The optic nerve is confirmed by one million axons that derives from the retinal ganglion cells and constitutes an extension of the central nervous system (CNS). We usually refer to the optic nerve as the tract that extends from the eye to the optic chiasm. It has four anatomic portions well defined: intraocular or optic disc, intraorbital, intracanalicular and intracranial [1]. The optic disc is the only structure of the entire tract that has not myelin. One classic classification of optic neuritis has been anterior (or papilitis) and posterior (retrobulbar). The first one designs an inflammation of the optic disc and can be seen in the fundus examination as a peripapillary edema; the second one designs an inflammation in any portion between the eye and the optic chiasm and can be only seen in neuroimaging test. It was classically described as the disease in which “neither the patient nor the physician see anything”. Anastomosing arterioles supplied by posterior ciliary arterioles, pial arteriole plexus, and choroid supplies the blood flow of the optic disc. Arteriosclerosis or arteritis of these vessels can lead to cause hypoperfusion of the optic nerve head and, subsequently, an anterior ischemic optic neuropathy (AION). The intraorbital segment receives blood from perforating branches of the ophthalmic artery. The intracanalicular and intracraneal portions are supplied by pial branches of the ophthalmic, internal carotid, anterior cerebral, and anterior communicating arteries [2].

Clinical features of an optic nerve lesion usually produce monocular vision loss. Pain is a variable feature that, when is present, suggest an inflammatory disorder. Nevertheless, some ischemic lesions can cause pain as well [3,4]. Other common features includes relative afferent pupilary defect (RAPD) (if the lesion is unilateral or asymmetric), central vision loss on visual field testing and dyschromatopsia [5]. Swinging flashlight test evidence the RAPD and may suppose the most valuable test in the clinical examination (Figure 1). It is found in most cases and, when not present, usually signifies that there is bilateral involvement or a previous damage, sometimes subclinical, of the fellow pregenicular afferent pathway. It presence is a required clinical feature for the diagnosis of unilateral optic neuropathy.

Worldwide, the principal cause of optic neuropathy is glaucoma. Briefly, we will summarize the main differential signs in a fundus examination between glaucomatous damage of the optic nerve head and a non- glaucomatous optic neuropathy (NGON). In glaucomatous eyes, neurorretinal ring appears to have a good healthy color but markedly thin, usually at superior and inferior, showing a focal enlargement of the cup. Other characteristic signs are asymmetry of cupping between patient eyes, paripapillary atrophy and disc hemorrhages without swelling. The principal funduscopic signs in NGON are the neurorretinal ring`s pallor, especially in temporal (showing a horizontal enlargement of the cup) or an optic nerve head swelling (if anterior portion is affected) in the acute phase (Figure 2). Therefore, acquired enlargement of the cup does not always suggest glaucoma. Arteritic anterior ischemic optic neuropathy seen in giant cell arteritis (GCA- AAION) causes an enlargement of the cup in most of the patients affected [6]. As glaucoma is a bilateral disease, these patients do not usually present a RAPD. Known risk factors are higher intraocular hypertension, steroids treatment, age and familiar history of the disease [7].

Figure 1:Swinging flashlight test showing a RAPD of the left eye. When the right eye is illuminated, light reflex appears in both eyes (direct and consensual); but, when the left eye is illuminated, neither of them response. This discloses a defect in the left pregenicular visual afferent pathway. Courtesy of Spanish Society of Ophthalmology.

The approach of the etiology of NGON can be difficult for both ophthalmologists and neurologists, because neither the appearance of the optic disc, the perimetry, nor the findings in Optical Coherence Tomography (OCT) or Magnetic Resonance Imaging (MRI) are specific.

Mainly, there are nine big groups that summarize the etiology of a NGON: Inflammatory- optic neuritis (ON), ischemic, compressiveinfiltrative, hereditary, toxic, nutritional deficiency, post- traumatic, post- radiotherapy, or associated with intracraneal hypertension (ICH) (Table 1). ON is the most common cause of optic nerve disease in younger adults while ischemic optic neuropathy is the most common etiology in elderly patients [8].

This variety of possibilities does not allow us to perform the same test to all the patients who have been clinically diagnosed of an optic neuropathy. We must follow a rational algorism from the most common cause to the most unlikely in each case, with a previous well defined clinical diagnosis [9].

It is essential to know the way of onset and progression of the symptoms, the age of the patient, the presence or not of peripapillary edema, if it is a unilateral o bilateral disorder, personal history (trauma, neoplasia, drugs, etc.) and family history.

