Optic nerve atrophy and anomalies: clinical guidelines

List of Abbreviations

AZN – optic nerve atrophy

ACTH – adrenocorticotropic hormone

AMP – adenosine monophosphate

ATP – adenosine triphosphate

RGC – retinal ganglion cells

ONH – optic nerve head

VEP – visual evoked potentials of the cerebral cortex

ON – optic nerve

CT – computed tomography

ICD-10 – International Classification of Diseases, 10th Revision

MRI – magnetic resonance imaging

ON – optic neuritis

LGN – lateral geniculate nucleus

RAPD – relative afferent pupillary defect

OCT – optical coherence tomography (an optical examination of the retina or optic nerve head and retinal nerve fiber layer using a computer analyzer)

OCT-A – optical coherence tomography angiography (an optical examination of the retina or optic nerve head and retinal nerve fiber layer using a computer analyzer in angiography mode)

RNFL – retinal nerve fiber layer

FA – fluorescein angiography of the eye

US – ultrasound examination

CDI – color Doppler imaging

CNS – central nervous system

NMDA – ionotropic glutamate receptor that selectively binds N-methyl-D-aspartate

AMPA – an ionotropic glutamate receptor that mediates fast excitatory synaptic transmission in the nervous system

Terms and Definitions

Optic nerve atrophy (ONA) is the outcome of pathological processes of various etiologies, characterized by a decrease in visual functions (up to complete loss) due to the irreversible loss of retinal ganglion cell (RGC) axons, impaired pupillary reactions, and structural changes in the optic disc (OD).

Ascending ONA is an optic nerve condition characterized by damage to ganglion cells at the retinal level.

Congenital anomalies of the optic disc are a group of optic disc disorders caused by impaired formation during the prenatal period.

Secondary ONA is a condition that develops following inflammatory processes (most commonly as a consequence of prior ON), due to optic nerve ischemia in vascular disorders, or secondary to papilledema caused by elevated intracranial pressure.

Optic disc hypoplasia – impaired formation of the optic nerve due to a reduced number of its axons with normal development of supporting tissues and the retinal vascular system.

Optic disc drusen – hyaline-like calcified deposits within the optic disc, localized anterior to the lamina cribrosa, either intracellularly or extracellularly.

Optic disc coloboma – a congenital anomaly of varying sizes, appearing as a well-demarcated white excavation located within an enlarged optic disc.

Megalopapilla – an abnormally large optic disc with a diameter greater than 2.1 mm, without any other morphological changes.

Myelinated nerve fibers – a type of nerve fiber covered by a myelin sheath composed of lipids and proteins, formed by oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system.

Descending ONA is an optic nerve condition characterized by damage to any part of the visual pathway with the gradual involvement of the optic disc in the pathological process.

Primary (simple) ONA – a condition that develops due to direct damage to optic nerve fibers without preceding inflammation, impaired blood supply, or papilledema.

Peripapillary staphyloma – a congenital pathology characterized by staphylomatous excavation of the fundus around the optic disc and a relatively normal appearance of the optic nerve head at the base of the excavation.

Morning glory syndrome – a congenital funnel-shaped anomaly in the posterior fundus involving the optic disc, which is covered by a tuft of glial tissue.

Tilted disc syndrome – a congenital binocular defect of the inferior and/or inferonasal optic disc segment, accompanied by thinning of the peripapillary retina and choroid.

Toxic ONA – a specific variant of secondary atrophy developing as a result of exogenous toxins acting on the optic nerve.

Optic disc pit – a congenital anomaly representing a localized depression of the optic disc.

Glaucomatous ONA – a specific variant of secondary atrophy associated with typical glaucomatous changes of the optic disc and RNFL.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Optic nerve atrophy is the outcome of pathological processes of various etiologies, characterized by a decrease in visual functions (up to complete loss) due to the irreversible loss of retinal ganglion cell (RGC) axons.

Characteristic clinical signs of ONA include: impaired visual functions and pupillary reactions, as well as structural changes in the optic disc.

Congenital anomalies of the optic disc are a group of optic disc disorders caused by impaired formation during the prenatal period. They may occur as an isolated condition, combine with other developmental anomalies of eyeball structures, or form part of congenital syndromes involving multisystem pathology. The most common congenital optic disc anomalies include optic nerve hypoplasia and aplasia, myelinated nerve fibers, optic disc drusen, optic disc pit, optic disc coloboma, morning glory syndrome, tilted disc syndrome, megalopapilla, and peripapillary staphyloma.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

1.2.1 Etiology and pathogenesis of optic nerve atrophy

Any ONA is accompanied by a reduction in optic nerve diameter throughout its length, with impaired trophism, loss of myelinated fibers, and glial proliferation [1-3].

ONA is subdivided into ascending and descending. Ascending ONA is characterized by damage to ganglion cells at the retinal level. In descending ONA, damage can occur at any segment of the visual pathway (optic nerve, chiasm, optic tract, lateral geniculate bodies) with subsequent involvement of RGCs in the pathological process [4].

The primary damaging factor leading to ONA is the cessation of axonal transport, resulting either from damage to the neuron cell body or from injury to its glial elements, where degenerative processes spread toward both the neuronal cell bodies and the synapse [5].

1.2.1.1 Mechanisms of ganglion cell atrophy

Acute axonal degeneration

In the first minutes after optic nerve fiber injury, acute axonal degeneration develops [6]. The rapid influx of extracellular calcium into the axon at this moment triggers an apoptotic signal to the neuronal cell body [7, 8]. According to experimental data, as early as 30 minutes after injury, organelle disorganization is observed and axon diameters are significantly reduced, indicating the development of apoptosis [9].

