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.

Without a known family history of LHON the diagnosis usually requires a neuro-ophthalmological evaluation and blood testing for mitochondrial DNA assessment. It is important to exclude other possible causes of vision loss and important associated syndromes such as heart electrical conduction system abnormalities. The prognosis for those affected left untreated is almost always that of continued significant visual loss in both eyes. Regular corrected visual acuity and perimetry checks are advised for follow up of affected individuals. There is beneficial treatment available for some cases of this disease especially for early onset disease. Also, experimental treatment protocols are in progress. Genetic counselling should be offered. Health and lifestyle choices should be reassessed particularly in light of toxic and nutritional theories of gene expression. Vision aides assistance and work rehabilitation should be used to assist in maintaining employment.

For those who are carriers of a LHON mutation, preclinical markers may be used to monitor progress. For example, fundus photography can monitor nerve fiber layer swelling. Optical coherence tomography can be used for more detailed study of retinal nerve fiber layer thickness. Red green color vision testing may detect losses. Contrast sensitivity may be diminished. There could be an abnormal electroretinogram or visual evoked potentials. Neuron-specific enolase and axonal heavy chain neurofilament blood markers may predict conversion to affected status.

Cyanocobalamin (a form of B12) may also be used.

Avoiding optic nerve toxins is generally advised, especially tobacco and alcohol. Certain prescription drugs are known to be a potential risk, so all drugs should be treated with suspicion and checked before use by those at risk. Ethambutol, in particular, has been implicated as triggering visual loss in carriers of LHON. In fact, toxic and nutritional optic neuropathies may have overlaps with LHON in symptoms, mitochondrial mechanisms of disease and management. Of note, when a patient carrying or suffering from LHON or toxic/nutritional optic neuropathy suffers a hypertensive crisis as a possible complication of the disease process, nitroprusside (trade name: Nipride) should not be used due to increased risk of optic nerve ischemia in response to this anti-hypertensive in particular.

Idebenone has been shown in a small placebo controlled trial to have modest benefit in about half of patients. People most likely to respond best were those treated early in onset.

α-Tocotrienol-quinone, a vitamin E metabolite, has had some success in small open label trials in reversing early onset vision loss.

There are various treatment approaches which have had early trials or are proposed, none yet with convincing evidence of usefulness or safety for treatment or prevention including brimonidine, minocycline, curcumin,

glutathione, near infrared light treatment, and viral vector techniques.

"Three person in vitro fertilization" is a proof of concept research technique for preventing mitochondrial disease in developing human fetuses. So far, viable macaque monkeys have been produced. But ethical and knowledge hurdles remain before use of the technique in humans is established.

It is important to differentiate CPEO from other pathologies that may cause an ophthalmoplegia. There are specific therapies used for these pathologies.

CPEO is diagnosed via muscle biopsy. On examination of muscle fibers stained with Gömöri trichrome stain, one can see an accumulation of enlarged mitochondria. This produces a dark red staining of the muscle fibers given the name “ragged red fibers”. While ragged red fibers are seen in normal aging, amounts in excess of normal aging give a diagnosis of a mitochondrial myopathy.

Polymerase Chain Reaction (PCR), from a sample of blood or muscle tissue can determine a mutation of the mtDNA.

Elevated acetylcholine receptor antibody level which is typically seen in myasthenia gravis has been seen in certain patients of mitochondrial associated ophthalmoplegia.

It is important to have a dilated eye exam to determine if there is pigmentary retinopathy that may signify Kearns-Sayre syndrome which is associated with cardiac abnormalities.

MRI may be helpful in the diagnosis, in one study volumes of medial rectus, lateral rectus, and inferior rectus muscles in CPEO were not smaller than normal (in contrast to the profound atrophy typical of neurogenic paralysis). Although volumes of the superior rectus muscle-levator complex and superior oblique were significantly reduced.

Those diseases understood as congenital in origin could either be specific to the ocular organ system (LHON, DOA) or syndromic (MELAS, Multiple Sclerosis). It is estimated that these inherited optic neuropathies in the aggregate affect 1 in 10,000

Of the acquired category, disease falls into further etiological distinction as arising from toxic (drugs or chemicals) or nutritional/metabolic (vitamin deficiency/diabetes) insult. It is worth mentioning that under-nutrition and toxic insult can occur simultaneously, so a third category may be understood as having a combined or mixed etiology. We will refer to this as Toxic/Nutritional Optic Neuropathy, whereby nutritional deficiencies and toxic/metabolic insults are the simultaneous culprits of visual loss associated with damage and disruption of the RGC and optic nerve mitochondria.

