para>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, etc.)
- 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, PDE-5 inhibitors (e.g., sildenafil), ethambutol, vincristine, linezolid, streptomycin
- ONA secondary to medication-induced pseudotumor cerebri (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 ²-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 inα-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 (VLCFA) ’ 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 IKB 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 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
DIAGNOSIS
HISTORY
- Family history of visual loss
- History of congenital or other neurologic disorders
- History of known etiology for ONA
- Painless loss of visual acuity
- Bilateral; can be synchronous or metachronous
- In primary optic atrophies, often the only clinical feature
- Pain with eye movement in acute demyelinating or inflammatory optic neuritis
- Headache, transient visual obscurations, tinnitus or other symptoms of compression or increased ICP
- Tempo and laterality of visual loss
PHYSICAL EXAM
- Funduscopic exam
- Pallor of the optic disc is characteristic of ONA, but clinical correlation with objective signs of optic neuropathy is necessary (described below).
- Might show band (or bowtie) configuration ONA in optic tract (or optic chiasm) lesions
- Relative afferent pupillary defect in asymmetric bilateral case or in frankly unilateral cases
- Visual field defects (typically central or cecocentral if papillomacular bundle affected, nerve fiber layer defects, bitemporal [chiasmal], or homonymous retrochiasmal but pregeniculate loss)
- Variable abnormalities in visual acuity, color vision, and contrast sensitivity
DIFFERENTIAL DIAGNOSIS
- Glaucomatous optic atrophy can mimic other causes of ONA with cupping (especially vertical cupping with thinning of neuroretinal rim), but typically, nonglaucomatous ONA has concomitant pallor of the remaining neuroretinal rim.
- Myopia can produce physiologic optic pallor.
- Pre- or postoperative cataract extraction can accentuate physiologic pallor and asymmetry between the two eyes on ophthalmoscopic exam (a.k.a. "pseudophakic pseudopallor " )
- Physiologic pallor does not demonstrate any other clinical finding for true ONA (e.g., normal visual acuity, normal visual field, and normal exam).
DIAGNOSTIC TESTS & INTERPRETATION
- A complete ophthalmic examination, including a comprehensive history, will lead to an underlying diagnosis for ONA in up to 92% of cases.
- Ancillary testing is only indicated when the cause is not apparent by clinical evaluation.
- Automated visual field test (e.g., Humphrey) can demonstrate specific central, nerve fiber layer, or hemianopic visual field loss.
- Color vision testing
- Visual-evoked potentials
- Fluorescein angiography
- Optical coherence tomography (OCT) to measure thickness of the retinal nerve fiber layer
- Depending on history and exam
- CBC (e.g., infections, macrocytic anemia in nutritional deficiencies)
- Electrolytes (renal failure)
- Antinuclear antibody (ANA) for lupus
- Angiotensin-converting enzyme (ACE) for sarcoid
- Erythrocyte sedimentation rate (ESR) and C-reactive protein (e.g., GCA)
- Vitamin B12, folate, and thiamine levels in suspected nutritional cases (e.g., alcoholism, gastric bypass)
- Serologic tests for syphilis (e.g., fluorescent treponemal antibody-antibody absorption test [FTA-ABS], rapid plasma reagin [RPR])
- Heavy metal screen
- Genetic testing, if indicated, especially for LHON
- Paraneoplastic antibodies panel
- NMO antibody (to aquaporin 4)
- Thyroid function tests
Diagnostic Procedures/Other
Radiography and neuroimaging
- CT scan of head and orbit in acute setting/trauma
- Pre- and postcontrast MRI (preferred) of head and orbit (with fat saturation) may be indicated for unexplained or isolated ONA.
- Chest radiography or other chest or body imaging for sarcoid (e.g., chest CT, Gallium scan, PET scan)
- Lumbar puncture for CSF studies, including opening pressure in suspected increased ICP or meningitis
TREATMENT
GENERAL MEASURES
- Optic nerve damage may be reversible, so early detection and treatment of the underlying etiology is critical.
- Correction of an underlying nutritional deficiency and discontinuation of the causative drug may halt progression.
- Medical or surgical treatment of the underlying etiology for ONA
- Demyelinating conditions, sarcoid and other autoimmune etiologies may require immune suppression/modulation.
- Papilledema secondary to PTC may be relieved medically (e.g., with Diamox), or by surgery (e.g., CSF shunting procedure or optic nerve sheath fenestration
MEDICATION
- Treatment should be directed at underlying etiology for ONA (if available).
- There is no proven effective therapy for ONA other than treating underlying etiologies.
- IV corticosteroids may improve the rate of recovery of visual function if inflammatory/demyelinating optic neuritis is present.
