INTRODUCTION — The normal optic nerve head (optic disc) usually is round or oval and pink in color; typically it is flat or mildly elevated and has a central depression called the cup (picture 1). The horizontal diameter of the normal optic nerve is approximately 1.5 mm. The ratio between the cup and disc diameters is important to note because acquired optic nerve damage can cause cupping, an increase in the cup/disc ratio.
Optic nerve abnormalities can be categorized as congenital or acquired. Congenital optic nerve anomalies are distinguished by the appearance of the optic disc and surrounding retina. As a general rule, these anomalies are classified according to abnormalities of optic disc size or conformation and by the presence of abnormal tissue at the nerve head (pseudoswelling). Acquired abnormalities of the optic nerve are classified according to the reaction of the optic nerve to insult: cupping, swelling, and atrophy.
CONGENITAL ANOMALIES
Disc size — The optic nerve head may be absent (aplasia), small (hypoplasia), or large (megalopapilla).
Aplasia — Optic nerve aplasia is an extremely rare, nonhereditary occurrence of unknown etiology. It is characterized by complete lack of the optic nerve, disc, retinal nerve fiber layer, ganglion cells, and retinal vasculature [1,2]. Optic nerve aplasia typically is associated with a variety of other ocular malformations, including microphthalmia, cataract, anterior chamber angle malformation, retinal dysplasia, anterior coloboma (fissure or cleft of the iris or ciliary body), iris hypoplasia, and persistent fetal vasculature (formerly called persistent hyperplastic primary vitreous). Although individuals who are affected unilaterally usually are healthy otherwise, with rare exception, bilaterally affected individuals die shortly after birth [3,4].
Hypoplasia — Optic nerve hypoplasia is the most common congenital optic disc anomaly [5]. In a population-based study (1984-2008), the annual incidence was 2.4 per 100,000 children <19 years (1 in 2287 live births) [6].
Bilateral involvement is more common than is unilateral [6-8]. The hypoplastic disc is small and often pale and surrounded by a yellowish halo bordered by a ring of pigmentation (double-ring sign) (picture 2). Major retinal blood vessels may be tortuous and have anomalous branching patterns. Histopathology shows subnormal numbers of axons. The normal junction between sclera and lamina cribrosa (outer ring) and termination of an abnormal extension of pigment epithelium over the lamina cribrosa (inner ring) constitute the "double ring" [9]. Visual function can vary from 20/20 to no light perception and is nonprogressive [10]. Thus, visual prognosis in an infant is variable.
Optic nerve hypoplasia can occur in isolation, but more commonly there are additional abnormalities:
●Septo-optic dysplasia – Optic nerve hypoplasia is associated with a variety of central nervous system (CNS) and endocrine abnormalities [8,10-15]. The combination of optic nerve hypoplasia, abnormal formation of structures along the midline of the brain, and pituitary hypoplasia is known as septo-optic dysplasia (de Morsier syndrome; MIM #182230). Septo-optic dysplasia has been linked to mutations in the HESX1 gene [16,17].
Magnetic resonance imaging (MRI) is the study of choice for examination of the CNS in children with optic nerve hypoplasia. MRI may show thinning of the optic nerves and chiasm, absence of the septum pellucidum, and agenesis of the corpus callosum. Other common CNS structural abnormalities in children with septo-optic dysplasia include hemispheric migration anomalies, encephalomalacia, schizencephaly, and posterior pituitary ectopia [14,15]. In a study of 73 children with optic nerve hypoplasia, 63 percent had at least one MRI abnormality, including agenesis or hypoplasia of the corpus callosum (38 percent), absent septum pellucidum (38 percent), pituitary gland abnormalities (13 percent), hydrocephalus (6 percent), and migrational abnormalities (schizencephaly, holoprosencephaly, pachygyria; 6 percent collectively) [13]. Developmental delay was present in 71 percent of patients at age 5 years.
