In the visual pathway, when nerve fibers are damaged, degeneration can occur in two directions.
Wallerian degeneration (anterograde degeneration) is the process in which, when an axon is damaged, the axon degenerates distal to the injury site. The axonal skeleton and myelin sheath break down, and macrophages remove the degenerated debris. This is named after Augustus Waller, who first described it in 1850 in experiments cutting the glossopharyngeal and hypoglossal nerves of frogs.
Retrograde degeneration is a process in which the axon degenerates proximal to the injury site (toward the cell body). It leads to destruction of the cell body and cell death, and regeneration is impossible.
The optic nerve is embryologically derived from the diencephalon and is part of the central nervous system (CNS). Anterior to the lamina cribrosa, RGC (retinal ganglion cell) axons are unmyelinated, but posteriorly they become myelinated by oligodendrocytes. In peripheral nerves, one Schwann cell nourishes one axon, whereas in the CNS, one oligodendrocyte nourishes multiple axons.
In peripheral nerves, Schwann cells promote regeneration via growth factors. In contrast, in the CNS, the regeneration-promoting effect of oligodendrocytes is weak, and axonal regeneration in the mature CNS is extremely poor.
Demyelination refers to a condition in which the myelin sheath primarily degenerates and is lost. Rapid demyelination often accompanies axonal degeneration. Representative demyelinating diseases include multiple sclerosis, neuromyelitis optica, and leukodystrophy.
Wallerian degeneration occurs distal to the site of axonal injury, while retrograde degeneration occurs proximal to the injury (toward the cell body). Retrograde degeneration leads to cell body death and irreversible damage, whereas Wallerian degeneration in peripheral nerves may leave room for regeneration. Both often occur together after the same injury.
The pattern of symptoms varies depending on the site of damage.
The time course of optic nerve atrophy and degeneration is an important finding.
Wallerian Degeneration
Course after injury: Degeneration begins within 24 hours of nerve injury. It takes approximately 7 days for the breakdown of the axonal skeleton and myelin sheath to complete.
Spared proximal optic nerve: Axons proximal to the injury site may appear normal and function for 3–4 weeks.
Fundus findings: The optic disc, distal to the injury, becomes atrophic and pale over weeks to months.
Retrograde degeneration
Timing of RGC death: Retinal ganglion cell (RGC) death may occur 6–8 weeks after injury.
Pattern after optic tract lesion: On the affected side, temporal optic disc pallor with arcuate nerve fiber layer defects. On the contralateral side, band atrophy occurs. Appears over about one month.
Trans-synaptic degeneration: Damage to the LGN (lateral geniculate nucleus) or visual cortex can cause optic atrophy. Usually occurs more easily with occipital lobe damage during fetal or early infant periods1).
Fundus findings in optic atrophy vary in morphology depending on the cause.
RAPD (relative afferent pupillary defect): In optic tract lesions, RAPD may be observed in the contralateral eye. Lesions beyond the lateral geniculate body do not affect the pupillary light reflex.
MRI findings: Wallerian degeneration is detected as T2 hyperintensity on T2-weighted images (suggesting gliosis). In the acute phase, diffusion restriction is observed on diffusion-weighted imaging (DWI)1)2).
Kihira et al. (2021) reported a case of progressive left visual acuity loss over 5 years in a 47-year-old woman1). Optical coherence tomography (OCT) confirmed left optic atrophy, and T2 hyperintensity along the left optic radiation was detected on MRI T2-weighted images. This case is notable as a report of trans-synaptic degeneration from optic atrophy without associated infarction or inflammatory disease.
Wallerian degeneration begins within 24 hours after injury, but the proximal portion of the axon may appear normal for 3–4 weeks. Retrograde degeneration leading to RGC death can occur within 6–8 weeks. It often takes several weeks to months after injury for optic disc pallor to become clearly visible on fundus examination.
The main causative diseases leading to Wallerian and retrograde degeneration of the optic pathway are listed below.
| Disease Category | Representative Diseases | Main Direction of Degeneration |
|---|---|---|
| Glaucoma | Primary open-angle glaucoma, etc. | Retrograde and anterograde |
| Demyelinating diseases | Multiple sclerosis, neuromyelitis optica | Anterograde |
| Ischemic disease | Anterior ischemic optic neuropathy (AION), PION, stroke | Anterograde and retrograde |
| Compressive lesions | Pituitary adenoma, craniopharyngioma, aneurysm | Retrograde |
| Trauma | Head trauma | Anterograde |
| Hereditary optic neuropathy | LHON, ADOA, Wolfram syndrome | Retrograde |
| Brain tumor | Glioblastoma, etc. | Anterograde |
| Neurodegenerative disease | Alzheimer’s disease | Retrograde |
The characteristics of each causative disease are supplemented below.
The basic step is to confirm optic atrophy (pale optic disc). There are two pathways: one that progresses from optic disc swelling to atrophy, and another that directly progresses from a normal optic disc to atrophy.
OCT plays a central role in the quantitative evaluation of optic atrophy.
OCT angiography (OCTA): Non-invasively visualizes the fine structure of retinal and choroidal vessels. It has been reported that decreased vessel density in radial peripapillary capillaries (RPCs) corresponds to areas of nerve fiber layer defects.
| Imaging modality | Main findings / uses |
|---|---|
| T2-weighted imaging | T2 hyperintensity of Wallerian degeneration (gliosis), ipsilateral cerebral peduncle atrophy1)2) |
| DWI (diffusion-weighted imaging) | Detection of acute Wallerian degeneration (requires differentiation from secondary infarction) 2) |
| DTI (diffusion tensor imaging) FA value | Quantification of degeneration, predictor of functional recovery (subacute ischemic phase) 2) |
T2 hyperintensity of the optic radiation requires differentiation from leukomalacia, prior infarction, and demyelinating diseases (multiple sclerosis)1).
