Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.149370
Source of Support: None, Conflict of Interest: None
Visual loss consequent to anterior visual pathway involvement can occur in a variety of clinical settings. In a tropical country like India, apart from the usual suspects, nutritional, infective, and toxic amblyopia have to be considered in the differential diagnosis. The mode of onset (acute/chronic), unilateral versus bilateral involvement, accompanying occular pain or the lack of it, and pattern of visual loss are some of the pointers which help to differentiate optic neuropathy clinically. The presence of concurrent neurological deficits, evidence of other systemic illnesses, and the results of serological and radiological investigations help to confirm the diagnosis. This article briefly describes the important causes of optic neuropathy in the Indian context and outlines a practical approach to management.
Keywords: Ischemic optic neuropathy, multiple sclerosis, neuromyelitis optica, optic neuropathy, toxic optic neuropathy
Visual loss is a frequently encountered symptom in neurologic practice. It may occur in the background of established metabolic disorders like diabetes mellitus or appear as a primary symptom of neurological dysfunction. A thorough clinical examination allows the streamlining of investigations such as magnetic resonance imaging (MRI) scan of the brain/orbit, optical coherence tomography (OCT), electrophysiological studies such as visual evoked potentials (VEP), serology, and genetic studies.
A good clinical history is important. Patients with acute onset visual loss and those with central loss of vision are aware of their dysfunction early in the course of disease. On the other hand, visual loss may go undetected because of preservation of binocular visual acuity. In disease like multiple sclerosis (MS), the impaired visual loss may be subclinical.
Tempo of visual loss- Acute versus subacute/chronic: An ischemic optic neuropathy may be sudden and painless as opposed to a compressive optic nerve pathology which is insidious and progressive.
Ocular pain: Pain related to eye movement is a classical feature of retrobulbar neuritis. The ocular muscle takes origin from the annulus of Zinn, which closely envelopes the optic nerve sheath. Inflammation of the optic nerve causes painful eye movements as a consequence of its proximity to the extraocular muscle. 
Age at onset: Elderly patients with concomitant history of weight loss, myalgia, and fatigue accompanied by temporal pain are more likely to have an arteritic form of ischemic optic neuropathy due to temporal arteritis. Young onset, acute unilateral painful visual loss particularly in young women may herald the first attack of optic neuritis (OPN) associated with MS, whereas the same in an elderly woman may be a sign of neuromyelitis optica (NMO).
Concomitant illness: Coexisting hypertension, diabetes, and hyperlipidemia favor a diagnosis of non-arteritic ischemic optic neuropathy.
Drug/Toxin history: Drug-induced optic neuropathy may be seen particularly with Ethambutol, Amiodarone, and anti-cancer drugs. Inquiry into the patient's general health, eating and social habits (drinking, smoking) is important in suspected toxic/nutritional optic neuropathy.
Family history: Hereditary disorders of autosomal and mitochondrial origin may present with optic atrophy and visual dysfunction. History of familial blindness is therefore useful.
Clinical examination: Prior to interpreting visual loss, refractive error must be excluded by asking the patient to read with his or her prescription glasses or reading through a pin hole (Pinhole test). Loss of visual acuity, color desaturation, and a relative afferent pupillary defect (RAPD) are common for all forms of optic neuropathies. The commonly used Snellen's chart tests for high-contrast central vision. Subtle visual loss may be picked up by doing a low-contrast visual acuity testing.  Loss of color vision disproportionate to visual acuity is typical. Axons connecting cone photoreceptors to the retinal ganglion cells make up a significant portion of the optic nerve and hence are affected disproportionately in optic nerve dysfunction. The RAPD test is not useful if there is bilateral optic neuropathy.
Pattern of visual loss often offers a clue to underlying diagnosis. Central visual loss is characteristic of OPN and compressive etiology. Ischemic optic neuropathy produces field defects that start from the blind spot but respect the horizontal meridian (according to arrangement of the retinal nerve fiber layers). A fundoscopic examination to examine the optic disc provides useful information. Disc edema can be easily differentiated from pseudo papilledema (myelinated nerve fibers, optic nerve head Drusen) by looking for the peri pappillary blood vessels which are hazy in true papilledema but clearly visualized in other situations.
