks of onset, there was visual acuity improvement in 70% in the treated group compared to 41% in the untreated group [8]. Hayreh and Zimmerman performed a nonrandomized, open-label trial of systemic corticosteroids for acute NAION, and the untreated group had more vascular risk factors than the treated group, and therefore, this study was very criticized and not accepted by most neuro-ophthalmologists worldwide.

#### **2.2. NAION treatments attempted with no specific success to improve vision**


**Figure 2.** Visual field in NAION and lower altitudinal hemianopia.

#### *2.2.1. Ischemic optic neuropathy decompression trial (IONDT)*

The trial was done to assess the safety and efficacy of optic nerve decompression surgery compared with careful follow-up alone in patients with nonarteritic anterior ischemic optic neuropathy (NAION). The ischemic optic neuropathy decompression trial (IONDT) is a randomized, single-masked, multicenter trial and was carried out in 1994. Study was done by 244 patients with NAION and visual acuity of 20/64 or worse.

First group of 125 patients had been randomized to careful follow-up, and second group with 119 patients had been randomized to surgery, with 6 months of follow-up.

Patients in the surgery group received optic nerve decompression surgery and follow-up ophthalmologic examinations; those in the careful follow-up group received ophthalmologic examinations at the same times as the surgery group. A parameter of gain and loss of three or more lines of visual acuity on the New York Lighthouse chart at 6 months after randomization was used by the research group and measured by technicians.

Results showed that patients assigned to surgery did no better when compared with patients assigned to careful follow-up regarding improved visual acuity of three or more lines at 6 months: 32.6% of the surgery group improved compared with 42.7% of the careful followup group. According to the results, IONDT indicates that optic nerve decompression surgery for NAION is not effective and may be harmful [14].

#### *2.2.2. Bevacizumab (Avastin®) trial*

Intravitreal bevacizumab for the treatment of NAION neuropathy: a prospective trial [15].

#### *2.2.2.1. Methods*

Additional risk factor such as obstructive sleep apnea, migraine, and hyperhomocysteinemia, smoking and optic disk drusen [6]. Ipsilateral carotid disease does not seem to be a risk factor for NAION. Association between cerebral and cardiac vascular disease seems to be very circumstantial. Drugs associated with NAION are amiodarone, phosphodiesterase-5 inhibitors

Most experts throughout the world believe that there is no accepted treatment to reverse the damage. However, a recent large study by Hayreh has shown that if patients are treated with large doses of corticosteroid therapy during the early stages of NAION, in eyes with initial visual acuity of 20/70 or worse, seen within 2 weeks of onset, there was visual acuity improvement in 70% in the treated group compared to 41% in the untreated group [8]. Hayreh and Zimmerman performed a nonrandomized, open-label trial of systemic corticosteroids for acute NAION, and the untreated group had more vascular risk factors than the treated group, and therefore, this study was very criticized and not accepted by most neuro-ophthalmologists worldwide.

**2.2. NAION treatments attempted with no specific success to improve vision**

• Intravitreal: anti-VEGF agents (e.g., Bevacizumab), (see more information)

• Surgical: optic nerve sheath fenestration, optic neurotomy (see more information)

such as sildenafil [7], and interferon-a.

36 Causes and Coping with Visual Impairment and Blindness

• Medical [9–11]

• Diphenylhydantoin

• Hyperbaric oxygen [13]

• Systemic: aspirin [12], corticosteroids [8]

• Erythropoietin/erythropoietin receptor agonists

**Figure 2.** Visual field in NAION and lower altitudinal hemianopia.

In this non-randomized controlled clinical trial, 1.25-mg intravitreal Bevacizumab was compared with natural history [15]. Twenty-five patients were enrolled (17 with treatment and 8 controls). Patients were examined at baseline, 1, 3, and 6 months with a full neuro-ophthalmic exam, automated perimetry, and optic nerve optical coherence tomography (OCT) measurements. The primary outcome measure was change in mean deviation on Humphrey visual field testing. Secondary outcome measures were changed in visual acuity and optic nerve OCT thickness.

#### *2.2.2.2. Results*

(A) There was no significant effect of treatment on the primary outcome measure of mean deviation score (P = 0.4). (B) There was no effect of group assignment on the secondary outcome measures of change in mean Early Treatment Diabetic Retinopathy Study (ETDRS) letters (P = 0.33). (C) No change in nerve fiber layer thickness on OCT (P = 0.11).

Results show optic disc in NAION the results, there was no difference between Bevacizumab and natural history for change in visual acuity, visual field, or optic nerve OCT thickness [15].