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.

In Northern European populations about one in 9000 people carry one of the three primary LHON mutations.

The LHON ND4 G11778A mutation dominates as the primary mutation in most of the world

with 70% of Northern European cases and 90% of Asian cases. Due to a Founder effect, the LHON ND6 T14484C mutation accounts for 86% of LHON cases in Quebec, Canada.

More than 50 percent of males with a mutation and more than 85 percent of females with a mutation never experience vision loss or related medical problems. The particular mutation type may predict the likelihood of penetrance, severity of illness and probability of vision recovery in the affected. As a rule of thumb, a woman who harbors a homoplasmic primary LHON mutation has a ~40% risk of having an affected son and a ~10% risk of having an affected daughter.

Additional factors may determine whether a person develops the signs and symptoms of this disorder. Environmental factors such as smoking and alcohol use may be involved, although studies of these factors have produced conflicting results. Researchers are also investigating whether changes in additional genes, particularly genes on the X chromosome,

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.

Once visual loss has occurred, it becomes more problematic, but there are reports of recovered vision if blood transfusions and agents that raise blood pressure are administered within hours.

Diagnosis commonly occurs later in childhood and often occurs incidentally in asymptomatic patients or as a cause of visual impairment. The first symptoms are commonly found during routine vision screenings.

A number of examinations can be used to determine the extent of the syndrome and its severity. Fluorescein angiography is quite useful in diagnosing the disease, and the use of ultrasonography and optical coherence tomography (OCT) are helpful in confirming the disease. Neuro-ophthalmic examinations reveal pupillary defects (see Marcus Gunn Pupil). Funduscopic examinations, examinations of the fundus of the eye, allow detection of arteriovenous malformations. Neurological examinations can determine hemiparesis and paresthesias. Malformations in arteriovenous connections and irregular functions in the veins may be distinguished by fluorescein angiographies. Cerebral angiography examinations may expose AVMs in the cerebrum. MRIs are also used in imaging the brain and can allow visualization of the optic nerve and any possible atrophy. MRI, CT, and cerebral angiography are all useful for investigating the extent and location of any vascular lesions that are affecting the brain. This is helpful in determining the extent of the syndrome.

A neuro-ophthalmologist is usually involved in the diagnosis and management of KSS. An individual should be suspected of having KSS based upon clinical exam findings. Suspicion for myopathies should be increased in patients whose ophthalmoplegia does not match a particular set of cranial nerve palsies (oculomotor nerve palsy, fourth nerve palsy, sixth nerve palsy). Initially, imaging studies are often performed to rule out more common pathologies. Diagnosis may be confirmed with muscle biopsy, and may be supplemented with PCR determination of mtDNA mutations.

It is not necessary to biopsy an ocular muscle to demonstrate histopathologic abnormalities. Cross-section of muscle fibers stained with Gömöri trichrome stain is viewed using light microscopy. In muscle fibers containing high ratios of the mutated mitochondria, there is a higher concentration of mitochondria. This gives these fibers a darker red color, causing the overall appearance of the biopsy to be described as "ragged red fibers. Abnormalities may also be demonstrated in muscle biopsy samples using other histochemical studies such as mitochondrial enzyme stains, by electron microscopy, biochemical analyses of the muscle tissue (ie electron transport chain enzyme activities), and by analysis of muscle mitochondrial DNA. "

It is estimated that the incidence of AION is about 8,000/year in the U.S.

There is currently no defined treatment to ameliorate the muscle weakness of CPEO. Treatments used to treat other pathologies causing ophthalmoplegia has not been shown to be effective.

Experimental treatment with tetracycline has been used to improve ocular motility in one patient. Coenzyme Q has also been used to treat this condition. However, most neuro-ophthalmologists do not ascribe to any treatment.

Ptosis associated with CPEO may be corrected with surgery to raise the lids, however due to weakness of the orbicularis oculi muscles, care must be taken not to raise the lids in excess causing an inability to close the lids. This results in an exposure keratopathy. Therefore, rarely should lid surgery be performed and only by a neuro-ophthalmologist familiar with the disease.