Figure 2:Differences between glaucomatous optic neuropathy and NGON. A. Glaucomatous optic neuropathy: Neuroretinal ring has a good healthy color but appears markedly thin, especially in superior. Enlargement of the cup is obvious. Parapapillary atrophy is shown in the nasal and temporal borders. This is a classically sign of glaucomatous optic disc, but it can also be seen in elderly patients. We also can see the vessels displaced to the nasal side and a notch in the inferior border. B. NGON: Neuroretinal ring has a pronounced pallor, showing a whole atrophy of the optic disc. This picture corresponds to a past NAION. C, D. Evolution of a disc hemorrhage in the inferior border in a glaucomatous disc. Usually disappears in 2- 6 months, and means progression of the optic nerve head damage. E. Optic atrophy in a NGON with superior and temporal pallor of neuroretinal ring. Courtesy of Spanish Society of Ophthalmology.

Table 1: Common features of optic neuropathies.

Toxic and nutritional deficiency optic neuropathies are usually presented as a bilateral disease. They must be discarded in patients with bilateral optic pallor and vision loss. The main treatment consists in withdrawing the toxic agent (methanol, ethanol, etc.) and vitamins supplementation, but a lot more treatments are actually being investigated [10]. In a peripapillary edema without or minimal vision loss, we must suspect ICH. Hence, the treatment in this scenario would be the cause of ICH.

Hereditary, post-traumatic and post-radiotherapy optic neuropathy has clear personal records. Nonetheless, some optic neuropathies considered hereditary, such as Leber's hereditary optic neuropathy (LHON), can onset without clear family records [10]. Nowadays, there is not an effective treatment for LHON [11]. Post- radiotherapy usually occurs several months after radiation of skull base tumors. Although rare, visual prognosis is usually poor.

ON must be suspected in a young adult with acute loss of vision; if, however, it occurs in a medium age adult (≥ 50 years) we must suspect an AION. This does not mean that ON or AION can occur out of this range of age, but are forms that will present atypical features. The exact pathogenic mechanisms for either ischemic or inflammation of the optic nerve remains unknown. Nowadays, there is not an effective treatment in terms of recovery to normal visual acuity, visual field or contrast sensitivity in neither of them [10,12].

Compressive and infiltrative optic neuropathies can present with any clinical feature. Therefore, if there is not a clear clinical diagnosis of typical ON, image tests should be done because a diagnosis`s delate may suppose a life threatening condition [13]. The treatment is basically etiological with antibiotics, corticosteroids and/ or surgery [10].

In this text we will focus on the diagnosis approach of ON. The most common basis for idiopathic or multiple sclerosis- related optic neuritis (MS- ON) is an inflammatory demyelination of the optic nerve. One sign`s onset of the disease is the activation of T cells which precedes changes in the cerebrospinal fluid (CF) [14]. B activated cells against myelin basic protein can be found in the CF but not in peripheral blood, which suggests a primary autoimmune disease of the CNS [15]. The clinical approach to diagnose an inflammation of the optic nerve consists in identifying some clinical features common to optic neuropathies (vision loss, RAPD and dyschromatopsia), usually presented with peribulbar pain in a short period of time. Clinical examination of these patients at first requires a well distinction of the typical and atypical features, because both the early diagnosis and treatment are overriding in the second ones.

Clinical features: Typical vs. atypical optic neuritis

Idiopathic demyelinating ON or MS- ON accounts for a considerable proportion of cases of unilateral acute or subacute vision loss in young and otherwise healthy individuals, in a range of age between 25-45 years old [16]. The Optic Neuritis Treatment Trial (ONTT) revealed that over 90% of the patients enrolled had ipsilateral peribulbar pain, usually worsened with eye movements [17]. It typically carries a good prognosis and visual acuity (VA) recovery without treatment. RAPD and color desaturation often persist despite recovery of normal vision. Basically, this pattern [young patient, unilateral, acute or subacute presentation (over a period of 1-2 weeks), pain worsened with eye movements and good prognosis] defines a typical ON [18] (Table 2). The main causes in this scenario would be idiopathic and MS- ON. Any modification of this clinical pattern should be considering atypical [19]. Other characteristics enrolled with typical ON are female patients (77%) and Caucasian (85%) [17]. VA reduction has a widely range. The Optic Neuritis Study Group reported a 20/40 or better: 10% were 20/20, 29% were 20/50–20/190, and 36% were 20/200 or worse; 72% had a VA ≥ 20/20 after 15 years of follow-up [16]. Therefore, the physician should consider this diagnosis even if VA is not clearly decreased. Red desaturation is the most sensitive indicator of dyschromatopsia, but not a very specific one. Recently, Moss et al. analyzed ONTT data and reported a relationship between Black ethnicity and poorer VA and contrast sensitivity [20]. One recent study in which 291 patients with MS and ON as first symptom were retrospectively reviewed, reported that men and patients with severe vision loss are more likely to have worse recovery, in contradistinction to pediatric patients, who had better visual recovery [21]. Low vitamin D levels were associated with more severe visual loss but not with VA improvement. The pathophysiology of this association remains unclear.

