AON is a rare disease and the natural history of the disease process is not well defined. Unlike typical optic neuritis, there is no association with multiple sclerosis, but the visual prognosis for AON is worse than typical optic neuritis. Thus AON patients have different treatment, and often receive chronic immunosuppression. No formal recommendation can be made regarding the best therapeutic approach. However, the available evidence to date supports treatment with corticosteroids and other immunosuppressive agents.

Early diagnosis and prompt treatment with systemic corticosteroids may restore some visual function but the patient may remain steroid dependent; vision often worsens when corticosteroids are tapered. As such, long-term steroid-sparing immunosuppressive agents may be required to limit the side-effects of steroids and minimize the risk of worsening vision.

Based on the presence of extraocular findings, such as neurological, auditory and integumentary manifestations, the "revised diagnostic criteria" of 2001 classify the disease as complete (eyes along with both neurological and skin), incomplete (eyes along with either neurological or skin) or probable (eyes without either neurological or skin) . By definition, for research homogeneity purposes, there are two exclusion criteria: previous ocular penetrating trauma or surgery, and other concomitant ocular disease similar to VKH disease.

AQP4-Ab-negative NMO presents problems for diagnosis. The behavior of the oligoclonal bands respect MS can help to establish a more accurate diagnosis. Oligoclonal bands in NMO are rare and they tend to disappear after the attacks, while in MS they are nearly always present and persistent.

It is important to notice for differential diagnosis that, though uncommon, it is possible to have longitudinal lesions in MS

Other problem for diagnosis is that AQP4ab in MOGab levels can be too low to be detected. Some additional biomarkers have been proposed.

The Mayo Clinic proposed a revised set of criteria for diagnosis of Devic's disease in 2006. Those new guidelines require two absolute criteria plus at least two of three supportive criteria. In 2015 a new review was published by an international panel refining the previous clinical case definition but leaving the main criteria unmodified:

Absolute criteria:

1. Optic neuritis

2. Acute myelitis

Supportive criteria:

1. Brain MRI not meeting criteria for MS at disease onset

2. Spinal cord MRI with continuous T2-weighted signal abnormality extending over three or more vertebral segments, indicating a relatively large lesion in the spinal cord

3. NMO-IgG seropositive status (The NMO-IgG test checks the existence of antibodies against the aquaporin 4 antigen.)

If tested in the prodromal phase, CSF pleocytosis is found in more than 80%, mainly lymphocytes. This pleocytosis resolves in about 8 weeks even if chronic uveitis persists.

Functional tests may include electroretinogram and visual field testing. Diagnostic confirmation and an estimation of disease severity may involve imaging tests such as retinography, fluorescein or indocyanine green angiography, optical coherence tomography and ultrasound. For example, indocyanine green angiography may detect continuing choroidal inflammation in the eyes without clinical symptoms or signs. Ocular MRI may be helpful and auditory symptoms should undergo audiologic testing. Histopathology findings from eye and skin are discussed by Walton.

The diagnosis of VKH is based on the clinical presentation; the diagnostic differential is extensive, and includes (almong others) sympathetic ophthalmia, sarcoidosis, primary intraocular B-cell lymphoma, posterior scleritis, uveal effusion syndrome, tuberculosis, syphilis, and multifocal choroidopathy syndromes.

There is no specific pathological testing or technique available for the diagnosis of the disease, although the International Study Group criteria for the disease are highly sensitive and specific, involving clinical criteria and a pathergy test. Behçet's disease has a high degree of resemblance to diseases that cause mucocutaneous lesions such as "Herpes simplex" labialis, and therefore clinical suspicion should be maintained until all the common causes of oral lesions are ruled out from the differential diagnosis.

Visual acuity, or color vision loss with concurrent mucocutaneous lesions or systemic Behçet's disease symptoms should raise suspicion of optic nerve involvement in Behçet's disease and prompt a work-up for Behçet's disease if not previously diagnosed in addition to an ocular work-up. Diagnosis of Behçet's disease is based on clinical findings including oral and genital ulcers, skin lesions such as erythema nodosum, acne, or folliculitis, ocular inflammatory findings and a pathergy reaction. Inflammatory markers such ESR, and CRP may be elevated. A complete ophthalmic examination may include a slit lamp examination, optical coherence tomography to detect nerve loss, visual field examinations, fundoscopic examination to assess optic disc atrophy and retinal disease, fundoscopic angiography, and visual evoked potentials, which may demonstrate increased latency. Optic nerve enhancement may be identified on Magnetic Resonance Imaging (MRI) in some patients with acute optic neuropathy. However, a normal study does not rule out optic neuropathy. Cerebrospinal fluid (CSF) analysis may demonstrate elevated protein level with or without pleocytosis. Imaging including angiography may be indicated to identify dural venous sinus thrombosis as a cause of intracranial hypertension and optic atrophy.