Ganglion cell excitotoxicity

Excitotoxicity (from Engl. to excite — to excite, activate, and toxicity) is the effect of excitotoxins (neurotransmitters capable of hyperactivating NMDA-(N-methyl-D-aspartate ) and AMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) on the dendrites and axons of retinal neurons, causing prolonged activation of these specific amino acid receptors [9]. The resulting excessive influx of calcium ions into the cell activates enzymes (phospholipasess, endonucleasess, proteasess) that destroy basic cellular structures; thus triggering cell apoptosis . Excitotoxins can act as L-glutamate i glutamate mimetics. During apoptosis, excitotoxins exit the damaged RGCs into the intercellular space. They are capable of inducing apoptosis in neighboring cells, thereby increasing the damage zone [10-12]. It is worth noting that unlike other CNS neurons, these specific amino acid receptors in the optic nerve are localized predominantly on the somata of RGCs. Therefore, the activation of such receptors does not affect the axons of ganglion cells for a relatively long time, and only their cell bodies are damaged [13]. These processes also explain the secondary degeneration of optic nerve axons in a number of neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, and others [14].

1.2.1.2 Descending ONA

Descending ONA is associated with the spread of RGC axon damage from the center to the periphery, culminating in their death [15-17]. The duration of descending atrophy depends on the localization of the primary lesion: the further it is from the eyeball, the faster fundus changes become visible.

When the posterior visual tract is damaged, thinning of the RGC complex is observed as early as 6–12 weeks, as demonstrated in animal experiments [13, 18]. In clinical practice, a reduction in peripapillary retinal nerve fiber layer (RNFL) thickness on optical coherence tomography (OCT) is seen as early as 4–6 weeks after visual tract injury and has a sectoral character (band atrophy) in the fellow eye [19]. Similar changes have been noted in patients with bilateral intraoperative chiasmal injuries as early as 3–5 weeks [20].

According to experimental studies, when the intracranial part of the optic nerve near the chiasm is damaged, marked thinning of the deep retinal layers, including the RNFL, is observed at 4–8 weeks; when the intracanalicular part of the optic nerve is damaged, optic disc pallor is typically recorded at 7–8 weeks; and when the intraorbital part is damaged, at 5 weeks [15, 21-22]. In traumatic optic neuropathy at the intraorbital optic nerve segment, OCT of the optic disc reveals RNFL thinning 2 weeks after trauma, with the most rapid progression at 2–4 weeks, and at the intracanalicular optic nerve level, at 3–6 weeks [23].

1.2.1.3 Ascending ONA

In ascending (antegrade) ONA of various etiologies, including glaucomatous optic neuropathy, atrophic processes begin in the RGC cell bodies, subsequently causing axon degeneration down to its synapses in the LGN [21, 24]. In this process, damage (axon fragmentation, microtubule disorganization, and phagocytosis of intracellular organelles) [25] begins within 24 hours and results in cell death along the entire length within a week. It should be noted that degeneration proceeds more slowly in thinner axons [26].

In post-traumatic ONA (traumatic optic neuropathy), Wallerian degeneration is observed, regulated by the activation of the slow Wallerian degeneration gene WldS ("slow Wallerian degeneration"). In ONA of other etiologies, WldS activity remains low, and RGC axons exhibit cytoskeleton disintegration and fragmentation via myelin ovoid bodies, which are subsequently cleared by glia and macrophages [27].

1.2.1.4 Transynaptic ONA

Transsynaptic atrophy is observed in a number of neurological diseases affecting the retrogeniculate visual pathway and can be either ascending or descending. Currently, the mechanism of this form of atrophy is not fully understood, but the first signs of neurodegeneration are observed after 1 month, and the process is completely finished in 420 days [27]. These changes are accompanied by RNFL thinning, while new visual field defects are typically not detected.

1.2.2 Pathogenesis and etiology of congenital optic disc anomalies

Proper optic disc development is regulated by a complex interplay of genes and molecular signals. Among the genes whose pathological impact on structure and function during ontogenesis leads to congenital optic disc anomalies are PAX6, PAX2, SHH, BMP4, Rx, netrin, POUF1, PROP1, SF-1, PITX2, NeuroD1, GATA-2, LHX3, TPIT, SOX3, SOX2, CDH7, HESX1 [28-29].

Optic nerve hypoplasia

It develops due to impaired optic nerve formation between 6 weeks and 4 months of prenatal development as a consequence of a reduced axon count in the affected nerve, with normal development of supporting tissues and the retinal vascular system. It most commonly occurs sporadically; in familial cases, an autosomal recessive inheritance pattern is typically noted [29]. The underlying anomaly may stem from genetic or metabolic disorders, though in 70% of cases no risk factors can be identified [30]. Regarding genetic disorders, no specific genotype-phenotype correlation explaining the majority of optic nerve hypoplasia cases has yet been found.

Optic nerve aplasia

It is the result of damage occurring roughly at 3 to 4 months of prenatal development that affects normal retinal development and angiogenesis, causing retinal ganglion cell degeneration. Various theories proposed to explain optic nerve aplasia pathogenesis include developmental disorders of mesodermal elements or fetal fissure closure, primary ganglion cell deficiency, and mesodermal induction failure, although no single consensus hypothesis exists. Histopathological studies typically reveal a rudimentary dura mater penetrating the sclera in its normal position, along with retinal dysplasia. Cases of mutations in the PAX6 and OTX2 genes are known, although the precise genetic basis remains unknown [31].

Myelinated nerve fibers

In the 5th month of intrauterine development, myelination spreads from the optic tract towards the optic tracts, then to the optic chiasm, and reaches the optic nerve by the 8th month. Abnormal myelinated nerve fibers develop when myelination extends beyond the posterior lamina cribrosa into the optic disc and peripapillary regions [32-33]. The exact pathogenesis of this abnormal myelin extension remains unclear.

Optic disc drusen

There are three theories of drusen formation: the first is axonal metabolism impairment with slowed axoplasmic flow; the second is congenital optic disc dysplasia predisposing to drusen development; and the third is a narrow scleral canal leading to optic nerve compression, which causes retinal ganglion cell death with extrusion and mitochondrial calcification. However, this theory is controversial since OCT results have not revealed a decreased optic canal diameter in drusen [34].