Edema of the optic nerve head is found in one third of cases and is typically mild, diffuse and without hemorrhages (Figure 3). Retrobulbar ON is presented in two thirds of the cases [16]. Fundus exam in this case is normal. It is important to emphasize that the optic nerve head swelling is not a differential clinical feature between typical and atypical ON (do not misunderstand “typical” with “frequent”). When optic nerve head swelling is seen, it is essential to search for phlebitis (focal or diffuse), in both eyes, mostly in the equatorial zone. This sign can be easily unnoticed and it is associated with ON relapse and evolution to Multiple Sclerosis (MS). In the worst cases, optic atrophy can result from a previous intense inflammation (even in retrobulbar forms), which can be diffuse or temporal. This consequence can appear in any optic neuropathy, but it is more likely in AION.

The clinical pattern of AION can be overlapped with ON (acute monocular vision loss, RAPD and disc edema) and can be hard to differentiate in elderly patients. Peribulbar pain worsened with eye movements is a classic symptom in ON that can help in the differential diagnosis. However, there have been reports of mild ocular discomfort in AION in 8- 12% of individuals [3,4,18]. If pain is a prominent complaint, AION should not be considering a likely diagnosis. Other clinical features more likely of AION are: altitudinal scotoma, often noticed upon awakening that can even progress over the first few days, amaurosis fugax, prodromal ocular or systemic symptoms in arteritic forms and history of cardiovascular risk factors [22].

Optic nerve head swelling in ON can be differentiated from ischemic forms through some funduscopic signs. 25% of the patients with AION have a segmental disc edema, usually involving the superior portion of the disc (due to anatomic distribution of the circle of Zinn- Haller) [3,19,23]. Segmental disc edema may not correspond to distribution of vision loss. Disc hyperemia with splinter or flame hemorrhages and telangiectatic capillaries are common in AION, but not in ON (Figure 4). The fellow eye often reveals a crowed optic disc with a small physiologic cup, which has been traditionally reported as “disk at risk” [24]. Technological innovations in gadolinium- contrast enhanced Magnetic Resonance Imaging (MRI), as fast espin echo (FSE), fluiattenuate inversion recovery with fat suppression techniques (FLAIR), short tau inversion recovery (STIR) or diffusion tensor imaging (DTI), have been widely investigated and appear to be a useful tool in order to discriminate ischemic from inflammatory conditions [19,25,26]. Thickening`s magnification of the optic nerve, with regular and diffuse restriction in the diffusion sequence suggests an inflammatory disorder; optic nerve`s normal size and focal restriction in the diffusion sequence suggests an ischemic disorder [27] (Figure 5). Computed tomography (CT) is necessary in atypical cases in order to see the orbit and paranasal sinuses. Nevertheless, in those cases MRI with gadolinium contrast is necessary to detect intracraneal complications and affection of intracanalicular and intracraneal portions of optic nerve. Anyway, the most valuable information of brain MRI in typical ON is its predictive value for risk of conversion to MS, rather than the ON diagnosis itself [19,28]. Therefore, clinical evaluation in these patients is essential because entails the m2ain feature to guide the decision whether or not steroid treatment is necessary. If atypical symptoms are present, the evaluation of MRI previous steroid treatment seems a prudent behavior, in order to not misdiagnose other possible etiologies and avoid treatment ineffectiveness and complications. Nevertheless, if GCAAAION is clearly suspected (acute optic neuropathy` symptoms and signs in elderly patients with increased erythrocyte sedimentation rate and reactive C protein) early treatment with intravenous corticosteroids is underlying in order to prevent permanent bilateral blindness, which is estimated that will develop in 25 to 50 percent of untreated patients who present with loss of vision in one eye [29]. Rebolleda et al. described, in an unmasked clinical trial, the uselessness of high-dose systemic steroid treatment when given during the acute phase of non arteritic optic neuropathy (NAION), because none beneficial effect in visual and anatomic outcomes was shown. They even described serious complications in a third of the treated patients [30]. Kinori et al. retrospectively compared two nonrandomized groups of 23 patients and concluded that high-dose intravenous treatment within 14 days of symptom onset of NAION provided no statistical benefit [31]. In the other hand, Radoi et al. noted statistically significant improvements in both visual acuity and visual fields at 6 months in 21 patients treated with corticosteroids (4 mg intravitreal triamcinolone) compared with 14 untreated [32]. Hayreh reported that corticosteroid treatment could be beneficial, in terms of VA at six months, after performing a “patient choice” study designed with 613 consecutive patients with NAION who chose either no treatment or systemic corticosteroids (80 mg/d for 2 weeks then tapered for approximately 8 weeks) [33]. Therefore, corticosteroid treatment for NAION remains controversial.

