Description

• Definition: irreversible death of the axons that composes the optic nerve
• Clinical manifestations: visual loss of variable degree, which can include loss of acuity (i.e., sharpness of vision) and/or the field of vision
• Exam findings: pale-appearing (i.e., atrophic) optic nerve
• Optic nerve atrophy (ONA) is a clinical sign that is not specific for any single pathology and is therefore not an etiologic diagnosis.
• ONA results from a heterogeneous group of disorders and may be inherited, congenital, primary, or secondary.
• Secondary ONA may result from compressive, inflammatory, traumatic, infectious, ischemic, drug-induced, toxic-nutritional, demyelinating, or degenerative processes.
• Synonym(s): optic atrophy; optic neuropathy

Pediatric Considerations
ONA in children may be more difficult to recognize because of the following:

• Physiologic pallor of the optic nerve
• Congenitally small optic nerve (e.g., optic nerve hypoplasia)
• Children may not complain of visual loss.
• Hereditary optic atrophy cases might be neurologically isolated or mild.

Epidemiology

• Acquired ONA is more common than hereditary and congenital ONA and tends to occur later in life: Glaucoma, ischemic optic neuropathy (older), optic neuritis (younger), compressive (any age), and toxic/nutritional are leading causes in adults.
• Leber hereditary optic neuropathy (LHON): typically affects males age 20 to 30 years but can also occur in females and at any age
• Dominant optic atrophy: predominantly 4 to 6 years, with most reporting impairment by age 11 years

Prevalence

• ONA may be seen in a large and heterogeneous group of disorders with varying prevalence depending on etiology.
• LHON is estimated to be 1/45,000 by meta-analysis in Europe (1).

Etiology and Pathophysiology

• Genetic etiologies usually involve defects in mitochondrial function. Exposure of retinal nerve cells to light normally results in the generation of free radical species. In individuals with dysfunctioning mitochondria, the free radicals cannot be adequately neutralized, resulting in retinal nerve cell damage/death.
• Nongenetic etiologies include the following:
  • Compressive ONA: compression of optic nerve fibers, such as by a mass, leading to optic nerve cell death
  • Glaucomatous ONA: idiopathic progressive loss of ganglion cell axons of the optic nerve; increased intraocular pressure (IOP) is a risk factor; however, glaucoma can occur in the absence of high IOP.
  • Chronic papilledema with secondary ONA: increased intracranial pressure (ICP) transmitted to the ganglion cell axons of the optic nerve
    • Tumor (e.g., pituitary adenoma, optic nerve meningioma)
    • Aneurysm
    • Hydrocephalus
    • Pseudotumor cerebri (PTC): idiopathic elevated ICP, often in obese young females
    • Cortical venous sinus thrombosis
  • Inflammatory causes of ONA
    • Graves disease: Antibodies attack orbital tissues including extraocular muscles, leading to muscle thickening and increased content of the orbit, which can result in compression of the optic nerve.
    • Sarcoidosis and other inflammatory optic neuritis
    • Demyelinating disorders
      • Multiple sclerosis
      • Neuromyelitis optica (NMO)
      • Other acute and chronic inflammatory demyelinating disorders
  • Traumatic ONA
    • Most commonly indirect mechanism (e.g., blunt injury to eye, orbital fracture, retrobulbar hematoma)
    • Also direct and indirect traumatic brain injury (e.g., intracranial hemorrhage leads to optic nerve compression or hydrocephalus-related ONA)
    • Iatrogenic (e.g., surgical)
  • Infectious causes of optic atrophy
    • Syphilis, Lyme disease, tuberculosis (TB)
    • Postmeningitis (e.g., viral, bacterial, fungal, cryptococcal)
    • Postintraocular infections
    • Postsystemic infectious (e.g., postviral)
  • Ischemic ONA
    • Arteritic ischemic optic neuropathy (AION) (also known as giant cell arteritis [GCA])
    • Nonarteritic AION (e.g., diabetes, hypertension, arteriosclerosis)
    • Central retinal artery/vein occlusion with secondary ischemia and secondary ONA
  • Drug-induced ONA
    • Amiodarone, PDE5 inhibitors (e.g., sildenafil), ethambutol, vincristine, linezolid, streptomycin
    • ONA secondary to medication-induced PTC (isotretinoin, oral contraceptive pills, tetracyclines)
  • Nutritional ONA
    • Vitamin B₁₂ (pernicious anemia, alcoholism)
    • Folic acid (alcoholism, malabsorption)
    • Thiamine (alcoholism, gastric bypass, Wernicke syndrome)
  • Toxic ONA
    • Cyanide, lead and other heavy metals, methanol, ethanol, renal failure (multiple proposed mechanisms), tobacco (rare)
    • Radiation
  • Retinal degeneration with secondary ONA (e.g., retinitis pigmentosa: a form of hereditary retinal dystrophy)
  • Congenital optic atrophy: possibly due to lack of oxygen during pregnancy or labor