Endocrine abnormalities are common and may progress over time [13,15,18-22]. Thus, children with bilateral optic nerve hypoplasia and septo-optic dysplasia should undergo endocrine evaluation at the time of diagnosis and at regular intervals. In the previously described case series, approximately 80 percent of affected children had at least one endocrinopathy, including growth hormone deficiency (70 percent), hyperprolactinemia (62 percent), hypothyroidism (43 percent), adrenal insufficiency (27 percent), and diabetes insipidus (5 percent) [13]. (See "Diagnosis of growth hormone deficiency in children" and "Clinical features and detection of congenital hypothyroidism".)
●Environmental factors – Optic nerve hypoplasia and septo-optic dysplasia are associated with numerous environmental factors, including maternal insulin-dependent diabetes mellitus [12,23]; fetal alcohol syndrome [12,24,25]; and maternal ingestion of quinine [26], anticonvulsants [27,28], and illicit drugs [29,30].
●Other associated disorders – Optic nerve hypoplasia is associated with many other syndromes and disorders, including Delleman syndrome (oculocerebrocutaneous syndrome; MIM #164180) [31,32], Duane syndrome (MIM #607323) [33,34], Klippel-Trenaunay-Weber syndrome (MIM #149000) [35], Goldenhar syndrome (hemifacial microsomia; MIM #164210) [36], linear sebaceous nevus syndrome (MIM #163200) [37], hemifacial atrophy (MIM #141300), Aicardi syndrome (MIM #304050) [38,39], Apert syndrome (MIM #101200) [40], Soto syndrome (MIM #117550) [41], chromosome 13q- [42], trisomy 18 [43], and nonsyndromic mitochondrial cytopathies [44].
Megalopapilla — Megalopapilla is present when the disc has a normal appearance but is greater than 2.1 mm in diameter, regardless of age [45]. Increased cupping will be noted because the same number of axons fills a larger space. Megalopapilla usually is bilateral, and cilioretinal arteries are often present [46]. Measurements of optic nerve function are normal. Megalopapilla probably represents a physiologic variant of normal [47]. However, a rare association between megalopapilla, anterior encephalocele, and midline facial anomalies has been reported [48]. Thus, no further evaluation is necessary for patients with megalopapilla unless they have abnormal optic nerve function, midline facial malformations, or proptosis.
Disc conformation — The optic disc may be of normal size but have abnormal shape, depth, blood vessel appearance, or surrounding retina.
Tilted discs — Tilted discs are characterized by elevation of the superotemporal disc, posterior displacement of the inferonasal disc, situs inversus of the retinal vessels, inferonasal conus, and thinning of the inferonasal retinal pigment epithelium (RPE) and choroid (picture 3) [49]. These findings are bilateral in 80 percent of patients. Visual acuity is normal. A superior pseudo-bitemporal visual field defect may be present, but it may cross the vertical midline [50]. The visual field abnormalities are caused by refractive scotomas produced by the regional myopia from the inferonasal retina. Subretinal neovascularization rarely is associated with a tilted disc [51]. As a general rule, no diagnostic evaluation is necessary. Tilted discs usually do not produce any visual loss and do not progress, thus no specific follow-up is indicated.
Morning glory disc — The morning glory disc anomaly consists of an enlarged, orange-pink optic disc at the center of a funnel-shaped peripapillary excavation (image 1). The disc is surrounded by chorioretinal pigmentation, and a white tuft of glial tissue overlies its central portion. Blood vessels emanate radially from the disc, and peripapillary arteriovenous communications can occur [52]. The appearance is thought to mimic that of the morning glory flower. The reported prevalence is 2.6 per 100,000 [53]. Morning glory discs usually are unilateral, occur more commonly in females, and occur rarely in African-Americans [54,55]. They can be associated with congenital cataracts. (See "Cataract in children".)
Visual acuity typically is 20/200 to finger counting, although all levels of vision have been reported [29]. Acquired visual loss associated with the morning glory disc anomaly can occur from serous retinal detachment [56,57], retinal folds [54], and subretinal neovascularization [58].