Figure 3:Superior: Evolution of an anterior MS- ON. A. Optic nerve head edema in the acute phase with reduction of VA. B. Reduction of edema. C. Complete resolution of the edema with VA reconstitution. Inferior: D. Pallor of the optic disc in the right eye with past anterior MS- ON. It is especially manifest in temporal side of neuroretinal ring when we compare it with the fellow eye (E). Courtesy of Spanish Society of Ophthalmology.

Figure 4:Differences between optic nerve head edema in AION and ON. A. AION: Superior segmental disc edema, one flame hemorrhage and attenuation of the vessels` caliber. B. ON: Diffuse edema of the optic disc without hemorrhages. Courtesy of Spanish Society of Ophthalmology.

Known risk factors for NAION include hypertension, diabetes mellitus and hypercholesterolemia. Bilgin et al. compared 27 patients with NAION and 27 matched controls, describing a statistically higher prevalence of obstructive sleep apnea in the NAION group [34]. Posterior ischemic optic neuropathy (PION) is much rarer and usually occurs in the setting of prolonged spine or cardiac surgical procedures, giant cell arteritis or dialysis.

Figure 5:Imaging test showing ON. A. MRI Coronal cut. Regular thickening of the left eye proving ON (arrow). B. Another coronal cut of a different patient above orbital apex in the sequence STIR- FLAIR. Left optic nerve hyperintensity, enhancement and swelling is remarkable comparing with the right one. C. Sagittal cut of MRI in a male of 14 years old with a clinic diagnosis of ON: T1 sequence with fat suppression, showing regular hyperintensity and thickening of all the optic nerve segments between the eye and chiasm. D. Computed tomography (CT) without contrast, showing regular and diffuse thickening of the right optic nerve (arrow). Courtesy of Spanish Society of Ophthalmology.

Figure 6:Humphrey SITA- Standard Perimetry. A. Papilitis of the right eye in the acute phase with arciform and cecocentral scotoma. B. Resolution of the optic nerve head edema and the VF defects within one year. Courtesy of Spanish Society of Ophthalmology.

Complementary tests in typical optic neuritis

The visual field (VF) defect in typical ON is usually characterized by a central scotoma with diffuse sensitivity reduction [35,36]. In the ONTT, almost all types of visual field defects were seen, including diffuse vision loss, arcuate, altitudinal, arcuate, hemianopic and cecocentral scotomas. Accordingly, perimetry is a helpless tool for the etiology diagnosis because is unspecific. Nonetheless, is helpful in order to rule out lesions in the optic chiasm and post- chiasm pathway by identifying bilateral defects which respect the vertical meridian. Traquair scotoma (union scotoma) is a rare pattern that was classically defined as a small superior- temporal scotoma in the fellow eye due to a lesion in the nasal fibers close to the optic chiasm. A defect that extends to the periphery should suggest a compressive lesion while an altitudinal defect is more common in AION [35,36]. VF defects usually have good prognosis and get improved while resolution of edema and VA takes place, independently of the initial severity (Figure 6). In the ONTT, almost 73 % of the patients had normalized VA at 10 years [37,38]. Automatic static perimetry has practically replaced kinetic perimetry (Goldmann). Humphrey full-threshold SITA standard VF has been the most widely perimetry used to study, not only optic neuropathies, but also the whole afferent vision pathway. Both horizontal and vertical VF meridians are best delineated with Humphrey rather than Octopus TOP. Nonetheless, variability of the VF is considerable during the follow up of these patients. Therefore, it may be replaced in the near future by other test with more sensitivity and reproducibility like OCT [39].

As we said before, MRI of the brain and orbits with gadolinium contrast provides confirmation of the diagnosis of acute demyelinating optic neuritis but it is not indispensable for the diagnosis. Global and longitudinal enhancement of the nerve is the typical pattern, and it`s extension has been shown to correlate with visual impairment and with visual prognosis [40,41]. Enhancement can persist for a mean of 30 days since onset, even after recovery of vision [42]. Davies MB et al. observed that signal abnormality in the nerve is also present in at least 60% of patients with MS who do not have a clinical history of optic neuritis [43]. Brain MRI is essential in these patients in order to determine the risk of developing MS in the near future. In ONTT, 40% of the patients presented white matter demyelinating abnormalities characteristic of MS, but other case series have noticed at least 40- 60% of MRI brain lesions at first episode of ON [44]. Global risk at 15 years is estimated as 50%, and gets increased with the number of lesions observed. Normal MRI reduces the risk of conversion to MS into 25%. Marques et al have recently reported a retrospectively evaluation of patients with normal brain MRI at the time of the first episode of ON to determine conversion to MS. 10 of the 42 patients developed MS during an 8-year follow-up, which suppose a less rate than reported in ONTT. Nonetheless, this study has a much lower sample size and the median follow up was too much shorter. Other reported data similar to ONTT was a more likely conversion when previous symptoms suggestive of MS, presence of cerebrospinal fluid oligoclonal bands and incomplete visual recovery were present. Optic disc swelling correlated with a lower MS conversion rate [45]. It is important to mention that a normal MRI does not protect from MS at 100%, the same way that pathological ones do not sentence the development of MS [45].