Optic disc pit

The following hypotheses of pathogenesis are considered: association with a partial delay in fiber ingrowth during the period when optic nerve fibers fill the optic canal; a "mild" form of optic nerve coloboma (incomplete closure of the proximal end of the embryonic fissure) [35]; a mutation in the PAX2 gene [36-38], leading to abnormal development of the primordial optic disc epithelium. Histologically, in the area of the optic disc pit, a defect of the lamina cribrosa and a reduced RNFL thickness of the papillomacular bundle are observed.

Optic disc coloboma

It can be sporadic or inherited in an autosomal dominant manner (development is linked to mutations in the PAX2, PAX6, CDH7 and other genes) [39-40]. The underlying mechanism is an incomplete or abnormal closure of the proximal end of the embryonic fissure, which normally completes by the 4th-5th week of gestation [35].

Morning glory syndrome

Genetic foundations are being studied (causation by mutations in PAX6, MMP19 genes has been described). The underlying development involves mesodermal disorders and embryonic developmental defects at the junction of the optic stalk with the optic vesicle [41-43].

Tilted disc syndrome

It results from incomplete closure of the fetal fissure at week 6 of gestation, resulting in a typical coloboma of the disc, peripapillary retina, retinal pigment epithelium, and choroid of varying degrees [44-46].

Peripapillary staphyloma

It presumably forms during the 5th month of gestation, when cells of the posterior sclera and neural crest cells are not fully differentiated. It is believed that normal intraocular pressure may contribute to the herniation of the weakened scleral wall [43, 47].

Megalopapilla

The exact pathogenesis is unknown. The relationship of the TGFBR3 gene on chromosome 1p22, ATOH7 on chromosome 10q21.3-22.1, and SALL1 on chromosome 16q12.5 with the development of this anomaly is being investigated [48].

1.3 Epidemiology of the Disease or Condition

Optic atrophy prevalence varies widely and is one of the five leading causes of blindness in Israel, Japan, Scotland, Zaire, and other countries according to published data [49-53]. In Oman, optic atrophy accounts for 5% of blindness cases [54], and in Egypt 4.1% among the urban population and 1.2% among the rural population [55]. In the USA, the prevalence of visual impairment and blindness associated with optic atrophy was 0.04% and 0.12%, respectively, with optic atrophy being more common in African Americans (0.3%) than in whites (0.05%) [56]. No gender or age differences are observed.

In the Russian Federation, according to federal statistics at the end of 2023, 50,852 patients were registered with a diagnosis of "optic atrophy" [57-58]. In the Russian Federation in 2021, the disease ranked third in the structure of primary visual disability among the adult population [59].

Congenital optic disc anomalies are rare diseases, yet they occupy an important place in the structure of causes of significant visual impairment and visual disability in pediatric and working-age populations.

Optic nerve hypoplasia is the most common optic disc malformation and the third most common cause of visual impairment, accounting for approximately 15–25% of cases of severe vision loss in children under 3 years of age [60]. The incidence is 1 per 2,287 live births and 2.4 per 100,000 patients under 19 years of age [61], 10.9 per 100,000 in England [62], and 17.3 per 100,000 in Sweden [63].

Myelination of optic nerve fibers in the peripapillary retina occurs with a frequency of 0.3% to 1% [64].

The prevalence of optic disc drusen is 0.4% in children and 0.5–2.4% in adults [65]; there is no sex predilection, and it is more common in Caucasians; >70% of cases are bilateral but asymmetric [66]. Autosomal dominant inheritance with incomplete penetrance is hypothesized [67].

The low detection rate of drusen in children can be explained by their deeper localization and diagnostic difficulty.

The prevalence of optic disc pits is about 0.1% of the population (1 per 10,000 population) [68-69]; men and women are affected equally; 30–75% of cases are complicated by maculopathy [70].

The incidence of optic disc coloboma is 3.7:100,000 to 8.9:100,000 population (no sex correlation) [71].

The prevalence of morning glory syndrome is 2.6 per 100,000 [72]; both sexes are affected equally, and it is less common in Black individuals. It is predominantly a unilateral disease [73], with bilateral involvement observed in approximately 16% of cases [74].

Tilted disc syndrome occurs in 1–2% of the population with equal frequency in men and women [47].

Epidemiological data on megalopapilla and peripapillary staphyloma are absent due to their extremely low frequency.

1.4 Features of Coding the Disease or Condition

H47 Other disorders of optic [2nd] nerve and visual pathways

H47.1 Unspecified optic disc edema

H47.2 Optic atrophy

H47.3 Other disorders of optic disc

H48 Disorders of optic [2nd] nerve and visual pathways in diseases classified elsewhere

H48.1* Optic atrophy in diseases classified elsewhere

Q14 Congenital malformations of posterior segment of eye

Q14.2 Congenital anomaly of optic disc

1.5 Classification of the disease or condition

Depending on the etiology, acquired and hereditary (congenital) optic atrophy are distinguished.

Pathogenetically, ascending and descending optic atrophies are isolated.

Depending on morphological changes in the disc tissue, primary and secondary optic atrophies are differentiated.

Glaucomatous optic atrophy (glaucomatous optic neuropathy) is usually classified separately.

Depending on the degree of nerve fiber damage, partial and complete optic atrophies are distinguished.

Acquired optic atrophy develops as an outcome of vascular, inflammatory, toxic, and other types of optic nerve damage due to the following causes.

• Infectious inflammation: bacterial infections (tuberculosis, syphilis, tick-borne borreliosis), viral infections (Herpes zoster, rubella viruses; viruses causing acute respiratory infections, cat-scratch disease), parasitic infections (toxoplasmosis, toxocariasis).

• Demyelinating diseases (multiple sclerosis).