Etiology of optic neuropathy
Causes of optic neuropathy may be broadly divided into inflammatory, infective, ischemic, toxic, metabolic, and heriditary [Table 1].
OPN is characterized by inflammation of the optic nerve [Table 2]. Classically it presents with ocular pain which often precedes visual loss and is typically associated with dyschromatopsia. After-recovery patients may have glare intolerance, reduced vision in bright light, or have Uthoff or Pullfrich phenomenon.  Uthoff phenomenon is characterized by worsening of vision when the core body temperature increases as when taking a hot bath, fever, stress, increase in ambient temperature, etc., It is due to transient conduction block and is typically seen during the recovery phase of OPN. Impaired perception of movement in depth is referred to as Pullfrich phenomenon. It can be typically tested with a swinging pendulum against a contrasting background. Patients with recovering OPN may not appreciate the direction of trajectory and report that the pendular movements are ellipsoid.
Inflammatory optic neuropathy of idiopathic origin constitutes an important differential diagnosis for acute onset painful unilateral (less often bilateral) visual loss. Immediate recognition and treatment are important for recovery of good visual functions. Besides OPN may be the initial clinical presentation of major neurological disorders such as MS and NMO. Occasionally, OPN recurs without any central nervous system involvement and is steroid responsive. The latter entity when it is steroid dependent is called relapsing idiopathic optic neuritis (RION) and when chronically recurrent as chronic relapsing idiopathic optic neuritis (CRION).
OPN related to MS
MS is moderately prevalent in India.  Clinical and demographic features are similar to that in the west. Several Indian studies have shown that OPN is the initial manifestation in 23.6-53.3% of patients with MS. , Long-term observational studies suggest that nearly 50% of patients with idiopathic OPN develop MS over the long term.  An abnormal MRI of the brain at disease onset is a strong predictor of conversion to MS. The hallmark of OPN in MS is acute onset unilateral visual loss accompanied by pain in predominantly young women in the second and third decade of life. Dyschromatopsia and relative afferent pupillary defect (RAPD ) are supportive of the diagnosis. Recovery of vision is generally good after a standard course of intravenous methyl prednisolone (1g daily for 5 days). It is mandatory that every patient with a diagnosis of OPN be kept under careful long-term follow-up and particularly when the initial brain MRI is abnormal.
OPN related to NMO
OPN is one of the absolute criteria required apart from long-segment myelitis for the diagnosis of NMO. It may be unilateral or occasionally be a sequential or simultaneous bilateral event. Clinical symptoms of OPN in NMO cannot be differentiated from that of MS, although visual loss tends to be more severe in former.  Seropositive recurrent OPN is one of the NMO spectrum disorders (NMOS) and need to be treated in the same manner as NMO with non-steroidal immunosuppressants indefinitely.
Chronic relapsing inflammatory optic neuritis
This terminology was coined before the revised diagnostic criteria for NMO and the term NMO spectrum disorders came into existence.  It was initially used to describe steroid-responsive recurrent OPN with normal brain MRI imaging. With the availability of a diagnostic test for NMO, some patients initially diagnosed as CRION are now recognized as seropositive NMO spectrum disorders. While the status of CRION and seronegative ROPN remain unclear, it is reassuring that treatment strategy for both these entities remain the same. Chronic immunosuppression preferably with non-steroidal drugs such as mycophenolate mofetil and azathioprine are the choice of treatment.
Post infectious/post vaccination OPN
Most often seen in childhood, it is often bilateral and simultaneous. Visual recovery is generally good in pediatric age-group though the outcome is frequently poor in adults. It may also be seen as a manifestation of acute disseminated encephalomyelitis (ADEM).