OCT measures the thickness in the peripapillary retinal nerve fiber layer (RNFL) without myelin and, therefore, quantifies the axonal injury, which has been shown to correlate with persistent visual dysfunction [46] (Table 3). Nevertheless, in acute phases the utility of OCT as a prognostic tool is limited in that abnormal values do not show up until early swelling disappears. In this phase, RNFL thickening appears (Figure 7). A month and half since the acute phase, RNFL thinning can be seen in most of patients (51- 74%) with optic neuritis, even if VA rises up to normality [47-49]. Recently, Kupersmith et al. prospectively studied the RNFL with OCT in 25 patients 1 month and 6 months after they had acute ON. They found that one month RNFL thickness correlated with 6-month thickness and thus could predict the structural outcome of the ON attack [50]. RNFL thinning is also common in patients with MS who do not have a clinical history of optic neuritis, but in a smaller range than ones who do [51]. Recently has been reported the significant correlation between RNFL thinning and atrophy of the posterior visual pathways and visual ina cross- sectional study with 100 patients with MS and posterior visual pathway damage [52]. Karl C Golnik suggests in a recent review that this could mean the possibility of transsynaptic degeneration [10]. Neither the presence or absence of disc edema, or it`s severity, have a prognosis value for visual outcome, RNFL thinning or VF defects in acute phase. The biological parameters that do really correlates with RNFL thinning are vision loss in the acute phase and the number of recurrences of ON. High-dose systemic steroid treatment does not affect final RNFL values [53]. RNFL thinning implies structural damage and a lower probability of VA recovery. A greater severity of optic nerve injury seen on OCT suggests neuromyelitis optica (NMO) rather than MS-ON [54]. OCT is a higher sensible test than perimetry for detection of subclinical damage once the acute phase has been resolved [55]. New macular layers segmentation softwares for Cirrus and Spectralis OCT have been recently studied in neuro-ophthalmologic patients. Gónzalez- López JJ et al. stated that macular ganglion cell-inner plexiform layer (GCIPL) thickness measured with Spectralis and Cirrus OCT had a better sensibility than peripapillary retinal nerve fiber layer (pRNFL) for detecting retinal thickness changes in patients with relapsingremitting multiple sclerosis [56]. Nonetheless, in one study, OCT was less sensitive than visual evoked response (VER) in detecting subclinical optic neuritis, seen as a delay in the P100 wave, which is the electrophysiological manifestation of slowed conduction in the optic nerve as a result of axonal demyelination [57]. After visual recovery, the pattern-shift visual evoked response can still be delayed in most patients [58].Thus, VER is useful to diagnose subclinical, latent, past or doubtful episodes of ON, but has not any value in the acute phase.

In a young adult with one clinical diagnosis of typical ON and normal MRI, atypical causes are exceptional. Therefore, if there are no other clinical findings, complementary test should not be performed.

Visual acuity recovery

Corticosteroids have been widely used for treatment in the acute phase of idiopathic or MS-ON. Patients in the ONTT were randomly assigned to either oral prednisone; intravenous methylprednisolone followed by oral prednisone or oral placebo. Patients were treated within eight days of symptom onset. The primary visual outcomes were VA and contrast sensitivity [59]. None of the treatment arms of the study overcame the natural history of the disease. Most of the patients reached spontaneously good visual outcomes. The main conclusion of this trial was that intravenous methylprednisolone accelerated the recovery of visual function; however one-year visual outcomes were similar among treatment groups. A meta-analysis of various trials, including this one, that compared treatment with intravenous methylprednisolone to placebo found no benefit of treatment on visual outcomes at six months and at one year [60]. The oral prednisone arm of the study was found to have a higher two-year risk of recurrent optic neuritis in both eyes, when compared with intravenous steroid therapy or with placebo. Nevertheless, a small randomized trial found out that oral methylprednisolone had a beneficial effect on visual function at one and three weeks compared with placebo, without differences between treatment groups with regard to visual outcome at eight weeks or to the risk of developing additional demyelinating events at one year [61]. Therefore, the observed risks associated with oral prednisone were only seen in ONTT, were unexpected and had no pathophysiological basis. The side effects of steroid treatment in this scenario are exceptional. The most common side effects in the ONTT were facial flushing, sleep perturbations, mood changes and weight gain [59]. Alternative treatments proposed for ON has been intravenous immunoglobulin (IVIG) and plasma exchange, but neither of them have proved efficacy (statistical difference in visual outcomes at six months) [62,63]. If VA rise up very fast after Corticosteroids treatment, other autoimmune causes should be suspected rather than MS- ON, such as sarcoidosis, lupus or vasculitis (see “atypical optic neuritis” below).