Genetics

• Inherited form in adults (LHON) shows mitochondrial inheritance, but ONA in children and younger adults can be autosomal recessive, autosomal dominant, X-linked recessive, or may be sporadic.
• Isolated hereditary optic atrophy
  • LHON: mitochondrial inheritance (maternal transmission). Affects complex I of mitochondrial respiratory chain (e.g., mtDNA 11778, 14484, 3460). Degeneration of retinal ganglion cells and their axons; bilateral subacute optic neuropathy, typically with simultaneous or rapidly sequential central or cecocentral visual loss with eventual ONA; onset of symptoms may be associated with metabolic stressor; poor prognosis. Some mitochondrial deletions, however, may have spontaneous recovery (e.g., 14484) (2).
  • Autosomal dominant optic atrophy: Kjer type is the most common. Autosomal gene affects mitochondrial function. Bilateral, slowly progressive loss of vision; OPA1 gene on chromosome 3q28 (2)
  • Autosomal recessive optic atrophy: OPA6 gene, rare (2)
• Optic atrophies associated with complex genetic disorders:
  • Disorders of amino acid metabolism
    • Hyperhomocysteinemia: Deficiency of cystathionine β-synthase → homocysteine accumulates, and less glutathione (antioxidant) can be produced, resulting in oxidative damage and, ultimately, optic neuropathy (3).
  • Peroxisomal disorders
    • Refsum disease: deficiency of phytanoyl-CoA hydroxylase (defect in α-oxidation of fatty acids) → accumulation of phytanic acid in tissues → retinitis pigmentosa, anosmia, cerebellar ataxia, and so forth
    • Adrenoleukodystrophy: deficiency of peroxisomal half-ABC transporter adrenoleukodystrophy protein → impaired oxidation of very long chain fatty acids (VLCFAs) → accumulate in tissues → rapidly progressive cerebral demyelination (4)
  • Lysosomal storage diseases
    • Tay-Sachs
    • Niemann-Pick
    • Mucopolysaccharidoses
  • Other inherited neurodegenerative conditions
    • Wolfram syndrome (DIDMOAD: diabetes insipidus, diabetes mellitus, optic atrophy, and deafness): autosomal recessive with incomplete penetrance, estimated prevalence of 1/770,000; results from a mutation in the wolframin protein, an endoplasmic reticulum membrane protein (5)
    • Hereditary ataxia: genetically heterogeneous spectrum of disease with widespread neurologic degeneration, of which ONA is one part
    • Charcot-Marie-Tooth disease: genetically heterogeneous spectrum of disease; demyelinating sensory and motor neuropathy, with a prevalence of 1/2,500 (6)
    • Familial dysautonomia (Riley-Day syndrome): autosomal recessive, predominantly in Ashkenazi Jewish population, with an incidence of 1/3,750; results from a deficiency of IκB kinase complex–associated protein (IKAP), impairing embryologic development of specific sensory and autonomic neurons, and is associated with progressive optic atrophy (7)
    • Friedreich ataxia
    • Hereditary sensory and autonomic neuropathy type 3 (HSAN3)

Risk Factors

• Family history of genetic forms
• Acquired forms: demyelinating disease, diabetes mellitus, hypertension, radiation exposure, alcoholism, renal failure, arteriosclerosis, increased ICP, certain medications/toxins, nutritional deficiencies, compressive lesions, infection, trauma, neoplasm, paraneoplastic syndromes

General Prevention

Regular ophthalmologic exam in high-risk groups depending on etiology