Morning glory disc anomaly may be associated with midline cranial defects, including transsphenoidal encephalocele [54,59,60]. Patients with transsphenoidal encephalocele may have wide heads, flat noses, cleft lip and/or palate, hypertelorism, agenesis of the corpus callosum, hypopituitarism, and absence of the optic chiasm [29,59,61]. The symptoms include rhinorrhea, mouth-breathing, and snoring because the encephalocele protrudes into the nasopharynx [62]. The diagnosis of transsphenoidal encephalocele is made with MRI [63]. (See "Congenital anomalies of the nose", section on 'Nasal encephaloceles'.)
Rare associations between the morning glory disc anomaly and capillary hemangiomas [64], abnormal carotid circulation (including moyamoya disease) [60,65,66], and renal disease [67,68] have been described.
Optic disc coloboma — Optic disc coloboma (fissure or cleft) appears as a sharply defined, white, inferiorly decentered excavation of the optic disc (picture 4). The inferior neuroretinal rim is thin or absent. The defect may extend inferiorly and involve the adjacent retina and choroid; rarely, the entire disc is affected. Optic disc colobomas occur unilaterally or bilaterally with equal frequency [54] and may be sporadic or inherited [69]. Visual loss is variable and difficult to predict based upon disc appearance. Macular sparing by associated chorioretinal coloboma is the best predictor of good visual acuity [70]. Colobomas of the iris and ciliary body often coexist. Other coexisting ocular malformations include orbital cyst [71], iris heterochromia [72], and retinal venous malformations [73].
Individuals with optic disc coloboma should undergo renal ultrasound to evaluate for associated kidney disease which occurs in the renal coloboma (papillorenal) syndrome (MIM #120330) [68,74]. Renal coloboma syndrome is an autosomal dominant disorder caused by mutations in the PAX2 gene [75-77]. Renal malformations include renal hypodysplasia, vesicoureteral reflux, and less often, multicystic dysplasia and ureteropelvic junction obstruction. (See "Renal hypodysplasia".)
Optic disc coloboma also has been associated with the CHARGE syndrome (MIM #214800) [78], Walker-Warburg syndrome (MIM #236670) [79], focal dermal hypoplasia (MIM #305600) [80], Aicardi syndrome (MIM #304050) [39], Goldenhar syndrome (hemifacial microsomia; MIM #164210) [81], linear sebaceous nevus syndrome (MIM #163200) [82], and Noonan syndrome (MIM #163950) [83].
Optic pit — An optic pit is an oval or round depression in the optic disc that typically occurs temporally, although any portion of the disc may be affected (picture 5). Pits may appear gray, white, or yellowish, and cilioretinal arteries emerge from the pit in at least 50 percent of cases [84]. Histologically, a pit consists of dysplastic retina that has herniated posteriorly through a defect in the lamina cribrosa [85]. The pits usually are unilateral (85 percent) [86]. The most common visual field defects are enlargement of the blind spot with connected paracentral arcuate scotoma [87]. Visual acuity usually is not affected by the pit, but associated serous macular detachments are common (25 to 75 percent) occurrences and typically produce central vision loss by the third and fourth decades [87]. Macular abnormalities are more likely if the pit is large and temporally located [87]. Ophthalmologic follow-up should be yearly or sooner if the patient notes any visual loss.
Peripapillary staphyloma — Peripapillary staphyloma is an anomaly characterized more by deep fundus excavation around the disc than by actual disc abnormality (picture 6) [54]. Mild temporal pallor of the disc may be present, but the blood vessels are normal. Atrophic changes in the RPE and choroid occur in the walls of the staphyloma. Occasionally, contractile movement of the walls of the staphyloma changes its shape from funnel- to tube-like [88]. With rare exception, visual acuity is markedly reduced and cecocentral scotoma is present; cecocentral scotomas are visual field defects that include central fixation and the physiologic blind spot. Peripapillary staphyloma typically is an isolated bilateral ocular anomaly associated with axial high myopia, although it may be associated with facial capillary hemangioma [89,90]. Children with peripapillary staphyloma should be seen by their ophthalmologist annually.