Figure 7:OCT. A. Cirrus OCT corresponding of the patients of Figure. 6. There is a significant thickening of RNFL (superior) in the acute phase (optic nerve head edema) with normal RNFL thickness within one year (inferior). B. Anterior ON in a young female patient with RNFL thickening in three of four quadrants. C. Within three months there is a diffuse pallor of the optic nerve head with severe thinning of the four quadrants. Courtesy of Spanish Society of Ophthalmology.

An important clinical decision in patients with optic neuritis is whether or not to begin immunomodulatory therapy in order to prevent, or at least delay, subsequent MS. The two bigger clinical trials that have studied this outcome have been CHAPMS (Controlled High- Risk Subjects Avonex Multiple Sclerosis Prevention Study) and ETOMS (Early Treatment of Multiple Sclerosis) [64,65]. Both of them studied interferon beta-1a as an immunomodulatory drug versus placebo (the first one by intramuscular administration and the second one by subcutaneous). The patients recruited had clinically isolated syndromes (192 ON in CHAPMS and 98 ON in ETOMS) and were at high risk for developing MS (defined as two or more demyelinating lesions on their brain MRI in CHAMPS and at least four white matter lesions or three lesions with at least one demonstrating gadolinium enhancement in ETOMS). Both trials concluded that the risk of developing significant MS was delayed after two years of follow up. Other clinical trials, which have evaluated interferon-1b (BENEFIT) and glatiramer acetate (PreCISe), also proved that early treatment in patients with clinically isolated syndromes, including optic neuritis, reduces the rate of MS development [66,67]. Posterior trials compared early with belated interferon therapy and concluded statistical differences between the disability progression, but the benefit of early treatment was clinically poor significant. Even more, this studies evaluated patients with a very high number of MRI lesions (>9) and multifocal syndromes. Thus, were not applicable to patients with isolate ON [68]. Common side effects of beta interferon treatment in these trials included depression, flu-like symptoms and injection site reactions; elevated liver enzymes were seen in a significant number of patients [66]. Newer immunotherapies for MS are currently being investigated (teriflunomide, alemtuzumab, fingolimod, dimethyl fumarate, natalizumab) and some of them are already being used. They offer advantages of efficacy or tolerability over the injectable therapies, but they also have greater risks [69].

Therefore, according to the actual knowledge, nowadays both the absence of treatment and intravenous or oral steroid treatment are justifiable attitudes. If the patients tolerates, immunomodulatory therapy should be offered in cases of high risk of conversion to MS (subclinical demyelinating lesions in MRI).

The common characteristics of atypical ON are summarized in Table 2. In children, para-infectious causes of optic nerve impairment should be considered as alternatives to MS- ON. It is very common the history of recent upper respiratory tract symptoms. Post-viral ON has been associated with measles, mumps, chickenpox, influenza, and Epstein-Barr, typically following the clinical infection by one to three weeks 58 [70]. Usually the prognosis is excellent with full vision recovery. Rappoport et al. reported a study with their experience and compared ten children and eight adults with para-infectious optic neuritis followed up for 8-years. They found that all patients had optic disc swelling and good visual outcomes. Nevertheless, children were more likely to have bilateral optic neuritis and disseminated encephalomyelitis [71]. They defined para-infectious optic neuritis as an ON occurring after an infectious disease (within one month), probably on an autoimmune basis.

As we have mentioned, in an older patient (>50 years old) ischemic optic neuropathy is the most likely diagnosis. Alternative diagnoses from idiopathic or MS- ON should be considered in patients with a painless or bilateral presentation; early corticosteroids responsive and corticosteroids unresponsive situations, the presence of neurologic or systemic symptoms and in immunocompromised patients.

Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON) should be consider in patients with subacute and painless vision loss in one eye, with sequential involvement of both eyes over a period of weeks to months; especially in those whose vision does not improve over time [72] . This disorder is inherited through a mitochondrial respiratory chain DNA mutation, so effects young males predominantly. Three mutations account for more than 90 percent of worldwide cases [73]. The classic fundus appearance in the acute phase includes pseudoedema of the optic nerve head with peripapillary telangiectasia and tortuous vessels (Figure 8). Nonetheless, one third of the patients can have a normal fundus exam [74]. Typically, fluorescein angiogram (FA) does not show peripapillary leakage. There are currently no proven treatments for LHON, but promising novel treatment modalities are being evaluated in several trials, such as Idebenone, a synthetic analog of coenzyme Q10 [75]. Nowadays, prognosis for recovery varies depending on the mutation [76].