The most common strabismus finding is large angle exotropia which can be treated by maximal bilateral eye surgery, but due to the progressive nature of the disease, strabismus may recur. Those that have diplopia as a result of asymmetric ophthalmoplegia may be corrected with prisms or with surgery to create a better alignment of the eyes.

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.

There is generally no treatment to cure achromatopsia. However, dark red or plum colored filters are very helpful in controlling light sensitivity.

Since 2003, there is a cybernetic device called eyeborg that allows people to perceive color through sound waves. Achromatopsic artist Neil Harbisson was the first to use such a device in early 2004, the eyeborg allowed him to start painting in color by memorizing the sound of each color.

Moreover, there is some research on gene therapy for animals with achromatopsia, with positive results on mice and young dogs, but less effectiveness on older dogs. However, no experiments have been made on humans. There are many challenges to conducting gene therapy on humans. See Gene therapy for color blindness for more details about it.

Once NAION happens, it was thought that there was no accepted treatment to reverse the damage. However, a recent uncontrolled retrospective large study 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 (odds ratio of improvement: 3.39; 95% CI:1.62, 7.11; p ¼ 0.001). That study and a natural history study on NAION (Ophthalmology 2008;115: 298–305.) showed that visual acuity can improve up to 6 months and not after that. To minimize the risk of further visual loss in the fellow eye or the same eye, it is essential to reduce the risk factors. Common sense dictates trying to control the cardiovascular risk factors for many reasons, including protection from this happening to the second eye. Sudden vision loss should lead to an ophthalmological consultation. If NAION is suspected, then ideally a neuro-ophthalmologist's consultation should be obtained.

A recent Cochrane Review sought to determine the extent of safety and efficacy of optic nerve decompression surgery for NAION, compared to other treatments, or no treatment. The one study included in the review found no improvements in visual acuity among patients who underwent surgery for NAION, and adverse events (pain, double vision) experienced by participants who underwent surgery.

There is much research currently underway looking at ways to protect the nerve (neuroprotection) or even regenerate new fibers within the optic nerve. So far there is no evidence in human studies that the so-called neuroprotectors have any beneficial effect in NAION.

However, there is a new current clinical trial for the treatment of NAION in the United States with plans to include sites in India, Israel, Germany and Australia (see NORDICclinicaltrials.com and https://clinicaltrials.gov/). This trial will test the use of a synthetic siRNA that blocks caspase 2, an important enzyme in the apoptosis cycle.

In addition to such research, patents have been applied for by Pfizer, The University of Southern California, Otsuka Pharmaceutical and other individual inventors for innovations related to the treatment of anterior ischemic optic neuropathy.

The diagnostic criteria as of 2015 define definite MD and probable MD as follows:

Definite

1. Two or more spontaneous episodes of vertigo, each lasting 20 minutes to 12 hours

2. Audiometrically documented low- to medium-frequency sensorineural hearing loss in the affected ear on at least 1 occasion before, during, or after one of the episodes of vertigo

3. Fluctuating aural symptoms (hearing, tinnitus, or fullness) in the affected ear

4. Not better accounted for by another vestibular diagnosis

Probable

1. Two or more episodes of vertigo or dizziness, each lasting 20 minutes to 24 hours

2. Fluctuating aural symptoms (hearing, tinnitus, or fullness) in the reported ear

3. Not better accounted for by another vestibular diagnosis

A common and important symptom of MD is hypersensitivity to sounds. This hypersensitivity is easily diagnosed by measuring the loudness discomfort levels (LDLs).

Symptoms of MD overlap with migraine-associated vertigo (MAV) in many ways, but when hearing loss develops in MAV is usually in both ears, and this is rare in MD, and hearing loss generally does not progress in MAV as it does in MD.

People who have had a transient ischemic attack (TIA) and stroke can present with symptoms similar to MD, and in people at risk for stroke magnetic resonance imaging (MRI) should be conducted to exclude TIA or stroke, and as TIA is often a precursor to stroke, that risk should be managed.

Other vestibular conditions that should be excluded include vestibular paroxysmia, recurrent unilateral vestibulopathy, vestibular schwannoma, or a tumor of the endolymphatic sac.