Measurement of cpRNFL thickness and macular GCC thickness is central. In the acute phase with optic disc swelling, GCC analysis has the advantage of detecting thinning earlier than cpRNFL. Normal values vary greatly among individuals, so follow-up with actual measurements and comparison with the fellow eye are important. Consistency checks with visual field, fundus findings, and other visual function tests are also essential.
Currently, there is no proven regenerative therapy for Wallerian degeneration or retrograde degeneration of the optic pathway. Treatment primarily focuses on the underlying disease.
After axonal injury, the distal side undergoes breakdown of the axonal skeleton and myelin sheath, and macrophages remove debris (Wallerian degeneration). In peripheral nerves, Schwann cells promote regeneration via growth factors. In the CNS, the regenerative-promoting effect of oligodendrocytes is weak, and axonal regeneration in the mature central nervous system is poor or impossible.
In retrograde degeneration, the axon degenerates proximal to the injury site, leading to cell body destruction and cell death. Retrograde RGC atrophy after optic tract damage is inevitable, and RGC death can occur within 6 to 8 weeks.
Like CNS neurons, RGCs exhibit axonal degeneration, myelin breakdown, scar formation, and secondary degeneration, with limited regenerative capacity after injury5).
Transport within axons (axonal transport) is classified by direction and speed.
Anterograde Transport
Fast transport: 400–1,000 mm/day. Involved in transport of membrane components such as synaptic vesicles.
Intermediate-speed transport: 5–400 mm/day.
Slow transport: 0.5–5 mm/day. Involved in transporting proteins necessary for axon maintenance.
Retrograde transport
Speed: 50–300 mm/day.
Function: Involved in transmitting information from the periphery to the cell body and recycling waste products.
Mitochondria: Damaged or aged mitochondria are transported retrogradely back to the RGC cell body for “recharging.” In glaucoma, axonal transport is impaired at the lamina cribrosa, leading to progressive optic atrophy.
In glaucoma, RGC axons are most susceptible to damage at the lamina cribrosa of the optic nerve head (ONH)4).
Pitha et al. (2024) reported detailed mechanisms of RGC axonal damage in glaucoma4). Mechanical stress from intraocular pressure is significantly greater at the ONH (lamina cribrosa) than in the retina, with circumferential hoop stress and translaminar pressure difference acting on RGC axons. Large αRGCs (especially OFF-type) are more selectively vulnerable, and large RGC axons passing through the superior and inferior poles of the ONH are preferentially damaged.
The pathway by which mechanical stress at the lamina cribrosa blocks axonal transport is as follows.
The phenomenon where neuronal degeneration on one side of a synapse affects the other side across the synapse is called “trans-synaptic degeneration.” Cases have been reported where degeneration spreads from optic atrophy to the optic radiation1), and retrograde trans-synaptic degeneration after occipital lobe stroke (Jindahra et al., 2012) is also known1). It is generally thought to occur more frequently with occipital lobe damage during the fetal or early infant period.
In Alzheimer’s disease (AD), brain lesions affecting neural connections in the visual pathway may cause thinning of the RNFL and GC-IPL 5). However, in the posterior cortical atrophy variant of AD, differences in peripapillary RNFL compared to controls have been reported to be difficult to distinguish 5).
Mechanical stress from intraocular pressure is significantly greater at the ONH (lamina cribrosa) than in the retina. Circumferential hoop stress and translaminar pressure gradient act on axons, blocking both anterograde and retrograde axonal transport 4). This mechanical load promotes RGC apoptosis through a combination of mechanisms including neurotrophic factor deprivation, mitochondrial dysfunction, and calcium influx.
Research is advancing on using fractional anisotropy (FA) values from diffusion tensor imaging (DTI) to quantify Wallerian degeneration in the subacute phase after stroke and predict functional recovery 2). The degree of cerebral peduncle atrophy has been shown to correlate with the extent of brain damage, and its clinical application as an imaging biomarker is anticipated 2).
Hustings & Lemmerling (2021) systematically reported MRI findings of Wallerian degeneration due to various causes including ischemic stroke, hemorrhagic stroke, brain tumor, trauma, arachnoid cyst, and cerebral cortical hypoplasia 2). They emphasized that careful interpretation based on clinical context is necessary in the acute phase to avoid misidentification as secondary infarction.
In experimental models of rats carrying the Wallerian degeneration slow (WLDS) gene, a primary axonal protective effect was demonstrated. However, retrograde degeneration still occurred, ultimately leading to cell body death. This model is used as a basic tool to separately evaluate axonal protection therapy and cell body protection therapy.
Weber et al. (2025) published the first report correlating SD-OCT and histopathological findings in Schnabel cavernous optic atrophy (SCONA)3). Previously, SCONA could only be diagnosed histologically, but they demonstrated that it can be detected in vivo as a hyporeflective pseudocyst within the lamina cribrosa using the ONH-RC scan of the BMO-MRW modality. The prevalence in histological studies of elderly individuals is reported to be approximately 1.7–2.1%3), and it is expected to serve as a new diagnostic tool for differentiating from glaucomatous optic atrophy.