Other acute, unilateral or painless presentations that could be misdiagnosed with ON are retinal vein occlusion and central serous chorioretinopathy. Fundus exam, FA and OCT are enough to confirm the diagnosis of these entities.

NMO (Devic disease) is an autoimmune demyelinating disorder which consist in ON (typically bilateral or unilateral rapidly sequential to the fellow eye) and transverse myelitis (TM) [77] (Figure 9). Attacks leads to severe vision loss and most often occur over days, generally with poor vision recovery over weeks to months. It has typically a relapsing course, and both anterior or retrobulbar optic nerve portion can be affected [78]. In this case, the prevalence in women is up to 10 times higher than in men [79]. The exactly pathogenesis remains unknown, but it is known that auto- antibodies IgG against Aquaporin-4 (AQP4), a water channel protein highly concentrated in spinal cord gray matter, causes an autoimmune inflammatory cascade that leads to demyelination and axonal injury through diverse pathways [80]. Lim et al reported recently that female sex and bilateral involvement at presentation are more likely in NMO patients than in MS-ON [81]. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders (NMOSD) have been reviewed [82]. Briefly, diagnosis confirmation of NMO should be done with at least one “clinical core characteristic” (ON/TM, simultaneously or not) and at least two of the three following criteria: spinal cord lesions in at least three adjacent segments, brain lesions not compatible with MS or a positive result for NMO antibodies (AQP4 IgG). Spinal lesions tend to be extended and hyperintense in T2 sequence. Petzold and Plant have published recently a review of autoimmune optic neuropathies in which recommend testing for NMO antibodies in all patients with severe, atypical, or recurrent optic neuritis [83]. Treatment includes intravenous glucocorticoids, followed by plasmapheresis and a long-term immunosuppression in order to prevent subsequent attacks. Recommended first-line treatments include azathioprine and rituximab. The relapse rate has been shown to be decreased with the use of rituximab in one study with 5-year follow-up [84]. Mycophenolate, methotrexate and mitoxanthrone are considered second-line treatments.

Figure 8:Leber's hereditary optic neuropathy. Superior. Both the left and the right images correspond to a young male with acute right anterior optic neuropathy (B) and rapidly sequential affection of the left eye (A). Notice the peripapillar telangiectasia. Inferior. C. FA showing absence of peripapillary leakage (pseudoedema). D. Evolution to optic atrophy. Courtesy of Spanish Society of Ophthalmology.

Figure 9:MRI of NMO. A. MRI coronal cut (sequence STIR- FLAIR) of the orbits showing bilateral hyperintensity and enhancement of both optic nerves (bilateral ON) (arrows). B. Four months later the patient developed TM. Cervical MRI sagittal cut showing hyperintense lesions in sequence T2 in C2- C7 segments (arrows). Courtesy of Spanish Society of Ophthalmology.

Chronic relapsing inflammatory optic neuritis

Chronic relapsing inflammatory ON (CRION) is a modern term that describes relapsing episodes of ON which are clearly responsive to corticosteroids, in patients with normal imaging test, CSF and serological testing for other autoimmune or infectious diseases [85]. This entity was initially evolved in the NMOSD, but it has been proved that only 5% of these patients are seropositive for AQP4 IgG [86]. Therefore, MS and NMO are the mainly differential diagnosis. Petzold Figure 10: Other atypical causes of optic neuropathy. A. Citomegalovirus retinitis in a patient with AIDS. B. Neuroretinitis: Notice the optic nerve swelling and the macular edema with hard exudates around the fovea. C. Sarcoid granuloma of the optic nerve head. D. Infiltrative optic neuropathy due to lekemia. Courtesy of Spanish Society of Ophthalmology. and Plant proposed revised criteria for diagnosis including at least 2 episodes of optic neuritis, NMO-IgG negative, contrast enhancement of the inflamed optic nerve in MRI and response to immunosuppressive treatment with relapse on withdrawal of treatment [87]. Treatment with intravenous steroids are necessary in the acute phases and immunosuppressing drugs, such as azathioprine, methotrexate, cyclophosphamide or mycophenolate, are obligated in order to prevent further episodes of ON [88-90].

Paraneoplastic ON has been described as a cause of bilateral ON, usually presented with subacute visual loss and other neurologic symptoms, including neuromuscular junction disorders (Lambert- Eaton myasthenic syndrome), autonomic neuropathy, dementia, ataxia and chorea [91]. It has also been described the association with paraneoplastic encephalomyelitis or retinitis [92]. This disorder is most commonly associated with lung cancer but other forms of cancer have been implicated [93]. Antibodies against collapsing response-mediator protein-5 (CRMP-5) seem to be a good biomarker for the diagnosis [94].