Upon clinical suspicion, diagnostic testing will often consist of measurement of amino acid concentrations in plasma, in search of a significantly elevated ornithine concentration. Measurement of urine amino acid concentrations is sometimes necessary, particularly in neonatal onset cases to identify the presence or absence of homocitrulline for ruling out ornithine translocase deficiency (hyperornithinemia, hyperammonemia, homocitrullinuria syndrome, HHH syndrome). Ornithine concentrations can be an unreliable indicator in the newborn period, thus newborn screening may not detect this condition, even if ornithine is included in the screening panel. Enzyme assays to measure the activity of ornithine aminotransferase can be performed from fibroblasts or lymphoblasts for confirmation or during the neonatal period when the results of biochemical testing is unclear. Molecular genetic testing is also an option.

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.

In general, children with a small isolated nevus and a normal physical exam do not need further testing; treatment may include potential surgical removal of the nevus. If syndrome issues are suspected, neurological, ocular, and skeletal exams are important. Laboratory investigations may include serum and urine calcium and phosphate, and possibly liver and renal function tests. The choice of imaging studies depends on the suspected abnormalities and might include skeletal survey, CT scan of the head, MRI, and/or EEG.

Depending on the systems involved, an individual with Schimmelpenning syndrome may need to see an interdisciplinary team of specialists: dermatologist, neurologist, ophthalmologist, orthopedic surgeon, oral surgeon, plastic surgeon, psychologist.

Although there is a diagnostic criterion for Behçet's disease, one for neuro-Behçet's disease does not exist. Three diagnostic tools are mainly used.

The treatment for Bonnet–Dechaume–Blanc syndrome is controversial due to a lack of consensus on the different therapeutic procedures for treating arteriovenous malformations. The first successful treatment was performed by Morgan et al. They combined intracranial resection, ligation of ophthalmic artery, and selective arterial ligature of the external carotid artery, but the patient did not have retinal vascular malformations.

If lesions are present, they are watched closely for changes in size. Prognosis is best when lesions are less than 3 cm in length. Most complications occur when the lesions are greater than 6 cm in size. Surgical intervention for intracranial lesions has been done successfully. Nonsurgical treatments include embolization, radiation therapy, and continued observation. Arterial vascular malformations may be treated with the cyberknife treatment. Possible treatment for cerebral arterial vascular malformations include stereotactic radiosurgery, endovascular embolization, and microsurgical resection.

When pursuing treatment, it is important to consider the size of the malformations, their locations, and the neurological involvement. Because it is a congenital disorder, there are not preventative steps to take aside from regular follow ups with a doctor to keep an eye on the symptoms so that future complications are avoided.

Bilateral vestibular schwannomas are diagnostic of NF2.

NF II can be diagnosed with 65% accuracy prenatally with chorionic villus sampling or amniocentesis.

Ferner et al. give three sets of diagnostic criteria for NF2:

1. Bilateral vestibular schwannoma (VS) or family history of NF2 plus Unilateral VS or any two of: meningioma, glioma, neurofibroma, schwannoma, posterior subcapsular lenticular opacities

2. Unilateral VS plus any two of meningioma, glioma, neurofibroma, schwannoma, posterior subcapsular lenticular opacities

3. Two or more meningioma plus unilateral VS or any two of glioma, schwannoma and cataract.

Another set of diagnostic criteria is the following:

- Detection of bilateral acoustic neuroma by imaging-procedures

- First degree relative with NF II and the occurrence of neurofibroma, meningiomas, glioma, or Schwannoma

- First degree relative with NF II and the occurrence of juvenile posterior subcapsular cataract.

The criteria have varied over time.

Lens subluxation is also seen in dogs and is characterized by a partial displacement of the lens. It can be recognized by trembling of the iris (iridodonesis) or lens (phacodonesis) and the presence of an aphakic crescent (an area of the pupil where the lens is absent). Other signs of lens subluxation include mild conjunctival redness, vitreous humour degeneration, prolapse of the vitreous into the anterior chamber, and an increase or decrease of anterior chamber depth. Removal of the lens before it completely luxates into the anterior chamber may prevent secondary glaucoma. A nonsurgical alternative involves the use of a miotic to constrict the pupil and prevent the lens from luxating into the anterior chamber.