• Autoimmune diseases (antiphospholipid syndrome, Vogt-Koyanagi-Harada disease, systemic lupus erythematosus, Behçet's disease, granulomatosis with polyangiitis, giant cell arteritis, Takayasu arteritis).

• Blood disorders (hemorrhagic or pernicious anemia, leukemia).

• Compressive effects (orbital neoplasms, pseudotumor, endocrine ophthalmopathy, intracranial mass lesions, hydrocephalus).

• Trauma (craniofacial and facial skeleton injuries).

• Vascular disorders (arteriosclerotic ischemic optic neuropathy, central retinal artery occlusion, ocular ischemic syndrome).

• Toxic effects (alcohol and tobacco abuse, poisoning with lead, arsenic, thallium, methyl alcohol, quinine salts [quinine hydrochloride, quinine dihydrochloride, quinine sulfate], medications: ethambutol**, chloramphenicol**, gentamicin**, isoniazid**,

• vincristine**, penicillamine**, fluorouracil**, etc.).

• Alimentary deficiency (B vitamin deficiency).

• Ocular hypertension (glaucoma), prolonged ocular hypotension (postoperative, inflammatory and degenerative diseases of the ciliary body, penetrating eye injuries).

Hereditary optic atrophy has three forms: autosomal dominant, autosomal recessive, and mitochondrial.

• Autosomal dominant atrophy occurs in severe and mild forms, and may be associated with congenital deafness.

• Autosomal recessive atrophy includes Behr, Bourneville, Wolfram, Vent, Jensen, Kenny-Caffey, and Rosenberg-Chutorian syndromes.

• The mitochondrial form of optic atrophy—Leber's atrophy—is caused by mtDNA mutations.

Optic atrophy occurs in hereditary diseases of the retina and optic nerve (tapetoretinal abiotrophy, optic disc drusen).

Optic atrophy in syndromic diseases is distinguished: optic-pyramidal syndrome, optic-retino-neuritic syndrome, Godtfredsen syndrome, adrenoleukodystrophy.

There is no classification of congenital optic disc anomalies; individual clinical forms are distinguished, the most common of which are: optic disc hypoplasia and aplasia, myelinated nerve fibers, optic disc drusen, optic disc pit, optic disc coloboma, morning glory syndrome, tilted disc syndrome, megapapilla, peripapillary staphyloma.

1.6 Clinical presentation of the disease or condition

Optic atrophy is the outcome of prior damage (the clinical picture is variable) and manifests as decreased vision down to blindness. Depending on the form and etiology, clinical manifestations may vary.

Initial manifestations are characterized by impaired contrast sensitivity or color vision with preserved visual acuity. More severe damage can lead to visual impairment and blindness. Damage to a portion of the optic nerve fibers may manifest as a decrease in visual functions only in the corresponding sector of the visual field. Other complaints are likely related to the underlying disease causing the atrophy or comorbid conditions.

Primary (simple) optic atrophy develops due to direct damage to optic nerve fibers without prior inflammation, circulatory disorders, or papilledema. It is accompanied by a gradual decrease in visual acuity in one or both eyes (in severe cases, down to complete blindness), constriction of visual fields (both concentric and sectoral loss; central scotomas are possible in rare cases), decreased photosensitivity, and impaired color vision. Ophthalmoscopy reveals pallor of the optic disc due to a decrease in the number of small vessels on the surface of the neuroretinal rim (Kestenbaum's sign), enlargement and altered shape of the cup, and OCT shows thinning of the peripapillary retinal nerve fiber layer.

Secondary optic atrophy develops after inflammatory processes (most commonly following optic neuritis), due to optic nerve ischemia from vascular disorders, or against the background of papilledema caused by increased intracranial pressure. Vision decreases rapidly, and an acute onset is possible. Visual fields may change diffusely or locally, including the presence of ring scotomas (sectoral or arcuate visual field defects are more common in ischemic damage). Ophthalmoscopically, signs of the underlying disease appear initially, but as atrophy progresses, the optic disc becomes pale and the arteries narrow.

Toxic optic atrophy is a distinct variant of secondary optic atrophy developing due to the effect of exogenous toxins on the optic nerve. It is characterized by sudden or gradual visual loss, most often bilateral (down to complete blindness), and central or paracentral scotomas can be detected. Ophthalmoscopy reveals pallor of the optic disc.

Glaucomatous optic atrophy is characterized by a gradual loss of the visual field followed by a decrease in visual acuity (down to blindness) against the background of typical glaucomatous changes of the optic disc and retinal nerve fiber layer. The main sign of optic atrophy is pallor of the optic disc. Its margins become more distinct due to thinning or complete atrophy of the retinal nerve fiber layer in this zone. Small vessels on the surface of the pale optic disc are usually absent.

In optic disc hypoplasia, there is a reduction in the size of the optic disc, which may appear gray or pale due to a decrease in the number of optic nerve axons with normal glial tissue. The optic disc is surrounded by a yellowish peripapillary scleral ring and an outer concentric ring of hyper- or hypopigmentation ("double ring"). The outer ring is located at the normal border between the sclera and the lamina cribrosa. The inner ring represents an abnormal "extension" of the retina and retinal pigment epithelium over the outer parts of the lamina cribrosa. Large retinal veins and/or arteries usually have a tortuous course, although a straight vascular course also occurs. Optic disc hypoplasia is characterized by an increase in the ratio of the disc-to-fovea distance to the disc diameter of greater than 3 (in 95% of the healthy population, this ratio is no more than 2.94). Visual acuity ranges from 1.0 to no light perception, is determined mainly by the integrity of the papillomacular bundle, and does not correlate with the size of the optic disc. It remains stable or may improve slightly as the postnatal visual pathways develop. Local visual field defects and/or peripheral constriction may be present [75].

