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.

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.

There is no cure for ONH; however, many therapeutic interventions exist for the care of its symptoms. These may include hormone replacement therapy for hypopituitarism, occupational, physical, and/or speech therapy for other issues, and services of a teacher of students with blindness/visually impairment. Special attention should be paid to early development of oral motor skills and acclimation to textured foods for children with texture aversion, or who are otherwise resistant to eating.

Sleep dysfunction can be ameliorated using melatonin in the evening in order to adjust a child's circadian clock.

Treatment for strabismus may include patching of the better eye, which may result in improved vision in the worse eye; however, this should be reserved for cases in which the potential for vision improvement in both eyes is felt to be good. Surgery to align the eyes can be performed once children with strabismus develop equal visual acuity in both eyes, most often after the age of three. Generally surgery results in improved appearance only and not in improved visual function.

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.

Although many perinatal and prenatal risk factors for ONH have been suggested, the predominant, enduring, most frequent risk factors are young maternal age and primiparity (the affected child being the first child born to the mother). Increased frequency of delivery by caesarean section and fetal/neonatal complications, preterm labor, gestational vaginal bleeding, low maternal weight gain, and weight loss during pregnancy are also associated with ONH.

There is no known curative treatment presently. Hearing aids and cataract surgery may be of use. Control of seizures, heart failure and treatment of infection is important. Tube feeding may be needed.

Treatment plans will vary depending on the severity of the condition and its evidences in each patient.

Areas that will probably need to be evaluated and assessed include speech, vision, hearing and EEG. Treatment measures may include physical therapy, occupational therapy, Speech therapy, anti-seizure drugs and orthotic devices. Surgery may be needed to assuage spastic motor problems. Various supportive measures such as joint contractures that could prevent complications.

Genetic counseling may also be recommended

While radiation or chemotherapy may be helpful, treatment is often not necessary. Optical gliomas often cannot be surgically resected. If no visual symptoms wait 6 months and then in 6 months only treat if there are symptoms (visual loss, eye pain), otherwise do not treat.

Idebenone is a short-chain benzoquinone that interacts with the mitochondrial electron transport chain to enhance cellular respiration. When used in individuals with LHON, it is believed to allow electrons to bypass the dysfunctional complex I. Successful treatment using idebenone was initially reported in a small number of patients.

Two large-scale studies have demonstrated the benefits of idebenone. The Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) evaluated the effects of idebenone in 85 patients with LHON who had lost vision within the prior five years. In this study, the group taking idebenone 900 mg per day for 24 weeks showed a slight improvement in visual acuity compared to the placebo group, though this difference was not statistically significant. Importantly, however, patients taking idebenone were protected from further vision loss, whereas the placebo group had a steady decline in visual acuity. Further, individuals taking idebenone demonstrated preservation of color vision and persistence of the effects of idebenone 30 months after discontinuing therapy. A retrospective analysis of 103 LHON patients by Carelli et al. builds upon these results. This study highlighted that 44 subjects who were treated with idebenone within one year of onset of vision loss had better outcomes, and, further, that these improvements with idebenone persisted for years.

Idebenone, combined with avoidance of smoke and limitation of alcohol intake, is the preferred standard treatment protocol for patients affected by LHON. Idebenone doses are prescribed to be taken spaced out throughout the day, rather than all at one time. For example, to achieve a dose of 900 mg per day, patients take 300 mg three times daily with meals. Idebenone is fat soluble, and may be taken with a moderate amount of dietary fat in each meal to promote absorption. It is recommended that patients on idebenone also take vitamin C 500 mg daily to keep idebenone in its reduced form, as it is most active in this state.

Optic gliomas often have a shifting clinical course, with sporadic periods of vision loss separated by long periods of visual stability. Optic gliomas rarely spontaneously regress.

The treatment, and therefore prognosis, varies depending upon the underlying tumour.

In utero exposure to cocaine and other street drugs can lead to septo-optic dysplasia.

ONSM does not improve without treatment. In many cases, there is gradual progression until vision is lost in the affected eye. However, this takes at least several months to occur, and a minority of patients remain stable for a number of years.

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.

Orbital apex syndrome, also known as Jacod syndrome, is a collection of cranial nerve deficits associated with a mass lesion near the apex of the orbit of the eye. This syndrome is a separate entity from Rochon–Duvigneaud syndrome, which occurs due to a lesion immediately anterior to the orbital apex. Most commonly optic nerve is involved.

The most common finding is oculomotor nerve dysfunction leading to ophthalmoplegia. This is often accompanied by ophthalmic nerve dysfunction, leading to hypoesthesia of the upper face. The optic nerve may eventually be involved, with resulting visual impairment.

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.

Most ophthalmologists will not advocate any treatment unless visual loss is present and ongoing. Reports of patients with ONSM having no change in their vision for multiple years are not uncommon. If loss of vision occurs, radiation therapy will improve vision in about ⅓ of cases, and preserve vision in about ⅓ of cases. Surgery has traditionally been associated with rapid deteroriation of vision. However, newer surgical techniques may prove better for the treatment of ONSM.

Bilateral frontoparietal polymicrogyria (BFPP) is a genetic disorder with autosomal recessive inheritance that causes a cortical malformation. Our brain has folds in the cortex to increase surface area called gyri and patients with polymicrogyri have an increase number of folds and smaller folds than usual. Polymicrogyria is defined as a cerebral malformation of cortical development in which the normal gyral pattern of the surface of the brain is replaced by an excessive number of small, fused gyri separated by shallow sulci and abnormal cortical lamination. From ongoing research, mutation in GPR56, a member of the adhesion G protein-coupled receptor (GPCR) family, results in BFPP. These mutations are located in different regions of the protein without any evidence of a relationship between the position of the mutation and phenotypic severity. It is also found that GPR56 plays a role in cortical pattering.

A combination of lifestyle modifications and medications can be used for the treatment of dolichoectasias.

- Antihypertensive medications such as Thiazides, Beta Blocker, ACE Inhibitor

- Trental or other Pentoxifylline drugs

- Dietary changes

- Weight loss

- Regular exercise

Although both optic nerve colobomas and morning glory disc anomaly (MGDA) involve mutations of the PAX6 gene, these two separate diseases represent two distinct causes. An optic nerve coloboma is easily differentiated from morning glory anomaly. Colobomas affect only the inferior aspect of the nerve as it represents an incomplete closure of the embryonic fissure, whereas MGDA encompasses all aspects of the nerve and represents more generally a dysgenesis of the mesoderm.

Coloboma of optic nerve, is a rare defect of the optic nerve that causes moderate to severe visual field defects.

Coloboma of the optic nerve is a congenital anomaly of the optic disc in which there is a defect of the inferior aspect of the optic nerve. The issue stems from incomplete closure of the embryonic fissure while in utero. A varying amount of glial tissue typically fills the defect, manifests as a white mass.

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.

MRI will help with the diagnosis of structural abnormality of the brain. Genetic testing may also be pursued.

Aniridia is the absence of the iris, usually involving both eyes. It can be congenital or caused by a penetrant injury. Isolated aniridia is a congenital disorder which is not limited to a defect in iris development, but is a panocular condition with macular and optic nerve hypoplasia, cataract, and corneal changes. Vision may be severely compromised and the disorder is frequently associated with a number of ocular complications: nystagmus, amblyopia, buphthalmos, and cataract. Aniridia in some individuals occurs as part of a syndrome, such as WAGR syndrome (kidney nephroblastoma (Wilms tumour), genitourinary anomalies and intellectual disability), or Gillespie syndrome (cerebellar ataxia).