Pseudoswelling — The following congenital anomalies of the optic nerve may be confused with acquired optic disc swelling. (See 'Acquired abnormalities' below.) In these conditions, abnormal tissue at the nerve head appears to cause swelling (eg, pseudoswelling).
Hyperopia — Hyperopia, or farsightedness, typically occurs in small eyes that have a small scleral opening through which optic nerve axons traverse. Such optic nerves appear small and elevated and can be mistaken for true optic disc swelling (picture 7). (See 'Swelling' below.)
Myelinated fibers — Myelinated nerve fibers appear as striated white patches with feathery borders (picture 8). These pathognomonic borders are caused by differential myelination of individual axons. True optic disc swelling does not have this feathery appearance. Myelinated nerve fibers are ophthalmoscopically evident in 0.3 to 0.6 percent of the population and are seen in 1 percent at postmortem examination [91-93]. Occurrence is bilateral in 17 to 20 percent, and they are continuous with the disc in 81 percent [29]. Visual acuity usually is normal, although enlarged blind spots and scotomas can occur if the myelinated area is of sufficient density. High myopia and amblyopia can occur when the myelination is severe [94]. Myelination of the nerve fiber layer may progress after birth [95], rarely may be acquired [96], and will disappear when affected nerve fibers are damaged. Myelinated nerve fibers may be inherited in an autosomal dominant fashion and are a component of the Gorlin syndrome (also called the basal cell nevus syndrome) [97]. No particular ophthalmologic follow-up is necessary. (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)
Optic disc drusen — Optic disc drusen are multilobulated, globular concretions composed of mucoprotein matrix with acid mucopolysaccharides and ribonucleic acids that progressively calcify [98]. Ophthalmoscopically, disc drusen appear as multiple round to irregular, whitish-yellow dots or granules within the nerve substance, on the surface of the disc, and occasionally in the peripapillary retina (picture 9). Drusen usually are not directly visible at an early age and are said to be "buried." The disc then appears elevated, and although its borders may be blurred, there should be no obscuration of disc vessels. Anomalous vascular patterns often are present on the disc surface. These "buried" drusen become visible as calcification progresses and nerve fibers atrophy.
The prevalence of clinically evident disc drusen is 0.34 percent, but it increases to 3.4 percent in individuals whose family members are affected [98]. They are more often bilateral and without gender predilection [99]. African-Americans are much less often affected than are Caucasians. Disc drusen occur at a higher prevalence in patients with retinitis pigmentosa [100,101], Usher syndrome [102], Alagille syndrome [103], and angioid streaks [104].
Peripheral visual field defects are the most common consequence of drusen, occurring in approximately three-quarters of patients. Visual field defects usually are slowly progressive and asymptomatic, although abrupt and episodic changes can occur. Central visual loss due to disc drusen is sufficiently rare that other causes (eg, tumor and inflammation) must be ruled out [105].
Superficial disc drusen have a characteristic appearance and usually do not create a diagnostic dilemma. However, "buried" drusen often are mistaken for true optic nerve head swelling; a variety of tests can establish their presence [106]. Ultrasonography reveals elevation of the nerve head, and when the gain is decreased, noncalcified ocular tissue loses brightness, whereas the calcified drusen remain bright [107]. Computed tomography (CT) shows calcification at the nerve head. Ocular coherence tomography has been shown to detect buried drusen as well [108]. Superficial drusen also can be identified with red-free photography, fluorescein angiography, and photographs, using the filters for fluorescein angiography (autofluorescence) [109].
Bergmeister papilla — Bergmeister papilla is white, fibrous tissue that represents persistence of the normal hyaloid vascular system. This tissue may overlay the disc or peripapillary retina in varying amounts (picture 10). Visual function should be normal.