AON was first described in 1982. It presents with visual loss and signs of optic nerve dysfunction, such as loss of color vision, afferent pupil defect, and sometimes abnormalities of the optic disc. The clinical features of AON can be variable and present in several unilateral or bilateral forms:

- Acute anterior or retrobulbar optic neuritis sometimes associated with pain.

- Anterior or retrobulbar ischemic optic neuropathy not associated with pain.

- Chronic progressive vision loss that mimics a compressive lesion.

The main features that differentiate AON from the more common typical demyelinating optic neuritis is the poor recovery of vision and the chronic or recurrent or bilateral course of AON. Furthermore, the workup for multiple sclerosis including MRI, will be negative. Thus, it may be necessary to diagnose AON after a period of observation, noting the problem is not behaving as expected for demyelinative disease.

In most MS-associated optic neuritis, visual function spontaneously improves over 2–3 months, and there is evidence that corticosteroid treatment does not affect the long term outcome. However, for optic neuritis that is not MS-associated (or atypical optic neuritis) the evidence is less clear and therefore the threshold for treatment with intravenous corticosteroids is lower. Intravenous corticosteroids also reduce the risk of developing MS in the following two years in patients with MRI lesions; but this effect disappears by the third year of follow up.

Paradoxically, oral administration of corticosteroids in this situation may lead to more recurrent attacks than in non-treated patients (though oral steroids are generally prescribed after the intravenous course, to wean the patient off the medication). This effect of corticosteroids seems to be limited to optic neuritis and has not been observed in other diseases treated with corticosteroids.

A Cochrane Systematic Review studied the effect of corticosteroids for treating people with acute optic neuritis. Specific corticosteroids studied included intravenous and oral methylprednisone, and oral prednisone. The authors conclude that current evidence does not show a benefit of either intravenous or oral corticosteroids for rate of recovery of vision (in terms of visual acuity, contrast sensitivity, or visual fields)..

According to the International Study Group guidelines, for a patient to be diagnosed with Behçet's disease, the patient must have oral (aphthous) ulcers (any shape, size, or number at least 3 times in any 12 months period) along with 2 out of the following 4 "hallmark" symptoms:

- eye inflammation (iritis, uveitis, retinal vasculitis, cells in the vitreous)

- genital ulcers (including anal ulcers and spots in the genital region and swollen testicles or epididymitis in men)

- pathergy reaction (papule >2 mm dia. 24–48 hrs or more after needle-prick). The pathergy test has a specificity of 95 percent to 100 percent, but the results are often negative in American and European patients

- skin lesions (papulo-pustules, folliculitis, erythema nodosum, acne in post-adolescents not on corticosteroids)

Despite the inclusive criteria set forth by the International Study Group, there are cases where not all the criteria can be met and therefore a diagnosis cannot readily be made. There is however a set of clinical findings that a physician can rely upon in making a tentative diagnosis of the disease; essentially Behçet's disease does not always follow the International Study Group guidelines and so a high degree of suspicion for a patient who presents having any number of the following findings is necessary:

- arthritis/arthralgia

- cardio-vascular problems of an inflammatory origin

- changes of , psychoses

- deep vein thrombosis

- epididymitis

- extreme exhaustion

- inflammatory problems in chest and lungs

- mouth ulcers

- nervous system symptoms

- problems with hearing or balance

- stomach or bowel inflammation

- superficial thrombophlebitis

- any other members of the family with a diagnosis of Behçet's disease.

Prompt diagnosis is critical, since the sudden blindness in the one eye is often followed, within days, by similar sudden blindness in the second eye. Treatment may prevent further damage (see below). Any patient diagnosed with non-arteritic AION over the age of 50 must be asked about the constitutional symptoms mentioned above. Furthermore, AION patients over the age of 75 should often be blood tested regardless.

The repetition of an idiopathic optic neuritis is considered a distinct clinical condition, and when it shows demyelination, it has been found to be associated to anti-MOG and AQP4-negative neuromyelitis optica

When an inflammatory recurrent optic neuritis is not demyelinating, it is called "Chronic relapsing inflammatory optic neuropathy" (CRION)

When it is anti-MOG related, it is demyelinating and it is considered inside the anti-MOG associated inflammatory demyelinating diseases.