Unilateral optic disc aplasia is usually associated with normal brain structure, whereas bilateral aplasia is associated with congenital hypopituitarism and ectopic posterior pituitary, meningoencephalocele, and septo-optic dysplasia. Optic disc aplasia may be accompanied by esotropia, enophthalmos, trabeculodysgenesis, partial aniridia, cataract, microcornea, and uveoretinal coloboma. The prognosis is unfavorable, and follow-up aims to detect any associated systemic anomalies [76].

Optic disc drusen (hyaline bodies) are formed by hyaline-like calcified deposits within the optic disc substance, localized anterior to the lamina cribrosa intracellularly or extracellularly. Optic disc drusen usually do not affect visual acuity. The optic disc appears elevated; superficial or deep hemorrhages may be present. Drusen are typically located on the nasal side and appear bumpy when superficial. Deep drusen are difficult to distinguish on slit-lamp examination, but can sometimes be seen near vessels or the disc margin with oblique illumination [77].

Myelinated nerve fibers have a whitish, feathery appearance. Myelination can progress after birth, but does not extend to the macula. Visual acuity is usually normal. If myelination is more pronounced, amblyopia, strabismus, nystagmus, enlargement of the blind spot, and relative scotomas may develop. Myopia occurs in about half of all cases [64].

Optic disc pit clinically presents as an oval, gray-white depression of the optic disc ranging from 0.1 to 0.8 disc radii in size, most often located in the temporal or inferotemporal segment of the disc; the optic disc is often increased in diameter. In 85% of cases, the pathology is unilateral. An "uncomplicated" optic disc pit is usually asymptomatic [69].

Optic disc coloboma appears ophthalmoscopically as a well-defined white depression (excavation) located within an enlarged optic disc. Unlike morning glory syndrome, there is no central glial stalk, no abnormal retinal vascular network, and only minimal peripapillary pigmentary changes are present. Involvement of the adjacent retina and choroid in the coloboma can be combined with microphthalmia, iris and ciliary body coloboma. Retinochoroidal coloboma can "merge" with the optic nerve coloboma or have an area of healthy tissue between them ("bridge" colobomas). It can be either unilateral or bilateral with equal frequency. Visual acuity is reduced, and the degree of reduction varies widely [78].

Morning glory syndrome is usually a unilateral anomaly (bilateral involvement is described in 16% of cases). It is a congenital funnel-shaped excavation in the posterior fundus involving the optic disc. It may be associated with basal encephalocele and midface anomalies (hypertelorism, cleft lip, cleft palate). The optic disc is markedly enlarged, orange or pink. A raised ring-like zone of hyperpigmentation surrounds the excavation. A white tuft of glial tissue covers the excavated central part of the lesion. Numerous blood vessels originate from the disc periphery. They have an abnormally straight course across the peripapillary retina and tend to branch at acute angles. It is often difficult to distinguish arterioles from venules. The macula may be included in the excavation (funnel). Visual acuity ranges from 0.1 to finger counting at arm's length [79].

Oblique optic disc insertion syndrome is more often a bilateral pathology, characterized by a rather variable ophthalmoscopic picture determined by the degree of involvement of the disc and peripapillary retina. Most commonly, the superotemporal part of the disc is prominent, while the inferonasal part is displaced posteriorly, resulting in an oval optic disc whose long axis is oriented obliquely; these changes are accompanied by situs inversus of the retinal vessels, a congenital inferonasal conus, and thinning of the retinal pigment epithelium and choroid in the inferonasal quadrant [80]. The anomaly is accompanied by myopic astigmatism. Best-corrected visual acuity is generally high.

In megalopapilla, the optic disc is increased in size but has a normal appearance in terms of color, margin clarity, and blood vessel configuration. Visual acuity is generally high [81].

Peripapillary staphyloma on ophthalmoscopy appears as a deep cup-shaped excavation with a relatively normal, properly formed optic disc (some discoloration of the temporal half may be noted). The optic disc is located at the bottom of the staphyloma. Unlike morning glory syndrome, central glial tissue and anomalous retinal vasculature are absent. Retinal pigment and choroidalrophic changes are determined in the walls of the staphyloma. Contractile movements of the staphyloma walls may be observed. Peripapillary staphyloma is usually not associated with other congenital anomalies. Visual acuity is usually markedly reduced due to a cecocentral scotoma [82].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnosis of optic nerve atrophy and optic disc anomalies should be aimed at identifying pathological changes in the optic nerve and retina, as well as diagnosing the main systemic risk factors for the onset and progression of this pathology.

Table 1. Main diagnostic criteria for establishing optic nerve atrophy

2.1 Complaints and Anamnesis

2.2 Physical Examination

• Physical examination for patients with optic nerve atrophy or suspected presence thereof for diagnostic and treatment purposes is not recommended [58].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Physical examination is performed by specialists of relevant profiles (neurologist, neurosurgeon, rheumatologist, otorhinolaryngologist, phthisiatrician, general practitioner, pediatrician, infectious disease specialist, or family physician) as part of managing the disease that acts as a risk factor for optic nerve atrophy development. The choice of specialist profile depends on the clinical course of optic nerve atrophy, planned treatment, and the presence of concomitant systemic disease and/or risk factors for systemic complications in the patient.

2.3 Laboratory Diagnostics

Comments: The choice of laboratory test is determined by the presence of a concomitant disease in the patient or when it is suspected.

Comments: In the absence of a rheumatologist, an initial consultation (examination) with a general practitioner or an initial consultation (examination) with a general practitioner (family physician) is possible.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

2.4 Instrumental Diagnostics

Comments: fundus biomicroscopy with aspheric lenses using a slit lamp (or ophthalmoscopy) is the primary method for diagnosing fundus changes during an ophthalmological examination across any setting (primary health care, specialized care) and care delivery mode (inpatient, outpatient). It is important to remember that prior to pharmacological pupil dilation, the depth of the anterior chamber, the state of the iris, and the pupillary reaction must be evaluated.

