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.

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.

Patients with optic disc drusen should be monitored periodically for ophthalmoscopy, Snellen acuity, contrast sensitivity, color vision, intraocular pressure and threshold visual fields. For those with visual field defects optical coherence tomography has been recommended for follow up of nerve fiber layer thickness. Associated conditions such as angioid streaks and retinitis pigmentosa should be screened for. Both the severity of optic disc drusen and the degree of intraocular pressure elevation have been associated with visual field loss. There is no widely accepted treatment for ODD, although some clinicians will prescribe eye drops designed to decrease the intra-ocular pressure and theoretically relieve mechanical stress on fibers of the optic disc. Rarely choroidal neovascular membranes may develop adjacent to the optic disc threatening bleeding and retinal scarring. Laser treatment or photodynamic therapy or other evolving therapies may prevent this complication.

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.

Optic pits should be diagnosed by an eye care professional who can perform a thorough exam of the back of the eye using an ophthalmoscope.

More recently, the development of a special technology called optical coherence tomography (OCT) has allowed better visualization of the retinal layers. It has been used to demonstrate a marked reduction in the thickness of the retinal nerve fiber layer in the quadrant corresponding to the optic pit. This is not yet in standard use for diagnosis of an optic pit, but may be helpful in supporting a diagnosis.

In most patients, optic disc drusen are an incidental finding. It is important to differentiate them from other conditions that present with optic disc elevation, especially papilledema, which could imply raised intracranial pressure or tumors. True papilledema may present with exudates or cotton-wool spots, unlike ODD. The optic disc margins are characteristically irregular in ODD but not blurred as there is no swelling of the retinal nerve fibers. Spontaneous venous pulsations are present in about 80 percent of patients with ODD, but absent in cases of true disc edema. Other causes of disc elevation clinicians must exclude may be: hyaloid traction, epipapillary glial tissue, myelinated nerve fibres, scleral infiltration, vitreopapillary traction and high hyperopia. Disorders associated with disc elevation include: Alagille syndrome, Down syndrome, Kenny-Caffey syndrome, Leber Hereditary Optic Neuropathy and linear nevus sebaceous syndrome.

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.

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.

Currently there is no effective therapy for dominant optic atrophy, and consequently, these patients are simply monitored for changes in vision by their eye-care professional. Children of patients should be screened regularly for visual changes related to dominant optic atrophy. Research is underway to further characterize the disease so that therapies may be developed.

Treatment of toxic and nutritional optic neuropathy is dictated by the cause of the disorder.

- Toxic optic neuropathy is treated by identification and removal of the offending agent. Depending upon the individual affected, the nature of the agent, total exposure prior to removal, and degree of vision loss at the time of diagnosis, the prognosis is variable.

- Nutritional optic neuropathy is treated with improved nutrition. A well-balanced diet with plenty of protein and green leafy vegetables, vitamin supplementation (thiamine, vitamin B, folic acid, multivitamins), and reduction of smoking and/or drinking are the mainstay of treatment. Again, prognosis is variable and dependent upon the affected individual, treatment compliance, and degree of vision loss at diagnosis.

In both toxic and nutritional neuropathy, vision generally recovers to normal over several days to weeks, though it may take months for full restoration and there is always the risk of permanent vision loss. Visual acuity usually recovers before color vision.

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.

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

The most recognized cause of a toxic optic neuropathy is methanol intoxication. This can be a life-threatening event that normally accidentally occurs when the victim mistook, or substituted, methanol for ethyl alcohol. Blindness can occur with drinking as little as an ounce of methanol, but this can be counteracted by concurrent drinking of ethyl alcohol. The patient initially has nausea and vomiting, followed by respiratory distress, headache, and visual loss 18–48 hours after consumption. Without treatment, patients can go blind, and their pupils will dilate and stop reacting to light.

- Ethylene glycol, a component of automobile antifreeze, is a poison that is toxic to the whole body including the optic nerve. Consumption can be fatal, or recovery can occur with permanent neurologic and ophthalmologic deficits. While visual loss is not very common, increased intracranial pressure can cause bilateral optic disc swelling from cerebral edema. A clue to the cause of intoxication is the presence of oxalate crystals in the urine. Like methanol intoxication, treatment is ethanol consumption.

- Ethambutol, a drug commonly used to treat tuberculosis, is notorious for causing toxic optic neuropathy. Patients with vision loss from ethambutol toxicity lose vision in both eyes equally. This initially presents with problems with colors (dyschromatopsia) and can leave central visual deficits. If vision loss occurs while using ethambutol, it would be best to discontinue this medication under a doctor’s supervision. Vision can improve slowly after discontinuing ethambutol but rarely returns to baseline.

- Amiodarone is an antiarrhythmic medication commonly used for abnormal heart rhythms (atrial or ventricular tachyarrythmias). Most patients on this medication get corneal epithelial deposits, but this medication has also been controversially associated with NAION. Patients on amiodarone with new visual symptoms should be evaluated by an ophthalmologist.

- Tobacco exposure, most commonly through pipe and cigar smoking, can cause an optic neuropathy. Middle-aged or elderly men are often affected and present with painless, slowly progressive, color distortion and visual loss in both eyes. The mechanism is unclear, but this has been reported to be more common in individuals who are already suffering from malnutrition.

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)..

Optic neuritis typically affects young adults ranging from 18–45 years of age, with a mean age of 30–35 years. There is a strong female predominance. The annual incidence is approximately 5/100,000, with a prevalence estimated to be 115/100,000.