ACQUIRED ABNORMALITIES — The normally developed optic disc responds to injury in three ways: increased cupping, swelling, and atrophy.
Cupping — The central depression in the optic nerve head is called the cup. Its size varies according to the size of the scleral opening through which the optic nerve axons traverse. The cup is characterized by the ratio between the cup diameter and the disc diameter. Thus, a cup that has a diameter 50 percent of the disc diameter would be 0.5 (picture 11). Normal cupping can vary between 0.0 and 0.6, with rare instances of 0.8 being normal.
Cupping of the optic disc increases in glaucoma as elevated intraocular pressure damages axons. Axons at the superior and inferior poles of the disc are preferentially affected. Thus, the cup tends to increase vertically in glaucomatous eyes (picture 12). Asymmetry of cupping in fellow eyes may be a sign of abnormality [110].
Congenital glaucoma often causes photophobia and tearing. The corneal diameter and the overall size of the eye (buphthalmos) increase as a result of increased intraocular pressure in the developing eye. Normal corneal diameter is 10 to 11 mm. Patients suspected of having congenital glaucoma should be referred immediately for ophthalmologic evaluation because congenital glaucoma is a sight-threatening disorder. (See "Primary infantile glaucoma".)
Processes other than glaucoma occasionally can cause increased cupping. Compressive etiologies are reported most often [110,111], but ischemia, inflammation, and periventricular leukomalacia also have been implicated [14,112-114]. Patients with normal intraocular pressure and increased cupping should be evaluated for compressive lesions. (See 'Compression' below.)
Swelling — Optic disc swelling is characterized by elevation of the disc, blurred or indistinct disc margins, and hemorrhage and/or exudates on the disc surface (picture 13). Concentric folds (Paton lines) may be present around the disc because the retina is being pushed aside into ridges by the swollen axons.
Papilledema — Papilledema is a subset of optic disc swelling caused by increased intracranial pressure (ICP). Thus, the term "papilledema" should not be applied indiscriminately to any swollen optic disc but should be reserved for cases caused by increased ICP. Papilledema occurs when alteration of axonal transport causes swelling of individual axons. The disc swelling is usually, but not always, bilateral, and vision may be normal. Very brief episodes (2 to 10 seconds) of blurry vision may occur, often with a change in posture. Patients typically have symptoms of increased ICP (eg, headache, tinnitus). Neuroimaging (MRI or CT) urgently is required to rule out space-occupying lesions and/or hydrocephalus. (See "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis" and "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis" and "Overview and differential diagnosis of papilledema" and "Hydrocephalus in children: Clinical features and diagnosis".)
Inflammation — Inflammation of the optic nerve is known as optic neuritis. "Optic neuritis" is a nonspecific term for optic neuropathy caused by any inflammatory condition, including multiple sclerosis, sarcoidosis, contiguous sinus disease, or infection. It may also be idiopathic ("post-viral"). Optic disc swelling usually is mild (or may be absent altogether). (See "Optic neuritis: Pathophysiology, clinical features, and diagnosis".)
Optic neuritis usually is unilateral and is accompanied by signs of optic neuropathy such as decreased visual acuity, a relative afferent pupillary defect (Marcus Gunn pupil), and visual field defects. A patient with optic neuritis often complains of pain with eye movement. An MRI should be performed to determine etiology. As an example, plaques suggestive of multiple sclerosis typically are found in the periventricular region, corpus callosum, centrum semiovale, and, to a lesser extent, deep white matter structures and basal ganglia. Optic neuritis usually is treated with intravenous corticosteroids and should be managed in consultation with a neurologist. (See "Optic neuritis: Prognosis and treatment".)
Neuroretinitis is said to be present if a macular star of exudate occurs in an eye with optic disc swelling (picture 14). It may be idiopathic or caused by cat-scratch disease (Bartonella henselae). MRI is not necessary because no association exists between neuroretinitis and multiple sclerosis [115].