Comments: the necessity and frequency of ultrasonography are determined by the ophthalmologist depending on the clinical course of the disease. It should include an echographic assessment of the anatomical and structural characteristics of the optic nerve, measuring its thickness with and without sheaths, as well as determining the state of extraocular muscles and retrobulbar adipose tissue.

Comments: the necessity and frequency of OCT and OCT-A are determined by the ophthalmologist depending on the clinical course of the disease, as well as during follow-up. OCT is performed to determine retinal thickness and assess the ganglion cell layer of the retina; OCT-A is used to evaluate macular and peripapillary hemoperfusion. Optical examination of the retina using a computer analyzer must be performed under pharmacological mydriasis, as this significantly improves the quality of the study.

Comments: the necessity and frequency of OCT and OCT-A are determined by the ophthalmologist depending on the clinical course of the disease, as well as during follow-up. OCT is performed to evaluate the optic disc and the nerve fiber layer; OCT-A is used to evaluate peripapillary hemoperfusion. Optical examination of the optic disc region and the nerve fiber layer using a computer analyzer in angiography mode must be performed under pharmacological mydriasis, as this significantly improves the quality of the study.

Comments: the decision to prescribe other additional diagnostic methods is made by the physician based on the results of the baseline examination. Recording of visual evoked potentials (VEPs) of the cerebral cortex to pattern stimulation is indicated when visual acuity does not correspond to the fundus status (retina, optic nerve), as well as in pathology of the visual pathways and visual cortical areas.

Comments: the necessity and frequency of FA are determined by the ophthalmologist depending on the clinical course of the disease.

2.5 Other Procedures

Comments: Ultrasound examination with blood flow assessment in retrobulbar vessels is performed by an ultrasound diagnostics physician. The necessity and frequency of the examination, as well as the analysis and interpretation of the results, are carried out by an ophthalmologist. The assessment of blood flow in retrobulbar vessels is performed to determine the blood supply deficit of the intraocular and intraorbital sections of the optic nerve and for differential diagnosis with diseases accompanied by optic nerve damage with signs of impaired optic nerve blood flow.

Comments: the necessity of CT and MRI, as well as the need for a contrast agent, is determined by specialists (neurologist, neurosurgeon) depending on concomitant diseases. The use of contrast-enhanced MRI makes it possible to identify signs of demyelinating diseases. The sensitivity of detecting focal optic nerve lesions on MRI is up to 93%.

Comments: the necessity of CT and MRI, as well as the need for contrast agent administration, is determined by specialists (neurologist, neurosurgeon) depending on concomitant diseases.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Optic atrophy is characterized by irreversible loss of nerve fibers; therefore, no effective treatment method exists [58, 110].

Clinical management of the patient is determined, whenever possible, by the treatment of the underlying optic neuropathy and is carried out in conjunction with the appropriate specialist (neurosurgical treatment for compressive optic neuropathy, "mitochondrial stimulation" and gene therapy for hereditary optic neuropathies, acute-phase therapy for optic neuritis) [111].

Approaches to supportive therapy in optic atrophy are conventionally divided into neuroprotection, neurostimulation, and neuroregeneration. Neuroprotection aims to increase the resistance of optic nerve neurons to pathological influences, while neurostimulation aims to improve conductivity in retinal ganglion cell axons. Neuroregeneration, the concept of stimulating the development of new neurons to replace dead ones, remains at the preclinical testing stage today.

Methods of affecting the optic nerve can be divided into drug therapy, surgical interventions, and physical therapy techniques.

3.1 Drug therapy for optic nerve atrophy

Supportive therapy for optic atrophy is initially aimed at improving blood supply and trophic support of surviving retinal ganglion cell axons and is prescribed in accordance with the underlying disease [58].

Comments: the drug is a synthetic analogue of an ACTH fragment devoid of hormonal activity, belonging to the class of regulatory peptides. The pharmacological effect is associated with the elimination of cytokine imbalance due to a reliable decrease in the level of inflammation inducers and an increase in anti-inflammatory and neurotrophic factors, which leads to the suppression of the local inflammatory reaction and improvement of the trophic supply of the optic nerve [112–114].

From an evidence-based medicine standpoint, the prescription of neuroprotective drugs is not entirely justified; therefore, there is currently no "gold standard" of metabolic therapy for optic atrophy. The literature also describes isolated studies on the efficacy of neuropeptide drugs (according to N06BX – other psychostimulants and nootropics), the positive effect of which is due to the activation of metabolic processes in nerve tissue by accelerating glucose utilization by cells and increasing their resistance to hypoxia [115].

A promising direction in the treatment of optic atrophy today appears to be stem cell therapy, as the possibility of stimulating axonal regeneration of ganglion cells upon intravitreal administration of stem cells in animals has been demonstrated [112]. Currently, several studies are underway evaluating stem cell therapy in patients with optic atrophy of various etiologies: ischemic, inflammatory, demyelinating, glaucomatous, and others [116–119].

3.2 Pain management

Pain management methods are not used, as optic atrophy is not accompanied by pain syndrome.

3.3 Surgical treatment of optic nerve atrophy

Currently, there are no proven effective surgical methods for treating optic atrophy. Despite the data available in the literature on the efficacy of revascularization interventions in optic atrophy, the question of performing them remains controversial. Choroidal and optic nerve revascularization is an intervention aimed at implanting various materials into the suprachoroidal space: bundles of fibers of the oblique or straight eye muscles, Tenon's capsule, conjunctiva, episcleral strips with terminal branches of the anterior ciliary arteries, allografts to improve hemodynamics of the peripheral section of the optic nerve [120–121]. Revascularization interventions can be performed in patients with bilateral optic atrophy with initially low visual functions (visual acuity less than 0.1) and ineffectiveness of conservative therapy in order to improve visual functions and stabilize the atrophic process [122].