Diagnosis of AIR can be difficult due to the overlap of symptoms with other disorders. Examination of the fundus (inner surface of eye) can show no results or it can show narrowing of the blood vessels, abnormal colouration of the optic disc, and retinal atrophy. Fundus examination results are not indicative of autoimmune retinopathy but they are used to initiate the diagnostic process. An electroretinogram (eye test used to see abnormalities in the retina) is used to detect AIR. An abnormal electroretinogram (ERG) with respect to light and dark adaptations indicates AIR. The ERG also allows differentiation between cancer-associated retinopathy and melanoma-associated retinopathy. If the ERG shows cone responses, CAR can be prematurely diagnosed. If the ERG shows a significant decrease in b-wave amplitude, MAR can be prematurely diagnosed. To confirm, analysis for anti-retinal antibodies through Western blotting of serum collected from the patient is done.

Diagnosis is made by an ophthalmologist during eye examination. Further tests such as fluorescein angiography or lumbar puncture are usually performed to confirm the diagnosis.

Neurosarcoidosis is a similar autoimmune disorder that can be confused with APMPPE.

Myelitis has an extensive differential diagnosis. The type of onset (acute versus subacute/chronic) along with associated symptoms such as the presence of pain, constitutional symptoms that encompass fever, malaise, weight loss or a cutaneous rash may help identify the cause of myelitis. In order to establish a diagnosis of myelitis, one has to localize the spinal cord level, and exclude cerebral and neuromuscular diseases. Also a detailed medical history, a careful neurologic examination, and imaging studies using magnetic resonance imaging (MRI) are needed. In respect to the cause of the process, further work-up would help identify the cause and guide treatment. Full spine MRI is warranted, especially with acute onset myelitis, to evaluate for structural lesions that may require surgical intervention, or disseminated disease. Adding gadolinium further increases diagnostic sensitivity. A brain MRI may be needed to identify the extent of central nervous system (CNS) involvement. Lumbar puncture is important for the diagnosis of acute myelitis when a tumoral process, inflammatory or infectious cause are suspected, or the MRI is normal or non-specific. Complementary blood tests are also of value in establishing a firm diagnosis. Rarely, a biopsy of a mass lesion may become necessary when the cause is uncertain. However, in 15–30% of people with subacute or chronic myelitis, a clear cause is never uncovered.

Below are various methods/techniques used to diagnose demyelinating diseases.

- Exclusion of other conditions that have overlapping symptoms

- Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to visualize internal structures of the body in detail. MRI makes use of the property of nuclear magnetic resonance (NMR) to image nuclei of atoms inside the body. This method is reliable because MRIs assess changes in proton density. "Spots" can occur as a result of changes in brain water content.

- Evoked potential is an electrical potential recorded from the nervous system following the presentation of a stimulus as detected by electroencephalography (EEG), electromyography (EMG), or other electrophysiological recording method.

- Cerebrospinal fluid analysis (CSF) can be extremely beneficial in the diagnosis of central nervous system infections. A CSF culture examination may yield the microorganism that caused the infection.

- Quantitative proton magnetic resonance spectroscopy (MRS) is a non-invasive analytical technique that has been used to study metabolic changes in brain tumors, strokes, seizure disorders, Alzheimer's disease, depression and other diseases affecting the brain. It has also been used to study the metabolism of other organs such as muscles.

- Diagnostic criteria refers to a specific combination of signs, symptoms, and test results that the clinician uses in an attempt to determine the correct diagnosis.

- Fluid-attenuated inversion recovery (FLAIR) uses a pulse sequence to suppress cerebrospinal fluid and show lesions more clearly, and is used for example in multiple sclerosis evaluation.

The diagnosis of toxic or nutritional optic neuropathy is usually established by a detailed medical history and careful eye examination. If the medical history clearly points to a cause, neuroimaging to rule out a compressive or infiltrative lesion is optional. However, if the medical history is atypical or does not clearly point to a cause, neuroimaging is required to rule out other causes and confirm the diagnosis. In most cases of suspected toxic or nutritional optic neuropathy that require neuroimaging, an MRI scan is obtained. Further testing, guided by the medical history and physical examination, can be performed to elucidate a specific toxin or nutritional deficiency as a cause of the optic neuropathy. Examples include blood testing for methanol levels or vitamin B levels.