#### **2.3. New treatment opportunities (ongoing studies)**

NAION is still an enigma regarding pathogenesis and treatment. The current therapeutically efforts are to preserve vision and minimize the damage from the primary insult. QPI-1007 is a small interfering ribonucleic acid (siRNA) designed to temporarily block cells from making Caspase 2 (controls cell apoptosis). Quark pharmaceuticals and NORDIC collaborated in a study that uses the possible effect of this drug as a possible neuroprotection therapy for NAION.

by a milk-pale edema that may extend to the retina. In some cases, even central retinal occlusion with "cherry -red spot" may occur. Diagnosis is confirmed by temporal biopsy, and if the histological result is negative, it is necessary to biopsy the other side. Biopsy is taken from several segments along the temporal artery because the inflammation is segmental and may be missed by one site biopsy. Another possibility for diagnosis is ultrasound of the temporal

Visual Loss in Neuro-Ophthalmology http://dx.doi.org/10.5772/intechopen.80682 39

Neuroimaging is not usually required in patients with typical presentations of giant cell arteritis (GCA) and when performance is generally normal [18]. However, some patients have already undergone imaging before neuro-ophthalmic evaluation, and these studies may be

Other important MRI findings in GCA include those involving the vascular supply not only extracranially but also intracranial, particularly vessel wall enhancement of the intramural ICA. MRI findings may hold some diagnostic value in distinguishing between A-AION as in GCA and in nonarteritic AION, in which they are typically normal. Differential diagnosis for these MRI findings can lead to inappropriate testing and delay diagnosis and

**1.** GCA is a vascular disorder that may result in devastating visual loss if not treated promptly. **2.** Biopsy is the gold standard for diagnosing, and neuroimaging plays a role only in atypical

**3.** Neuroimaging findings in GCA are often nonspecific and can lead to delay in diagnosis

Patients are hospitalized for evaluation and intravenous corticosteroid treatment with at least 1 g/day (3–5 days) of methylprednisolone followed by prednisone 1 g/kg for 10 days and then tapering down. The dosage is decreased to 20–40 mg/day in 3 weeks, and treatment is continued for 12–18 months. A steroid sparing agent is tocilizumab, a monoclonal humanized antibody against interleukin 6 receptor. The dosage is 1 g/day for 12–24 months, and it is not given in the first trimester of pregnancy. It can be combined with corticosteroids, and this allows decreasing the dosage of the later. During the follow-up period, the inflammatory parameters including sedimentation rate, CPR, platelets, etc. is monitored, and if they increase, the dosage is accordingly increased. Treatment is very urgent to avoid AAION in the fellow eye, as it can happen even within days or weeks after the first eye was affected.

Treatment generally does not improve the vision of the affected eye.

abnormal. They report four main imaging findings described in the literature:

artery but it is less accurate compared to biopsy.

**1.** Nonspecific orbital enhancement.

**3.** Perineural sheath enhancement.

**4.** Optic chasmal enhancement.

treatment [18].

*2.4.1. Summary of AAION*

presentations.

and treatment.

**2.** Optic nerve parenchymal enhancement.

#### **2.4. Arteritic anterior ischemic optic neuropathy (AAION)**

Distinction between AAION and different etiologies of anterior ischemic optic neuropathy. will be discussed. AAION is due to temporal arteritis (also called giant cell arteritis (GCA)), an inflammatory disease of medium-sized blood vessels that occurs especially with advancing age (more than 60 years, mostly 70–80 years). Annual incidence rate in population age 50 years or older is estimated as 15–30/10,000. Female-to-male preponderance of 3.5:1 is prevalent in white population of European origin. GCA is associated with polymyalgia rheumatica. About 50% of the GCA patients have polymyalgia rheumatica, and 10–20% of the patients with polymyalgia rheumatica have GCA. Polymyalgia rheumatica may precede GCA or can occur simultaneously.