There are no methods of treatment and prevention for congenital optic disc anomaly. Treatment is carried out if complications develop; the main ones include serous retinal detachment and the formation of a choroidal neovascular membrane: for local detachment, barrier laser photocoagulation of the retina is performed; for widespread, subtotal, or total detachment, micro-invasive vitrectomy with endotamponade of the vitreous cavity in various modifications is used; for the formation of a choroidal neovascular membrane, intravitreal administration of anti-angiogenic drugs is performed.

3.4 Physiotherapy for optic nerve atrophy

3.5 Diet therapy

There is no special diet for optic atrophy.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation is provided on a scheduled basis within the framework of primary health care and specialized, including high-tech, medical care.

Medical rehabilitation is carried out under the following conditions:

• outpatient setting (under conditions not providing for round-the-clock medical observation and treatment).

Comment: the frequency of examinations by an ophthalmologist and the scope of investigations are determined individually. Rehabilitation improves vision-related quality of life in patients with optic nerve atrophy. A multidisciplinary approach, including follow-up by related specialists (neurologists, rheumatologists, infectious disease specialists, etc.) increases the effectiveness of treatment and rehabilitation in patients with optic neuritis.

Comment: sanatorium-resort treatment is carried out during the remission phase of the disease, no earlier than 3 months after recovery.

5. Prevention and Dispensary Observation

Comments: the organization of follow-up examinations for patients with optic nerve atrophy is considered by the expert working group as the only effective measure to provide qualified care aimed at assessing disease dynamics, clarifying the etiology of optic nerve atrophy, determining the need for therapy and rehabilitation, and preventing the development of the condition in the fellow eye. Routine dispensary examination of patients with optic nerve atrophy is carried out once every 6 months for 2 years from the date of diagnosis. The scope of additional tests and the need for consultation with subspecialists (neurologist, rheumatologist, infectious disease specialist) are determined by the ophthalmologist taking into account the etiology of the disease.

6. Organization of Medical Care

Primary specialized health care is provided by an ophthalmologist in the outpatient department of a medical organization.

Treatment of optic nerve atrophy is carried out by an ophthalmologist in an outpatient setting or in a day care setting,

Indication for patient discharge from a medical organization:

1) completion of treatment or one of the stages of specialized medical care in an inpatient or day care setting, provided there are no treatment complications;

2) refusal of specialized medical care in an inpatient or day care setting by the patient or their legal representative;

3) the need to transfer the patient to another medical organization or to another department of the same medical organization (to change the profile of medical care provided).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Fursova Anzhella Zhanovna, Head of the Group, MD, Professor, Honored Doctor of the Russian Federation, Head of the Department of Ophthalmology at Novosibirsk State Medical University, Head of the Ophthalmological Department at the State Novosibirsk Regional Clinical Hospital, member of the Association of Ophthalmologists;

2. Shadrichev F.E., PhD, Head of the Ophthalmological Department at the St. Petersburg Territorial Diabetology Center of the City Clinical Diagnostic Center No. 1, Assistant at the Department of Ophthalmology with the Prof. Yu.S. Astakhov Clinic at the First Pavlov State Medical University of St. Petersburg, member of the Association of Ophthalmologists;

3. Nechiporenko P.A., PhD, Associate Professor at the Department of Ophthalmology with the Prof. Yu.S. Astakhov Clinic at the First Pavlov State Medical University of St. Petersburg, member of the Association of Ophthalmologists;

4. Grigorieva N.N., Ph.D. (Med.), Assistant Professor, Department of Otorhinolaryngology and Ophthalmology, Faculty of Medicine, Saint Petersburg State University of the Ministry of Health of the Russian Federation; member of the Association of Ophthalmologists;

5. Kiseleva Tatyana Nikolaevna, MD, Professor, Chief Researcher at the Ultrasound Diagnostics Department, Professor at the Department of Continuing Medical Education at the National Medical Research Center of Eye Diseases named after Academician V.N. Helmholtz of the Russian Ministry of Health;

6. Bobykin Evgeny Valerievich, MD, Associate Professor at the Department of Ophthalmology at the Ural State Medical University of the Ministry of Health of the Russian Federation, member of the Association of Ophthalmologists;

7. Tultseva Svetlana Nikolaevna, MD, Professor at the Department of Ophthalmology with the Prof. Yu.S. Astakhov Clinic at the First Pavlov State Medical University of St. Petersburg, member of the Association of Ophthalmologists;

8. Lisochkina Alla Borisovna, PhD, Associate Professor at the Department of Ophthalmology with the Prof. Yu.S. Astakhov Clinic at the First Pavlov State Medical University of St. Petersburg, member of the Association of Ophthalmologists;

9. Belskaya Galina Nikolaevna, MD, Professor, Head of the Multidisciplinary Clinical and Diagnostic Center at the Research Center of Neurology, Honored Doctor of the Russian Federation, member of the All-Russian Society of Neurologists;

10. Simonova Simona Valentinovna, Assistant at the Department of Ophthalmology at the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, ophthalmologist at the City Clinical Hospital No. 15 named after O.M. Filatova of the Moscow Healthcare Department;

11. Antonov Vladimir Aleksandrovich, PhD, ophthalmologist at the ophthalmology department of the Department of Ophthalmology with the Prof. Yu.S. Astakhov Clinic at the First Pavlov State Medical University of St. Petersburg, member of the Association of Ophthalmologists.

12. Turgel Vadim Alekseevich, ophthalmologist at Diagnostic Center No. 7 of St. Petersburg, member of the Association of Ophthalmologists.

