Toxic optic neuropathy refers to the ingestion of a toxin or an adverse drug reaction that results in vision loss from optic nerve damage. Patients may report either a sudden loss of vision in both eyes, in the setting of an acute intoxication, or an insidious asymmetric loss of vision from an adverse drug reaction. The most important aspect of treatment is recognition and drug withdrawal.

Among the many causes of TON, the top 10 toxins include:

- Medications

- Ethambutol, rifampin, isoniazid, streptomycin (tuberculosis treatment)

- Linezolid (taken for bacterial infections, including pneumonia)

- Chloramphenicol (taken for serious infections not helped by other antibiotics)

- Isoretinoin (taken for severe acne that fails to respond to other treatments)

- Ciclosporin (widely used immunosuppressant)

- Acute Toxins

- Methanol (component of some moonshine, and some cleaning products)

- Ethylene glycol (present in anti-freeze and hydraulic brake fluid)

Metabolic disorders may also cause this version of disease. Systemic problems such as diabetes mellitus, kidney failure, and thyroid disease can cause optic neuropathy, which is likely through buildup of toxic substances within the body. In most cases, the cause of the toxic neuropathy impairs the tissue’s vascular supply or metabolism. It remains unknown as to why certain agents are toxic to the optic nerve while others are not and why particularly the papillomacular bundle gets affected.

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.

The incidence of dominant optic atrophy has been estimated to be 1:50000 with prevalence as high as 1:10000 in the Danish population (Votruba, 1998). Dominant optic atrophy is inherited in an autosomal dominant manner. That is, a heterozygous patient with the disease has a 50% chance of passing on the disease to offspring, assuming his/her partner does not have the disease. Males and females are affected at the same rate. Although Kjer's has a high penetrance (98%), severity and progression of DOA are extremely variable even within the same family.

Retinitis pigmentosa is the leading cause of inherited blindness, with approximately 1/4,000 individuals experiencing the non-syndromic form of their disease within their lifetime. It is estimated that 1.5 million people worldwide are currently affected. Early onset RP occurs within the first few years of life and is typically associated with syndromic disease forms, while late onset RP emerges from early to mid-adulthood.

Autosomal dominant and recessive forms of retinitis pigmentosa affect both male and female populations equally; however, the less frequent X-linked form of the disease affects male recipients of the X-linked mutation, while females usually remain unaffected carriers of the RP trait. The X-linked forms of the disease are considered severe, and typically lead to complete blindness during later stages. In rare occasions, a dominant form of the X-linked gene mutation will affect both males and females equally.

Due to the genetic inheritance patterns of RP, many isolate populations exhibit higher disease frequencies or increased prevalence of a specific RP mutation. Pre-existing or emerging mutations that contribute to rod photoreceptor degeneration in retinitis pigmentosa are passed down through familial lines; thus, allowing certain RP cases to be concentrated to specific geographical regions with an ancestral history of the disease. Several hereditary studies have been performed to determine the varying prevalence rates in Maine (USA), Birmingham (England), Switzerland (affects 1/7000), Denmark (affects 1/2500), and Norway. Navajo Indians display an elevated rate of RP inheritance as well, which is estimated as affecting 1 in 1878 individuals. Despite the increased frequency of RP within specific familial lines, the disease is considered non-discriminatory and tends to equally affect all world populations.

Genetic tests and related research are currently being performed at Centogene AG in Rostock, Germany; John and Marcia Carver Nonprofit Genetic Testing Laboratory in Iowa City, IA; GENESIS Center for Medical Genetics in Poznan, Poland; Miraca Genetics Laboratories in Houston, TX; Asper Biotech in Tartu, Estonia; CGC Genetics in Porto, Portugal; CEN4GEN Institute for Genomics and Molecular Diagnostics in Edmonton, Canada; and Reference Laboratory Genetics - Barcelona, Spain.

Most people with the disease need laser repairs to the retina, and about 60 per cent need further surgery.

The cause of this condition is not presently known. It appears to be inherited in an autosomal dominant fashion.

Dominant optic atrophy is also known as autosomal dominant optic atrophy, Kjer type; Kjer optic atrophy; or, Kjer's autosomal dominant optic atrophy.