Ischemia — Ischemia of the anterior optic nerve results in optic disc swelling (nonarteritic anterior ischemic optic neuropathy). Although it occurs commonly in older individuals (>50 years) with atherosclerotic risk factors, it has been reported in younger individuals (30 to 50 years) [116]. Severe blood loss or hypotension can also result in ischemia of the optic nerve and disc swelling may be unilateral or bilateral. The disc swelling may be diffuse or sectoral (picture 15). Signs of optic nerve dysfunction (eg, decreased visual acuity, a relative afferent pupillary defect (Marcus Gunn pupil), and visual field defects) usually are present.
Compression — Compression of the optic nerve within the orbit may result in optic disc swelling. Proptosis usually is present, and abnormalities of eye movements may occur. Orbital MRI or CT scan is necessary to determine the source of compression. Causes of optic nerve compression include intracranial or intraorbital tumors [117,118], aneurysmal bone cysts [119,120], orbital hemorrhage or vascular anomalies [121-125], orbital emphysema [126], fibrous dysplasia [127], Graves' ophthalmopathy [128], or osteopetrosis [129]. (See "Acute and chronic bone complications of sickle cell disease" and "Clinical features and diagnosis of thyroid eye disease".)
Infiltration — Infiltration of the optic disc by leukemia, lymphoma, metastases, or sarcoid can produce the appearance of massive disc swelling (picture 16). Severe visual loss typically is present.
Atrophy — Optic nerve damage from any cause except glaucoma (see 'Cupping' above) results in a change in the normal pink disc color to a pale or whitish appearance. This change is permanent and indicates irreversible optic nerve damage. The color change usually occurs within two to three months of the nerve damage.
Diffuse atrophy — Diffuse optic atrophy is a nonspecific sign of optic nerve damage (picture 17). It does not help identify the etiology of the damage. Any of the acquired conditions discussed above (except glaucoma) can result in diffuse optic atrophy. Unexplained optic atrophy requires neuroimaging.
Segmental atrophy — Segmental optic atrophy may be helpful in identifying the etiology of the optic nerve damage. Superior or inferior hemi-atrophy typically occurs after ischemic insult (picture 18A) [2]. Wedge-shaped temporal optic atrophy is seen in dominant optic atrophy, the most common type of hereditary optic neuropathy (picture 18B).
Dominant optic atrophy is characterized by insidious onset of visual impairment in childhood, temporal disc pallor, color vision deficits, and centrocecal scotoma of variable density [130,131]. It is caused by a mutation in the OPA1 gene on chromosome 3q28-q29. A possible association with Ewing sarcoma has been described [132].
SUMMARY
●The normal optic nerve head (optic disc) usually is round or oval and pink in color; typically it is flat or mildly elevated and has a central depression called the cup (picture 1). The horizontal diameter of the normal optic nerve is approximately 1.5 mm. (See 'Introduction' above.)
●Congenital anomalies of the optic nerve are classified according to size, conformation, and the presence of abnormal tissue at the nerve head. (See 'Congenital anomalies' above.)
•Anomalies of size include aplasia, hypoplasia (picture 2), and megalopapilla. (See 'Disc size' above.)
•Anomalies of conformation include tilted discs (picture 3), morning glory disc (image 1), optic disc coloboma (picture 4), optic pit (picture 5), and peripapillary staphyloma (picture 6). (See 'Disc conformation' above.)
•Anomalies with abnormal tissue at the nerve head include hyperopia (picture 7), myelinated fibers (picture 8), optic disc drusen (picture 9), and Bergmeister papilla (picture 10). (See 'Pseudoswelling' above.)
●Acquired abnormalities of the optic nerve are classified according to the reaction of the optic nerve to insult: cupping (picture 11 and picture 12); swelling due to increased intracranial pressure (papilledema) (picture 13), inflammation (picture 14), ischemia (picture 15), compression, or infiltration (picture 16); and atrophy, which may be diffuse (picture 17) or segmental (picture 18A-B). (See 'Acquired abnormalities' above.)