The symptoms and signs of severe optic neuropathy [16] include the presence of preceding transient visual loss, temporal pain, jaw claudications, fatigue, fever, anemia, weight loss, and myalgias are strongly suggestive of arteritic ischemic optic neuropathy (AAION). In contrast, NAION results from the coincidence of cardiovascular risk factors in a patient with "crowded" optic discs. Nonarteritic AION occurs in a slightly younger group and is much more common than AAION. Most cases of AAION involve nearly complete vision loss (light perception to no light perception), while only a few cases of NAION result in near total loss of vision (**Figure 3**). Swollen disk, elevated CRP, and ESR (60–120 mm/h) are highly suggestive of temporal arteritis (arteritic AION) [3, 17]. At times, the optic disk in AAION is characterized

**Figure 3.** Shock white disk in arteritic anterior ischemic optic neuropathy.Ó 2018 American Academy of Ophthalmology.

by a milk-pale edema that may extend to the retina. In some cases, even central retinal occlusion with "cherry -red spot" may occur. Diagnosis is confirmed by temporal biopsy, and if the histological result is negative, it is necessary to biopsy the other side. Biopsy is taken from several segments along the temporal artery because the inflammation is segmental and may be missed by one site biopsy. Another possibility for diagnosis is ultrasound of the temporal artery but it is less accurate compared to biopsy.

Neuroimaging is not usually required in patients with typical presentations of giant cell arteritis (GCA) and when performance is generally normal [18]. However, some patients have already undergone imaging before neuro-ophthalmic evaluation, and these studies may be abnormal. They report four main imaging findings described in the literature:

**1.** Nonspecific orbital enhancement.

**2.3. New treatment opportunities (ongoing studies)**

38 Causes and Coping with Visual Impairment and Blindness

**2.4. Arteritic anterior ischemic optic neuropathy (AAION)**

NAION.

simultaneously.

NAION is still an enigma regarding pathogenesis and treatment. The current therapeutically efforts are to preserve vision and minimize the damage from the primary insult. QPI-1007 is a small interfering ribonucleic acid (siRNA) designed to temporarily block cells from making Caspase 2 (controls cell apoptosis). Quark pharmaceuticals and NORDIC collaborated in a study that uses the possible effect of this drug as a possible neuroprotection therapy for

Distinction between AAION and different etiologies of anterior ischemic optic neuropathy. will be discussed. AAION is due to temporal arteritis (also called giant cell arteritis (GCA)), an inflammatory disease of medium-sized blood vessels that occurs especially with advancing age (more than 60 years, mostly 70–80 years). Annual incidence rate in population age 50 years or older is estimated as 15–30/10,000. Female-to-male preponderance of 3.5:1 is prevalent in white population of European origin. GCA is associated with polymyalgia rheumatica. About 50% of the GCA patients have polymyalgia rheumatica, and 10–20% of the patients with polymyalgia rheumatica have GCA. Polymyalgia rheumatica may precede GCA or can occur

The symptoms and signs of severe optic neuropathy [16] include the presence of preceding transient visual loss, temporal pain, jaw claudications, fatigue, fever, anemia, weight loss, and myalgias are strongly suggestive of arteritic ischemic optic neuropathy (AAION). In contrast, NAION results from the coincidence of cardiovascular risk factors in a patient with "crowded" optic discs. Nonarteritic AION occurs in a slightly younger group and is much more common than AAION. Most cases of AAION involve nearly complete vision loss (light perception to no light perception), while only a few cases of NAION result in near total loss of vision (**Figure 3**). Swollen disk, elevated CRP, and ESR (60–120 mm/h) are highly suggestive of temporal arteritis (arteritic AION) [3, 17]. At times, the optic disk in AAION is characterized

**Figure 3.** Shock white disk in arteritic anterior ischemic optic neuropathy.Ó 2018 American Academy of Ophthalmology.


Other important MRI findings in GCA include those involving the vascular supply not only extracranially but also intracranial, particularly vessel wall enhancement of the intramural ICA. MRI findings may hold some diagnostic value in distinguishing between A-AION as in GCA and in nonarteritic AION, in which they are typically normal. Differential diagnosis for these MRI findings can lead to inappropriate testing and delay diagnosis and treatment [18].

#### *2.4.1. Summary of AAION*


Patients are hospitalized for evaluation and intravenous corticosteroid treatment with at least 1 g/day (3–5 days) of methylprednisolone followed by prednisone 1 g/kg for 10 days and then tapering down. The dosage is decreased to 20–40 mg/day in 3 weeks, and treatment is continued for 12–18 months. A steroid sparing agent is tocilizumab, a monoclonal humanized antibody against interleukin 6 receptor. The dosage is 1 g/day for 12–24 months, and it is not given in the first trimester of pregnancy. It can be combined with corticosteroids, and this allows decreasing the dosage of the later. During the follow-up period, the inflammatory parameters including sedimentation rate, CPR, platelets, etc. is monitored, and if they increase, the dosage is accordingly increased. Treatment is very urgent to avoid AAION in the fellow eye, as it can happen even within days or weeks after the first eye was affected. Treatment generally does not improve the vision of the affected eye.