Individuals with a history of high blood pressure, diabetes, and smoking are most susceptible to PION as they have a compromised system of blood vessel autoregulation. Hence, extra efforts may need to be taken for them in the form of careful or staged surgery or the controlling the anemia from blood loss (by administration of blood transfusions), and the careful maintenance of their blood pressure.

A thorough history is essential and should cover family history, diet; drug/toxin exposure social history, including tobacco and alcohol use; and occupational background, with details on whether similar cases exist among coworkers. Treatment of any chronic disease such as pernicious anemia should always be elucidated.

In most cases of nutritional/toxic optic neuropathy, the diagnosis may be obtained via detailed medical history and eye examination. Additionally, supplementary neurological imaging studies, such as MRI or enhanced CT, may be performed if the cause remains unclear.

When the details of the examination and history indicate a familial history of similar ocular or systemic disease, whether or not there is evidence of toxic or nutritional causes for disease, certain genetic tests may be required. Because there are several congenital causes of mitochondrial dysfunction, the patients history, examination, and radiological studies must be examined in order to determine the specific genetic tests required. For example, 90% of cases of Leber’s Hereditary Optic Neuropathy (LHON) are associated with three common mtDNA point mutations (m.3460G>A/MT-ND1, m.11778G>A/MT-ND4, m.14484T>C/MT-ND6) while a wider range of mtDNA mutations (MT-ND1, MT-ND5, MT-ND6; http://www.mitomap.org/) have been associated with overlapping phenotypes of LHON, MELAS, and Leigh syndrome.

AAION requires urgent and critical intervention with a very long course of corticosteroids to prevent further damage. While this treatment is in itself problematic, non-treatment leads to bilateral blindness and strokes.

There is much research currently underway looking at ways to protect the nerve (neuroprotection) or even regenerate new fibers within the optic nerve.

At the onset of symptoms, ophthalmoscope examination can differentiate AION from PION. If optic nerve head involvement is observed, it is AION. PION does not produce optic atrophy that is observable via ophthalmoscope until four to eight weeks after onset. In addition, AION often shows a characteristic altitudinal defect on a Humphrey Visual Field test.

Owing to the self-limiting nature of the disease, treatment is generally not required. In cases where lesions appear to be interfering with the optic nerve, methyl prednisone is prescribed.

Immunoglobulin samples are obtained from a large pool of healthy, matched donors (10000 - 20000). The immunoglobulin mixture is then administered through IV at a rate of 0.4g/kg/day for 5 days. Antibodies in the IVIG mixture interact with binding sites of the disease-associated antibodies (such as anti-recoverin antibodies). This prevents binding to proteins targeted as antigenic and reduces disease activity. Responses to this treatment can vary and are impacted if the patient is diagnosed with any type of cancer. Patients who respond positively show improvement in the clarity of their vision and their visual field.

MRI is the most sensitive imaging technique that can be used for diagnosing NBD. As for the parenchymal NBD, medical doctors mainly monitor the upper brainstem lesion. In fact, it is possible that lesions extends to thalamus and basal ganglia. Another advantage of using MRI is the ability to perform Diffusion-weighted imaging, or diffusion MRI. This technique is the most sensitive tool to image an acute infarct. In the case of NBD, Diffusion MRI can determine whether the lesion were due to cerebral infarction. In other words, it can distinguish NBD from non-NBD neural disease. When only spinal cord is affected by NBD, brain looks perfectly normal when scanned by MRI. Therefore, it is necessary to scan the spinal cord as well when diagnosing possible NBD involvement. As for the non-parenchymal NBD, venous sinus thrombosis can be detected.

Demyelinating diseases can be divided in those affecting the central nervous system and those presents in the peripheral nervous system, presenting different demyelination conditions. They can also be divided by other criteria in inflammatory and non-inflammatory, according to the presence or lack of inflammation, and finally, a division can also be made depending on the underlying reason for demyelination in myelinoclastic (myelin is attacked by an external substance) and leukodystrophic (myelin degenerates without attacks)

Patients presenting with acute episodes often have high levels of inflammatory markers such as erythrocyte sedimentation rate or C-reactive protein, ESR or CRP. Patients often have cartilage-specific antibodies present during acute relapsing polychondritis episodes. Antinuclear antibody reflexive panel, rheumatoid factor, and antiphospholipid antibodies are tests that may assist in the evaluation and diagnosis of autoimmune connective-tissue diseases.