Optic neuritis associated with infections
OPN may occur in isolation or associated with other neurologic/opthalmic complication of infections. Sub-acute progressive visual loss in the background of fever or systemic infection is a typical presentation.
Some of the viral infections commonly implicated in the causation of OPN include herpes simplex virus (HSV1 and 2), varicella, Epstein-Barr virus (EBV), heptatis B, measles, mumps, rubella, and coxsackie. More common in children, they present as bilateral acute visual loss following a symptomatic infective prodrome of 1-4 weeks. It is usually self-limited with good recovery of visual function. In human immunodeficiency virus (HIV)-associated OPN visual loss is most often due to opportunistic infection with toxoplasmosis, Cryptococcus, tuberculosis, or varicella among others. More rarely it may result from a direct toxic effect of HIV-1 on retinal ganglion cells and optic nerve when it is associated with a progressive decline in visual function that is unresponsive to treatment.
Bacterial infections may result in OPN by a variety of mechanisms including direct infection of the optic nerve during meningitis, compression from an abscess, an infective endarteritis, or raised intracranial tension. In tuberculosis (TB), optic neuropathy may arise as result of infiltration of the optic nerve or chiasma by granulation inflammation, by compression from a tuberculoma, or during treatment with ethambutol.
Fungal OPN is more common in immunocompromised patients. Aspergillus and Cryptococcus infection are particularly important causes. Often subacute in onset, they have an indolent course. Recovery of vision is generally poor.
Ischemic optic neuropathies
Ischemic optic neuropathies may be anterior or posterior (AION and PION) and are further subdivided into arteritic and non-arteritic (NA) types.
These forms are much more common and are usually due to transient non/hypoperfusion of the optic nerve head circulation. Predisposing risk factors include hypertension, diabetes mellitus, and ischemic heart disease. Rarely embolism of arteries/arterioles feeding the optic nerve head may cause the same. Majority of patients notice visual loss on awakening in the morning which is painless. Fundoscopic examination may reveal disc edema which resolves spontaneously over 6-8 weeks, leaving behind optic pallor. Patients typically describe altitudinal hemianopsia and have often involvement of inferior nasal quadrants on visual field testing. No definitive treatment is available. 
Giant cell arteritis (GCA) is the primary cause of arteritic-AION. It has a special predilection for involving the posterior ciliary artery resulting in its thrombotic occlusion. It is much more common among women (70%) and among caucasians. Clinically GCA often presents as sudden and painless visual loss. Associated systemic symptoms includes jaw claudication, headache, scalp/temporal artery tenderness, neck pain, and myalgia. Elevated sedimentation rate (ESR) and C-reactive protein (CRP) are highly suggestive. Temporal artery biopsy is confirmatory. One should not wait for the biopsy for starting treatment, which should be immediate. High-dose steroids (intravenous, IV, methyl prednisolone 1g daily for 3-5 days followed by oral prednisolone in the dose of 1-2 mg/kg/day to be tapered over 12-18 months) followed by a maintenance dose of 5-7.5 mg/day lifelong is to be given. 
Toxic and nutritional optic neuropathies
The anterior visual pathway may be affected by toxic/nutritional deficiencies which cause papillomacular bundle damage. Both toxicity and malnutrition acting independently or together have been implicated in the pathogenesis of these disorders. Though classified under optic neuropathy, the primary lesion may be localized to even retinal ganglion cells, nerve fiber layers, chiasm, or even the optic tracts.
Most patients have multifactorial etiologies which include alcohol, tobacco abuse, and malnutrition. Concommitant deficiency of vitamin B12, thiamine, other B vitamins (riboflavin, niacin, pyridoxine), and folic acid may play a role. All deficiencies/toxicities affect mitochondrial oxidative phosphorylation and may be considered as acquired mitochondrial optic neuropathies.