It is usually autosomal recessive; however, importantly for family planning, it is sometimes autosomal dominant. It is a disorder thought to be caused by abnormal development of photoreceptor cells.

OMIM currently recognizes 18 types of LCA.

The gene has been associated with Joubert syndrome, as well as type 10 LCA.

RP may be:

(1) Non-syndromic, that is, it occurs alone, without any other clinical findings,

(2) Syndromic, with other neurosensory disorders, developmental abnormalities, or complex clinical findings, or

(3) Secondary to other systemic diseases.

- RP combined with deafness (congenital or progressive) is called Usher syndrome.

- Alport's syndrome is associated with RP and an abnormal glomerular-basement membrane leading nephrotic syndrome and inherited as X-linked dominant.

- RP combined with ophthalmoplegia, dysphagia, ataxia, and cardiac conduction defects is seen in the mitochondrial DNA disorder Kearns-Sayre syndrome (also known as Ragged Red Fiber Myopathy)

- RP combined with retardation, peripheral neuropathy, acanthotic (spiked) RBCs, ataxia, steatorrhea, is absence of VLDL is seen in abetalipoproteinemia.

- RP is seen clinically in association with several other rare genetic disorders (including muscular dystrophy and chronic granulomatous disease) as part of McLeod syndrome. This is an X-linked recessive phenotype characterized by a complete absence of XK cell surface proteins, and therefore markedly reduced expression of all Kell red blood cell antigens. For transfusion purposes these patients are considered completely incompatible with all normal and K0/K0 donors.

- RP associated with hypogonadism, and developmental delay with an autosomal recessive inheritance pattern is seen with Bardet-Biedl syndrome

Other conditions include neurosyphilis, toxoplasmosis and Refsum's disease.

The first symptom is typically diabetes mellitus, which is usually diagnosed around the age of 6. The next symptom to appear is often optic atrophy, the wasting of optic nerves, around the age of 11. The first signs of this are loss of colour vision and peripheral vision. The condition worsens over time, and people with optic atrophy are usually blind within 8 years of the first symptoms. Life expectancy of people suffering from this syndrome is about 30 years.

Acorea, microphthalmia and cataract syndrome is a rare genetically inherited condition.

Wagner's syndrome has for a long time been considered a synonym for Stickler's syndrome. However, since the gene that is responsible for Wagner disease (and Erosive Vitreoretinopathie) is known (2005), the confusion has ended. For Wagner disease is the Versican gene (VCAN) located at 5q14.3 is responsible.

For Stickler there are 4 genes are known to cause this syndrome: COL2A1 (75% of Stickler cases), COL11A1 (also Marshall syndrome), COL11A2 (non-ocular Stickler) and COL9A1 (recessive Stickler).

The gene involved helps regulate how the body makes collagen, a sort of chemical glue that holds tissues together in many parts of the body. This particular collagen gene only becomes active in the jelly-like material that fills the eyeball; in Wagner's disease this "vitreous" jelly grabs too tightly to the already weak retina and pulls it away.

There is no known direct treatment. Current treatment efforts focus on managing the complications of Wolfram syndrome, such as diabetes mellitus and diabetes insipidus.

Behr syndrome is characterized by the association of early-onset optic atrophy with spinocerebellar degeneration resulting in ataxia, pyramidal signs, peripheral neuropathy and developmental delay.

Although it is an autosomal recessive disorder, heterozygotes may still manifest much attenuated symptoms. Autosomal dominant inheritance also being reported in a family. Recently a variant of OPA1 mutation with phenotypic presentation like Behr syndrome is also described. Some reported cases have been found to carry mutations in the OPA1, OPA3 or C12ORF65 genes which are known causes of pure optic atrophy or optic atrophy complicated by movement disorder.

This condition is linked to the X chromosome.

- Siberian Husky - Night blindness by two to four years old.

- Samoyed - More severe disease than the Husky.

Commonly affected breeds:

- Akita - Symptoms at one to three years old and blindness at three to five years old. Selective breeding has greatly reduced the incidence of this disease in this breed.

- Miniature longhaired Dachshund - Symptoms at six months old.