Checking the eyes for signs of papilledema should be carried out whenever there is a clinical suspicion of raised intracranial pressure, and is recommended in newly onset headaches. This may be done by ophthalmoscopy or fundus photography, and possibly slit lamp examination.

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.

Optic neuritis is inflammation of the optic nerve, which is associated with swelling and destruction of the myelin sheath covering the optic nerve. Young adults, usually females, are most commonly affected. Symptoms of optic neuritis in the affected eye include pain on eye movement, sudden loss of vision, and decrease in color vision (especially reds). Optic neuritis, when combined with the presence of multiple demyelinating white matter brain lesions on MRI, is suspicious for multiple sclerosis.

Several causes and clinical courses are possible for the optic neuritis. It can be classified in:

- Single isolated optic neuritis (SION)

- relapsing isolated optic neuritis (RION)

- chronic relapsing inflammatory optic neuropathy (CRION)

- the neuromyelitis optica (NMO) spectrum disorder

- multiple sclerosis associated optic neuritis (MSON)

- unclassified optic neuritis (UCON) forms.

Medical examination of the optic nerve with an ophthalmoscope may reveal a swollen optic nerve, but the nerve may also appear normal. Presence of an afferent pupillary defect, decreased color vision, and visual field loss (often central) are suggestive of optic neuritis. Recovery of visual function is expected within 10 weeks. However, attacks may lead to permanent axonal loss and thinning of the retinal nerve fiber layer.

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.

Optic pits themselves do not need to be treated. However, patients should follow up with their eye care professional annually or even sooner if the patient notices any visual loss whatsoever. Treatment of PVD or serous retinal detachment will be necessary if either develops in a patient with an optic pit.

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.

Imaging studies such as ultrasonography (US), Computerized Tomography (CT) and Magnetic Resonance Imaging (MRI) can aid diagnosis. On ultrasound, Coats' disease appears as a hyperechoic mass in the posterior vitreous without posterior acoustic shadowing; vitreous and subretinal hemorrhage may often be observed.

On CT, the globe appears hyperdense compared to normal vitreous due to the proteinaceous exudate, which may obliterate the vitreous space in advanced disease. The anterior margin of the subretinal exudate enhances with contrast. Since the retina is fixed posteriorly at the optic disc, this enhancement has a V-shaped configuration.

On MRI, the subretinal exudate shows high signal intensity on both T1- and T2-weighted images. The exudate may appear heterogeneous if hemorrhage or fibrosis is present. The subretinal space does not enhance with gadolinium contrast. Mild to moderate linear enhancement may be seen between the exudate and the remaining vitreous. The exudate shows a large peak at 1-1.6 ppm on proton MR spectroscopy.

Currently, human clinical trials are underway at GenSight Biologics (ClinicalTrials.gov # NCT02064569) and the University of Miami (ClinicalTrials.gov # NCT02161380) to examine the safety and efficacy of mitochondrial gene therapy in LHON. In these trials, participants affected by LHON with the G11778A mutation will have a virus expressing the functional version of ND4 – the gene mutated in this variant of LHON – injected into one eye. A sham injection will be administered to the other eye for comparison. It is hypothesized that introduction of the viral vector may be able to rescue the function of the mutant gene. Preliminary results have demonstrated tolerability of the injections in a small number of subjects.

Stealth BioTherapeutics is presently investigating the potential use of elamipretide (MTP-131), a mitochondrial protective agent, as a therapy for LHON. Elamipretide helps stabilize cardiolipin – an important component of mitochondrial inner membranes – and has been shown to reduce damaging reactive oxygen species in animal models. Clinical trials in LHON patients are planned for the future.

Visual fields associated with chiasmal syndrome usually leads to an MRI. Contrast can delineate arterial aneurysms and will enhance most intrinsic chiasmal lesions. If a mass is confirmed on MRI, an endocrine panel can help determine if a pituitary adenoma is involved.

In patients with functional adenomas diagnosed by other means, visual field tests are a good screen to test for chiasmal involvement. Visual fields tests will delinate chiasmal syndromes because the missing fields will not cross the midline. Junctional scotomas classically show ipsilateral optic disc neuropathy with contralateral superotemporal defects. Bitemporal hemianopia with or without central scotoma is present if the lesions have affected the body of the chiasm. A posterior chiasm lesion should only produce defects on the temporal sides of the central visual field.

Ischemic optic neuropathy (ION) is the loss of structure and function of a portion of the optic nerve due to obstruction of blood flow to the nerve (i.e. ischemia). Ischemic forms of optic neuropathy are typically classified as either anterior ischemic optic neuropathy or posterior ischemic optic neuropathy according to the part of the optic nerve that is affected. People affected will often complain of a loss of visual acuity and a visual field, the latter of which is usually in the superior or inferior field.

When ION occurs in patients below the age of 50 years old, other causes should be considered. Such as juvenile diabetes mellitus, antiphospholipid antibody-associated clotting disorders, collagen-vascular disease, and migraines. Rarely, complications of intraocular surgery or acute blood loss may cause an ischemic event in the optic nerve.

Anterior ION presents with sudden, painless visual loss developing over hours to days. Examination findings usually include decreased visual acuity, a visual field defect, color vision loss, a relative afferent pupillary defect, and a swollen optic nerve head. Posterior ION occurs arteritic, nonarteritic, and surgical settings. It is characterized by acute vision loss without initial disc edema, but with subsequent optic disc atrophy.

Although there is no recognized treatment that can reverse the visual loss. Upon recent reports, optic nerve health decompression may be beneficial for a select group of patients with a gradual decline in vision due to ION.