Clinical features of toxic/nutritional optic neuropathy include painless bilateral and simultaneous visual loss of subacute onset. Dyschromatopsia is present early and may be the initial symptom. Patients often notice a blur at the point of fixation early in the disease course followed by progressive decline. Severe blindness limited to light perception is unusual except in methanol poisoning. On examination, presence of a central or centrocecal scotoma with sparing of peripheral visual field is typical. Pupils have normal responses to light and near stimulation except in methanol poisoning. In the early stages, the disc is normal, slightly hyperemic, or swollen. Optic atrophy develops after a variable interval.
Ethambutol causes optic neuropathy in 1-5% of patients in the dose of 25 mg/kg/day or more and in around 1% of patients receiving the currently recommended dose of 15-25 mg/kg/day. It takes an average of 2-8 months for the symptoms to appear but it may be earlier especially if there is concurrent renal disease. Chelation of copper or zinc containing enzymes within human mitochondria is the suggested mechanism for optic neuropathy. Dyschromatopsia is the earliest sign of toxicity and blue-yellow color changes are most common. OCT can quantify the loss of retinal nerve fibers earlier before the fundus changes become apparent. It is ideal to have baseline ophthalmological examination including visual acuity, color vision, and visual fields at the commencement of Ethambutol therapy. It should be repeated every 1-3 months during the treatment course. Once toxicity is detected, therapy with ethambutol should be immediately stopped. In most instances, visual recovery is complete over a period of time after stopping medications.  Occasionally, visual deficits may be permanent. 
Vitamin B12 deficiency
Deficiency of vitamin B12 whether from inadequate diet or interference with absorption can cause optic neuropathy. Lesions in the optic nerve and optic chiasm have been demonstrated. Optic nerve involvement may be subclinical. Abnormal VEP can be recorded in patients with pernicious anemia who have no visual symptoms. Unless optic atrophy becomes established, one can expect recovery of vision with treatment.  Serum vitamin B12 assay is important in all cases of unexplained bilateral optic neuropathy. A megaloblastic bone marrow is virtually diagnostic of vitamin B12 deficiency.
Visual loss results from damage to the pappilomacular bundle after years of chronic smoking. Optic nerve is usually normal, but peripapillary dilated vessels and hemorrhages are described. Vision loss may precede optic disc changes and may be detected early by OCT. Many patients have concurrent nutritional deficiencies and visual improvement seems to be related to improved nutrition. Gradual improvement is noted after cessation of smoking, vitamin B12, folic acid, and thiamine supplementation.
Methanol poisoning is not an uncommon cause of visual loss in tropical settings particularly in developing countries. Poisoning results from consumption of adulterated alchoholic beverages or from accidental/suicidal consumption of methanol. Methanol by itself is fairly non-toxic. It is metabolized in the liver by the enzyme alchohol dehydrogenase to formic acid. Within 6-24 hours of consumption severe metabolic acidosis, blindness, and cerebral dysfunction sets in. Treatment consists of general measures such as gastric lavage, treatment of acidosis, and administration of antidotes like Ethanol or Fomepizole (an alcohol dehydrogenase inhibitor). IV Methyl prednisolone and hemodialysis have been helpful in some cases. , Visual recovery is most likely with early intervention.
Connective tissue disorders and systemic vasculitis
Among connective tissue disorders, systemic lupus erythamatosis (SLE) may present as acute OPN or as a progressive optic neuropathy. Mixed connective tissue disorders are rarely reported to have relapsing bilateral optic neuropathy that is unresponsive to treatment. It is usually associated with anti- Sjogren Snydrome-A (SS-A) and anti- ribonucleoprotein (RNP) antibodies. Optic nerve may be compressed by inflammatory orbital mass or be compromised by vasculitis in Wegeners granulomatosis. Aggressive therapy with steroids may improve visual functions in the latter. Rheumatoid arthritis and polyarteritis nodosa can uncommonly present with anterior ischemic optic neuropathy.
Other uncommon causes include systemic inflammatory disorders, such as sarcoidosis and Behcet's disease, neurodegenrative and inherited disorders which are listed in [Table 1].
Investigations for optic neuropathy
Once the differential diagnosis has been narrowed down based on history and clinical examination, investigations should be tailored to suit the diagnosis [Table 3].