- Papillon - Slowly progressive with blindness at seven to eight years old.

- Tibetan Spaniel - Symptoms at three to five years old.

- Tibetan Terrier - PRA3/RCD4 disease of middle age dogs. http://www.ttca-online.org/html/Petersen-Jones_PRA_article.pdf

- Samoyed - Symptoms by three to five years old.

Optic disc drusen are found clinically in about 1% of the population but this increases to 3.4% in individuals with a family history of ODD. About two thirds to three quarters of clinical cases are bilateral. A necropsy study of 737 cases showed a 2.4% incidence with 2 out of 15 (13%) bilateral, perhaps indicating the insidious nature of many cases. An autosomal dominant inheritance pattern with incomplete penetrance and associated inherited dysplasia of the optic disc and its blood supply is suspected. Males and females are affected at equal rates. Caucasians are the most susceptible ethnic group. Certain conditions have been associated with disc drusen such as retinitis pigmentosa, angioid streaks, Usher syndrome, Noonan syndrome and Alagille syndrome. Optic disc drusen are not related to Bruch membrane drusen of the retina which have been associated with age-related macular degeneration.

Onset : Early childhood

Progression: Chronic progressive

Clinical: Cerebellar ataxia plus syndrome / Optic Atrophy Plus Syndrome

Ocular: Optic atrophy, nystagmus, scotoma, and bilateral retrobulbar neuritis.

Other: Mental retardation, myoclonic epilepsy, spasticity, and posterior column sensory loss. Tremor in some cases.

Musculoskeletal

Contractures, lower limbs, Achilles tendon contractures, Hamstring contractures, Adductor longus contractures

Systemic

Hypogonadotrophic hypogonadism.

Papillorenal syndrome, also called renal-coloboma syndrome or isolated renal hypoplasia, is an autosomal dominant genetic disorder marked by underdevelopment (hypoplasia) of the kidney and colobomas of the optic nerve.

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 terms of frequency, is estimated at 2 per 100,000, it has identified in different regions of the world. Some clusters of certain types of autosomal dominant cerebellar ataxia reach a prevalence of 5 per 100,000.

Age-related macular degeneration accounts for more than 54% of all vision loss in the white population in the USA. An estimated 8 million Americans are affected with early age-related macular degeneration, of whom over 1 million will develop advanced age-related macular degeneration within the next 5 years. In the UK, age-related macular degeneration is the cause of blindness in almost 42% of those who go blind aged 65–74 years, almost two-thirds of those aged 75–84 years, and almost three-quarters of those aged 85 years or older.

Macular degeneration is more likely to be found in Caucasians than in people of African descent.

Optic pits occur equally between men and women. They are seen in roughly 1 in 10,000 eyes, and approximately 85% of optic pits are found to be unilateral (i.e. in only one eye of any affected individual). About 70% are found on the temporal side (or lateral one-half) of the optic disc. Another 20% are found centrally, while the remaining pits are located either superiorly (in the upper one-half), inferiorly (in the lower one-half), or nasally (in the medial one-half towards the nose).

Aniridia may be broadly divided into hereditary and sporadic forms. Hereditary aniridia is usually transmitted in an autosomal dominant manner (each offspring has a 50% chance of being affected), although rare autosomal recessive forms (such as Gillespie syndrome) have also been reported. Sporadic aniridia mutations may affect the WT1 region adjacent to the AN2 aniridia region, causing a kidney cancer called nephroblastoma (Wilms tumor). These patients often also have genitourinary abnormalities and intellectual disability (WAGR syndrome).

Several different mutations may affect the PAX6 gene. Some mutations appear to inhibit gene function more than others, with subsequent variability in the severity of the disease. Thus, some aniridic individuals are only missing a relatively small amount of iris, do not have foveal hypoplasia, and retain relatively normal vision. Presumably, the genetic defect in these individuals causes less "heterozygous insufficiency," meaning they retain enough gene function to yield a milder phenotype.

- AN

- Aniridia and absent patella

- Aniridia, microcornea, and spontaneously reabsorbed cataract

- Aniridia, cerebellar ataxia, and mental deficiency (Gillespie syndrome)