- For LHON: idebenone (promotes mitochondrial function/antioxidant), coenzyme Q10 (8)[C]
ISSUES FOR REFERRAL
- Genetic counseling for hereditary optic neuropathies
- Neurosurgical referral for tumors, aneurysms, hydrocephalus
- Rheumatology referral for GCA, sarcoid, autoimmune disease
- Neurology referral for demyelinating CNS disease
ADDITIONAL THERAPIES
Associated conditions may require specific treatment, such as for nutritional deficiencies, coexistent inflammatory syndromes, or multiple sclerosis.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Determined by the associated cause
- Progressive ONA may require more frequent follow up and second- and third line evaluation for etiologies of ONA.
Patient Monitoring
Annual evaluations, if stable
DIET
Treat nutritional deficiencies if applicable
PATIENT EDUCATION
- Low-vision counseling
- Genetic counseling, if inherited
- Glaucoma education
- National Eye Institute, Information Officer, Department of Health and Human Services, 9000 Rockville Pike, Bethesda, MD 20892; 301-496 " 5248
- American Council of the Blind: 800-424-8666
PROGNOSIS
Visual loss can be static or progressive, depending on etiology, and prognosis depends on identification and treatment of underlying etiology. ONA is usually not reversible, but some etiologies have better visual prognosis or may spontaneously improve (e.g., optic neuritis).
REFERENCES
11 Mascialino B, Leinonen M, Meier T. Meta-analysis of the prevalence of Leber hereditary optic neuropathy mtDNA mutations in Europe. Eur J Ophthalmol. 2012;22(3):461 " 465.22 Newman NJ. Treatment of hereditary optic neuropathies. Nat Rev Neurol. 2012;8(10):545 " 556.33 Ramakrishnan S, Sulochana KN, Lakshmi S, et al. Biochemistry of homocysteine in health and diseases. Indian J Biochem Biophys. 2006;43(5):275 " 283.44 Wanders RJ, Komen J, Kemp S. Fatty acid omega-oxidation as a rescue pathway for fatty acid oxidation disorders in humans. FEBS J. 2011;278(2):182 " 194.55 Boutzios G, Livadas S, Marinakis E, et al. Endocrine and metabolic aspects of the Wolfram syndrome. Endocrine. 2011;40(1):10 " 13.66 Saporta AS, Sottile SL, Miller LJ, et al. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol. 2011;69(1):22 " 33.77 Mendoza-Santiesteban CE, Hedges TRIII, Norcliffe-Kaufmann L, et al. Clinical neuro-ophthalmic findings in familial dysautonomia. J Neuroophthalmol. 2012;32(1):23 " 26.88 Sitarz KS, Chinnery PF, Yu-Wai-Man P. Disorders of the optic nerve in mitochondrial cytopathies: new ideas on pathogenesis and therapeutic targets. Curr Neurol Neurosci Rep. 2012;12(3):308 " 317.
CODES
ICD10
- H47.20 Unspecified optic atrophy
- H47.22 Hereditary optic atrophy
- H47.219 Primary optic atrophy, unspecified eye
- H47.299 Other optic atrophy, unspecified eye
- H47.239 Glaucomatous optic atrophy, unspecified eye
- H47.293 Other optic atrophy, bilateral
- H47.292 Other optic atrophy, left eye
- H47.233 Glaucomatous optic atrophy, bilateral
- H47.232 Glaucomatous optic atrophy, left eye
- H47.231 Glaucomatous optic atrophy, right eye
- H47.213 Primary optic atrophy, bilateral
- H47.212 Primary optic atrophy, left eye
- H47.211 Primary optic atrophy, right eye
- H47.291 Other optic atrophy, right eye
ICD9
- 377.10 Optic atrophy, unspecified
- 377.16 Hereditary optic atrophy
- 377.11 Primary optic atrophy
- 377.12 Postinflammatory optic atrophy
- 377.13 Optic atrophy associated with retinal dystrophies
- 377.14 Glaucomatous atrophy [cupping] of optic disc
- 377.15 Partial optic atrophy
SNOMED
- Optic atrophy (disorder)
- Hereditary optic atrophy
- Primary optic atrophy
- Postinflammatory optic atrophy
- Glaucomatous atrophy of optic disc
- Partial optic atrophy
CLINICAL PEARLS
- ONA is an ophthalmoscopic sign and not an etiologic diagnosis. It is characterized by pale optic disc on funduscopic exam associated with clinical evidence for ONA.
- Symptoms of ONA might include blurred vision, abnormal central or peripheral vision, abnormal color vision, and decreased brightness.
- The best treatment for ONA is early diagnosis and treatment of the underlying etiology, which can assist in halting disease progression. However, the damage present may be irreversible.