MRI of brain and orbit: In suspected cases of OPN, it is mandatory to do contrast MRI of the brain. The MRI protocol for the orbit should include coronal fat suppressed T2-weighted (T2W) and T1W (fat suppressed) post-contrast images.  Standard imaging protocols previously established for the brain and cord for MS should be followed.  An abnormal brain at onset of OPN has a high predictive value for conversion to MS. The typical MRI features of OPN include hyperintense signals on T2W images with swelling of the optic nerve. Contrast enhancement may be seen. In old cases of OPN, thinning of the optic nerve with hyperintense signals on T2 weighted imaging will be seen. Patients with NMO have more extensive involvement of the optic nerve especially in the intracranial as opposed to the intraorbital segment.  Involvement of the optic chiasm and bilateral involvement is more common [Figure 1].
Optical coherence tomography: OCT provides high-resolution images of posterior eye structures, such as the retina. It gives an accurate measurement of the thickness of retinal layers.  Thinning of the retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) can be observed more than 3 months after an attack of OPN. A difference of RNFL values of more than 20% between the two eyes may suggest a previous "subclinical" episode. RNFL and GCL thinning is more pronounced in NMO and CRION as compared to MS-associated OPN.  Wedge-like thinning of the RNFL should arouse the suspicion of ischemic pathology such as AION. Thickening of the inner nuclear layer (INL) may be seen and is often associated with microcystic macular edema (MMO), otherwise known as retrograde maculopathy. MMO is strongly associated with NMO than MS associated OPN.  However, it is to be noted that MMO is not specific for OPN and can be observed in a host of ophthalmological conditions.
Visual evoked potentials: It is highly sensitive but not specific for OPN. VEP may be abnormal in retinal diseases and refractive errors. It is highly recommended that interpretation of an abnormal VEP in the background of visual loss should be done in conjuction with an electroretinogram (which provides information about the photoreceptors and retinal functions). In the acute phase of visual loss, there may be a fall in amplitude and delay in P100 latency which may be seen in both OPN and AION. Repeating the VEP at a later date may show P100 latency being further prolonged in OPN with improvement in amplitude (with resolution of conduction block). In AION, there will be no improvement in amplitude of VEP over time.
In most patients with optic neuropathy, there is no requirement for routine blood test and cerebrospinal fluid examination. Serum vitamin B12, folic acid, and methyl malonic acid levels can be done in suspected nutritional cause of OPN. In NMO, vitamin B12 levels may be low. For systemic and ischemic diseases, ESR, C reactive proteins, and serum angiotensin converting enzyme levels may be checked. Serum anti-nuclear antibody may be evaluated initially for the investigation of suspected collagen vascular disorders. If the test is positive, it may be cost-effective to do more targeted auto-antibody screening. 
Testing for NMO-IgG
This test should be done in a standardized laboratory using cell-based assay which are likely to be most sensitive.  Serum samples should be collected prior to starting steroid therapy and the mandatory cold chain has to be ensured during sample transport. Recurrent OPN, bilateral OPN, and OPN associated with poor recovery of visual function definitely need to be tested for NMO-IgG.
Diagnosing the cause of optic neuropathy in a clinical practice setting is not easy. Visual loss is accompanied by color desaturation and often a positive RAPD in a variety of clinical conditions. While recent knowledge about ischemic and toxic causes of optic neuropathy have not changed, the spectrum of OPN has expanded enormously in the last decade. We now know that OPN may be the initial manifestation of a number of closely related disorders that require an early and accurate diagnosis for treatment to be successful. Successful treatment algorithms have evolved from better imaging modalities such as OCT, refined MRI protocols for accurate diagnosis, and the availability of specific biomarkers such as NMO-IgG. A good clinical history and examination supported by a judicial choice of investigations and the knowledge of the different conditions that result in optic neuropathy allow for a quick diagnosis and early intervention.
[Table 1], [Table 2], [Table 3]