Relapsing forms of ON, especially closely after cessation of corticosteroids, is highly suggestive of an inflammatory optic neuropathy different from MS- ON or NMO. In this scenario, three main causes should be considered: sarcoidosis, vasculitis and systemic lupus erythematous (SLE). ON is the main neuro-ophthalmologic manifestation of neurosarcoidosis, usually with optic nerve head swelling (Figure 10). It can be caused through four main mechanisms: papilitis, posterior uveitis, granuloma of the optic nerve and ICH [95]. Vasculitis and SLE should be suspected in young patients with corticosteroid- responsive forms and serologic evidence of autoimmune disease. “Autoimmune ON” is a diagnosis of exclusion in which systemic manifestations are absent and MRI is normal, but nonspecific serologic autoimmune disorder is present (positive result for antinuclear antibodies, rheumatoid factor etc) or there is a cutaneous biopsy compatible with collagenous disease or vasculitis [96].

Figure 10:Other atypical causes of optic neuropathy. A. Citomegalovirus retinitis in a patient with AIDS. B. Neuroretinitis: Notice the optic nerve swelling and the macular edema with hard exudates around the fovea. C. Sarcoid granuloma of the optic nerve head. D. Infiltrative optic neuropathy due to lekemia. Courtesy of Spanish Society of Ophthalmology.

Compressive or infiltrative optic neuropathies

Persistent visual loss beyond four weeks of onset of ON, after corticosteroid treatment, generally signifies an alternative diagnosis. A compressive or infiltrative cause of optic neuropathy should be suspected in these cases. Thyroid eye disease frequently results in optic neuropathy from compression by enlarged extraocular muscles in the orbital apex. Orbital decompression is still generally considered to be the treatment of choice to alleviate this compressive optic neuropathy. Curro et al. retrospectively evaluated the efficacy of pulsed methylprednisolone for thyroid optic neuropathy in 44 of 24 patients and concluded that forty percent of patients had resolution of optic neuropathy without requiring orbital surgery [97]. Pituitary adenoma, carcinomatous meningitis, glioma, infiltrative leukemia o even aneurysms are possible etiologies. In this scenario, any clinical manifestation can be presented (acute, subacute, chronic vision loss, headache, orbital pain, etc.). Therefore, neuro-imaging tests are obligated for the diagnosis.

Infectious causes of optic neuropathy should be suspected in patients with history of potential exposures and/or immunosuppression. A 7% of patients seropositive for HIV with cerebral toxoplasmosis, cryptococcus or tuberculous meningitis present papilitis. Neuretinitis is a descriptive diagnosis that present with vision loss, optic nerve head edema along subretinal fluid and macular edema, usually with hard exudates in the posterior pole. Bartonella Henseale (cat scratch disease) and Borrelia Burgdorferi (Lyme disease) are usual suspects [98] (Figure 10).

The diagnosis of ON is mainly clinical. Typical cases of ON are defined as painful, monocular visual loss evolving over several hours to a few days, in young adults with generally good prognosis. One-third of these patients have visible optic nerve inflammation on funduscopic examination; in the remainder, the inflammation is retrobulbar. This clinical pattern is more likely due to a demyelinating process and closely associated with MS, although sometimes occurs in isolation. Typical ON tends to resolves spontaneously. Both the absence of treatment and intravenous or oral steroid treatment are justifiable attitudes. Experts recommend treatment if visual loss is functionally disabling or if the patient has pre-existing visual impairment of the other eye. Immunomodulatory therapy should be offered in cases of high risk of conversion to MS (subclinical demyelinating lesions in MRI). In cases of first clinical diagnosis of typical ON and normal MRI, atypical causes are exceptional. Brain MRI is essential in patients with typical ON in order to determine the risk of developing MS. Other complementary tests that should be performed in this patients are VF perimetry and OCT. VER is useful to diagnose past or doubtful episodes of ON, but has not any value in the acute phase. If atypical features develop or recovery does not begin, the atypical pathway for investigations and treatment should be performed. Higher dose of intravenous corticosteroids and, sometimes, chronic immunosuppression, are frequently required. If untreated, atypical ON can lead to irreversible visual loss.

The first author thanks Dr. Muñoz Negrete, Dra. Rebolleda Fernández and the Spanish Society of Ophthalmology for the awarding of the images shown in this article. Most of them appears in the book “Protocolos en Neuro- oftalmología. Mesa Redonda. Sociedad Española de Oftalmología. Madrid, 2010. Rebolleda G, Muñoz- Negrete FJ.” None of the authors has conflict of interest and no financial support was received.

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