13. Osipova Natalya Anatolievna, PhD, Senior Researcher at the Department of Eye Pathology in Children at the National Medical Research Center of Eye Diseases named after Academician V.N. Helmholtz of the Russian Ministry of Health.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. Ophthalmologists;

2. Neurologists;

3. General practitioners (family physicians);

4. Pediatricians;

5. Rheumatologists;

6. Neurosurgeons.

Methods used to collect/select evidence: electronic database search; analysis of modern scientific developments on the problem of AMD in Russia and abroad, synthesis of practical experience of Russian and foreign specialists. Description of methods used to collect/select evidence: the evidence base for the guidelines includes publications from the Cochrane Library, EMBASE, and MEDLINE databases, as well as monographs and articles in leading specialized peer-reviewed domestic medical journals on this topic. Methods used to assess the quality and strength of evidence: expert consensus, significance assessment according to the rating scheme.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for grading levels of clinical persuasiveness of recommendations (LCPR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The clinical guidelines update mechanism provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. International Classification of Diseases, Injuries and Causes of Death, 10th Revision (ICD-10). World Health Organization.

2. Federal Law No. 323-FZ dated November 21, 2011 (as amended on August 8, 2024, with amendments dated September 26, 2024) "On the Basics of Protecting the Health of Citizens in the Russian Federation" (with rev. and supp., effective from September 1, 2024).

3. Order of the Ministry of Health of Russia No. 902n dated November 12, 2012 (as amended on February 1, 2022) "On Approval of the Procedure for Providing Medical Care to the Adult Population for Diseases of the Eye, Its Adnexa and Orbit".

4. Order of the Ministry of Health of Russia No. 804n dated October 13, 2017 (as amended on September 24, 2020, with amendments dated October 26, 2022) "On Approval of the Nomenclature of Medical Services".

5. Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended on April 16, 2024) "On Approval of the List of Vital and Essential Medicines, as well as Lists of Medicines for Medical Use and the Minimum Assortment of Medicines Required for Medical Care".

6. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 44 dated December 24, 2020 (as amended on April 14, 2022) "On Approval of Sanitary Rules SP 2.1.3678-20 'Sanitary and Epidemiological Requirements for the Operation of Premises, Buildings, Structures, Equipment and Transport, as well as the Operating Conditions of Economic Entities Engaged in the Sale of Goods, Performance of Work or Provision of Services'."

7. Clinical Guidelines "Multiple Sclerosis" (ID: 739).

8. Order of the Russian Ministry of Health No. 205n dated May 2, 2023 (as amended on December 4, 2023) "On approval of the Nomenclature of positions of medical workers and pharmaceutical workers".

9. Order of the Ministry of Labor of Russia No. 259n, Ministry of Health of Russia No. 238n dated May 16, 2024 "On Approval of the List of Medical Examinations Required to Obtain Clinical and Functional Data Depending on the Disease for the Purpose of Medical and Social Expertise".

Current instructions for the medicinal products mentioned in these clinical guidelines can be found on the website http://grls.rosminzdrav.ru

Table 1. Dose, route of administration, and regimens of medicinal products.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Information about the outside world enters the eye to the retina, where numerous photoreceptors, nerve cells, and nerve fibers are located, forming the optic nerve. Nerve signals travel from each eye via the optic nerve and optic tract to the brain, where visual information is processed and interpreted. In the brain, beneath the hypothalamus, the fibers of the optic nerves partially decussate, as a result of which the right side of the brain receives information from the left visual field of both eyes, and the left side of the brain receives information from the right visual field of both eyes. After the decussation, the nerve fibers are called the optic tract. Through them, information is transmitted to subcortical centers and further to cortical centers. Damage to the eye or the visual pathway at any site leads to various visual impairments depending on the localization and severity of the lesion.

Optic atrophy (OA) is a dangerous and severe ophthalmological disorder. It is characterized by the partial or complete destruction of nerve fibers that transmit visual impulses from the retina to the visual centers of the brain. Clinical manifestations of the disease include decreased vision or complete loss of vision, changes in visual fields, impaired color perception, and night blindness.

OA is diagnosed quite rarely, but it requires special attention because the disease can cause an irreversible decrease in vision, up to blindness. At the same time, the restoration of visual function is subsequently impossible.

The main causes of OA development include:

• eye diseases - against the background of glaucoma (constant or periodic increase in intraocular pressure), degenerative diseases, pathological changes in retinal vessels, myopia, inflammatory lesions, neoplasms, etc.,

• mechanical injuries - head injuries accompanied by a violation of the integrity of the optic nerve,

• central nervous system disorders - as a consequence of pituitary tumors, abscesses, encephalitis,

• body intoxications - as a consequence of nicotine poisoning, exposure to substances such as lead, methanol (wood alcohol or methyl alcohol), ethylene glycol (antifreeze), or certain medications,

• general pathological processes occurring in the body - against the background of hypertension, deficiency of certain vitamins and minerals, atherosclerosis, diabetes mellitus, major hemorrhages, etc.,

• infections — a consequence of toxoplasmosis, tuberculosis, viral lesions,

• autoimmune diseases — lupus erythematosus, granulomatosis with polyangiitis, and other disorders.

Depending on the localization, unilateral and bilateral optic nerve atrophy (ONA) are distinguished.

According to the extent of tissue involvement, atrophy can be:

• Ascending. Caused by processes in the fundus (retina).

• Descending. Occurs when the peripheral parts of the visual pathways (nerves) are affected.

Depending on the degree of progression, a stationary form of atrophy is distinguished, characterized by a slow development, and a progressive form, characterized by rapid development.

Examination of a patient with suspected ONA begins with history-taking and physical examination. The physician identifies the patient's complaints, clarifies what medications are being taken, what lifestyle is maintained, whether there were any injuries to the organs of vision, etc.

• Additionally, the ophthalmologist may refer the patient for a consultation with a neurologist and other subspecialists. This is necessary because ONA frequently occurs against the background of general somatic diseases.

Subspecialists, in turn, can expand diagnostics with such modern methods as X-ray imaging (A06.03.005 - X-ray of the entire skull, in one or more projections), CT (computed tomography) or MRI (magnetic resonance imaging) of the brain.

Unfortunately, at present, ONA is classified as an incurable condition.

Any treatment is carried out comprehensively and on an individual basis.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.